Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccc(C#N)cc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.050 g (0.112 mmol) of {3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone, hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) of potassium carbonate was added to the solution, followed by 0.022 g (0.11 mmol) of 4-bromomethyl-benzonitrile. The reaction solution was shaken for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with water and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), and DCM/MeOH (10/1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cn1ccnc1S
Product: Cn1ccnc1SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 49 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-1-methylimidazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 49% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[N+:22]([CH3:25])([O-:24])=[O:23].CN(C)C(N(C)C)=N>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:25][N+:22]([O-:24])=[O:23])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1
Reactant: CCOC(=O)C=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC[C@H](Nc2nc(Cl)ncc2F)C1

Procedure:
To a solution of (5)-ethyl 2-(3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylidene)ethanoate, 62a, (2.58 g, 8.22 mmol) in nitromethane (44.53 mL, 822.3 mmol) was added 1,1,3,3-tetramethylguanidine (1.55 mL, 12.33 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc) then a second chromatography (CH2Cl2:20% MeOH in CH2Cl2). Fractions containing pure product were combined and concentrated to give 1.8 g of 62b
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[NH:33]1[C:34]2[C:30](=[C:29]([CH2:28][NH:27][C:26]([C:19]3[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:39])=[O:2])=[O:16])=[C:21]([C:22]([F:25])([F:23])[F:24])[CH:20]=3)=[O:38])[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-({5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (130 mg, 0.22 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.24 mmol) in water (6 mL). The mixture was then stirred at room temperature overnight. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 0.1159 g (93%). MS m/e 565.9 (M+H+).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:19]
Reactant: O=C(NNc1cccnc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NNc1cccnc1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-7-oxo-N′-(pyridin-3-yl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 238 (0.20 g, 0.54 mmol) and Pd/C (0.08 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 239 (0.13 g, 87%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:19])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:19])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CCC(=O)c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(2,6-difluorophenyl)-4-oxobutyrate (Step A, 9.52 g, 35.2 mmol) in dichloromethane (30 ml) was treated with trifluoroacetic acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>C(Cl)Cl.CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[C:10]=3[N:11]=[C:12]([S:14]([CH3:15])=[O:37])[N:13]=2)=[CH:4][N:3]=1
Reactant: CSc1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a suspension of tert-butyl(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-(methylsulfanyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (352 mg, 0.794 mmol) in DCM (8 mL) was added m-chloroperoxybenzoic acid (254 mg, 1.03 mmol, 70% purity) in three portions over 1 min at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Four drops of DMSO was added and the reaction mixture was stirred for 5 min. The reaction mixture was purified via HPLC reversed phase column (XBridge C18 30×250 mm, mobile phase: 0%-50% of water with 0.1% EtOAc to acetonitrile with 0.1% EtOAc over 30 min, flow rate 80 mL/min) to give the title compound (200 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2 H), 7.18 (s, 2 H), 3.89-3.75 (m, 2 H), 3.73-3.62 (m, 3 H), 3.42-3.34 (m, 3 H), 2.82 (s, 3 H), 2.41 (br s, 1 H), 2.15-2.01 (m, 1 H), 1.41 (s, 9 H), 1.33 (s, 3 H). m/z (APCI+) for C21H29N7O3S 460.6 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:11]1[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH2:17]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2.9 g) and dichloromethane (29 ml) were mixed, and TFA (7.3 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The aqueous layer was concentrated under reduced pressure, and CHCl3 was added to the residue, followed by stirring and filtrating. The filtrate was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain {2-fluoro-3-[3-(piperidin-4-yl)azetidin-1-yl]phenyl}methanol (1.25 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:16]([OH:19])[CH2:17][Br:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C@@H:16]([OH:19])[CH2:17][Br:18])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromoethanol (Org. Process Research and Development, 1998, 2, 96) (30.8 g, 95.6 mmol) in dichloromethane (300 ml) was treated with pyridine (9.3 ml, 115 mmol). The resulting solution was cooled to 5° C. and a solution of methanesulfonyl chloride (7.8 ml, 100.7 mmol) in dichloromethane (10 ml) added dropwise. The mixture was stirred at 5° C. for a further 30 minutes and then allowed to warm gradually to room temperature over a period of 16 hours. The reaction mixture was washed with 2N hydrochloric acid (110 ml) and the organic phase separated, dried (magnesium sulfate) and the solvent removed in vacuo to give an orange oil. The residue was crystallized from hot toluene (100 ml) to give the title compound as a pale pink solid (33.7 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[NH:5][CH:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([N:5]1[C:6]2[C:11](=[CH:10][N:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH:4]1[CH3:12])(=[O:22])[CH3:21]
Reactant: CC1CC(=O)c2cnccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccncc2C(=O)CC1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
[Step 4] 30 mg of the 4-oxo-2-methyl-2,3-dihydro-1H-[1,6]naphthyridine were dissolved in 2 mL of dichloromethane followed by adding 0.1 mL of triethylamine and 35 μL of acetic anhydride and stirring overnight at 40° C. Following completion of the reaction, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate) to obtain 7 mg of 1-acetyl-4-oxo-2-methyl-2,3-dihydro-1H-[1,6]naphthyridine in the form of a pale yellow oil (18%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]>CC(CC)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[CH:7][CH2:8][CH2:9][CH3:16])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(NN)cc2C1
Solvent: CCC(C)=O
Product: CCCC=NNc1cc2c(nn1)CCN(C(=O)OCC)C2

Procedure:
A suspension of 23.7 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in 100 cc of methylethyl ketone is heated at reflux for 4 hours while stirring. The title compound has a M.P. of 142°-146° (decomp., from methanol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)([OH:8])(=[O:7])=[O:6].[Na:18]>O>[Na:18].[S:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:16]([SH:17])=[N:3][N:2]=[N:1]2)=[CH:13][CH:14]=1)([OH:8])(=[O:6])=[O:7]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(O)c1ccc(N=C=S)cc1
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=S(=O)(O)c1ccc(-n2nnnc2S)cc1
Yield: 25 %

Procedure:
19.5 g of sodium azide was dissolved in 1.5 l of water, then 23.7 g of sodium 4-sulfophenylisothiocyanate synthesized in (1) above was added thereto. The resulting mixture was heated using a steam bath for 8 hours, followed by removing solids by filtration. After adding 125 ml of 20% sulfuric acid to the filtrate, it was concentrated under reduced pressure. Addition of 20 g of NaCl to the concentrate caused precipitation of crystals. The crystals were collected by filtration, then dissolved in a mixed solution of 80 ml of water and 20 ml of 2N HCl. Addition of NaCl thereto little by little caused precipitation of crystals. The crystals were collected by filtration and dried to obtain 7 g of Compound II-1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH:13]([Cl:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:16][CH2:13][CH2:14][CH2:15][O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:15][CH2:14][CH2:13][Cl:16])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCCCCl)c1ccc(OCCCCl)cc1F
Yield: 155.3 %

Procedure:
2-fluoro-4-hydroxybenzoic acid (1 g, 6.41 mmol, 1 eq) is reacted with bromochloropropane (0.82 ml, 8.33 mmol, 1.3 eq) in the presence of potassium carbonate (1.77 g, 12.81 mmol, 2 eq) in methyl ethyl ketone (18 ml) at 80° C. overnight, filtered, washed with acetone and concentrated under vacuum to afford 2 g of 3-chloropropyl 4-(3-chloropropoxy)-2-fluorobenzoate i76.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:10][C:11]=1[CH2:12]Br)=[O:5])[CH3:2].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:10][C:11]=1[CH2:12][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CBr)ccn(Cc2ccccc2)c1=O
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CN(CC(=O)OC)S(=O)(=O)c2ccc(C)cc2)ccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A mixture of 1-benzyl-4-bromomethyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid ethyl ester (860 mg, 2.46 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (660 mg, 2.70 mmol), sodium iodide (740 mg, 4.91 mmol) and potassium carbonate (680 mg, 4.91 mmol) in DMF (20 mL) was stirred at r.t. for 16 h. Brine (50 mL) were added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-70% EtOAc/hexanes) to give 940 mg of the title compound. MS: (+) m/z 512.97 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:12]([N:13]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:15]=[N:14]2)[C@@H:11]([O:22]C(=O)C)[C@@H:10]([CH2:26][O:27]C(=O)C)[O:9][C@H:6]1[S:7][CH3:8])(=O)C.C[O-].[Na+]>CO>[CH3:21][O:20][C:18]([C:16]1[N:15]=[N:14][N:13]([C@H:12]2[C@@H:11]([OH:22])[C@@H:10]([CH2:26][OH:27])[O:9][C@@H:6]([S:7][CH3:8])[C@@H:5]2[OH:4])[CH:17]=1)=[O:19]
Reactant: COC(=O)c1cn([C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H](SC)[C@@H]2OC(C)=O)nn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn([C@H]2[C@@H](O)[C@@H](CO)O[C@@H](SC)[C@@H]2O)nn1
Yield: 68.1 %

Procedure:
Compound 4 (10 mg, 0.023 mmol) was dissolved in methanol (1.5 mL) and stirred over night at room temperature with sodium methoxide solution 1M (0.5 mL). The mixture was neutralized with Duolite™ resin, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2:MeOH 25:1) to give 10 (5 mg, 70%).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:29]5[CH2:34][CH2:33][C:32]6[CH:35]=[CH:36][S:37][C:31]=6[CH2:30]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.COC(=O)C[C@H]1C2C=CC(O[C@H]3C4C(=C(CBr)C(C(F)(F)F)=CC=4)CC3)=CC=2OC1.S1C2CNCCC=2C=C1>>[S:37]1[C:31]2[CH2:30][N:29]([CH2:28][C:19]3[C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=[C:23]4[C:18]=3[CH2:17][CH2:16][C@H:15]4[O:14][C:12]3[CH:11]=[CH:10][C:9]4[C@H:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][O:7][C:8]=4[CH:13]=3)[CH2:34][CH2:33][C:32]=2[CH:35]=[CH:36]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ccsc4C3)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Agent: c1cc2c(s1)CNCC2
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ccsc4C3)ccc21

Procedure:
The methyl ester of the title compound, {(S)-6-[(R)-4-(4,7-dihydro-thieno[2,3-c]pyridin-6-ylmethyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester, is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4,5,6,7-tetrahydro-thieno[2,3-c]pyridine following a procedure analogous to that described for Intermediate 42. The crude product is directly submitted to the saponification conditions described for Example 1 to give the title compound upon chromatography on reversed phase (HPLC; acetonitrile/water). LC (method 6): tR=0.91 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [N:1]1([C:7](=[O:15])[CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:16].[CH3:17][O:18][C:19]1[C:27]2[O:26][C:25](C)(C)C[C:23]=2[C:22]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([C:41]3[CH:46]=[CH:45][C:44]([C:47](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:48])=[CH:43][CH:42]=3)[N:31]=2)=[CH:21][CH:20]=1>>[ClH:16].[CH3:25][O:26][C:27]1[CH:23]=[C:22]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:15])[CH2:14][CH2:13]4)=[O:48])=[CH:45][CH:46]=3)[N:31]=2)[CH:21]=[CH:20][C:19]=1[O:18][CH3:17]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CC(=O)N5CCOCC5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone as described for compound 8. M.p. 168–169° C.
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[C:28]([C:29](O)=[O:30])=[C:27]([CH3:32])[O:26][N:25]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([N:21]1[C:29](=[O:30])[C:28]2[C:24](=[N:25][O:26][C:27]=2[CH3:32])[C:22]1=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1onc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1onc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 91.5 %

Procedure:
6.3 g (62.2 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 14.6 g of a 50% strength solution of propanephosphonic anhydride (23 mmol) in dichloromethane were added dropwise in succession to 3.8 g (16.8 mmol) of 3-tert-butylaminocarbonyl-5-methylisoxazole-4-carboxylic acid in 150 ml of dichloromethane at -5° C. and the mixture was then refluxed for 6 hours. Working up was carried out as described above. 3.2 g (91%) of N-tert-butyl-5-methylisoxazole-3,4,-dicarboximide were obtained as a solid of melting point 48°-50° C. (Example No. 2.001).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:37]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]([CH3:37])[C:19]2[C:24]([C:25]=1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)n(C)c2c1
Reaction time: 12 h
Yield: 80.4 %

Procedure:
NaH (810 mg, 32.1 mmol) was added to a solution of intermediate 2 (9.4 g, 21.4 mmol) in dry DMF. Then, iodomethane (3.64 g, 25.7 mmol) was added at room temperature. After 12 h, the reaction mixture was partitioned between water (pH 6) and AcOEt. Organic layer was dried over anhydrous Na2SO4, filtered and then evaporated. The residue was purified by silica column chromatography (gradient heptane/AcOEt 1:0 to 80:20) to yield 7.8 g (80%) of methyl 2-[2-(benzyloxy)phenyl]-3-cyclohexyl-1-methyl-1H-indole-6-carboxylate 3: m/z=454 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].O>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate (Intermediate 10) (0.33 g, 1.09 mmol) in THF was added a 1M solution of DIBAL-H in toluene (2.3 mL, 2.1 eq) and the reaction was stirred at room temperature for 2 hours. The reaction was not completed. Two more equivalents of a 1M solution of DIBAL-H in toluene were added and the reaction was stirred for a further 18 hours. Solid NH4Cl was added followed by water and the aqueous phase was extracted with ether, ethyl acetate, dried over sodium sulphate and evaporated. The title compound was obtained as a white powder after recrystallisation from isopropyl ether (170 mg, 60%). LC/MS: m/z 258 (M+H)+ Rt: 2.45 min.