Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24](Cl)(Cl)=[S:25].O.C(=O)([O-])[O-].[Ca+2]>ClCCl>[CH:1]1([C:7]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:8]=2[N:9]=[C:24]=[S:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: S=C(Cl)Cl
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C2CCCCC2)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(Oc2ccccc2)cc(C2CCCCC2)c1N=C=S
Reaction time: 5 h

Procedure:
A solution of 7.0 g of 2-cyclohexyl-4-phenoxy-6-isopropylaniline in 20 ml of dichloromethane is added dropwise, with efficient stirring, to 3.1 g of thiophosgene, 40 ml of dichloromethane, 20 ml of water and 5.0 g of ground calcium carbonate. The reaction mixture is stirred for 5 hours under reflux, then cooled and filtered over kieselguhr. The organic phase is separated, washed with water, dried over sodium sulfate and the solvent is removed under vacuum. The title compound of formula ##STR10## is obtained in the form of yellow crystals which melt at 58°-60° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][O:6][NH2:7].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:24]4=[N:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:10]=1>>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][O:6][N:7]=[CH:30][C:28]1[CH:27]=[CH:26][N:25]2[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:11]4[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=4)[CH:16]=3)=[CH:22][N:23]=[C:24]2[CH:29]=1
Reactant: O=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1
Reactant: CN(C)CCON
Agent: Cl
Product: CN(C)CCON=Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using O-(2-dimethylaminoethyl)hydroxylamine hydrochloride and 3-[3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyridine-7-carboxaldehyde to afford a brown oil, essentially as a single geometric isomer. 1H NMR (400 MHz, CDCl3) δH 2.97 (6H, s), 3.43-3.47 (2H, m), 4.65-4.69 (2H, m), 7.28-7.33 (2H, m), 7.42-7.47 (1H, m), 7.62-7.82 (4H, m), 7.94-7.98 (1H, m), 8.20 (1H, s), 8.32-8.35 (1H, m), 8.25 (1H, s), 8.61-8.65(1H, m), 8.90 (1H, s); m/z (ES+) 386 (M++H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:25])[CH2:14][N:15]3[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[CH:35]1([C:45](Cl)=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1>ClCCl>[CH3:20][C:19]1[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:4]3[S:5][CH:6]=[C:2]([NH:1][C:45]([CH:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:38][CH2:37][CH2:36]4)=[O:46])[N:3]=3)[CH2:8][CH2:9]2)=[O:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Reactant: O=C(Cl)C1CCCc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(NC(=O)C3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (120 mg, 0.32 mmol) and diisopropylethylamine (0.2 mL, 0.96 mmol) in dichloromethane (5 mL) is added dropwise a solution of 1,2,3,4-tetrahydro-naphthalene-1-carbonyl chloride (74 mg, 0.38 mmol) in dichloromethane (3 mL) at 0° C. After stirring overnight at RT, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (ethylacetate/cyclohexane 1:1) to give 1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)amide (Compound No. 1.g.011, 82 mg, 48%). M.p.=179.2-181.3° C. 1H-NMR (400 MHz, CDCl3): δ=1.60-1.75 (m, 3H), 1.81-1.89 (m, 2H), 2.05-2.15 (m, 2H), 2.31 (s, 3H), 2.32-2.40 (m, 1H), 2.77-2.94 (m, 3H), 3.05-3.18 (m, 1H), 3.19-3.29 (m, 1H), 3.87 (t, 1H), 3.95-4.04 (m, 1H), 4.50-4.59 (m, 1H), 4.90-5.06 (2d, 2H, diastereotopic protons), 6.32 (s, 1H), 7.25-7.30 (m, 4H), 7.49 (s, 1H), 7.79 (br, 1H). MS: m/z=532 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:16]
Reactant: ClCc1cc2ccccc2cn1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cc2ccccc2cn1
Temperature: 20 °C
Yield: 88.6 %

Procedure:
A mixture of 3-chloromethylisoquinoline hydrochloride (40 g) and sodium ethoxide (40 g) in ethanol (700 cc) is heated under reflux for 8 hours. After cooling to 20° C., the mixture is filtered and the filtrate is evaporated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (500 cc), the mixture is washed with water (3×100 cc), the organic phase is dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The oily residue is distilled at 110°-114° C. under a pressure of 0.6 mm Hg. 3-Ethoxymethylisoquinoline (31 g), a colourless oil, is obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:31]([NH2:33])[CH3:32]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][C@H:9]1[C:10]([NH:33][CH2:31][CH3:32])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)C2CCC(F)(F)CC2)C[C@H]1C(=O)O
Product: CCNC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(F)(F)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1 using (4S)-1-BOC-4-[(4,4-difluorocyclohexyl)(2,2-dimethylpropanoyl)amino]-L-proline (0.95 g, 2.2 mmol) prepared in Step C of Example A5 and commercially available ethylamine (0.93 g, 93%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](O)(=O)CC(O)=O>N1C=CC=CC=1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])(=[O:5])[CH3:12]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)c1ccccc1C(=O)O

Procedure:
Heating at 80° to 85° C. of the phthalic anhydride (5) derived from (1) with malonic acid in pyridine affords the o-acetylbenzoic acid (6). ##STR15##
Reaction SMILES: N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:29]1([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][OH:44])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[N:29]1([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH:43]=[O:44])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: OCCCc1ccc(CN2CCCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CCCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.87 mL (35.56 mmol) pyridine and 2.11 g (4.98 mmol) Dess-Martin periodinane are added to a solution of 780 mg (3.56 mmol) 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-1-ol in 30 mL DCM. The reaction mixture is stirred for 4 h at RT, then added to 100 mL saturated, aqueous NaHCO3 solution, exhaustively extracted with tert-butylmethylether, the organic phase is washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the crude product is further reacted without purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:30]([OH:33])[CH2:31][CH3:32])=[CH:10][CH:9]=1.[C:34](OC=C)(=O)[CH3:35]>C1C(Cl)=CC=C(Cl)C=1>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:30]([O:33][CH:34]=[CH2:35])[CH2:31][CH3:32])=[CH:10][CH:9]=1
Reactant: C=COC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccc(Cl)cc1
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To a suspension of sodium carbonate (16.4 mg, 0.155 mmol) in dichlorobenzene (0.5 mL) were added di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium(I)] (8.7 mg, 0.0129 mmol), 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100.0 mg, 0.155 mmol) and vinyl acetate (47.7 μL, 0.517 mmol). The reaction mixture was stirred at 100° C. for 3.5 hrs. The mixture was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (66.4 mg, 0.161 mmol, 62%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]=[C:15]=S)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19]1[CH:35]=[C:34]([NH:36][CH3:37])[C:33]([N+:38]([O-])=O)=[CH:32][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=1.CI>CO>[CH3:31][NH:30][C:28]([C:24]1[CH:23]=[C:22]([O:21][C:20]2[CH:19]=[CH:35][C:34]3[N:36]([CH3:37])[C:15]([NH:14][C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:9]=4)=[N:38][C:33]=3[CH:32]=2)[CH:27]=[CH:26][N:25]=1)=[O:29]
Reactant: S=C=Nc1cccc(Oc2ccccc2)c1
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Solvent: CO
Solvent: CI
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2cccc(Oc4ccccc4)c2)n3C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 dram vial was charged with a solution of 3-phenoxyphenylisothiocyanate (23 mg, 0.1 mmol), diamine 1 (27 mg, 0.1 mmol), and MeOH (0.5 mL) and the reaction was shaken at rt overnight. Methyl iodide (8 uL, 0.13 mmol) was added and the mixture shaken overnight. The reaction was concentrated and the resulting residue purified on reverse phase HPLC. LCMS m/z 466.3 (MH+), tR=2.40 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([NH:24][C:25]([NH:34]C(OC(C)(C)C)=O)=[N:26]C(OC(C)(C)C)=O)=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:42][C:43]1[CH:48]=[C:47]([C:49]#[N:50])[CH:46]=[CH:45][C:44]=1[NH:51][CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([NH:24][C:25]([NH2:34])=[NH:26])=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:42][C:43]1[CH:48]=[C:47]([C:49]#[N:50])[CH:46]=[CH:45][C:44]=1[NH:51][CH2:52][CH3:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc3N2C)C(=O)N1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=N)N)ccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of the product of Example 273 (116 mg, 0.15 mmol) in anhydrous DCM (6 mL) was added TFA (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then at ambient temperature for 14 h. The solvent was removed in vacuo, and the residue was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to afford the title compound (25 mg, 30%) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.65 (1H, s), 7.72 (1H, d), 7.48 (1H, d), 7.41-7.25 (8H, m), 7.15 (1H, d), 6.65 (1H, d), 5.14 (2H, s), 3.84 (3H, s), 3.07 (2H, m), 1.01 (3H, t); MS(ESI): 555 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:4].[NH2:32][C:33]([NH2:35])=[S:34]>CC(C)=O>[NH2:35][C:33]1[S:34][CH2:2][C:3]([NH:5][C:6]2[C:7]([CH3:31])=[C:8]3[C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:16]=4)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]3[CH:30]=2)([OH:4])[N:32]=1
Reactant: NC(N)=S
Reactant: Cc1c(NC(=O)CBr)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: CC(C)=O
Product: Cc1c(NC2(O)CSC(N)=N2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A mixture of 425A (20 mg, 0.04 mmol) and thiourea (5.4 mg, 0.068 mmol) in acetone (2 ml) was heated at 70° C. for 2.5 h, then stirred at rt overnight. Filtered, the solid was washed with cold acetone and hexanes, dried to give the hydrobromide salt of 425 (14 mg, 63%) as a white solid. It has a retention time of 5.47 min (standard LC1 method, 8 min run). MS Found: (M+H)+=472.0
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:13]2[CH2:14][O:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 8 g of 3-phenyl-1-propanol, 9.64 ml of epibromohydrin, 2.56 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 100 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.2 g of the title compound as a colorless oil having an Rf value of 0.36 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH:10]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A solution of (2′,6′-dimethylbiphenyl-3-yl)methanol (1.0 g, 4.71 mmol), 5-hydroxyindole (0.63 g, 4.73 mmol) and tributylphosphine (1.5 mL, 6.02 mmol) in tetrahydrofuran (30 mL) was stirred, and 1,1′-(azodicarbonyl)dipiperidine (1.6 g, 6.34 mmol) was added by portions, and the mixture was stirred at room temperature for 18 hr. Diethyl ether (30 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (0.95 g, yield 62%) as a pale-brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][CH2:32][CH2:33]Br.O>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:33][CH2:32][CH2:31][Br:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22]
Reactant: BrCCCBr
Reactant: CC(C)c1c(S(=O)(=O)c2ccc(O)cc2)c2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1c(S(=O)(=O)c2ccc(OCCCBr)cc2)c2ccccc2n1C
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2.8 g (0.0085 mol) of 1-methyl-2-isopropyl-(4-hydroxy-benzenesulphonyl)indole in 100 ml of N,N-dimethyl formamide were added 14 g of anhydrous and crushed potassium carbonate. After that 6.8 g (0.037 mol) of 1,3-dibromopropane were added and the medium was heated at 100° C. for 0.5 hour. The mixture was poured into water, extracted with ethyl ether and the ethereal fraction was washed with water, dried on anhydrous sodium sulphate, filtered and evaporated to obtain 2.7 g of 1-methyl-3-[4-(3-bromo-propoxy)benzenesulphonyl]-2-isopropyl-indole (yield: 69%). This crude bromopropoxy derivative was dissolved in 60 ml of dimethylsulphoxide and 2.2 g (0.03 mol) of tert-butylamine were added. The medium was then stirred at room-temperature for 48 hours, poured into water and extracted with ethyl ether. The ethereal solution was then washed with water, dried on anhydrous sodium sulphate, filtered and evaporated. The crude product so obtained (2.3 g) was then purified by chromatography on a silica column (solvent:methanol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:29][C:30]3[CH:42]=[CH:41][C:33]4[C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[O:36][C:32]=4[CH:31]=3)=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:34]2[C:33]3[CH:41]=[CH:42][C:30]([O:29][C:23]4[C:22]5[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[N:26]=[CH:25][CH:24]=4)=[CH:31][C:32]=3[O:36][C:35]=2[CH3:37])=[O:39])=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)nc1
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)c(C)oc4c3)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccc(CN)cn5)c(C)oc4c3)ccnc2c1

Procedure:
117-C was coupled with 6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylic acid 117-D (as prepared in Scheme II discussed previously). After work up the mixture was treated with 50% TFA in CH2Cl2 to give N[5-(aminomethyl)pyridin-2-yl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide 117-E.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][C:14]([CH2:17][OH:18])([CH3:16])[C:13](=[O:19])[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20]1[CH:25]=[C:24]2[C:26]([O:28][S:29](=[O:31])(=[O:30])[C:23]2=[CH:22][CH:21]=1)=[O:27]>O1CCCC1>[S:29]([C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][C:24]=1[C:26]([O:18][CH2:17][C:14]1([CH3:16])[CH2:15][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:12][C:13]1=[O:19])=[O:27])([OH:31])(=[O:30])=[O:28]
Reactant: COc1ccc(N2CC(C)(CO)C(=O)N2)cc1OC
Reactant: O=C1OS(=O)(=O)c2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(N2CC(C)(COC(=O)c3ccccc3S(=O)(=O)O)C(=O)N2)cc1OC
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a suspension of {1-(3,4-dimethoxyphenyl)-4-hydroxymethyl-4-methyl-3-pyrazolidinone (1.0 g, 3.76 mmol) in dry tetrahydrofuran (20 ml) was added 2-sulfobenzoic acid cyclic anhydride (0.69 g, 3.76 mmol), in a single portion at room temperature with stirring. The reaction medium was heated to reflux under nitrogen for 24 hours until complete dissolution was observed. The mixture was cooled in a ice/water bath and the solid was recovered by filtration and washed with acetonitrile. After drying under vacuum, 0.93 g (55%) of {1-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-pyrazolidin-4-yl}methyl 2-sulfobenzoate (Compound IV) was isolated in the form of a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]([C:9](=[O:11])[CH3:10])=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]([C:9](=[O:11])[CH2:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC=C(OC(C)=O)C(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC=C(OC(C)=O)C(=O)CC(=O)c1ccccc1
Temperature: -78 °C

Procedure:
To a solution of 545 mg (3.5 mmol) of 1-methoxy-3-oxobut-1-en-2-yl acetate in THF (14.2 mL) at −78° C. was added LHMDS (3.45 mL of a 1 M solution in toluene) dropwise. After stirring for min at −78° C., the reaction mixture was treated with 0.4 mL (3.5 mmol) of benzoyl chloride dropwise, then removed from the cold bath and allowed to warm to room temperature and continue stirring for 18 h. The reaction was quenched with 10 mL 10% aq HCl and extracted with diethyl ether (3×10 mL). The organic fractions were combined, washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate which was used the subsequent step without further purification. To a solution of crude 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate (3.5 mmol) in toluene (35 mL) was added pyridinium p-toluenesulfonate (130 mg, 0.5 mmol). The reaction mixture was heated at reflux under a nitrogen atmosphere for 1 h before being cooled and concentrated under reduced pressure and purified by flash chromatography (80 g SiO2, 0-100% ethyl acetate/hexanes gradient elution) to provide 4-oxo-6-phenyl-4H-pyran-3-yl acetate. LC/MS (M+H)+ 231.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[NH:27]([C:39]([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:36]([C@@H:28]([NH:27][C:39](=[O:40])[O:41][CH2:42][CH:43]2[C:55]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[C:49]3[C:44]2=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:37])[CH2:21][C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)OCC1c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 19, by condensing (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide with Fmoc-Phe-OH there was obtained 9H-fluoren-9-ylmethyl [(S)-α-[[(S)-1-[[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate which, by reaction with piperidine in methylene chloride, was converted into (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide. Further condensation with Boc-D-Pro-OH, analogously to Example 19, yielded (R)-2-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylic acid tert-butyl ester as an amorphous solid, MS: 709 (M+H)+.