Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].O[CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]([CH3:13])([CH3:12])[C:6]1=[O:14]>C(Cl)(Cl)Cl>[CH3:12][C:7]1([CH3:13])[C:6](=[O:14])[C:5](=[CH:4][NH:2][CH3:1])[C:9]([CH3:11])([CH3:10])[O:8]1
Reactant: CC1(C)OC(C)(C)C(=CO)C1=O
Reactant: CN
Solvent: ClC(Cl)Cl
Product: CNC=C1C(=O)C(C)(C)OC1(C)C
Yield: 74 %

Procedure:
Methylamine gas was bubbled through a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (5.0 g, 29 mmol) in 50 mL of chloroform for 30 min. The solvents were evaporated. The solid residue was recrystallized from hexanes to give 4.Og (74%) of dihydro-2,2,5,5-tetramethyl-4-methylaminomethylene-3(2H)furanone as a light yellow solid: mp 80°-82° C.; Anal Calc'd for C10H17NO2 : C, 65.57; H, 9.29; N, 7.65. Found: C, 65.47; H, 9.30; N, 7.60.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.CO[CH:14](OC)[CH2:15][CH:16](OC)OC>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:16]=[CH:15][CH:14]=[N:11]2)=[CH:6][CH:5]=1
Reactant: COC(CC(OC)OC)OC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of (4-methoxyphenyl)hydrazine hydrochloride (8.0 g, 0.046 mol) and 1,1,3,3-tetramethoxypropane (8.3 g, 0.05 mol) in ethanol (120 mL) was heated to reflux for 1 hour. The reaction was then cooled to room temperature and concentrated. The residue was diluted with saturated sodium bicarbonate (50 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 1-(4-methoxyphenyl)-1H-pyrazole (7.7 g, 97%) as a yellow oil. 1H NMR (400 MHz, CDCl3, δ): 7.82 (m, 1H), 7.69 (m, 1H), 7.59 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 6.43 (m, 1H), 3.83 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(O)(=O)=O.[CH2:13]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[N+:1]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)([O-:4])=[O:2]
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 78 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
70% Nitric acid (3.16 mL) was added dropwise to a suspension of trifluoromethanesulfonic acid (9.34 mL, 105.6 mmol) in dichloromethane (250 mL). The suspension was cooled in a dry ice-acetone bath and a solution of 4-benzyl-benzoic acid (10.19 g, 48 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was stirred for about 2 hours at−78° C. and an additional 2 hours at room temperature. The reaction mixture was poured into crushed ice. The separated organic layer was washed with dichloromethane (2×) and the combined organic layers were dried over (Na2SO4), and solvents were evaporated. Recrystallization of the crude product from methanollethyl acetate gave 4-(4-nitrobenzyl)-benzoic acid (9.27 g, 58%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].[CH3:12]COCC>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:12][C@H:9]1[CH2:10][OH:11]
Reactant: CCOCC
Reactant: OC/C=C/c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: OC[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Pd(OAc)2 (13.3 mg, 0.06 mmol) was added to a solution of trans-3-(2-chlorophenyl)-2-propen-1-ol (100 mg, 0.59 mmol) in a solution of CH2N2 in Et2O (ca. 0.6 M, 25 mL). The reaction mixture was stirred at room temperature for 1 h. An additional amount of CH2N2 solution in Et2O (25 mL) was added and the mixture was stirred for 1 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to yield the title compound (85.5 mg, 79% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:18])=[N:10][O:11][C:12]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O.C1(C)C=CC=CC=1>[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9]([CH3:18])=[N:10][O:11][C:12]=3[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1onc(C)c1-c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(-c3c(C)noc3CC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a 50 mL two neck RB flask fitted with magnetic stirrer was charged with 15 mL of toluene. To the stirred solvent were added methyl [4-(4-hydroxyphenyl)-3-methyl-1,2-oxazol-5-yl]acetate (0.3 g, 1.21 mmol), (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.33 g, 1.21 mmol) and tri-(n-butyl)phosphine (0.39 g, 1.94 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (0.49 g, 1.94 mmol) was added portion wise and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents. The product was obtained as colorless oil (0.47 g, yield: 77%). 1H NMR (300 MHz, CDCl3): δ 7.57-7.61 (m, 2H), 7.26-7.30 (m, 5H), 7.11-7.14 (d, 2H), 6.94-6.97 (d, 2H), 6.85-6.88 (d, 2H), 5.14 (s, 2H), 4.93 (s, 2H), 3.99 (s, 3H), 3.68 (s, 2H), 3.65 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:27](/B(O)O)=[CH:28]\[CH3:29].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2/[CH:27]=[CH:28]/[CH3:29])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C/C=C/B(O)O
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccc(F)cc2C1
Yield: 50.9 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and trans-1-propen-1-ylboronic acid (294 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (153) as white solid (165 mg, 51%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[C:21]([Br:22])=[CH:20][CH:19]=[C:18]([OH:23])[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([Br:22])=[CH:20][C:19]([I:1])=[C:18]([OH:23])[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(Br)c(Cc2ccccc2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Oc1nc(Cc2ccccc2)c(Br)cc1I
Reaction time: 8 h
Yield: 85.8 %

Procedure:
1.19 g of N-iodosuccinimide was added to a mixture of 1.16 g of 2-benzyl-3-bromo-6-hydroxypyridine (Production Example 3-b) and 10 ml of N,N-dimethylformamide at room temperature, followed by stirring at the same temperature overnight. 50 ml of water was added to the reaction solution and the resulting crystals were collected by filtration, washed with water and then vacuum-dried, to give 1.47 g of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30]1([CH2:36][CH:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:37]([OH:38])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:2]
Reactant: O=CCc1ccccc1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 17.4 ml (77.6 mmol) phenylacetaldehyde were added and stirring was continued overnight. The mixture was allowed to warm to room temperature, water was added and most of the organic solvent was removed by distillation. About 20 g citric acid were dissolved in the aqueous residue. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 5.4 g (19%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100) and as second eluting fraction 4.1 g (15%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH3:25]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:23][CH2:24][CH3:25])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CCCNCCOC
Product: CCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.16 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-(2-methoxyethyl)propan-1-amine to give after working up and purification 293 mg (71%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][N:17]([CH3:30])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)(=[O:20])=[O:19]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[C:21]([S:18]([N:17]([CH3:30])[CH3:16])(=[O:19])=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][C:4]=2[CH3:15])=[N:9][CH:10]=1
Reactant: Cc1cc(Br)ccc1-c1cnc(N)cn1
Reactant: CN(C)S(=O)(=O)c1ccccc1B(O)O
Product: Cc1cc(-c2ccccc2S(=O)(=O)N(C)C)ccc1-c1cnc(N)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 589 using 5-(4-bromo-2-methylphenyl)pyrazin-2-amine and (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for C19H20N4O2S, 368.46; m/z found, 369.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=1.5, 1H), 8.12 (dd, J=8.0, 1.3, 1H), 8.10 (d, J=1.5, 1H), 7.60-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.43 (d, J=7.8, 1H), 7.35-7.29 (m, 3H), 4.77 (s, 2H), 2.44 (s, 3H), 2.42 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[N:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=[C:14]2[N:13]=[C:12]([S:25][CH3:26])[N:11]=1>>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[N:15]3[N:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[C:14]3[N:13]=[C:12]([S:25][CH3:26])[N:11]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: CSc1nc(Cl)n2nc(-c3ccccc3)cc2n1
Product: CSc1nc(NCCc2c[nH]cn2)n2nc(-c3ccccc3)cc2n1

Procedure:
4-[4-imidazolylethylamino]-2-methylthio-7-phenylpyrazolo[1,5-a]-1,3,5-triazine is prepared from histamine and 4-chloro-2-methylthio-7-phenylpyrazolo[1,5-a]-1,3,5-triazine according to conventional methods.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Product: O=C(O)c1c(F)cccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting 6-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.96 (s, 2H), 7.87-7.82 (m, 1H), 7.70 (td, J=8.1, 5.1 Hz, 1H), 7.59 (ddd, J=9.7, 8.4, 1.4 Hz, 1H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]5[CH2:35][O:34]C(C)(C)[O:32]5)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:32])[CH2:35][OH:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2cnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)s2)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(C(O)CO)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole (470 mg) in tetrahydrofuran (3 mL) was added 1M hydrochloric acid (3 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (280 mg, yield 64%) as a colorless amorphous solid. MS: 503 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:18]=[CH:17]4)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].BrC[CH2:47][O:48][C:49](=[O:51])[CH3:50].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:18]=[CH:17]4)[N:11]2[CH2:50][C:49]([O:48][CH3:47])=[O:51])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc4nc(-c5cc(OC)ccc5-c5ccc(Cl)cc5)ccc4c3)[nH]c2c1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
To a mixture of intermediate 15-2 (1.024 g, 1.7 mmol) and bromoethylacetate (388 mg, 1.5 eq) in dry DMF (30 mL) was added NaH (60% dispersion in mineral oil, 122 mg, 1.8 eq) at 0° C. After stirring for 20 min at this temperature, the reaction mixture was warmed up to room temperature. After 24 h, the reaction mixture was poured into 300 mL of ice-cold water. The formed yellow solid was filtered off, washed with petroleum ether and purified by column chromatography (CH2Cl2) to give 450 mg (39%) of 2-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1-methoxycarbonylmethyl-1H-indole-6-carboxylic acid methyl ester 15-3; m/z=674 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13]O)[C:6]=2[CH:15]=1.S(Cl)([Cl:18])=O.C>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][Cl:18])[C:6]=2[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCCl
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a stirred mixture of 22.6 parts of 6-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one and 300 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux. After stirring with activated charcoal, the reaction mixture is filtered hot over hyflo. The filtrate is evaporated and the residue is dissolved in methylbenzene. The solution is washed a few times with water, dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The solid product is filtered off and dried, yielding 19 parts (77.5%) of 6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 122° C.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:3]1=[O:19].Br.O=C1C2C(=C(CC(O)=O)C=CC=2)CC1.BrBr>C(O)(=O)C.O>[Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:11][C:12]([OH:14])=[O:13])[C:3]1=[O:19]
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1CC(Br)C2=O
Agent: Br
Agent: BrBr
Agent: O=C(O)Cc1cccc2c1CCC2=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cccc2c1CC(Br)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The (2-bromo-1-oxoindan-4-yl)acetic acid can be obtained in the following manner: 4 ml of hydrobromic acid at 47% are added to a solution of 38 g of (1-oxoindan-4-yl)acetic acid in 800 ml of acetic acid. 11 ml of bromine are added dropwise and over 10 minutes to this solution cooled to a temperature close to 15° C. and then the reaction medium is kept stirring for one hour at a temperature close to 15° C. The reaction medium is allowed to return to a temperature close to 20° C. and the reaction is continued for 2 hours. The reaction medium is poured into a mixture of 800 g of ice and 800 ml of water and then filtered on sintered glass. The filtrate is taken up in three times 800 ml of dichloromethane and the combined organic phases are washed with twice 800 ml of distilled water, dried over magnesium sulphate, filtered on paper and concentrated under reduced pressure at 50° C. The solid residue thus obtained is triturated in 240 ml of diisopropyl ether, filtered on sintered glass and air dried. 45.4 g of (2-bromo-1-oxoindan-4-yl)acetic acid are thus obtained in the form of a cream-coloured solid melting at 120° C.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[C:18]=1[C:19]#[N:20])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 25 %

Procedure:
Prepared as in Example 197c from 4-(tert-butyldimethyl-silyloxy)butan-1-ol and 2,6-dinitrobenzonitrile in 25% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 0.01 (s, 6H), 0.81-0.83 (m, 9H), 1.61-1.66 (m, 2H), 1.76-1.81 (m, 2H), 3.63 (t, J=6.8 Hz, 2H), 4.26 (t, J=6.4 Hz, 2H), 7.68-7.70 (m, 1H), 7.84-7.89 (m, 2H).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:58])([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])[NH2:43])=[O:36])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:11]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH2:12][NH:43][C@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])=[O:45])[CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:35]([O:34][C:32]([CH3:58])([CH3:31])[CH3:33])=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CSC(CN[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.59 g. 1.40 mmole), 1-[N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (1.55 g., 3.88 mmole), and crushed 3 A° molecular sieves (2.0 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After stirring for 2 hours, sodium cyanoborohydride (0.27 g., 3 eq.) is added and stirring continued for 18 hours. The reaction mixture is filtered through Celite to remove the sieves. The filtrate is then diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed at reduced pressure to give the desired product, a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone 4:1) isomer A at Rf =0.31, and isomer B at Rf =0.15. Repeated chromatography (flash, silica gel LPS-1; chloroform:methanol, 98:2; hexane-acetone, 65:35; benzene:acetone, 4:1; ethyl acetate:hexane, 6:4; ethyl acetate:hexane, 6:4) gives 0.41 g. of 1-[N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a colorless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18]>C1C=CC=CC=1>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(CNC(C)=O)OC

Procedure:
A solution of 32 g (313 mmol) of acetic anhydride in 200 ml of benzene is added, drop by drop, to a suspension, stirred and heated to reflux, of 40 g (290 mmol) of potassium carbonate and 30 g (285 mmol) of aminoacetaldehyde dimethyl acetal in 200 ml of benzene. Reflux is maintained for 30 min., then the mixture is cooled and filtered, the precipitate is washed with benzene, the filtrate is evaporated and the residual oil is treated with vegetable charcoal in 300 ml of diethyl ether. After filtration and evaporation, 36.8 g (250 mmol) of product are obtained. n25D =1.4450.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:24])[CH2:22][CH3:23]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Product: CCC(=O)c1ccc(OC)cc1C(=O)O

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methylpropionamide. It is used in crude form in the following reaction.