Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH:33]=[CH2:34]>C(C(C)=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([O:13][CH2:34][CH:33]=[CH2:32])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Yield: 73.3 %

Procedure:
To a 250 mL flask stirring under nitrogen was charged 3.55 g (0.010 mole) of a 4-(4-chlorophenyl)-2-phenyl-2-[(1,2,4-triazol-1-yl)methyl]butanoic acid in 40 mL of methyl ethyl ketone and 10 mL of dimethyl formamide. To the mixture was added 2.07 g (0.015 mole) of potassium carbonate and 1.85 g (0.011 mole) of allyl iodide. The reaction was stirred for 16 hours at 45° C. The reaction was quenched by adding 150 mL of ether and 25 mL of water. The organic phase was washed with 50 mL of saturated sodium bicarbonate and 20 mL of 10% sodium hydroxide, then 50 mL of water. After decolorizing with charcoal, the solvent was filtered and concentrated and gave 2.9 g (79.4% yield) of a solid, Example 137 of Table 1.
Reaction SMILES: [CH:1]1([CH:9]=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(O)(=O)C>[Zn].C1C=CC=CC=1>[CH:1]1([CH2:9][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=CC1CCCCCCC1
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCC2CCCCCCC2)cc1

Procedure:
Cyclooctane carboxaldehyde (14.72 g, 0.105 mole) was added dropwise to a stirred and refluxing mixture of 13.7 g (0.1 mole) p-aminobenzoic acid, 25 g zinc dust, 25 ml glacial acetic acid and 125 ml of benzene. Water which evolved was collected in a Dean-Stark trap as the reaction mass was refluxed overnight. Following the reflux period, the resulting product mass was filtered while still hot. Upon cooling the filtrate, crystals formed therein. The benzene was evaporated and the residue recrystallized from acetonitrile. The crude product weighed 18.77 g. It was decolorized and recrystallized from benzene. The resulting purified 4-[(cyclooctylmethyl)amino]benzoic acid product weighed 12.93 g. It had a melting point of 160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][O:8][P:9]([O:12]C)[O:10][CH3:11]>C(O)C(C)C>[CH3:7][O:8][P:9]([O:10][CH3:11])([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])=[O:12]
Reactant: COP(OC)OC
Reactant: C=CC(=O)OC
Solvent: CC(C)CO
Product: COC(=O)CCP(=O)(OC)OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
86 g of methylacrylate and 100 g of isobutanol are mixed under nitrogen at room temperature and heated to 80° C. 124 g of trimethylphosphite are added dropwise to the reaction solution in the course of 1 hour. The reaction mixture is stirred for 5 hours at reflux temperature and the solvent (remainder of isobutanol and isobutyl methyl ether) is removed by vacuum distillation. The crude product is obtained in a yield of 173 g with a 94.1% purity, which corresponds to a theoretical yield of 83.0%. The boiling point is 104°-106° C. at 0.93 mbar.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:37][CH2:38][CH3:39]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:37][CH2:38][CH3:39])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 35.1 %

Procedure:
A solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (160 mg; 0.471 mmol) in dry DMF (2.5 mL) was cooled to −15° C. LHMDS (0.519 mL; 0.519 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.069 mL; 0.707 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 63 mg (34%) of the title compound as a yellow oil. ESI/APCI(+): 382 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][OH:18]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][OH:18]
Reactant: OCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCOc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromophenol (14) (36.38 g, 210.3 mmol) in acetone (175 ml) was added K2CO3 (0.033 g, 237 mmol) and 2-bromoethanol (20 ml, 283.3 mmol). The reaction mixture was heated at reflux under argon for 4 days. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (150 ml) and the solution was washed successively with water, 10% aqueous NaOH, 5% aqueous NaOH, water, and brine. The solution was dried over MgSO4 and concentrated under reduced pressure to give 2-(3-bromophenoxy)ethanol (15) as a light brown oil. Yield (21.07 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 6.85 (ddd, J=7.8, 2.4, 1.3 Hz, 1H), 4.06 (m, 2H), 3.95 (m, 2H), 2.11 (t, J=12.3 Hz. 1H).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13](SC)=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13]([CH2:4][CH3:5])=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Reactant: CC[Zn]CC
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(I)cc1
Temperature: 60 °C
Yield: 60 %

Procedure:
Add dropwise diethylzinc (1.0M in hexanes, 7 ml, 6.99 mmol, 3 eq) to a mechanically stirring suspension of 4-cyano-3-(4-iodo-phenyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (1 gr, 2.33 mmol) and 1,3-bis-(diphenylphosphino)propane nickel (II) chloride (24 mg, 0.0466 mmol, 0.02 eq) in dry THF (12 ml) and heat the resulting mixture 60° C. for 30 min. Cool the reaction to room temperature and remove solvents in vacuo. Purify the solid by chromatography on silica gel (eluting with 10-80% Ethyl acetate/hexane) to provide the title compound in 60% yield: Mass spectrum (EI+): m/z 412 (M++1); 1H NMR (CDCl3, 200 MHz): δ 7.72 (d, 2H, J=8.5); 7.05 (d, 2H, J=8.5); 4.14 (q, 2H, J=7.2); 3.01 (q, 2H, J=7.2); 1.36 (t, 3H, J=7.5); 1.17 (t, 3H, J=7.2).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:12]1[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=2[CH:15]=[C:14]2[C:23]([O:25][C:26](=[O:27])[C:13]=12)=[O:24])=[O:19].Cl>C(OCC)(=O)C.O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:26]([C:13]2[CH:12]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([C:21](=[O:22])[C:6]3[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][CH:7]=3)=[CH:15][C:14]=2[C:23]([OH:25])=[O:24])=[O:27])=[CH:8][CH:7]=1
Reactant: [Cl-]
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(C(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1C(=O)c1ccc(Cl)cc1
Temperature: 65 °C
Yield: 24.3 %

Procedure:
A mixture of 497.6 grams (3.732 moles, 4.2 eq) of aluminum chloride, 2000 grams (17.77 moles, 20 eq) of chlorobenzene, and 193.8 grams (0.8885 moles, 1 eq) of benzene-1,2,4,5-tetracarboxylic acid dianhydride (pyromellitic dianhydride) was stirred and heat to 65° C. for 3 hrs. The mixture was cooled to room temperature while stirring overnight. This mixture was slowly added to a mixture of 1048 grams of 12M hydrochloric acid and stirred for one hour. Six liters of water was added and the organic layer was separated. The organic layer was washed with water until the water layer had a pH of greater than 1. To the organic layer was added 1429 mL of ethyl acetate, and 400 mL THF and the aqueous phase was separated and the organic phase was washed with 500 mL saturated NaCl and split. The organic phase was dried with magnesium sulfate and the solvent removed in vacuum to give 287.9 grams. This material was heated with three liters of ethyl acetate at 75° C. for five hours and then cooled. The solid was collected and air dried to give 95.73 grams of the desired product. 1H NMR (400 MHz, DMSO-d6): δ7.951 (s, 2H), 7.748 (d, J=8.60 Hz, 4H), 7.58 (d, J=8.60 Hz, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 0.336 mmol), was combined with 3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg, 0.336 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (115 mg, 0.195 mmol) in 58% yield. MS m/z 590.6 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:15])[N:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][CH2:10][CH:11]=1.CO.[NH2:19][O:20][K].C(O)(=O)C>C(OCC)(=O)C>[CH2:12]([N:8]1[CH2:9][CH2:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([NH:19][OH:20])=[O:2])[C:7]1=[O:15])[CH:13]=[CH2:14]
Reactant: NO[K]
Reactant: C=CCN1CCC=C(CCC(=O)OC)C1=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: C=CCN1CCC=C(CCC(=O)NO)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
24 mg of 3-(1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (i1) prepared from the above Step 2 was dissolved in methanol solution (0.11 mmol) and then 0.122 ml of 1.7M NH2OK suspension solution (0.207 mmol) was added thereto at 0° C. and stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:10) solvent mixture as an eluant to give 11 mg (yield: 48%) of the title compound (j1).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[C:24](=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])/[CH3:25])[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>O1CCCC1.[Zn]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C@@:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:19]=1)([NH:26][S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH3:25])[CH3:7]
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Zinc (5.07 g, 77.5 mmol) and cuprous chloride (2.64 g, 25.8 mmol) were stirred in a dried apparatus and heated for 1 minute with a heat gun under a flow of argon. After cooling to room temperature, tetrahydrofuran (85.1 ml) was added. The reaction mixture was stirred in a 70° C. oil bath for 30 minutes, then cooled to room temperature. A solution of ethyl bromodifluoroacetate (13.5 g, 8.54 ml, 64.6 mmol) in tetrahydrofuran (25.5 ml) was added dropwise while maintaining the temperature between 26 and 29° C. After stirring for 10 minutes at 23° C., a solution of (R,E)-N-(1-(3-(benzyloxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (intermediate A2.6) (8.51 g, 25.8 mmol) in tetrahydrofuran (25.5 ml) was added dropwise and stirring continued for 24 hours at room temperature. For the workup, the reaction mixture was cooled to 0° C. and ethanol (3 ml) was added dropwise. The mixture was filtered through a pad of Dicalite® and washed with ethyl acetate. The filtrate was concentrated at reduced pressure. The residue was taken in ethyl acetate (40 ml) and water was added. The emulsion was filtered again through a pad of Dicalite®. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product (13.7 g, yellow oil) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The (R)-3-(3-benzyloxy-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (7.72 g, 66% yield) was obtained as a yellow oil. MS (ISP): m/z=454.2 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(OCC)(=O)C>[Cl:1][C:29]1[CH:28]=[CH:27][C:26]([S:31]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)[CH2:4]2)(=[O:33])=[O:32])=[CH:25][CH:30]=1
Reactant: Cl
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl (2-aminoindan-5-yl)acetate hydrochloride (2.43 g), potassium carbonate (5.52 g), water (60 ml), ethyl acetate (60 ml) and 4 chlorophenylsulfonyl chloride (2.11 g) is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with aqueous saline solution, dried, and distilled under reduced pressure to remove the solvent. The resulting crude product is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl [2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (3.02 g).
Reaction SMILES: [CH3:1][C:2]1(B(O)OC(O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.BrC1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([CH3:25])[CH:16]=1.[C:26]([O-])([OH:28])=[O:27].[Na+].CCOC(C)=O>C1COCC1.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>[CH3:25][C:17]1[CH:16]=[C:1]([C:2]2[CH:3]=[CH:4][C:5]([C:26]([OH:28])=[O:27])=[CH:6][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: CC1(B(O)OC(=O)O)C=CC=CC1
Reactant: Cc1cc(Br)c2ccccc2n1
Reactant: O=C([O-])O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)c2ccccc2n1
Temperature: 70 °C

Procedure:
To 1-methylcarboxyphenylboronic acid (1.0 g, 5.6 mmol) and 4-bromo-2-methylquinoline (1.24 g, 5.6 mmol) in THF/aq K2CO3 was added Pd(PPh3)4 and the reaction was heated to 70° C. for 16 hr. Aqueous workup using NaHCO3 and EtOAc, column chromatography and saponification using the same conditions as for Example 214 gave the final product. MS found: (M+H)=264.
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=O)[CH3:6].Cl.C([O-])(O)=O.[Na+]>CO.O>[CH2:1]([O:3][N:4]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CCON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
0.42 g of a 40% strength aqueous O-ethylhydroxylamine solution was added to a solution of 0.4 g (1.3 mmol) of the compound from Example 1 in 20 ml of methanol. Using 10% strength hydrochloric acid, the mixture was acidified to pH 4, and the solution was then stirred at 20-25° C. for about 18 hours. The reaction solution was poured into water and adjusted to pH 8 using NaHCO3. The mixture was then extracted with methyl tert-butyl ether (MtBE), and the combined organic phases were washed with water and dried. Removal of the solvent gave 0.4 g of the title compound as a viscous oil.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]2[N:28]=[C:27]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:26]([CH:40]=[O:41])=[C:25]([I:42])[C:24]1=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1>[Si:15]([O:22][C@H:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]2[N:28]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[C:26]([C@H:40]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)[OH:41])=[C:25]([I:42])[C:24]1=2)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(C(F)(F)F)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To 300 mg magnesium turnings and 2 crystals of iodine were added 1 ml tetrahydrofurane. Afterwards a few drops of a solution of 2 ml 4-bromobenzotrifluoride in 15 ml tetrahydrofurane were added and the mixture was gently heated to start the reaction. Then the rest of the 4-bromobenzotrifluoride solution is added dropwise. After complete formation the Grignard reagent is added dropwise via syringe to a solution of 880 mg (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 10 ml tetrahydrofurane at −50° C. The reaction is stirred for 1 hour at −50° C. and then quenched by dropwise addition of 10 ml methanol. The mixture is partitioned between dichloromethane and saturated ammonium chloride. The organic phase is washed with brine and dried with sodium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 100:0 to 95:5).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:27]([C:25]2[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=2)(=[O:29])=[O:28])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 1-methylimidazole-4-sulfonyl chloride (524 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(1-methylimidazole-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (730 mg).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:16]2[N:20](C(OC(C)(C)C)=O)[C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=O)(C)(C)C.[NH:40]1[CH2:45][CH2:44]S[CH2:42][CH2:41]1.C1C=C(Cl)C=C(C(OO)=O)C=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].[O-:70][S:71]([O-:74])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[O:70]=[S:71]1(=[O:74])[CH2:44][CH2:45][N:40]([C:12]2[N:11]=[C:10]([C:16]3[NH:20][C:19]4[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]=4[N:17]=3)[C:9]([NH2:8])=[N:14][CH:13]=2)[CH2:41][CH2:42]1
Reactant: C1CSCCN1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3nc(N4CCS(=O)(=O)CC4)cnc3N)[nH]c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of tert-butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-6-methyl-benzimidazole-1-carboxylate (70 mg, 0.1158 mmol) in DMF (2 mL) was treated with thiomorpholine (59.74 mg, 0.5790 mmol) and heated to 60° C. for 3 hours. The mixture was then diluted with EtOAc, washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (10 mL), treated with mCPBA (59.95 mg, 0.3474 mmol) and stirred at RT for 1 hour. After washing with a 1:1 Na2CO3/Na2S2O3 solution, TFA (264.1 mg, 178.4 μL, 2.316 mmol) was added and the mixture stirred at RT for 1 hour. This was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (13.1 mg, 31% Yield).
Reaction SMILES: Cl.[OH:2][N:3]1[C:7](=[O:8])[CH2:6][C:5]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:4]1=[O:14].[C:15](=[O:18])([O-:17])O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:17][C:15]([N:11]1[CH2:10][CH2:9][C:5]2([C:4](=[O:14])[N:3]([O:2][C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[C:7](=[O:8])[CH2:6]2)[CH2:13][CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CC2(CCNCC2)C(=O)N1O
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=C(OCc1ccccc1)ON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxy-2,8-diazaspiro-[4,5]decane-1,3-dione.hydrochloride (3.3 g) were added sodium hydrogencarbonate (2.43 g) and benzyloxycarbonyl chloride (3.2 ml). The mixture was stirred for 3 hours at room temperature, which was extracted with ethyl acetate (100 ml). The organic layer was dried over anydrous magnesium sulfate, then the solvent was evaporated off. The residual solid was recrystallized from diethyl ether-n-hexane to obtain 6.0 g of a colorless solid, m.p. 114° C.