Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:11]([C:13]1(F)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH2:14]1)#[N:12]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: N#CC1(F)CC=Cc2ccccc21
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC3(CC2)OCCO3)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.2 %

Procedure:
1.4-dioxa-8-azaspiro[4.5]decane (332 mg, 2.32 mmol) was added to a solution of 1-cyano-1-fluoronaphthalene (120 mg, 0.70 mmol) in anhydrous THF (1 mL). After 48 hours stirring at rt the mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was washed with a mixture of ethyl acetate and n-heptane (50:50). Purification by silica gel column chromatography, eluting with 5% methanol in dichloromethane afforded the desired compound (126 mg, 43%). The compound was converted to the corresponding hydrochloride salt as described above.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]([OH:18])[C:15]([S:19](=[O:26])(=[O:25])[N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[CH2:27]([O:7][C:8]1[CH:17]=[C:16]([O:18][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:8]=2)[C:15]([S:19](=[O:26])(=[O:25])[N:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)OC)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2.7 71.25 g of potassium carbonate are added to a solution of 75 g of methyl 2,4-dihydroxy-5-(N-methyl-N-propylsulfamoyl)benzoate in 800 ml of acetonitrile. 60 ml of benzyl bromide are subsequently added dropwise. The mixture is refluxed for 3 hours, cooled and subjected to conventional work-up. HPLC gives 113 g of methyl 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoate.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH3:32])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][C:4]1([CH3:32])[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCC(C)(O)CC3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(C)(O)CC2)nc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 1 h
Yield: 0 %

Procedure:
A solution of aqueous 2N NaOH (5.00 ml) is added to a stirred solution of methyl 3-[[6-(4-hydroxy-4-methyl-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate (0.27 g, 656.13 mmol) in THF:MeOH (10 ml:5 ml). After 1 hour 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with 5N HCl, and extracted with ethyl acetate. The organic layers are combined and concentrated under reduced pressure. The solids are triturated with acetone/acetonitrile and filtered. The filtrate is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (75 mg, 29%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][N:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[S:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[N:46]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C1COCC1>[S:43]1[C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=[C:42]1[C:39]1[N:40]=[CH:41][C:36]([C:17]2[CH:16]=[N:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:7]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3s2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(-c5nc6ccccc6s5)nc4)cn3)cc2)cc1
Yield: 80.9 %

Procedure:
Following the procedure for 3, 2 (0.521 g, 1.16 mmol), 9 (0.338 g, 1.16 mmol), tetrakis(triphenylphosphine)palladium(0) (67.1 mg, 58.1 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded 10 (0.50 g, 81% yield) as a bright yellow solid after flash chromatography (SiO2, 100% CH2Cl2 to 99:1 CH2Cl2—CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([NH:16][NH2:17])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([NH:16][NH:17][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([OH:18])[CH:20]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NN
Reactant: COc1ccc(C(=O)Cl)cc1O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)cc1O
Yield: 24.6 %

Procedure:
In pyridine (4 ml), 2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid hydrazide (120 mg) and 3-hydroxy-4-methoxy-benzoyl chloride (84 mg) were stirred for 24 hours at a room temperature. The mixture was concentrated under a reduced pressure, and then diluted hydrochloric acid was added thereto. The precipitated crystal was separated by filtration and dried, and the resulting crystal was recrystallized from ethanol to give the title compound (46 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:32])=[O:33]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(S(=O)(=O)n2ccc3c(CN(C)C)c(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.7 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,5-dimethoxybenzenesulfonyl chloride (26 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a beige solid. MS (ESI+) for C20H24N2O5S m/z 405 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([N:1]2[CH2:6][CH2:5][C:4]3([CH2:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[O:7]3)[CH2:3][CH2:2]2)=[O:30])=[CH:24][CH:23]=1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(=O)N2CCC3(CC2)Cc2ccccc2O3)cc1

Procedure:
A stirred suspension of 3.5 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7 and 7.5 g of sodium bicarbonate in 40 ml of chloroform are reacted with a solution of 4.4 g of 4-methoxyphenylacetyl chloride in 10 ml of chloroform and thereafter treated according to the procedure of Example 13 to provide a yellow oil. The oil is chromatographed on a silica column with a 3% methyl alcohol in chloroform eluant to provide a white solid which is recrystallized thrice from hexane to provide the product, 2,3-dihydro-1'-[(4-methoxyphenyl)acetyl]spiro[benzofuran-2,4'-piperidine], mp 87°-88° C.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[CH:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH2:7][CH:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([C:21]1[C:22]([CH:27]([F:29])[F:28])=[N:23][N:24]([CH3:26])[CH:25]=1)=[S:20].O>CN(C)C=O.C1CCCCC1.C(OCC)(=O)C>[CH:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH2:7][CH:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]([C:21]1[C:22]([CH:27]([F:29])[F:28])=[N:23][N:24]([CH3:26])[CH:25]=1)[S:20][CH3:3]
Reactant: CI
Reactant: Cn1cc(C(=S)Nc2ccccc2C2CC3CCC2C3)c(C(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=Nc1ccccc1C1CC2CCC1C2)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
At 0° C., 0.1 g (3.6 mmol) of sodium hydride (80% pure) and 1.2 g (8.3 mmol) of methyl iodide in 5 ml of dimethylformamide are added to a solution consisting of 1.0 g (2.8 mmol) of N-(2-bicyclo[2.2.1]hept-2-ylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiocarboxamide in 10 ml of dimethylformamide. The reaction mixture is slowly warmed to room temperature and stirred at this temperature for 1 hour. For work-up, the reaction mixture is poured into water and extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (cyclohexane/ethyl acetate 4:1) gives 0.7 g (1.9 mmol, 67% of theory) of methyl N-(2-bicyclo[2.2.1]hept-2-ylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbimidothioate [logP (pH 2.3)=4.75].
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CC(C)([O-])C.[K+].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(CN2CCCC23CCNC3)cc1
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCCC23CCN(c2cccnc2)C3)cc1
Temperature: 90 °C

Procedure:
A mixture of 1-benzyl-1,7-diazaspiro[4.4]nonane (2.00 g, 9.26 mmol), 3-bromopyridine (1.38 g, 8.73 mmol), potassium tert-butoxide (2.50 g, 22.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.318 g, 0.347 mmol), 2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.324 g, 0.520 mmol) and dry toluene (50 mL) was placed in a pressure tube under argon. The mixture was stirred and heated at 90° C. (bath temperature) for 24 h and cooled. Water (20 mL) was added and the mixture was extracted with ethyl acetate (6×25 mL). The extracts were dried (K2CO3) and concentrated. Column chromatography of the residue on Merck silica gel 60 (70-230 mesh), with 6:4 (v/v) chloroform/acetone, gave 1.80 g (66.2%) of light brown oil, after concentration of selected fractions.
Reaction SMILES: C([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=O)C1C=CC=CC=1.O.[OH-].[K+].C(O)(=O)C>CO>[CH2:20]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:10]([OH:9])([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[C:11]1=[O:22])[CH3:21]
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCN1C(=O)C(O)(Cc2cc(OC)c(OC)c(OC)c2)c2cc(C)ccc21
Temperature: 130 °C
Yield: 85 %

Procedure:
Alternative route: To an oven dried Biotage microwave vial cooled under argon was added 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate (0.053 grams, 0.11 mmol). This was taken up in 0.6 mL of methanol, 0.6 mL of deionized water. A solution of KOH (223 μl, 2.0M in water) was added and the sealed vial was placed in the microwave and heated to 130° C. for 12 minutes, and 18 minutes at 140° C. Upon cooling the solution was neutralized with a stoichiometric amount of glacial acetic acid (Fisher scientific), and concentrated. Purification on a Teledyne ISCO using a C18 reverse phase column (water with 0.1% formic acid/acetonitrile gradient) afforded the desired compound. 85% yield. 1H NMR 7.22 (s, 1H), 7.08 (d, 1H), 6.55 (d, 1H), 6.06 (s, 2H), 4.38 (bs, OH), 3.72 (s, 3H), 3.66 (m, 1H), 3.61 (s, 6H), 3.34 (m, 1H), 3.23 (d, 1H), 3.17 (d, 1H), 2.35 (s, 3H), 0.87 (t, 3H). Calculated mass for C21H25NO5, 371.43. Observed 394.1 (M+Na)
Reaction SMILES: C[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[CH2:10][O:11]C(C)=O>>[CH3:10][O:11][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(N)cc1
Product: COc1ccc(N)cc1

Procedure:
Column chromatography was performed in the dark, using 50% EtOAc/50% hexanes as eluent. Three bands emerged; the first band was a fluorescent impurity, the second and third bands were the di-(rf˜0.7) and monomethyl aniline (rf˜0.65), respectively. Rotary evaporation of the middle fractions gave the product in modest yield (˜1 gram, 16% based on starting p-anisidine). The off-white solid was further purified by sublimation (high vacuum, heated at 30° C., collected on a small cold finger). Product isolated at this stage was sufficiently pure for reductive quenching purposes. Due to its short shelf-life (stored at 4° C., under argon, protected from light), the compound was frequently recrystallized from warm water before use. 1H NMR (CDCl3): δ 3.30 (s, N—CH3, 6H), 3.88 (s, O—CH3, 3H), 7.58 (d, 21), 7.15 (d, 21). GC-MS calcd for C9H13NO (M−H+) m/z 150, found 150.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:23])[N:9]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=4)[N:10]=[C:4]3[C:3]=2[C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[CH:34][CH:33]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4C)nc3c2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (135 mg, 0.32 mmol), 4-methoxyphenylboronic acid (190 mg, 1.29 mmol), and 2.0 M aqueous sodium carbonate (0.70 mL) in toluene (2.5 mL) was added (Ph3P)4Pd (55 mg, 0.048 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 1.5 h. Analysis by HPLC/MS indicated the starting 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 15 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 82 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.56 min, [M+H]+=492.0.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])[C:5]([C:7]1([S:15]CC2C=CC(OC)=CC=2)[CH2:12][CH2:11][N:10]([O:13][CH3:14])[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+]>FC(F)(F)C(O)=O.O>[OH:6][C:5]1[C:7]2([CH2:8][CH2:9][N:10]([O:13][CH3:14])[CH2:11][CH2:12]2)[S:15][C:3](=[O:2])[C:4]=1[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33]
Reactant: COC(=O)C(C(=O)C1(SCc2ccc(OC)cc2)CCN(OC)CC1)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CON1CCC2(CC1)SC(=O)C(c1c(C)cc(C)cc1C)=C2O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
470 mg 3-[1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester (from Step 6) was dissolved in 15 ml trifluoroacetic acid and heated on reflux for 18 hours. The mixture was cooled to room temperature, diluted with water, the pH adjusted to 4.2 by the addition of aqueous sodium hydroxide, then extracted with t-butylmethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent evaporated. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:1, then 2:1) as a solvent, to yield 156 mg 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-2-one (compound P2.4) as a solid, mp 67-71° C.
Reaction SMILES: S(Cl)([Cl:3])=O.C(N(CC)C1C=CC=CC=1)C.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26](O)[CH3:27])[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18].CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:3][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=1)[CH3:27]
Reactant: CC(O)c1cccc(S(C)(=O)=O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CC(Cl)c1cccc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
Thionyl chloride (0.11 g, 0.91 mmol) was added to a solution of N,N-diethylaniline (0.19 g, 1.3 mmol) and 1-[3-(methylsulfonyl)phenyl]ethanol (0.26 g, 1.3 mmol) in toluene (4 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes followed by addition of EtOAc. The organic phase was washed subsequently with 2M HCl (aq), water, saturated sodium bicarbonate, and brine, and then dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (ethyl acetate:hexane gradient elution 20:80 to 25:75) to give the title compound (60 mg) that was used in the next step without any further purification (approximate purity 75%).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([O:11][C:12]([C:14]1([NH3+:17])[CH2:16][CH2:15]1)=[O:13])[CH3:10].[N:18]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[N:20][CH:19]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[N:18]1[CH:23]=[C:22]([C:24]([NH:17][C:14]2([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:15]2)=[O:25])[CH:21]=[N:20][CH:19]=1
Reactant: CCOC(=O)C1([NH3+])CC1
Reactant: O=C(O)c1cncnc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Reaction time: 16 h

Procedure:
Triethylamine (7.026 g, 69.44 mmol) was added to a suspension of 1-(ethoxycarbonyl)cyclopropanaminium chloride (11.50 g, 69.44 mmol), pyrimidine-5-carboxylic acid (8.617 g, 69.44 mmol), EDC (13.312 g, 69.44 mmol), and HOAT (0.945 g, 69.44 mmol) in CH2Cl2 (125 mL) and allowed to stir for 16 hours. The reaction was adsorbed onto silica and purified by silica gel chromatography and eluted with ethyl acetate to yield ethyl 1-[(pyrimidin-5-ylcarbonyl)amino]-cyclopropanecarboxylate as a white solid. Low resolution mass spectrometry: (M+H+)=236.2.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=[N:21][OH:22])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(N1CCc2ccc(C=NO)cc2CC1)C(F)(F)F
Yield: 81.5 %

Procedure:
3-Trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde (20.0 g) and hydroxylamine hydrochloride (6.1 g) in pyridine (140 ml) were stirred overnight and the reaction then evaporated in vacuo. The residue was partitioned between ethyl acetate and 10% sodium carbonate solution and the combined organic layers dried and evaporated to give 3-trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde oxime (17.2 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][N:11]=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1cccc(Cl)c1CBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24 g (0.1 mol) of 2,6-dichlorobenzyl bromide in 50 ml of dimethyl sulphoxide are added at room temperature to a suspension of 7.2 g (0.11 mol) of sodium azide in 50 ml of dimethyl sulphoxide and the whole is stirred for 2 hours at room temperature. The mixture is then diluted with 250 ml of water and extracted with cyclohexane and the organic phase is washed several times with water. After drying over sodium sulphate, the cyclohexane is distilled off in vacuo at 50°. 2,6-dichlorobenzyl azide is obtained in the form of a colourless liquid. It is used without further purifification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (200 mg, 1 mmol) in tetrahydrofuran (5 mL) were added 4-fluorobenzenesulfonyl chloride (195 mg, 1 mmol), triethylamine (0.2 mL) and the mixture was stirred at RT. After 2 h, the volatiles were removed in vacuo and the water was added to the residue. The solid formed was filtered, washed successively with water, 1N HCl, and water to afford tert-butyl 1-(4-fluorophenylsulfonyl)piperidin-4-ylcarbamate (350 mg, 98%) as a solid. LC/MS; (M+H)+=359.