Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([OH:25])[CH3:24])[CH3:20].[H-].[Na+]>>[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([O:25][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)[CH3:24])[CH3:20]
Reactant: CCOC(=O)[C@H](C)O
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.77 g), TIM (15 mL), 2-hydroxy-(2S)-propanoic acid ethyl ester (0.40 mL) and 60% sodium hydride (0.14 g) to give the subtitle compound as a clear, colourless oil. Yield: 1 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:25]2[CH2:26][CH2:27][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:24]2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc(CC=O)cc2OC)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(-c2ccc(CCN3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)cc1
Reaction time: 16 h

Procedure:
A solution of Example 491C (400 mg, 1.41 mmol) and tert-butyl 1-piperazinecarboxylate (289 mg, 1.55 mmol) in 1,2-dichloroethane (5 mL) at room temperature was treated with sodium triacetoxyborohydride (329 mg, 1.55 mmol), and stirred for 16 hours. The solution was purified by flash column chromatography on silica gel with 90:10:0.25 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH:12](Br)[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O>[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH:12]([N:16]=[N+:17]=[N-:18])[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cccc(NC(=O)C(C)Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(NC(=O)C(C)N=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a stirred a solution of N-(3-Acetylphenyl)-2-bromopropionamide (800 mg, 2.97 mmol) in DMF (10.0 mL) was added NaN3 (290 mg, 4.46 mmol). The reaction was stirred at room temperature under N2 atmosphere for 12 h, diluted with water, and the precipitated solid was filtered and dried to give the title product in 50% yield. 1H NMR (CDCl3, 400 MHz): 8.36 (br s, NH), 8.08-8.07 (m, 1H), 7.90-7.87 (m, 1H), 7.74-7.71 (m, 1H), 7.44 (t, J=8.0 Hz, 1H), 4.25 (q, J=6.8 Hz, 1H), 2.61 (s, 3H), 1.65 (d, J=6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz): 197.7, 168.2, 137.8, 137.5, 129.4, 124.6, 124.5, 119.5, 59.4, 26.7, 17.1. ESI-MS calcd for C11H11N4O2 (M−H)+231.09. found 231.1.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH2:26])=[C:24]([O:30][CH3:31])[CH:23]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH:26][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[C:4]=3[N:3]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1cc(Cl)cc(C)c1N
Reactant: CCC(CC)c1ccc(C(F)(F)F)c2nc(Cl)n(C)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C(F)(F)F)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 110 °C
Yield: 33.7 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole (290 mg, 0.95 mmol), 4-chloro-2-methoxy-6-methylaniline (491 mg, 2.86 mmol) and N-methyl-2-pyrrolidinone (3 drops) was heated at 110° C. for 72 h. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 10% ethyl acetate/n-hexane and recrystallized from diisopropylether/n-hexane to give 140 mg (0.32 mmol, 34%) of the title compound as a white powder.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[OH-].[Na+]>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][C:22]=3[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2sccc2S(C)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccsc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 83.3 %

Procedure:
6.09 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-methylsulfonyl-2-thienyl)ethyl]piperidine obtained in Example 43 and 2 ml of thionyl chloride were dissolved in 50 ml of ethanol, and the mixture was heated under reflux for 2 hours. The reaction mixture was basified by adding a 1N aqueous sodium hydroxide thereto, and then extracted with dichloromethane. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by NH form silica gel column chromatography (ethyl acetate), to give 4.89 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:13](=[O:14])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])[CH:6]=[N:7]2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(O)C(Cc1ccccc1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(Cc2ccccc2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 57 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid (Intermediate 30) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionamide as a light yellow solid (1.07 g, 57%); ES+-HRMS m/e calcd for C30H35N5O4SiF2 [M+H+] 596.2499 found 596.2499. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.06 (s, 6H) 0.80 (s, 9H) 3.36-3.50 (m, 2H) 3.86 (t, J=5.1 Hz, 2H) 4.08 (t, J=5.1 Hz, 2H) 5.75-5.88 (m, 1H) 5.93 (d, J=2.7 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.06-7.53 (m, 8H) 7.56 (d, J=2.1 Hz, 1H) 8.25 (d, J=2.7 Hz, 1H) 10.99 (s, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.C([O:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][N:24]=[C:25]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[N:21]([CH3:37])[CH:20]=1)=O)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][N:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)[N:21]([CH3:37])[CH:20]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cn(C)c2cnc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
At 0° C., a solution of 2.0M AlCl3 in toluene (0.14 mL) is added to a solution of 4-chlorobenzylamine (0.044 mL) in CH2Cl2 (5 mL). The compound from ethyl-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxylate (Preparation 46, 0.058 g) is added and the mixture allowed to stir at room temperature for 3 hours at which time the mixture is partitioned between CH2Cl2 (30 mL) and water (30 mL). The organics are dried with Na2SO4, filtered and the solvent evaporated. The remaining solid is chromatographed with MeOH/CH2Cl2 (1-4%) to obtain 0.049 g (67%) of the title compound as an off-white solid. Physical characteristics: MS (ESI+) m/z 427 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:7]1[C:2]([F:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Cl)cnc21
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 10.258 mmol) was placed in THF (15 mL) at −78° C. s-BuLi (16.12 mL, 22.57 mmol) was then added dropwise and stirred for 30 minutes. Hexachloroethane (6.07 g, 25.6 mmol) in THF (10 mL) was then added rapidly, and the reaction was stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted into hexanes. The combined organic fractions were dried, filtered and concentrated to give the crude product that was purified by column chromatography (hexanes) to give 5-chloro-4-fluoro-1-(tri isopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.1 g, 62% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC>C1COCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([B:13]([OH:18])[OH:14])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccnc(Cl)c2c1
Temperature: -20 °C
Yield: 66.8 %

Procedure:
7-Bromo-1-chloroisoquinoline (1.38 g, 5.69 mmol) in THF (15 mL) under nitrogen, at −78° C. and triisopropyl borate (2.99 g, 15.93 mmol) added, followed by dropwise addition of n-butyllithium (7.11 mL of 1.6M in hexanes, 11.38 mmol). Allowed reaction mixture to warm to −20° C. over 30 minutes and quenched with 1N HCl (30 mL). Added triethylamine to give pH 7, presorbed solution directly onto silica and flash column chromatography on silica gel to give the product as pale yellow solid (0.78 g, 3.8 mmol). 1H NMR (DMSO) δ 8.73 (s, 1H), 8.48 (br s, 2H), 8.35-8.28 (m, 1H), 8.25-8.13 (m, 1H), 8.06-7.92 (m, 1H), 7.91-7.82 (m, 1H). ESI MS (M+1)+: 208, 210 (Cl).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:36]=[C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])[CH:32]=[CH:33][CH:34]=3)=[N:7][C:6]1=2
Reactant: CN1CCN(C(=O)c2cccc(B(O)O)c2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: CN1CCN(C(=O)c2cccc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCN4)c2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 3-(4-Methylpiperazine-1-carbonyl)phenylboronicacid, pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][Si:4](Cl)(Cl)Cl.C([O:11][C:12](=[O:14])[CH3:13])(=O)C>>[Cl:1][CH2:2][CH2:3][Si:4]([O:11][C:12](=[O:14])[CH3:13])([O:14][C:12](=[O:11])[CH3:13])[O:14][C:12](=[O:11])[CH3:13]
Reactant: ClCC[Si](Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)O[Si](CCCl)(OC(C)=O)OC(C)=O
Reaction time: 21 h
Yield: 80.5 %

Procedure:
An amount of 40.8 g of 2-chloroethyl-trichlorosilane is dissolved in 71.5 g of acetic acid anhydride, and the solution allowed to stand at room temperature for 21 hours in a closed vessel. The reaction product is concentrated in vacuo to obtain 44.6 g of 2-chloro-ethyl-tris-(acetyloxy)-silane, B.P.: 85° - 88° /0.1 Torr, nD20 = 1.6687.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=2)[O:22][CH2:23][C:24]([O:26]C)=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>CO>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:13]1[N:14]([S:16]([C:19]2[CH:30]=[CH:29][CH:28]=[C:21]([O:22][CH2:23][C:24]([NH:39][CH3:38])=[O:26])[CH:20]=2)(=[O:17])=[O:18])[CH:15]=[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=1
Reactant: CN
Reactant: COC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Solvent: CO
Product: CNC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 1i (110 mg, 0.20 mmol) was dissolved in 10 mL of a solution of methylamine in methanol (33%), and the reaction solution was heated up to 40° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((3-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1j (60 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].I[CH:28]([CH3:30])[CH3:29]>O>[CH:28]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1)([CH3:30])[CH3:29]
Reactant: CC(C)I
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
A mixture of 5 g of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 50 ml of dimethylformamide, 5.25 g of sodium carbonate and 2.7 ml of 2-iodopropane were stirred under an inert atmosphere and the mixture was then added dropwise over 20 hours to 400 ml of water. The mixture was stirred for 30 minutes, was allowed to crystallize and was then vacuum filtered. The recovered product was washed and dried at 50° C. under reduced pressure to obtain 5.8 g of 3-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 178° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([N:20]([CH2:31][CH2:32][CH3:33])C(=O)OCC3C=CC=CC=3)[N:19]=[C:6]2[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]>CO.[Pd]>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@H:8]2[N:7]3[N:17]=[C:18]([NH:20][CH2:31][CH2:32][CH3:33])[N:19]=[C:6]3[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=3)[C:4]([CH3:44])=[C:3]2[C:1]#[N:2])=[CH:10][CH:11]=1)#[N:16]
Reactant: CCCN(C(=O)OCc1ccccc1)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCCNc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(propyl)carbamate (17.0 mg, 28 μmol) was dissolved in degassed methanol (5 ml). After addition of palladium on activated carbon (10%; 5 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.7 mg, 81% of theory).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[OH:14].[O-]CC.[Na+]>C(O)C>[C:3]([CH2:2][S:1][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[OH:14])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: OC(CCCCCl)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCCCC(O)c1ccco1

Procedure:
To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 g of 5-chloro-1-(2-furyl)-1-pentanol (Example 55), and 10 ml of 1.5 M sodium ethoxide in ethanol is added an additionan 300 ml of 1.5 M sodium ethoxide during 15 minutes. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again concentrated to give an oil, pmr spectrum (CDCl3): δ 3.24 (singlet, --S--CH2CO2C2H5) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][C@@H:23]([C:36]([NH:38][C@H:39]([C:47]([N:49]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:50])=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH:34]=[O:35])[CH:26]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([NH:15][C@H:16]([C:20]([NH:22][C@@H:23]([C:36]([NH:38][C@H:39]([C:47]([N:49]([CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH3:50])=[O:48])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:37])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH:34]=[O:35])[CH:26]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18])=[O:6]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
Boc-βAla-OH (0.19 g), HCl.H-Thr-D-Trp(CHO)-Phe-NMeBzl (0.62 g) and HOBT (0.14 g) were dissolved in DMF (10 ml). To this solution was added WSC (0.18 ml) under ice cooling and the mixture was stirred for four hours at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, 2% sodium hydrogencarbonate solution, water, 2% hydrochloric acid, water and saturated sodium chloride solution, and dried over magnesium sulfate. The evaporated residue was crystallized from a mixed solvent of ethanol and water. Filtration and drying gave Boc-βAla-Thr-D-Trp(CHO)-Phe-NMeBzl (0.66 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[C:27]([CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:19])[CH2:35][CH2:36]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.154 g, 0.409 mmol), N,N-dimethylpyridin-4-amine (0.00499 g, 0.0409 mmol), and 4-tert-butylcyclohexanamine (0.0875 ml, 0.490 mmol) in DMF (2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0940 g, 0.490 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 37 mg of the title compound (18% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:4]1[CH:3]=[C:2]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[S:1][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)Cc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(Br)cs1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a solution of methyl 2-(thiophen-2-yl)acetate (5 g, 32 m mol) and anhydrous AlCl3 (10.7 g, 80 mmol) in CHCl3 (50 ml) was added dropwise bromine (1.8 ml, 34 mmol) at 0˜5° C. over 30 min. When the addition was complete, the mixture was allowed to warm to room temperature overnight. Then it was poured into icy water (50 ml), extracted with EtOAc (30 ml×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE/EtOAc=10/1) gave the product (3.1 g, 41%) as light yellow oil.