Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCOc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CCOc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-hydroxy-4-chromanone (18.6 g, 113 mmol), benzyl bromide (20 g, 116 mmol), and K2CO3 (21 g, 152 mmol) in acetone (110 ml) was refluxed for 20 hrs. The mixture was cooled, diluted with EtOAc, and filtered through celite. The filtrate was concentrated to an oil, which was triturated with 10% Et2O in hexane (150 ml) to gives, after filtration and washing, 28 g (87%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH2:23][CH3:24])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH2:23]([C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][O:29][C:30]3=[O:34])=[CH:3][C:4]=2[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]1)[CH3:24]
Reactant: CCc1cc(C)ccc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Reactant: O=C1NCCO1
Product: CCc1cc(C)ccc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2S(C)(=O)=O)CC1
Yield: 1.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2-ethyl-4-methylphenyl)piperazin-1-yl]methanone (1.8 g) described in Preparation Example 15 and oxazolidin-2-one (418 mg), the title compound (22 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22])[CH:17]=O>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH:9]=[CH:17][C:16]1[CH:19]=[C:20]([CH3:23])[C:21]([OH:22])=[C:14]([CH3:13])[CH:15]=1
Reactant: COc1cc(Cl)ccc1C(C)=O
Reactant: Cc1cc(C=O)cc(C)c1O
Product: COc1cc(Cl)ccc1C(=O)C=Cc1cc(C)c(O)c(C)c1

Procedure:
This compound was synthesized from 4′-chloro-2′-methoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1>[N:16]1([S:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:14])=[O:13])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1

Procedure:
2-(4-Nitro-phenyl)-ethanesulfonyl chloride (from Example 33 (A), 300 mg) was suspended in 5 mL of THF. To the stirring solution was added morpholine (1 mL) dropwise at r.t. After 5 hours the solvent was evaporated. The nitro product was purified by flash chromatography (CH2Cl2/CH3OH 10:1 v/v) and was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (167 mg, 52%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.01 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.72 (t, J=4.7 Hz, 4H), 3.23 (t, J=4.7 Hz, 4H), 3.11 (m, 2H), 2.98 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH:2]=[CH2:3].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1.O>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:9])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: Nc1nnn[nH]1
Reactant: C=CCOc1cc(C(=O)O)nc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reaction time: 1 h

Procedure:
N,N'-Carbonyldiimidazole (1.27 g) and 4-allyloxyquinaldic acid (1.2 g) in dimethylformamide (30 ml) were heated at 100° for 4 hours. 5-Aminotetrazole (1.33 g) was added and the mixture was stirred at 100° for 1 hour and cooled. Water (30 ml) was added and the solid was collected and dissolved in hot aqueous dimethylaminoethanol (15 ml, 5%). The solution was filtered and the filtrate was acidified with glacial acetic acid. 4-Allyloxy-N(1H-tetrazol- 5-yl)quinaldamide was collected and dried, m.p. 260° (d).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (1 mL) was stirred for 1 h at room temperature, concentrated under reduced pressure; NaOH (1 M, 15 mL) was added to the residue and the suspension was extracted with DCM, the extract was dried (anhydrous Na2SO4) and concentrated, to afford title compound 296 (90.4 mg, 69% yield) as a syrup. MS (m/z): 188.1 (M+1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)Cl
Reactant: OC(CNCc1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)N(Cc1ccccc1)CC(O)C(F)(F)F
Reaction time: 0.08 h

Procedure:
A solution of 3-(Benzylamino)-1,1,1-trifluoropropan-2-ol (2.68 g, 12.3 mmol) and triethylamine (1.7 mL, 12.2 mmol) in CH2Cl2 is cooled to 0° C. The solution is treated drop wise with 2-bromopropanoyl chloride (1.2 mL, 12 mmol, Aldrich) and stirred for 5 minutes. The solution is diluted to 100 mL with CH2Cl2 and washed sequentially with 1.0M HCl, saturated NaHCO3, and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation yielding (N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide as a golden oil. Dry NaH is suspended in dry, inhibitor free THF (25 ml) in a flame dried flask and the mixture is cooled to 0° C. with stirring on an ice bath. The N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide (4.25 g, 12 mmol) is added as a solution in dry, inhibitor free THF (25 ml) and the resultant suspension is warmed to RT. After stirring for one hour the reaction is quenched with MeOH over an ice bath until no more gas evolved and the mixture is poured into 1.0M HCl (200 mL). The aqueous mixture is extracted into MTBE (200 mL) and the organic layer is washed with saturated NaHCO3 and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered, and the solvent is removed by rotary evaporation yielding an amber oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: CC(C)(C)OC(=O)NC1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 92 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 and tert-butyl piperidin-4-ylcarbamate gave tert-butyl (S)-{1-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperidin-4-yl}carbamate (yield 92%) a yellow oil in the same manner as in Example 277.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][S:16][C:14]=2[N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:10]1[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][S:16][C:14]=2[N:15]=1
Reactant: OCC1CCNCC1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCC1CCN(c2nc(Cl)nc3scc(-c4ccccc4)c23)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Piperidinemethanol (987 mg, 8.57 mmol) was added to a stirred suspension of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (2 g, 7.14 mmol) and triethylamine (2.18 ml, 15.7 mmol) in dry ethanol (ml) at room temperature. Reaction was warmed to 40° C. and the resulting solution stirred for ˜2 h. Reaction was allowed to cool to room temperature and poured onto ice/water (50 ml). The resulting suspension was filtered and the solid dried in a vacuum oven at 40° C. The desired compound was obtained as a pale yellow solid (2.4 g, 93%). LCMS: (M+1) 360, RT=4.69 min.
Reaction SMILES: Br[C:2]1[N:3]([CH3:27])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]1)[N:7]=[CH:6][N:5]=2.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C(N(C(C)C)CC)(C)C.[H-].[Na+]>C(O)C>[N:28]1([C:2]2[N:3]([CH3:27])[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[NH:19][C:18]4=[O:26])[CH2:15][CH2:16]2)[N:7]=[CH:6][N:5]=3)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-n2ccnc2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-[1-(8-Bromo-9-methyl-9H-purin-6-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (50 mg, 0.12 mmol) was dissolved in ethanol (1 mL). To this solution was added imidazole (24 mg, 0.35 mmol) and diisopropylethylamine (39 μL, 0.23 mmol). This mixture was irradiated in the microwave at 180° C. for 6 hours. The ethanol was removed in vacuo and replaced by DMA (1 mL). To this solution was added 1 equiv. of sodium hydride. After heating to 100° C. for 1 hour, the mixture was filtered and purified by prep HPLC to obtain 24 mg of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.39-8.28 (m, 1H), 8.27-8.16 (m, 1H), 7.78 (m, 1H), 7.18 (m, 1H), 7.14 (m, 1H), 6.99-6.82 (m, 3H), 5.47 (s, 1H), 4.63-4.40 (m, 1H), 3.67 (s, 3H), 3.22 (m, 3H), 2.42-2.20 (m, 2H), 1.80 (m, 2H). EI (MS) for C21H21N9O, found 416 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (15 g, 61 mmol) and dihydro-2H-pyran-4(3H)-one (9.2 g, 92 mmol) in dichloroethane (300 mL), acetic acid (22 g, 368.4 mmol) was added and the reaction stirred at room temperature for 2 h. Then sodium triacetoxyborohydride (39 g, 184 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound (14 g, 69%).
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[Si:5]([O:22][C@H:23]([CH3:35])[C@H:24]([NH2:34])[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])(=O)(=O)=O.[Li+].C(Cl)Cl>C(OCC)C>[Si:5]([O:22][C@H:23]([CH3:35])[C@H:24]([NH:34][CH2:1][C@@H:2]([OH:4])[CH3:3])[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)([C:18]([CH3:19])([CH3:20])[CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Reactant: C[C@H]1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-(−)-propylene oxide (0.1 ml) and (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine (212 mg) in diethyl ether (1 ml) was added to a suspension of lithium perchlorate (750 mg) in diethyl ether (1 ml), and the reaction solution was stirred in a nitrogen atmosphere at room temperature overnight. Methylene chloride and ice water were added to the reaction solution. After stirring the reaction solution, the organic layer was separated. The aqueous layer was subjected to extraction with methylene chloride again. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:heptane=9:1 to 4:1) to obtain 172 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=[O:8].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:15]([C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: O=CC1=C(Cl)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=CC1=C(Oc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of residue (100 g, 0.77 mol) obtained in example 1 in acetone (400 mL), phenol (79.3 g, 0.84 mol) and K2CO3 (126.8 g, 0.92 mol) were added. The mixture was stirred under nitrogen for 12 hours at room temperature and monitored by TLC (petroleum ether/ethyl acetate=10:1). After the reaction completed, the solvent was removed on a rotary evaporator, and water (300 mL) was added. The mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with aqueous sodium carbonate (2×50 mL) and water (50 mL). After dried over sodium sulfate, the solvent was removed and 2-phenoxy-1-formyl-1-cyclopentene was obtained (155 g, contains some phenol), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[N:13][C:12]=2[N:20]2[CH2:25][CH2:24][CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]2)[CH2:5][CH2:4]1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CN(C=O)C.CC(C)N=C=NC(C)C>O>[F:32][C:2]([F:1])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[CH:16]=[C:15]3[N:17]=[C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C:34]=4[Cl:33])[N:18]([CH3:19])[C:14]3=[N:13][C:12]=2[N:20]2[CH2:25][CH2:24][CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]2)=[O:30])[CH2:5][CH2:4]1
Reactant: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CCC(C(F)(F)F)CC3)nc21
Reaction time: 72 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-5-amino-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid amide (compound Ic; 130 mg, 0.27 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (98 mg, 0.31 mmol) and DMF (3 mL) is stirred for 3 d. Then DIC (57 μl, 0.32 mmol) is added and it is stirred for 1 d. The crude mixture is poured into water and the precipitate is collected by filtration and purified by prep. HPLC. Yield: 90 mg. Melting Point: 185-186° C. MS m/z: 750 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([CH2:11][CH:12]=[CH2:13])C(OCC)=O)C.C([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])C>COCCOCCOC>[CH2:11]([CH:5]([CH:19]([CH3:20])[C:18]([OH:17])=[O:22])[C:4]([OH:14])=[O:3])[CH:12]=[CH2:13]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)C(C)Br
Solvent: COCCOCCOC
Product: C=CCC(C(=O)O)C(C)C(=O)O
Yield: 96 %

Procedure:
90.5 g (0.5 moles) of 2-allylmalonic acid diethyl ester are reacted in diethylene glycol dimethyl ether with 0.5 moles of alcohol-free sodium ethoxide. 0.5 moles of 2-bromopropionic acid ethyl ester is added dropwise to this solution, with stirring. The mixture is heated for a further 2 hours under reflux and the solvent is then removed. The residue is subsequently subjected to hydrolysis in alcoholic KOH. After drying the organic layer that has separated, it is fractionated. The desired 2-allyl-1-methylethane-tricarboxylic acid 1,2,2-triethyl ester boils under 0.02 torr at 92° to 95° C. The ester is hydrolyzed in alcoholic KOH and, after working up in the customary manner, is decarboxylated at 170° C. with water being split off. The anhydride of 2-allyl-3-methylsuccinic acid (b.p. at 0.1 torr: 108° to 110° C.) is obtained in a 96% yield (based on the ester).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]([C:14]2[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[O:19])=[CH:16][CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH:12]([C:14]2[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[O:19])=[CH:16][CH:15]=2)[CH3:13])[C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:32][CH:33]=2)=[O:39])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(Nc1ccc(C(C)(C)C)cc1)c1ccc(C(=O)Nc2nn[nH]n2)cc1
Solvent: CN(C)C=O
Product: CC(c1ccc(C(=O)Nc2nn[nH]n2)cc1)N(C(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Yield: 6.3 %

Procedure:
4-[1-(4-tert-Butylphenylamino)ethyl]-N-(2H-tetrazol-5-yl)benzamide (100 mg, 0.28 mmol) and 4-trifluoromethoxyphenyl isocyanate (70 mg, 0.30 mmol) was dissolved in DMF (0.6 mL) and the solution was heated to 80° C. for 3 hours. The mixture was cooled to room temperature and subsequently taken to dryness using rotary evaporation. The residual oil was dissolved in a minimum of DMF/acetonitrile (1:1), and submitted to preparative HPLC purification. Pure fractions were pooled and concentrated to dryness to afford 10 mg (8%) of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)=[CH:11][C:10]([Br:23])=[CH:9][N:8]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-].CC(=O)OCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([CH:26]=[CH2:27])=[N:8][CH:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyridin-2-yl trifluoromethanesulfonate (700 mg, 1.59 mmol), tributyl(vinyl)stannane (556 mg, 1.75 mmol), LiCl (202 mg, 4.78 mmol) and Pd(PPh3)2Cl2 (100 mg) in DMF (20 mL) was stirred at 60° C. for 3 hours under nitrogen atmosphere. The mixture was filtered through celite and concentrated in vacuo to remove DMF, and then the residue was suspended in water/EA. After extracted with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford 2-(5-bromo-2-vinylpyridin-3-yl)-4-fluoro-1H-indole (400 mg, yield: 79%) through the column chromatography (PE:EA=20:1). 1H-NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.14˜7.22 (m, 2H), 7.00˜7.07 (m, 1H), 6.82˜6.86 (m, 1H), 6.76 (s, 1H), 6.43˜6.47 (m, 1H), 5.54˜5.58 (m, 1H). MS (M+H)+: 317/319.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.23 mmol) and tetrahydro pyran-4-one (1.06 g, 10.66 mmol) in methanol (20 mL), acetic acid (0.5 g, 8.23 mmol) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (0.62 g, 9.83 mmol) was added and reaction stirred 3 h. On completion, solvent was removed under reduced pressure; water was added and extracted with DCM. Combined organic were dried, concentrated and purified by column chromatography using silica (100-200 mesh size) to afford the desired compound (1.6 g, 62%).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[Cl:23][C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:32][S:29]([C:27]2[S:28][C:24]([Cl:23])=[CH:25][CH:26]=2)(=[O:31])=[O:30])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(Cl)s1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 5-chloro-thiophene-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 3.66 (s, 3), 4.77 (s, 2), 6.49 (s, 1), 7.00 (overlapping m, 3), 7.26 (m, 2), 7.72 (m, 1). 13C NMR (125 MHz, CDCl3) δ: 48.29, 63.20, 92.61, 115.69, 115.87, 126.94, 130.23, 130.30, 131.01, 135.19, 135.85, 140.50, 159.01, 159.08, 161.69, 163.66, 170.84.
Reaction SMILES: [N+]([O-])(O)=O.C[C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[O:12][C:11](=[O:17])[CH:10]=[C:9]2[OH:18].[CH:19](Cl)(Cl)Cl>>[CH3:19][C:15]1[C:14]([CH3:16])=[C:13]2[C:8]([C:9]([OH:18])=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][CH:6]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1cc(C)c2oc(=O)cc(O)c2c1
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(O)cc(=O)oc2c1C
Reaction time: 2 h

Procedure:
Fuming nitric acid (13 ml) was added to a stirred suspension of 6,8-dimethyl-4-hydroxycoumarin (m.p. 253°- 255°; 2.21g) in chloroform (200 ml) at room temperature over 2 hours. After standing for a further 2 hours, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (50 ml) added to the residue. Filtration and recrystallisation from ethanol gave the product, m.p. 169.5°-170°(d), (C11H9NO5 requires C, 56.18; H, 3.86; N, 5.96. Found; C, 56.22; H, 3.99; N, 5.84).