Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[Br:28]N1C(=O)CCC1=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[C:15]([Br:28])=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc2oc(=O)[nH]c2cc1Br)NC(=O)OCc1ccccc1
Temperature: 105 °C
Yield: 34.4 %

Procedure:
A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (1.07 g, 2.89 mmol), N-bromosuccinimide (643 mg, 3.61 mmol), and acetic acid (150 mL) was heated at 105° C. for 14 h. After cooling to room temperature, the solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3), then (1:1) as eluent to afford the title compound (446 mg, 34%). The structure of the title compound was confirmed by 2D NMR. 1H-NMR (CD3COCD3, 500 MHz) δ 10.46 (s, 1H), 7.36-7.28 (m, 7H), 6.82 (d, J=8.5 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 5.00 (d, J=12.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.73 (s, 3H), 3.43 (dd, J=14.0, 5.0 Hz, 1H), 3.10 (dd, J=14.0, 10.5 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 154.2, 143.7, 137.6, 131.1, 130.6, 128.7, 128.2, 128.0, 118.2, 113.9, 112.9, 66.2, 54.3, 52.1, 38.3; Mass spec. 448.03 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2B2OC(C)(C)C(C)(C)O2)[N:24]([S:40]([C:43]2[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOCC.O.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>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:30]=3[C:22]([CH3:21])=[CH:23][N:24]4[S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(B4OC(C)(C)C(C)(C)O4)cccc32)cc1
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: COCCOC
Solvent: O
Solvent: CCOCC
Product: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Temperature: 140 °C

Procedure:
To a solution of 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.0 g, 3.45 mmol) in DME (10.0 mL) in a 20 mL microwave reaction vial was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (1.57 g, 3.80 mmol). Then 2 M aqueous Na2CO3 (5.6 mL, 11.22 mmol) was added. The reaction mixture was degassed via a series of 3 argon/vacuum cycles and then placed under an atmosphere of argon. Then Pd(Ph3P)4 (0.399 g, 0.345 mmol) was added and the vial was sealed and heated via microwave irradiation at 140° C. for 90 minutes. The reaction mixture was cooled to room temperature and diluted with Et2O and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (27-48% ethyl acetate/heptanes) to provide 6-benzyl-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as a white solid. MS (ESI+) m/z 539.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([Br:22])=[C:14]([O:23][CH2:24][CH3:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Br:22])=[C:14]([O:23][CH2:24][CH3:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc2cc3n(c2nc1Br)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOc1cc2c(nc1Br)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 2, intermediate, from (R)-6-bromo-7-ethoxy-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyanoborohydride.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=O.O.[NH2:38][NH2:39]>>[NH:38]([C:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:10][CH:11]=1)=[O:2])[NH2:39]
Reactant: NN
Reactant: COC(=O)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NN)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 102 mg (0.21 mmol) of tert-butyl (3RS,4RS)-4-(4-methoxycarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 0.5 ml of hydrazine hydrate was heated to 120° C. for 18 hours. For the working-up, the reaction mixture was cooled to room temperature, treated with 3 ml of ice-water and extracted twice with 5 ml of methylene chloride each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. There were obtained 63 mg (63% of theory) of tert-butyl (3RS,4RS)-4-(4-hydrazinocarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless foam; Rf : 0.22 (SiO2, methylene chloride:methanol:ammonia=95:5:0.1).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=1)=[O:12]>CN(C=O)C>[CH3:9][O:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]([Br:19])[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Cyclopentanol (1 mL, 11 mmol) was dissolved in DMF (25 mL) and a dispersion of sodium hydride in oil (55-65%, 480 mg) was added at room temperature. The mixture was stirred for 1 h at room temperature and 5-bromo-6-chloro-3-pyridinecarboxylic acid methyl ester (2.5 g, 10 mmol) was added. Stirring was continued for 1 h at room temperature and the mixture was afterwards partitioned between water and diethyl ether. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 9:1) to yield 0.48 g of the title compound as a colorless oil, MS (EI) 299.0, 301.0 (M)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@H:3]([OH:5])[CH3:4].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[F:1][C:2]([F:7])([F:6])[C@H:3]([O:5][C:9](=[O:10])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[CH3:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)C(F)(F)F
Product: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-1,1,1-trifluoro-propan-2-ol and 4-nitrophenyl chloroformate following a procedure analogous to that described for Intermediate 20.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][N:18]=3)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)C(=O)C2=CC=CC=C12.CCO>>[NH2:5][CH2:6][CH:7]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][N:18]=2)[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: O=C1c2ccccc2C(=O)N1CC(OC1CCCCO1)c1cc2cccnc2[nH]1
Solvent: CCO
Product: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Yield: 98.9 %

Procedure:
To a solution of 2-[2-Phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (10.2 g, 26 mmol) in EtOH (630 ml) NH2NH2.H2O (1.53 ml, 31 mmol) was added. The mixture was refluxed for 3 h. The solvent was evaporated, the residue dissolved in CH2Cl2 and washed with saturated aq. NaHCO3. The aqueous layer was extracted three times with CH2Cl2. The organic solutions were evaporated together to obtain a diastereomeric mixture (1:1) of 9a (6.72 g, 100%) as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH2:23].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][NH:23][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: CN
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜666 mL, ˜121.5 mmol) was added 2.0 M methylamine (95 mL, 190 mmol, in THF) and T3P (50 wt % solution in EtOAc, 96.6 mL, 152 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 mL of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75 L Biotage™ column, eluting with gradients of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (18.9 g, 48% yield). Rf=0.35 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C17H23ClN2 O2, 322.2, found, 323.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47-7.45 (m, 2H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 5.94 (brs, 1H), 5.67 (brs, 1H), 3.75 (s, 3H), 2.85 (d, J=4.9 Hz, 3H), 2.86-2.73 (m, 3H), 2.62-2.56 (m, 4H), 2.54-2.47 (m, 2H), 1.84-1.76 (m 4H); 100 MHz 13C NMR (CDCl3) δ 177.6, 146.0, 135.5, 134.0, 130.8, 126.3, 123.6, 74.3, 56.8, 54.3, 41.1, 33.3, 26.9, 23.7.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)=[CH:20][CH:19]=[CH:18][C:17]=2[C:31]([F:34])([F:33])[F:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3([CH3:57])[NH:54][C:53](=[O:55])[NH:52][C:51]3=[O:56])=[CH:49][C:44]=2[O:43][CH2:42]1>O>[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3([CH3:57])[NH:54][C:53](=[O:55])[N:52]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]4[C:21]5[C:16](=[C:17]([C:31]([F:34])([F:33])[F:32])[CH:18]=[CH:19][CH:20]=5)[N:15]=[CH:14][C:13]=4[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:51]3=[O:56])=[CH:49][C:44]=2[O:43][CH2:42]1
Reactant: CC1(c2ccc3c(c2)OCO3)NC(=O)NC1=O
Reactant: FC(F)(F)c1cccc2c(OCCCCCCBr)c(Cc3ccccc3)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccc3c(c2)OCO3)NC(=O)N(CCCCCCOc2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)C1=O
Reaction time: 8 h
Yield: 121 %

Procedure:
A DMF (0.1 mL) solution of 3-benzyl-4-(6-bromohexyloxy)-8-(trifluoromethyl)quinoline (12.5 mg, 0.03 mmol) was added with potassium carbonate (9 mg, 0.06 mmol) and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione (46.8 mg, 0.20 mmol), and stirred overnight. The reaction solution was added with water, extracted with ethyl acetate, subsequently dried using anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane:ethyl acetate), and the title compound (22.5 mg, yield 49%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:25])[NH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:25])[N:21]([CH3:36])[CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc[nH]c3=O)cc2)C(=O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15.5 mg, 0.036 mmol) in dry DMF (1 mL) was cooled to 0° C. Sodium hydride (60% in mineral oil, 3 mg, 2 equiv) was added. After 20 min, iodomethane (4.5 μL, 2 equiv) was added. The mixture was stirred another 20 min before being warmed to rt slowly and stirred for 2 h. LC-MS found the reaction completed. The mixture was quenched with satd aq NH4Cl (1 mL) and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 83% yield). LC-MS Method 1 tR=1.63 min, m/z 447 (M+1).
Reaction SMILES: [Br:1][C:2]([Br:17])=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[N+:14]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]([Br:17])=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH:11]([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH2:14]
Reactant: O=[N+]([O-])c1ccc(OC(F)F)cc1C=C(Br)Br
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(OC(F)F)cc1C=C(Br)Br
Temperature: 25 °C
Yield: 34.2 %

Procedure:
To a suspension of 2-(2,2-dibromovinyl)-4-difluoromethoxynitrobenzene (534 mg) in ethanol (3.7 mL) was added tin (II) chloride dihydrate (742 mg) at room temperature, and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 1 mol/L Aqueous sodium hydroxide solution was added to the residue and this resulting mixture was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (168 mg).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]([CH3:31])[CH:12]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(C(C)(C)C)(C)C.N1C=CC=CC=1.F.C(OCC)(=O)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH:12]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[CH:11]([CH3:31])[CH2:10][CH2:9][OH:8])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: F
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(CCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
The 2-[4-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylbutyl]-1,4-difluorobenzene (Compound A (Isomer B)) (102 mg, 0.209 mmol) obtained in Example 237 was dissolved in tetrahydrofuran (3 ml), followed by the addition of hydrogen fluoride-pyridine (0.5 ml). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and then dried over magnesium sulfate. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (36.1 mg, 0.0963 mmol, 46%) was obtained as colorless columnar crystals.
Reaction SMILES: S([O:11][C:12]1[CH:13]=[N:14][C:15]([CH2:18][O:19]C(=O)C)=[CH:16][CH:17]=1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl>O.C(OCC)(=O)C>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[N:14][CH:13]=1
Reactant: CC(=O)OCc1ccc(OS(=O)(=O)c2ccc(C)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccc(O)cn1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 3-tosyloxy-6-acetoxymethylpyridine (50 g, 0.148 mol) and NaOH (25 g, 0.62 mol) in 150 mL of water was refluxed for 15 h. The reaction mixture was cooled to RT and neutralized with con. HCl. The solvent was evaporated under vacuum affording a solid residue, which was suspended in ethyl acetate (750 mL) and heated to 60° C. for 30 min. with stirring. The suspended material was filtered off and the filtrate was concentrated to give 5-hydroxy-2-hydroxymethylpyridine (15 g, 80%) as a pale yellow solid. It was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:4]2[C:31](=[O:34])[NH:32][CH2:33][C:3]=2[C:2]=1[F:1]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)c1
Yield: 63.7 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-fluoro-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (40.0 mg, 0.085 mmol) and TFA (2 mL, 26.0 mmol) in DCM (1 mL) was stirred at RT for 1 h. The mixture was concentrated and the resulting residue was purified by preparative HPLC to give the title compound as a white solid (20 mg, 63.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.97 (m, 8 H), 2.30 (s, 3 H), 3.70 (br s, 1 H), 4.27 (br s, 1 H), 4.33-4.46 (m, 2 H), 6.73 (d, J=6.35 Hz, 1 H), 6.79 (d, J=7.32 Hz, 1 H), 7.17 (t, J=7.57 Hz, 1 H), 7.43 (d, J=7.81 Hz, 1 H), 7.46 (s, 1 H), 7.76 (br s, 2 H), 8.29 (s, 1 H), 8.79 (s, 1 H). [M+H] calc'd for C20H24FN5O, 370; found, 370.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:12]=O)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:12]=[CH:17][N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCc1c(C=O)[nH]c2ccccc12
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(C=C[N+](=O)[O-])[nH]c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 3-ethyl-2-indolecarbaldehyde (4.0 g) and nitromethane [4.93 g) in methanol (80 ml) was added dropwise 50% aqueous sodium hydroxide solution at 0~-5° C. for an hour. After being stirred at the same temperature for an hour and at room temperature for an hour. The mixture was poured into a mixture of chilled water and 12N hydrochloric acid (4:1, 500 ml). The precipitates were collected, washed with water and dried to give 3-ethyl-2-(2-nitrovinyl)indole.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][S:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[CH:16][N:11]3[N:10]=[CH:9][N:8]=[C:12]3[CH:13]=2)=[N:18][N:19]=1
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Reactant: Fc1cccc(CCl)c1
Solvent: CCN(CC)CC
Product: Fc1cccc(CSc2nnc(-c3ccn4ncnc4c3)o2)c1
Yield: 27 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 27%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(OCC)(=O)C>[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([O:25][C:1](=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]2[C@:23]3([CH3:24])[C@H:9]([C@H:10]4[C@H:20]([CH2:21][CH2:22]3)[C@:18]3([CH3:19])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)[CH3:5])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](CCC(=O)Oc1ccc([N+](=O)[O-])cc1)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
Cholanic acid (3.6 g, 10.0 mmoles) is suspended in methylene chloride (200 mL) and stirred well at ambient temperature. 4-Nitrophenol (1.4 g, 10.1 mmoles) and N,N′-dicylcohexylcarbodiimide (2.1 g, 10.2 mmoles) are added, and the mixture is stirred overnight. The mixture is then filtered, the solid washed with a little methylene chloride, and the filtrate is evaporated to dryness to give a yellow solid. The crude product is dissolved in ethyl acetate (100 mL). The solution is filtered and the filtrate si evaporated to give an off-white solid. The solid is crystallized from hot hexanes. The yield is 3.9 g (80%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7][C:5]1[O:6][C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:32]=2)=[CH:3][CH:4]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)CN(Cc1ccc(Br)o1)S(=O)(=O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)o1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(5-bromo-furan-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-furan-2-ylmethyl]-benzenesulfonamide as a light yellow oil. MS: 498.9 ([M+NH4]+)