Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:7][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=2[CH3:28])=[O:20])[CH2:11][CH2:10]1)#[N:38]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of the above aniline (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) and Et3N (28 μL, 0.20 mmol) was added cyclopropanecarbonyl chloride (14 μL, 0.15 mmol) and the solution was stirred at room temperature for 16 hours to afford COMPOUND 154 as a white solid (56 mg, 96%) following work-up and purification. 1H NMR (CDCl3) δ 0.74-0.79 (m, 2H), 0.98-1.15 (m, 7H), 1.43 (m, 1H), 1.56 (m, 1H), 1.74-1.79 (m, 3H), 2.19 (m, 1H), 2.50 (s, 6H), 2.58 (m, 1H), 2.75-2.87 (m, 3H), 3.32 (m, 1H), 3.57 (m, 1H), 3.82 (m, 1H), 3.89 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.26 (m, 3H), 7.39-7.44 (m, 1H), 7.49-7.53 (m, 3H), 8.64 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 7.64, 13.36, 15.44, 21.95, 29.04, 30.17, 30.77, 39.86, 43.64, 48.46, 51.94, 56.68, 60.10, 112.48, 114.66, 118.98, 121.61, 129.27, 129.43, 130.06, 130.58, 130.84, 131.12, 141.85, 144.86, 157.51, 163.09, 166.38, 171.62. ES-MS m/z 580 (M+H). Anal. Calcd. for C34H41N7O2.0.45CH2Cl2: C, 66.96; H, 6.83; N, 15.87. Found. C, 66.99; H, 7.02; N, 15.55.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=C)[C:5]=2[N:6]=[CH:7][N:8]=1.[O:14]=[O+][O-].N#N.CSC>C(Cl)(Cl)Cl.CO>[CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=[O:14])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C=Cc1csc2c(SC)ncnc12
Reactant: O=[O+][O-]
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CSC
Solvent: CO
Product: CSc1ncnc2c(C=O)csc12
Temperature: 25 °C

Procedure:
4-(Methylthio)-7-vinylthieno[3,2-d]pyrimidine (350 mg, 1.68 mmol) was dissolved in CHCl3/MeOH (2 mL/2 mL) and treated with ozone at 78° C. for 30 minutes. When the starting material was disappeared, the reaction mixture was treated with N2 gas at the same temperature for 5 minutes, heated to room temperature, and dimethylsulfide (0.37 mL, 5.04 mmol) was added thereto. The reaction mixture was concentrated to obtain a yellow solid. The solid was filtered, washed with diethyl ether and dried with N2 gas to obtain the title compound without further purification.
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18]#[N:19])[CH2:16][CH2:15][C@H:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[C:18]([CH:17]1[NH:8][C@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][CH2:16]1)#[N:19]
Reactant: CCOC(=O)[C@@H]1CCC(C#N)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(C#N)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained from Step C (2.20 g) in CH2Cl2 (10 mL) was added trifluoroacetic acid (11.0 mL). The mixture was stirred at rt for 1.0 h before the solvent was removed under reduced pressure. The residue was further chased with toluene to remove residual trifluoroacetic acid. The TFA salt obtained was used in the next Step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:9][CH:8]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.19 g) as colorless crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C@@H:7]([C@@H:9]([CH:13]=[CH2:14])[C:10]([OH:12])=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([C@H:28]([O:30][C:31](=[O:33])[CH3:32])[CH3:29])=[N:25]2)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]([O:30][C@@H:28]([C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][C:18](/[CH:14]=[CH:13]/[C@H:9]([C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[CH3:8])[C:10]([OH:12])=[O:11])=[CH:19][CH:20]=2)[N:25]=1)[CH3:29])(=[O:33])[CH3:32]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(Br)cc2n1
Reactant: C=C[C@@H](C(=O)O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/[C@@H](C(=O)O)[C@@H](C)O[Si](C)(C)C(C)(C)C)cc2n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
A solution of (R)-2-[(R)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-but-3-enoic acid (200 mg, 0.82 mmol), acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (241 mg, 0.82 mmol), palladium(II) acetate (37 mg, 0.16 mmol), tri-(o-tolyl)phosphine (50 mg, 0.16 mmol) in anhydrous 1,4-dioxane (10 mL) was treated with N,N-dicylohexylmethylamine (280 μL, 1.31 mmol). After stirring at 100° C. for 6 h, the reaction was cooled to room temperature, filtered off and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and hydrochloric acid (1 M). The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of dichloromethane/methanol 1:0 to 9:1 to afford the title compound (115 mg, 31%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 1.25 (d, J=6.0 Hz, 3H), 1.68 (d, J=6.4 Hz, 3H), 2.17 (s, 3H), 3.22-3.37 (m, 1H), 3.65-3.80 (m, 1H), 4.26 (pentet, J=6.7 Hz, 1H), 6.08 (q, J=6.7 Hz, 1H), 6.40 (dd, J=15.8, 9.1 Hz, 1H), 6.76 (d, J=15.8 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.40-7.55 (m, 1H), 7.55-7.75 (m, 1H), 8.03 (s, 1H), 8.11 (d, J=8.5 Hz, 1H). LCMS (m/z) 458.2 [M+H], Tr=3.45 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[O:23][CH3:24])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10]C=1.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>O1CCCC1>[CH2:6]([NH:14][C:15]([C:16]1[CH:21]=[CH:20][C:19]([B:26]([OH:31])[OH:27])=[CH:18][C:17]=1[O:23][CH3:24])=[O:25])[C:7]1[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)NCCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
n-Butyl lithium (1.6 M in hexane solution, 8.5 ml, 13.54 mmol) was added slowly to a solution of N1-phenethyl-4-bromo-2-methoxybenzamide (1.81 g, 5.41 mmol) in tetrahydrofuran (40 mL) at −78° C. After 30 minutes, triisopropyl borate (1.87 mL, 8.12 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 3 hours. Hydrochloric acid (2.5N, 40 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile to give 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (0.916 g, 56%). 1H NMR (DMSO-d6) δ 2.85 (m, 2H), 3.53 (m, 2H) 3.88 (s, 3H), 7.31 (m, 7H), 7.70 (d, J=7.61 Hz, 1H), 8.19 (m, 2H), 9.10 (m, 1H).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:14])[CH:3]([CH:5]1[C:7]([CH3:9])([CH3:8])[CH:6]1[C:10]([O:12][CH3:13])=[O:11])O.P(Cl)(Cl)Cl.P(Cl)(Cl)[O-]>[Zn]>[Cl:1][C:2]([Cl:14])=[CH:3][CH:5]1[C:7]([CH3:9])([CH3:8])[CH:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1C(C(O)C(Cl)(Cl)Cl)C1(C)C
Agent: [O-]P(Cl)Cl
Agent: [Zn]
Solvent: ClP(Cl)Cl
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Methyl cis-2-formyl-3,3-dimethylcyclopropanecarboxylate (6.0 mmol) was added with stirring to a solution of sodium trichloroacetate (6.6 mmol) in N,N-dimethylformamide (3.2 ml) present in a 25-ml flask. After 15 minutes' stirring the conversion of the starting carboxylate was 97%, with a selectivity to sodium 2,2,2-trichloro-1-(2,2-dimethyl-3-methoxycarbonylcyclopropyl)ethyl carbonate of more than 90%. Then, 36% w aqueous hydrochloric acid (0.6 ml) and water (50 ml) were added and the mixture obtained was extracted with three 15-ml portions of n-pentane. The combined extract phases were washed with water (20 ml) and a saturated aqueous solution of sodium hydrogen carbonate (20 ml). The washed liquid was dried over anhydrous magnesium sulphate and the n-pentane was evaporated at sub-atmospheric pressure from the dried liquid to give a residue (1.47 g) having a content of methyl 2-(2,2,2-trichloro-1-hydroxyethyl)-3,3-dimethylcyclopropanecarboxylate of 95%, the yield thereof being 85%. The contents of a flask charged with the latter compound (0.73 mmol) and phosphorus trichloride (0.80 mmol) were stirred at 40° C. for 45 min. At the end of this period phosphorus trichloride was evaporated at sub-atmospheric pressure. The residue contained 2,2,2-trichloro-1-(2,2-dimethyl-3-methoxycarbonylcyclopropyl)ethyl dichlorophosphite (compound 2) and was dissolved in diethyl ether (5 ml) and glacial acetic acid (1 ml). After addition of zinc powder (1.5 mmol) the mixture was stirred under reflux for 1.5 hours (about 40° C.). At the end of this period the conversion of the dichlorophosphite was 92%, with a selectivity to the title compound of 79%. The excess of zinc was filtered off, the filtrate was diluted with n-pentane (30 ml), the diluted solution was washed with three portions of 15 ml water and one portion of a saturated aqueous solution of sodium hydrogen carbonate (10 ml), the washed solution was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to give a residue of the title compound. The cis content of this compound was 60%.
Reaction SMILES: [CH3:1][C:2]1([C:19]([OH:21])=[O:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.O.NN.[OH-].[K+].C(O)COCCOCCO>>[CH3:1][C:2]1([C:19]([OH:21])=[O:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCC(=O)c2cc(C3CCCCC3)ccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CC1(C(=O)O)CCCc2cc(C3CCCCC3)ccc21
Temperature: 195 °C

Procedure:
A mixture of 12 g of l-methyl-4-oxo-6-cyclohexyl-1,2,3,4-tetrahydronaphthalene-1 -carboxylic acid, 10 g of hydrazine hydrate, 13.7 g of potassium hydroxide, and 85 ml of triethylene glycol is heated at 130°-140°C for 2 hours. After that, while distilling off a mixture of hydrazine and water, the temperature is raised up to 195°C, and the batch is stirred until the evolution of nitrogen ceases. The mixture is then diluted with 50 ml of water, acidified with concentrated hydrochloric acid, then extracted with ethyl acetate. The resin-like crude product remaining after evaporation of the ethyl acetate is crystallized from toluene and yields 1-methyl-6-cyclohexyl-1,2,3,4-tetrahydronaphthalene-1carboxylic acid of the formula ##SPC12##
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH:19]5[CH2:29][CH2:28][CH:22]([C:23]=4[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[CH2:14]2)[CH2:21][CH2:20]5)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[O:17][C:16]2[C:18]3[CH:19]4[CH2:29][CH2:28][CH:22]([C:23]=3[C:24]([O:26][CH3:27])=[CH:25][C:15]=2[CH2:14]1)[CH2:21][CH2:20]4)=[N+:31]=[N-:32]
Reactant: COc1cc2c(c3c1C1CCC3CC1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1cc2c(c3c1C1CCC3CC1)OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methyl 4-methylbenzenesulfonate (5.45 g, 13.1 mmol) with sodium azide (3.419 g, 52.6 mmol) generally according to the procedure described for Intermediate 24 gave (±)-2-(azidomethyl)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.350 g) generally according to the procedure described for Example 2 gave 2.88 g (74%) of (±)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>210° C.; Anal. calcd. for C16H21NO2HCl: C, 64.97; H, 7.5; N, 4.74. Found: C, 64.71; H, 7.69; N, 4.54.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:35][O:36]C1C=CC(CO)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:36][CH3:35])=[CH:27][CH:26]=2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3cccc(Cl)c3)c2cc1F
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate c, from 1-(3-chloro-benzyl)-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 11, intermediate) and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Off-white powder (87%). MS (Turbo Spray): m/z=492.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[N:23][N:22]=1)([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[N:12]=2)=[CH:7][CH:6]=1)[CH3:3].[OH-].[Na+].O.Cl>C(O)C>[CH3:3][C:2]([C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[N:23][N:22]=1)([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[N:12]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCOC(=O)c1noc(-c2ccc(OC(C)(C)c3nnc(-c4ccccc4C(F)(F)F)n3C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(-c2nc(C(=O)O)no2)cc1
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Ethyl 5-[4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,2,4-oxadiazole-3-carboxylate (251 mg) was suspended in ethanol (5 ml) and a 1M aqueous sodium hydroxide solution (1 ml) was added thereto, followed by stirring for 5 minutes. Water and 1M hydrochloric acid were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain 5-[4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,2,4-oxadiazole-3-carboxylic acid (207 mg), as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:11]3[C:12]([CH3:16])=[N:13][CH2:14][CH2:15][N:10]3[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[BH4-].[Na+]>CO>[CH3:7][C:4]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CC1=NCCn2nc(-n3c(C)ccc3C)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C)n1-c1cc2n(n1)CCNC2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287f (3.56 g, 1.0 eq., 15.6 mmol), NaBH4 (2.96 g, 5.0 eq., 78.0 mmol), and methanol (50 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (50 mL). The water phase was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 287g as a colorless oil (1.54 g, 43% over two steps). MS-ESI: [M+H]+ 231.3. 1H NMR (500 MHz, CDCl3) δ 5.91 (s, 1H), 5.86 (s, 2H), 4.17-4.11 (m, 3H), 3.51-3.48 (m, 1H), 3.36-3.31 (m, 1H), 2.13 (s, 6H), 1.50 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[C:13](=[O:16])[CH2:14][O:15][C:11]=2[C:10]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH:42]=O)=[CH:34]1.N1CCCCC1>CO>[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](/[CH:42]=[C:14]2\[O:15][C:11]3[C:10]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=[CH:17][C:12]=3[C:13]\2=[O:16])=[CH:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A solution of tert-butyl 4-{[6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.198 g, 0.452 mmol) in methanol (1.8 mL) was added with indole-3-carboxaldehyde (0.0656 g, 0.452 mmol) and piperidine (0.0308 g, 0.362 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated yellow solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.141 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](OC)=[S:9].C[O-:14].[Na+]>C1(C)C=CC=CC=1>[O:14]=[C:5]1[CH2:6][CH2:7][CH2:8][S:9][CH:4]1[C:3]([O:2][CH3:1])=[O:12]
Reactant: C[O-]
Reactant: COC(=O)CCCCC(=S)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1SCCCC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A 250-mL round bottomed flask was charged with methyl 4-(2-methoxy-2-oxo-ethyl)thiobutanoate (26 g, 126 mmol, 1 eq.), sodium methoxide (30 g, 25 w % in methanol, 139 mmol, 1.1 eq.) and toluene (100 ml). The resulting mixture was stirred at 80° C. overnight and then methanol was removed by distillation until the temperature of the reaction mixture rose to 106° C. After cooling to room temperature, the mixture was poured into a mixture of ice (100 g) and 12N HCl (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×20 ml) and the combined organic layers were dried over Na2SO4. Removal of solvent under reduced pressure gave the title compound as an oil (19.3 g, 88% yield). The product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[N:7]=[C:8]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:30]([C:33]3[S:37][C:36]4[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:35]=4[CH:34]=3)(=[O:32])=[O:31])[CH2:26][C:25]2=[O:43])[S:9][C:10]=1[CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)[CH3:2].Br.CC(O)=O>CCOCC>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[N:7]=[C:8]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:30]([C:33]3[S:37][C:36]4[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:35]=4[CH:34]=3)(=[O:32])=[O:31])[CH2:26][C:25]2=[O:43])[S:9][C:10]=1[CH2:11][NH2:12])[CH3:2]
Reactant: CCOC(=O)Cc1nc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)sc1CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)Cc1nc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)sc1CN

Procedure:
{5-(Benzyloxycarbonylamino-methyl)-2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl}-acetic acid ethyl ester (40 mg, 0.06 mmol) is treated with 30% HBr/HOAc (1 mL) for 7 h. Ether (10 mL) is added and the resulting precipitate is washed twice with ether. The resulting salt is partitioned between EtOAc (15 mL) and NaHCO3 solution (10 mL). The organic phase is washed with NaHCO3 and brine (2×10 mL), dried (MgSO4) and concentrated to provide {5-aminomethyl-2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl}-acetic acid ethyl ester. 1H NMR (300 MHz, DMSO) δ 8.32 (d, 1H), 8.17 (s, 1H), 8.08-8.02 (m, 2H), 7.57 (dd, 1H), 4.62 (s, 2H), 4.02 (q, 2H), 3.81 (s, 2H), 3.74 (s, 2H), 3.64 (s, 2H), 3.48-3.35 (m, 4H), 2.48 (t, 3H); MS (ion spray) 543 (M+H)+.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]([C:22]2([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:37][C:22]1([C:20]([NH:19][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:16][C:17]#[N:18])=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CC#N)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
HCl (4M) in 1,4-dioxane (2.011 mL, 8.04 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-2-cyanoethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 114) (0.281 g, 0.54 mmol) in DCM (8 mL) at 20° C. The resulting solution was stirred at 20° C. for 18 hours. The reaction was vacuumed to dryness and was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-cyanoethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.096 g, 42.2%) as a white solid.