Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:31][CH3:32])[C:6]([NH:8][C@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][C:15]=3[C:25]([CH3:27])=[CH2:26])[N:11]([CH2:28][CH2:29][CH3:30])[CH2:10]1)=[O:7])[CH3:4]>>[CH2:31]([N:5]([CH2:3][CH3:4])[C:6]([NH:8][C@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][C:15]=3[CH:25]([CH3:26])[CH3:27])[N:11]([CH2:28][CH2:29][CH3:30])[CH2:10]1)=[O:7])[CH3:32]
Reactant: C=C(C)c1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1CCC
Agent: [BH4-]
Agent: [Na+]
Product: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(C(C)C)c(c34)C[C@H]21

Procedure:
In the reduction with sodium borohydride a mixture of the desired compound and 1,1-diethyl-3-(2-isopropenyl- 6-n-propyl-8α-ergolinyl)-urea) was produced. Therefore the raw mixture was further reduced with Na/NH3 (see example 12). Yield after crystallization (ethyl acetate): 28%, [α]D +17.6° (c=0.5 in chloroform).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:24][CH2:25][CH2:26][CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:8](=[O:16])[C:7](=[CH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:5]2.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:3]([O:24][CH2:25][CH2:26][CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:8](=[O:16])[CH:7]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: CCCOc1cc2c(c(OCCC)c1C)CCC(=Cc1cccnc1)C2=O
Agent: [Pd]
Solvent: CO
Product: CCCOc1cc2c(c(OCCC)c1C)CCC(Cc1cccnc1)C2=O
Yield: 68.5 %

Procedure:
A mixture of Compound 25 (3.96 g, 10.8 mmol) and 10% palladium on carbon (600 mg) in abs. methanol (100 mL) was hydrogenated at 1 atm for 12 hr. The hydrogen was replaced with nitrogen, the reaction was filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 20% ethyl acetate:hexanes) provided 2.72 g of Compound 26.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH:35]=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: O=C(NCCNCc1ccc(F)c(Cl)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-chloro-4-fluorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 444 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.27 (1H, s) 7.99-8.07 (2H, m) 7.77 (1H, d, J=5.47 Hz) 7.52 (1H, d, J=7.91 Hz) 7.46 (1H, d, J=5.42 Hz) 7.29 (3H, dd, J=1.24, 0.17 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.47, 1.85 Hz) 3.66 (2H, s) 2.61 (2H, t, J=6.59 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and p-toluidine (2.56 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[C:9]([C:11]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
A solution of LDA (107 ml, 214.01 mmol) was added to a stirred solution of tert-butyl 4-cyanopiperidine-1-carboxylate (30 g, 143 mmol) in THF (250 ml) at −78° C., under nitrogen. The resulting solution was stirred at −78° C. for 30 minutes. Ethyl chloroformate (16.37 ml, 171.2 mmol) was added. The resulting solution was stirred and allowed to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3 (250 ml), extracted with DCM, and the organic layer was washed with saturated brine (100 ml) then dried over MgSO4, filtered and evaporated to afford the crude material as a orange oil. This material was purified by flash silica chromatography, elution gradient 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-tert-butyl 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (20.8 g, 51.6%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[CH2:13]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[C:14]#[CH:15]>>[Cl:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=[C:8]([C:15]#[C:14][CH2:13][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:9]=1
Reactant: COC(=O)c1ncc(Br)cc1Cl
Reactant: C#CCOC1CCCCO1
Product: O=C(O)c1ncc(C#CCOC2CCCCO2)cc1Cl

Procedure:
The title compound was prepared by an analogous procedure to Acid-xx using 5-bromo-3-chloro-pyridine-2-carboxylic acid methyl ester instead of 3-amino-5-bromo-pyridine-2-carboxylic acid methyl ester and 2-prop-2-ynyloxy-tetrahydro-pyran instead of 3-methoxy-propyne [Acid-xx step a)].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39]O)[CH2:34][CH2:33]1.O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[O:31][CH2:39][CH2:38][N:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN1CCOCC1)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(2-morpholinoethoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-morpholinoethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[OH-].[Na+].[CH2:20](Br)[CH3:21]>CO.O>[CH2:20]([O:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)[CH3:21]
Reactant: CCBr
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 16 h
Yield: 52 %

Procedure:
The 2'-deoxy-5-hydroxyuridine (244 mg.,1mmol) was suspended in a mixture of methanol (10ml) and water (5ml) at room temperature, and 1 ml of 1.0N sodium hydroxide solution (1mmol) was added to generate the monoanion. Ethyl bromide (0.312ml, 4mmol) was added, and the reaction mixture was stirred for 16 hours. The solvent was removed in vacuo, and ethanol was added to and evaporated from the residue. The desired 5-ethoxy product was separated from small amounts of the 3 ethyl-5-ethoxy dialkyl byproduct by chromatography on a silica gel column using chloroform-methanol (9:1, v/v) as the solvent. Following crystallization from absolute ethanol, 5-ethoxy-2'-deoxyuridine was obtained in 52% yield (140 mg); mp 179°-181° C.; 1H NMR (methyl sulfoxide-d6),δ11.38 (1H, br s, NH), 7.58 (1H, s, H-6), 6.18 (1H, t, H-1'), 5.19 (1H, d, 3'-OH), 5.09 (1H, t, 5'-OH), 4.25 (1H, m, H-3'), 3.79 (3H, m. H4'and OCH2CH3 ), 3.59 (2H, br s,H-5'and H-5"), 2.10 (2H, m, H-2'and H-2") and 1.23ppm (3H, t, OCH2CH3). Anal. Calcd. for C11H16N2O6C, 48.53; H, 5.92; N, 10.29. Found: C, 48.69; H, 6.0-1; N, 10.36.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:41])[C:27]([O:29][CH2:30][CH2:31][S:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:28]>C(#N)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:26]([CH3:41])[C:27]([O:29][CH2:30][CH2:31][S:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:28])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)OCCSCc1ccc(Cl)cc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCSCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture consisting of 25.4 g of 4-(4-trifluoromethylphenoxy)phenol, 14.5 g of anhydrous potassium carbonate, 33.8 g of 2-(4-chlorobenzylthio)ethyl 2-bromopropionate and 150 ml of dry acetonitrile was refluxed for 3 hours with vigorous stirring. After cooling the reaction mixture to room temperature, the acetonitrile was removed under reduced pressure. Then, 150 ml of toluene were added to the residue and the resulting mixture was washed successively with 1% strength by weight aqueous sodium hydroxide solution and water, followed by dehydration. Upon distilling off the toluene under reduced pressure, there were obtained 46.4 g of 2-(4-chlorobenzylthio)-ethyl 2-[4-(4-trifluoromethylphenoxy)-phenoxy]-propionate in the form of a colorless oil. nD20 =1.5555.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[CH2:6][CH2:7][C:8]2([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]=1[C:15]1[C:10](=[CH:11][C:12]([NH2:18])=[C:13]([F:17])[CH:14]=1)[CH2:9]2)(=[O:3])[CH3:2].N#N.[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([C:4]1[C:5](=[O:23])[CH2:6][CH2:7][C:8]2([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]=1[C:15]1[C:10](=[C:11]([Br:26])[C:12]([NH2:18])=[C:13]([F:17])[CH:14]=1)[CH2:9]2)(=[O:3])[CH3:2]
Reactant: CCCCC12CCC(=O)C(C(C)=O)=C1c1cc(F)c(N)cc1C2
Reactant: O=C1CCC(=O)N1Br
Agent: N#N
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(C(C)=O)=C1c1cc(F)c(N)c(Br)c1C2
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A solution of 4-acetyl-7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (157 mg, 0.5 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was purged with N2, cooled in an ice bath, and treated with N-bromosuccinimide (89 mg, 0.5 mmol). The resulting solution was stirred at 0–5° C. for one hour, and then partitioned between EtOAc and water. The aqueous portion was extracted with more EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The oily residue was purified by flash chromatography on a Biotage 12M column, eluting with 4:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to afford 4-acetyl-7-amino-8-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (147 mg, 75%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)[CH2:16]2)SC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:32]([NH2:34])[CH3:33]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)[CH2:16]2)[NH:34][CH2:32][CH3:33])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CSC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCN(Cc1ccccc1)CC2
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1.35 g 4-amino-N-[(8-benzyl-2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)-methylsulfanyl-methylene]-benzenesulfonamide in 30 mL MeOH was added 2.26 mL (10 equiv.) of a 70% aqueous solution of ethylamine. The mixture was stirred for a weekend at room temperature and concentrated on silica. Purification with flash column chromatography (DCM→DCM/MeOH 99:1→DCM/MeOH 95:5) yielded 1.16 g (87%) of a pale yellow glass. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7 Hz, 3H), 1.50-1.60 (m, 2H), 1.73-1.84 (m, 2H), 2.11-2.26 (m, 2H), 2.63-2.76 (m, 2H), 3.41-3.53 (m, 2H), 3.79 (s, 2H), 3.98 (s, 2H), 6.62-6.70 (m, 2H), 6.76 (s, 1H), 6.97 (br s, 1H), 7.22-7.36 (m, 5H), 7.67-7.75 (m, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)=[O:20])[CH:14]=1>>[CH:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:10]3[CH2:11][C:6]4[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=4[CH2:9]3)[CH:18]=[CH:17][N:16]=2)=[O:20])=[CH:27][CH:26]=1)([CH3:30])[CH3:29]
Reactant: CSc1ncc2c(n1)CNC2
Reactant: CC(C)c1ccc(NC(=O)c2cc(Br)ccn2)cc1
Product: CSc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccc(C(C)C)cc3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 4-bromo-N-(4-isopropylphenyl)picolinamide were converted to the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:43])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=4[Cl:42])[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[Cl:42][C:36]1[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:35]=1[C:28]1[O:29][C:30]([C:31]([F:33])([F:34])[F:32])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:44])=[O:4])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)=[O:43])=[O:25])[N:27]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(Cl)cc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(Cl)cc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaOH (23.94 mg, 0.56 mmol) was added to trans-{4-[4-(3-{[2-(2,4-dichlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (75 mg, 0.12 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 15 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2, stirred for 30 minutes, and filtered. Then, the filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified. Accordingly, the desired compound (71 mg, 97%) was obtained as a white solid.
Reaction SMILES: [Cu]C#N.[CH:4]([Mg]Br)=[CH2:5].[C:8]([Si:12]([O:25][CH2:26][C@@H:27]1[CH2:29][O:28]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9]>>[Si:12]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:29][CH:4]=[CH2:5])([C:8]([CH3:10])([CH3:11])[CH3:9])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[Si](OC[C@@H]1CO1)(c1ccccc1)c1ccccc1
Agent: N#C[Cu]
Product: C=CC[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
Copper (I) cyanide (3.60 g, 40.2 mmol) was placed in a three-necked flask under nitrogen and dried by gentle heating with a heat gun under vacuum. It was then allowed to cool to room temperature under nitrogen. This process was repeated three times, and then anhydrous tetrahydrofuran (80 mL) was added. The resulting mixture was cooled to −78° C., and then vinyl magnesium bromide (1 M solution in tetrahydrofuran, 88.5 mL, 88.5 mmol) was added dropwise while maintaining the internal temperature below −68° C. The heterogeneous mixture was warmed to −20° C. and stirred at this temperature for 30 minutes. After cooling the solution back to −78° C., tert-butyl[(2S)-oxiran-2-ylmethoxy]diphenylsilane (296 h, 8.38 g, 26.8 mmol) was added dropwise. The mixture was stirred, and allowed to gradually warm to room temperature, overnight. The reaction mixture was quenched with 100 mL ammonium hydroxide/ammonium chloride (1/10 2M NH4Cl), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-20% ethyl acetate in heptane), to give (2S)-1-{[tert-butyl(diphenyl)silyl]oxy}pent-4-en-2-ol (296i, 5.68 g, 62% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.65-7.71 (m, 4H), 7.36-7.49 (m, 6H), 5.75-5.87 (m, 1H), 5.03-5.14 (m, 2H), 3.76-3.85 (m, 1H), 3.66-3.72 (m, 1H), 3.54-3.61 (m, 1H), 2.45 (d, J=4.03 Hz, 1H), 2.23-2.30 (m, 2H), 1.09 (s, 9H). MS: 358 [M+18].
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:11]([C:24]([OH:26])=[O:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]1([C:33]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:34]=[C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:35]([O:25][C:24](=[O:26])[C@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)OC(C(=O)c2ccccc2)c2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
To a mixture of cis4-(tert-butyldimethylsilyloxy)-N-benzyloxycarbonyl-D-proline (21.87 g), benzoin (12.25 g), and 4-dimethylaminopyridine (7.04 g) in CH2Cl2 (200 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (10.52 mL) at 5° C., and the mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated, and the residue was dissolved in EtOAc (250 mL), washed with 1N HCl (150 mL), water, saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 5:2 elution) to give cis4-(tert-butyldimethylsilyloxy)-N-benzyloxycarbonyl-D-proline 2-oxo-1,2-diphenylethyl ester (21.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[C:11]([C:13]1[CH:14]=[C:15]([S:20]([N:23](CC2C=CC(OC)=CC=2OC)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1F)#[N:12].C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>CS(C)=O.C(Cl)Cl.CO.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][OH:9])[O:10][C:18]1[CH:17]=[CH:16][C:15]([S:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)(=[O:21])=[O:22])=[CH:14][C:13]=1[C:11]#[N:12]
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: OCc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1ccc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.2 %

Procedure:
To a stirred solution of 3-chloro-4-(hydroxymethyl)phenol (120 mg, 0.54 mmol) and 3-cyano-N-(2,4-di methoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 18, 100 mg, 0.22 mmol) in DMSO (1.5 mL) was added potassium carbonate (78 mg, 0.56 mmol) and the reaction stirred at room temperature for 72 hours. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 3:2 EtOAc:heptanes. The residue (76 mg, 0.13 mmol) was dissolved in DCM (2 mL) and treated with TFA (2 mL). The reaction was stirred at room temperature for 18 hours. MeOH (1 mL) was added and the reaction concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 10-30% EtOAc in DCM to afford the title compound (25 mg, 44%) as a colourless solid (25 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CN(C)C=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Br)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 8.7 g of p-bromophenyl isocyanate and 80 ml of dimethylformamide, as yellow crystals having the following physical properties.
Reaction SMILES: O[C:2]1([C:30]([F:33])([F:32])[F:31])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]2[CH2:19][NH:20][CH:21](C(OC(C)(C)C)=O)[CH2:22][N:6]3[C:7]2=[C:3]1[CH:4]=[CH:5]3.C(Cl)Cl.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH2:11]([C:10]1([OH:40])[CH:9]=[C:8]2[CH2:19][NH:20][CH2:21][CH2:22][N:6]3[C:7]2=[C:3]([CH:4]=[CH:5]3)[CH:2]1[C:30]([F:31])([F:32])[F:33])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c2C(=CC(CCc2ccccc2)C3(O)C(F)(F)F)CN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(CCc2ccccc2)C=C2CNCCn3ccc(c32)C1C(F)(F)F

Procedure:
The Boc group was removed from tert-butyl 7-hydroxy-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (138 mg, 0.3 mmol) (prepared as in Example 2 above) under standard conditions (CH2Cl2/trifluoroacetic acid) yielded 6-phenethyl-7-(trifluoromethyl)-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indol-6-ol trifluoroacetate, which was dissolved in THF (5 mL) and the resulting mixture was cooled to 0° C. Triethylamine (3.75 eq) was added, followed by addition of isopropyl isocyanate (1.7 eq). The resulting mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred overnight. The resulting mixture was concentrated, dissolved in ethyl acetate (20 mL), and washed sequentially with water, NaHCO3 (sat. aq.) and brine, then dried (Na2SO4) and concentrated to yield 7-hydroxy-N-isopropyl-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (134 mg, MH+=448).