Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 2-naphthoyl chloride (164 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (175 mg, 65%).
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.CC(C)([O-])C.[K+].[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2)([O-:27])=[O:26].[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45]Br>C1COCC1>[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][N:33]1[C:34]2[C:30](=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)[CH:31]=[C:32]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 214 mg (0.81 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) are initially charged in 43 ml of THF, and 9.73 ml (9.73 mmol) of 1-molar potassium tert-butoxide solution in THF and 2000 mg (8.11 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate are added. The mixture is stirred at RT for 15 minutes and then cooled to 0° C. A solution of 1713 mg (8.11 mmol) of 2,4-difluorobenzyl bromide in 13 ml of TKF is slowly added dropwise. The ice-bath is removed and the mixture is stirred at RT for 1 hour. For work-up, the mixture is diluted with water and the THF is removed under reduced pressure using a rotary evaporator. The aqueous residue is extracted with ethyl acetate and the organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 5:1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[NH2:11])[CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[CH3:17][NH:18][C:19]([NH:11][N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)=[O:20]
Reactant: CN=C=O
Reactant: CCCc1cccc(N(N)CC(=O)OC)c1
Solvent: CC#N
Product: CCCc1cccc(N(CC(=O)OC)NC(=O)NC)c1

Procedure:
Methyl [1-(3-propylphenyl)hydrazino]acetate (700 mg) was dissolved in acetonitrile (10 ml) under nitrogen at room temperature. Methyl isocyanate (0.69 ml) was added to the solution which was then heated at 80° for 85 min. The solvent was removed in vacuo and the residue was dissolved in ether (10 ml). Hexane (20 ml) was added to precipitate a solid which was filtered off to give the title compound (677 mg), m.p. 76°-77°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([C:6]1([CH3:7])[O:13][CH2:12][CH2:11][O:8]1)[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)C1(C)OCCO1
Yield: 72.1 %

Procedure:
A mixture of 2-methyl-3-oxo-butyric acid ethyl ester (50 g, 0.347 mol), ethylene glycol (65 g, 1.05 mol) and p-toluenesulfonic acid monohydrate (0.2 g) in anhydrous toluene (200 mL) was refluxed using a Dean-Stark trap until the theoretical amount of water (6.3 mL) was collected. After cooling, the mixture was extracted with saturated bicarbonate solution (100 mL), water (100 mL×5), and brine (100 mL×2). After drying with sodium sulfate, filtration, and concentration on a rotary evaporator, the product was purified by distillation (fraction with b.p. 74-76° C./2 mm Hg) to yield 47.12 g (72%) of 2-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:24][CH2:23][CH:19]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:17]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: NC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), isonipecotamide (27.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C17H19N3O3: 313.1426, found 313.1431.
Reaction SMILES: ClC1C=CC(=O)N(C2C=CC(CC3N([CH2:20][C:21]4[CH:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:24]([C:33]#[N:34])=[CH:23][CH:22]=4)C=NC=3)=CN=2)C=1.[Li+].[BH4-].C1C[O:41]CC1>>[OH:41][CH2:20][C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]#[N:34])=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1-c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Product: N#Cc1ccc(CO)cc1-c1ccccc1
Temperature: 70 °C

Procedure:
6-Cyano-biphenyl-3-carboxylic acid methyl ester from step 2 (1.4 g, 5.9 mmol) was dissolved in THF (24 ml). LiBH4 in THF (2 M, 5.9 ml, 11.8 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl>[CH2:1]([NH:4][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol to give 63 mg (51%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.29 (br s, 1H, NH), 11.73 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.7 & 6.5 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.43 (m, 1H), 7.40 (s, 1H), 7.34 (t, J=9.05 Hz, 1H), 3.49 (m, 4H, 2×CH2), 2.29 (m, 4H, 2×CH2), 2.19 (s, 3H, CH3), 2.18 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:21]=[CH:22][C:23]([O:26][C@H:27]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixed solution of ethyl (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate (660 mg, 1.26 mmol) in THF (15 ml) and methanol (7 ml) was added 1N aqueous potassium hydroxide (4.0 ml, 4.0 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the object compound as an oily substance. 615 mg, (yield 98%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].Cl>C(Cl)Cl>[C:41]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1)(=[O:43])[CH3:42]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN)nc32)cc1OCc1c(F)cccc1OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CNC(C)=O)nc32)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2-aminomethyl-9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (94 mg) and pyridine (0.1 mL) in methylene chloride (3 mL) was added acetic anhydride (0.055 mL), and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate). The obtained product was suspended in diethyl ether, and collected by filtration. The collected material was dried under reduced pressure to give the title compound (44 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)([C:13]#[N:14])[C:9]2=[O:26])[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)C>C(O)CCC>[C:13]([C:10]1([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:39][CH:38]=3)[N:7]=2)[C:9]1=[O:26])#[N:14]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Cl)n3)C2=O)C1
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)C2=O)C1
Yield: 25.5 %

Procedure:
A solution of tert-butyl 3-(1-(2-chloropyrimidin-4-yl)-3-cyano-2-oxopyrrolidin-3-yl)azetidine-1-carboxylate (100 mg) obtained in Step D of Example 309, 4-morpholinoaniline (61 mg) and acetic acid (50 μL) in n-butanol (4.0 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>O1CCCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Palladium-on-carbon (10% w/w; 0.25 g.) was added to a solution of (C) (1.5 g.) in tetrahydrofuran (50 ml.) in a hydrogenation bottle. The mixture was hydrogenated at 3.45 bars for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residual oil was purified by flash chromatography on silica gel (200 ml.) eluting with 1:1 v/v ethyl acetate:hexane, to give methyl 4-(5-aminoindol-3-ylmethyl)-3-methoxybenzoate (A) (1.12 g., 82%) as a viscous oil; NMR: 3.29(br,2H,NH2), 3.88(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 4.03(s,2H, CH2.Ar), 6.64(dd,1H), 6.78(m,2H), 7.10(m,2H), 7.44(m,2H), 7.68(br,1H, H1 -indole).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>C1COCC1.O>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Yield: 43.5 %

Procedure:
A solution of 4-methylbenzenesulfonyl chloride (16.6 mg, 0.0870 mmol), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mmol), TEA (10.0 mg, 0.174 mmol) in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 2-methyl-N-{3-[1-(3-{[(4-methylphenyl)sulfonyl]amino}propyl)-4-piperidinyl]phenyl}propanamide (17.3 mg, 43.6%): 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.32-7.21 (m, 4H), 7.16 (s, 1H), 6.97 (d, 1H, J=7.9 Hz), 3.44 (t, 2H, J=6.3 Hz), 3.15 (d, 2H, J=9.8 Hz), 2.62-2.45 (m, 4H), 2.15 (m, 3H), 2.05 (s, 3H), 1.95-1.71 (m, 5H), 1.26 (d, 6H, J=6.6 Hz); ESMS m/e: 458.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH:12]=[C:13]([O:15][C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 2-(5-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[N:12][OH:13]
Reactant: NO
Reactant: Cc1ccc(C=O)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C=NO)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a stirred suspension of 3-bromo-4-methylbenzaldehyde (1.0 g, 5 mmol, 1.0 eq) in methanol (50 mL) was added a solution hydroxylamine hydrochloride (434 mg, 6.3 mmol, 1.2 eq) in water (2 mL) at room temperature. The resulting solution was cooled to 0° C. and then treated with an aqueous solution of sodium carbonate (2M, 2 mL). After stirring for 1 h at room temperature, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 0.85 g of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.87 (s, 1H, D2O exchangeable) 7.76 (d, J=1.5 Hz, 1H), 7.43 (dd, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 2.44 (s, 3H); ESI-MS (m/z) 214, 216 [(MH)+, Br79,81].
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29].O>C1COCC1>[F:29][C:28]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)C1CCNC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 7-oxoazepane-4-carboxylate (9.78 g) in THF (250 mL) was added 60% sodium hydride (2.33 g, containing mineral oil) under ice-cooling. The reaction mixture was stirred for 5 min under ice-cooling, and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (17.9 g) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (14.9 g).