Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:36])([F:35])[C@H:29]([OH:34])[CH2:30][C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][C@@H:29]([OH:34])[C:28]([F:36])([F:35])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 72%), MS (ISP) m/z=469.4 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (R)-4,4,4-trifluoro-3-hydroxy-butyric acid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH3:9][O:10][C:11]1[C:16]2[N:17]=[C:18]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=3)[S:19][C:15]=2[C:14]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:13][CH:12]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[C:16]2[N:17]=[C:18]([NH:20][C:21](=[O:30])[C:22]3[CH:23]=[CH:24][C:25]([CH2:28][N:3]4[CH2:7][CH2:6][CH2:5][C:4]4=[O:8])=[CH:26][CH:27]=3)[S:19][C:15]=2[C:14]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)=[CH:13][CH:12]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN4CCCC4=O)cc3)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Sodium hydride (48 ms, 0.48 mmol, 60% in mineral oil) are suspended in dimethyl formamide (2.0 ml) and at 0° C. treated with pyrrolidin-2-one. After stirring for 1 h at 50° C., N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamide (200 mg, 0.48 mmol) was added and the solution stirred for 5 h at 80° C. Removal of the volatile components in vacuo and flash chromatography (silica, eluent dichloromethane/methanol 19:1) afforded the title compound as off-white crystals (86% yield). MS: m/e=467(M+H+).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(=O)C.[Na+]>CC1(C)N(O)C(C)(C)CC(O)C1.ClCCl>[CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Agent: CC(=O)[O-]
Agent: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCC=O
Yield: 90.2 %

Procedure:
1-Octanol (2.0 g, 15.4 mmol), sodium acetate (1.8 g, 21.6 mmol), 4-hydroxy TEMPO (53 mg, 0.31 mmol) and dichloromethane (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice bath, and thereto was added NBA (2.5 g, 18.5 mmol)divided in two portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give 1-octanal (1.78 g, yield 90%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:17]2[CH2:18][C@@H:13]3[CH2:19][C@H:16]2[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nnc(Cl)c2ccccc12
Yield: 62 %

Procedure:
1,4-Dichlorophthalazine (Aldrich Chemical Company) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (62% yield). 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 4.5H), 1.47 (s, 4.5H), 1.95-2.08 (m, 2H), 3.46-3.58 (m, 1H), 3.64 (d, J=8.47 Hz, 0.5H), 3.75 (d, J=8.81 Hz, 0.5H), 3.91 (d, J=10.51 Hz, 1H), 4.19 (dd, J=2.03, 6.78 Hz, 1H), 4.59 (br s, 0.5H), 4.69 (br s, 0.5H), 5.15 (s, 1H), 7.26-7.81 (m, 2H), 8.04-8.12 (m, 1H), 8.21 (dd, J=1.70, 7.80 Hz, 1H); MS (DCI/NH3) M/Z 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:24]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[CH:3]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1

Procedure:
In analogy to Example 70.4–6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, glutaric anhydride and Hünig's base in DMF there was obtained (RS)-4-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid, which was subsequently converted via (RS)-4-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid into (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenylcarbamoyl)-butyric acid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:27][N:14]2[C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([NH2:25])[C:16]=3[N:26]=[C:13]2[CH2:12][N:11]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:25][C:17]1[C:16]2[N:26]=[C:13]3[CH2:12][N:11]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:10][CH:9]([OH:8])[CH2:27][N:14]3[C:15]=2[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(S(C)(=O)=O)Cc2nc3c(N)nc4ccccc4c3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1Cc2nc3c(N)nc4ccccc4c3n2CC(O)C1
Temperature: -20 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A suspension of 11-{[tert-butyl(dimethyl)silyl]oxy}-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine (1.0 g, 2.2 mmol) in anhydrous THF (30 mL) was cooled to −20° C., and tetrabutylammonium fluoride (2.383 mL of a 1 M solution in THF) was slowly added. The reaction was stirred overnight, and a precipitate formed. The cold reaction mixture was filtered, and the isolated precipitate was washed with THF and dried under high vacuum to provide 313.7 mg of 6-amino-9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-ol as white crystals, mp 282-283° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([C:44](Cl)=O)[CH:42]=[CH:43][C:36]1=2>>[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH2:44][C:4]3[C:8]4[C:7](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[Cl:11])[N:6]([C@@H:12]4[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]4[OH:14])[CH:5]=3)[CH:42]=[CH:43][C:36]1=2
Reactant: O=C(Cl)c1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc4occc4c3)c3c(Cl)cc(Cl)cc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4,6-Dichloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 28-(3) and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 478/480 (M+H). 1H-NMR (DMSO-d6) δ 3.20-3.50 (m, 4H), 3.59 (m, 1H), 3.67 (m, 1H), 4.34 (s, 2H), 4.55 (t, J=5.7 Hz, 1H), 5.11 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.1 Hz, 1H), 5.24 (d, J=5.8 Hz, 1H), 5.46 (d, J=9.0 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.19 (dd, J=8.5, 1.4 Hz, 1H), 7.33 (s, 1H), 7.42 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.93 (d, J=2.1H, z, 1H).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH2:12][CH:13]=[CH2:14])=[C:6]([OH:15])[CH:5]=1>C(O)(=O)C>[CH3:11][O:10][C:8]1[C:7]2[CH2:12][CH:13]([CH3:14])[O:15][C:6]=2[CH:5]=[C:4]([C:3]([OH:2])=[O:16])[CH:9]=1
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1OC
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc2c1CC(C)O2
Yield: 60 %

Procedure:
1 gram of 4-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester in 5 cc of glacial acetic acid and 1.5 cc of 48%HBR is refluxed for 3 hours. After this time the mixture is concentrated to dryness and the crude residue is dissolved in an aqueous alkali solution. 0.3 grams of dimethyl sulfate are added to the resulting solution which is refluxed for two additional hours. The compound of the title which precipitates upon acidification of the cooled reaction mixture is recrystallized from ethyl ether-petroleum ether. Yield 60%. M.p. 180°-182° C.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:42]2[CH:43]=[C:44]([NH2:47])[NH:45][N:46]=2)[CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:35]([O:34][C:32]1[CH:31]=[C:30]([C:42]2[CH:43]=[C:44]([NH:47][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:45][N:46]=2)[CH:29]=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:33]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n[nH]1
Agent: Cl
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n[nH]1

Procedure:
The named compound is prepared by substituting 5-(3,5-bis-benzyloxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.030 gms.) is reacted with 0.114 gms. of 5-(3,5-bis-benzyloxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride by refluxing in tetrahydrofuran (2.0 mL).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C=O)c(C)o2)cn1
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 82%) as a yellow crystal.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]([CH3:10])=[C:7]([Cl:9])[CH:8]=1.CS([N:18]1C2C(=CC=C(CC#N)C=2)C=[CH:19]1)(=O)=O.CS(N1C2C(=CC=C(CBr)C=2)C=C1)(=O)=O>>[Cl:9][C:7]1[CH:8]=[C:3]([CH2:2][C:19]#[N:18])[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]=1[CH3:10]
Reactant: Cc1c(Cl)cc(CBr)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)n1ccc2ccc(CC#N)cc21
Agent: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Product: Cc1c(Cl)cc(CC#N)cc1[N+](=O)[O-]

Procedure:
(3-Chloro-4-methyl-5-nitrophenyl) acetonitrile was prepared from 5-bromomethyl-1-chloro-2-methyl-3-nitrobenzene in a manner similar to that described in Example 10 for the preparation of N-methanesulfonyl-6-cyanomethyl indole from N-methanesulfonyl-6-bromomethyl indole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: NCC1CC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(NCC2CC2)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (0.5 g, 3.36 mmol), cyclopropylmethylamine (275 μL, 3.18 mmol), and diisopropylethylamine (1.17 mL, 6.72 mmol) in iso-propanol (2 mL). Irradiate in microwave (300 watts) at 130° C. for 15 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 1:3 over 45 min; 40 mL/min) to obtain the desired intermediate (374 mg, 65%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:27]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution N1-(4-methoxybenzoyl)-1,2-benzenediamine hydrochloride (558 mg, 2.08 mmol) in methylene chloride (100 mL) was added 0.5 N aqueous sodium hydroxide (8 mL) and the resulting mixture was cooled in an ice-water bath. 2,4-Dimethoxybenzoyl chloride (0.40 g, 2.0 mmol) was added slowly with vigorous stirring. The mixture was allowed to warm slowly to room temperature and stirred for 18 h. The organic layer was separated and washed with dilute aqueous sodium bicarbonate solution, dilute aqueous hydrochloric acid, and water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 0.52 g (64%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C@H:32]([NH:37]S(C(C)(C)C)=O)[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[N:23][N:22]=2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][N:8]=1>CO>[NH2:37][C@@H:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[O:25][C:21]([C:4]3[C:3]([NH2:2])=[N:8][CH:7]=[C:6]([C:9]4[CH:14]=[CH:13][C:12]([S:15]([CH:18]([CH3:19])[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=4)[N:5]=3)=[N:22][N:23]=2)=[CH:27][CH:28]=1)[C:33]([F:34])([F:35])[F:36]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc([C@H](NS(=O)C(C)(C)C)C(F)(F)F)cc4)o3)n2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc([C@H](N)C(F)(F)F)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
HCl (35.27 μL of 3 M, 0.1058 mmol) was added to a solution of N-[(1S)-1-[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide (253.3 mg, 0.05288 mmol) in MeOH (1 mL) and the resulting solution stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the residue triturated with acetonitrile and filtered. The solid was taken up in a mixture of acetonitrile/water/MeOH and passed through the bicarbonate cartridge. The eluent was concentrated in vacuo and then triturated with acetonitrile to give the product as a yellow solid (26 mg, 99% yield); 1H NMR (400.0 MHz, DMSO) d 1.20 (d, 6H), 2.68 (d, 2H), 3.41-3.51 (m, 1H), 4.65-4.75 (m, 1H), 7.81 (d, 2H), 7.98 (d, 2H), 8.20 (d, 2H), 8.41 (d, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 519.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH:26]=[O:27])[N:9]=2)=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+]>CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([OH:34])=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C=O)c1nnc(C)n1-2
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C(=O)O)c1nnc(C)n1-2
Reaction time: 3.5 h

Procedure:
To a solution of crude (1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carbaldehyde (298 mg, 0.752 mmol) in t-BuOH (5 mL) was added 2-methylbut-2-ene (1055 mg, 15.04 mmol) and a pH 7 buffer solution (5 mL). Then sodium chlorite was added at rt, and the biphasic reaction was vigorously stirred for 3.5 h. When the starting material was entirely consumed, sat. aq. NH4Cl was added, and the product was extracted with DCM/MeOH (19:1) (repeated 3 times). The organic layers were combined, dried over Na2SO4, filtered and concentrated to dryness. The residue was used in the next step without purification. LRMS (M+H)+: 413 m/z.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8](N2[C@@H](C(C)C)COC2=O)=[O:9])=[CH:3][CH:2]=1.OO.[OH-:33].[Li+].S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([C@@H:7]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:8]([OH:9])=[O:33])=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.1 %

Procedure:
A solution of 3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (127.4 mg, 0.31 mmol) in tetrahydrofuran (1.3 ml,) and water (300 μL) was cooled to 0° C. and then sequentially treated with a 30% aqueous hydrogen peroxide solution (39 μL, 1.25 mmol ) and an 0.8M aqueous lithium hydroxide solution (628 μL, 0.50 mmol). The reaction mixture was allowed to warm to 25° C. where it was stirred for 7 h. At this time, the reaction mixture was treated with solution of sodium sulfite (158.4 mg, 1.26 mmol) in water (952 μL). The reaction mixture was stirred at 0° C. for 30 min and then concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous layer was extracted with diethyl ether (1×100 mL). The aqueous layer was then acidified to pH=1 with a 10% aqueous hydrochloric acid solution and extracted with ethyl acetate (1×100 mL). The organic extract was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 2(R)-biphenyl-4-yl-3-cyclopentylpropionic acid (43 mg, 46%) as a white solid: mp 136-137° C.; EI-HRMS m/e calcd for C20H22O2 (M+) 294.1620, found 294.1618.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-])=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O.[OH-].[K+]>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2
Reactant: O=[N+]([O-])C=Cc1cccc2[nH]ccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(2-nitrovinyl)indole (II) (3 g, 15.9 mmol) in THF (10 ml) was added to a suspension of DIBAH (1M THF, 159 ml, 159 mmol) under an inert atmosphere and was stirred at room temperature for 30 min, then it was heated at 60° C. and stirred for 5 hours. The obtained mixture was cooled to 0° C., AcOEt, water and KOH 10% were added and the ontained product was filtered. The aqueous layer was extracted with AcOEt and the organic layer was dried and evaporated to obtain 4-[(2-amino)ethyl]indole (III).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20]O)[O:17][C:16]2=[O:22])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][N:35]=[N+:36]=[N-:37])[O:17][C:16]2=[O:22])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(N2CCSCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(c2cc(F)c(N3CCSCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(5R)-3-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-oxazolidin-2-one (Intermediate 12) (15 g, 45.5 mmol) was dissolved in a mixture of triethylamine (9.6 ml, 68 mmol) and dichloromethane (200 ml). The resulting solution was cooled to 0° C. and methane sulfonyl chloride (4.6 ml, 59 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours then allowed to warm to room temperature. Water (200 ml) was added and then the organic layer separated, dried over magnesium sulfate, filtered and concentrated in vacuo. This intermediate was dissolved in dry DMF (120 ml). Sodium azide (11.8 g, 181 mmol) was added and the reaction mixture stirred at 70° C. overnight. It was diluted with dichloromethane (700 ml), washed with water (200 ml) and brine (200 ml) and dried over magnesium sulfate. Concentration in vacuo gave 16 g of the title compound.