Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.O.[S-2:19].[Na+].[Na+].Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:19])[NH2:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1c(F)cccc1F
Temperature: 25 °C
Yield: 76 %

Procedure:
Into a 3 L three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (550 mL), 2,6-difluorobenzonitrile (208 g, 1.50 mol), triethylamine (202 g, 279 mL, 2.0 mol), and sodium sulfide hydrate (521 g, 2.17 mol, broken into pieces small enough to fit into the flask). The temperature of the stirred mixture was lowered to approximately 5° C. and to the slurry was added dropwise concentrated hydrochloric acid (143 g, 288 mL, 3.99 mol). An exotherm was noted and the rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. for a total addition time of 75 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. The mixture was poured into water (2 L) and was extracted with ether (3×500 mL). The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 232 grams of crude product. The starting material was removed from the product via bulb-to bulb distillation to give 197 g (76%) of 2,6-difluorobenzenethioamide. This material was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=1)=[O:4].[N+](=[CH2:18])=[N-].O.[OH-].[Li+]>CO.O>[CH3:15][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([CH3:14])[C:8]=1[C:9]([O:11][CH3:18])=[O:10])[C:3]([OH:2])=[O:4]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)c1cc(C)c(C(=O)O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C)cc(C(=O)O)cc1C
Reaction time: 8 h

Procedure:
A solution of 4-(methoxycarbonyl)-2,6-dimethylbenzoic acid (2.08 g: 10 mmol) in methanol (25 mL) is treated with ethereal diazomethane until the yellow color persists and the solution is left at room temperature overnight. The solution is concentrated in vacuo to remove the remaining diethyl ether, then tetrahydrofuran (25 mL) is added. The solution is stirred in an ice-water bath as a solution of lithium hydroxide monohydrate (0.462 g, 11 mmol) in water (25 mL) is added. After the cooling bath is removed, the reaction is allowed to proceed at room temperature overnight. The volatiles are removed under reduced pressure on a rotary evaporator (bath temperature <30° C.), then the concentrate is diluted with brine and extracted with dichloromethane to remove residual 2,6-dimethylterephthalic acid dimethyl ester. The aqueous phase is acidified to pH 2 using 3N hydrochloric acid (4 mL), then is extracted with dichloromethane (2×25 mL). The combined organic extracts are washed with brine, then are dried (MgSO4), filtered and evaporated in vacuo to yield 3,5-dimethyl-4-(methoxycarbonyl)benzoic acid.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl[C:13]1[C:14](=[O:26])[NH:15][S:16](=[O:25])(=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][N:35]=1)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:13]2[C:14](=[O:26])[N:15]([CH2:40][C:37]3[CH:38]=[CH:39][C:34]([NH:33][C:32](=[O:42])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:35][CH:36]=3)[S:16](=[O:25])(=[O:24])[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=C1NS(=O)(=O)C(c2ccccc2)=C1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Nc3ccc(OC(F)F)cc3)=C(c3ccccc3)S2(=O)=O)cn1
Temperature: 0 °C
Yield: 12.3 %

Procedure:
[4-[Difluoromethoxy)phenyl]amine (0.27 g, 1.7 mmol) was added to an ice cold solution of 4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.41 g, 1.7 mmol) in DMF (4 ml) and the mixture was stirred for 1 h. tert-Butyl[5-(bromomethyl)pyridin-2-yl]carbamate (0.48 g, 1.7 mmol) and anhydrous potassium carbonate (0.23 g, 1.7 mmol) were added. The reaction mixture was stirred over night, concentrated and the residue was dissolved in DCM. The mixture was washed with water and concentrated and the residue was purified using preparative HPLC to give the title compound (0.12 g, 13%). 1H NMR (400 MHz, d6-DMSO): δ 1.41 (s, 9H), 3.77 (dd, 2H), 7.22-7.24 (m, 3H), 7.27 (t, 1H), 7.39-7.45 (m, 5H), 7.48 (d, 1H), 7.78 (d, 1H), 7.86 (dd, 2H), 9.57 (s, 1H), 11.18 (s, 1H); Mass Spectrum: M+H+ 573.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3]2)=[O:21]
Reactant: CS(=O)(=O)NC1Cc2ccccc2C1
Reactant: O=C(Cl)CCCCCl
Product: CS(=O)(=O)NC1Cc2ccc(C(=O)CCCCCl)cc2C1

Procedure:
Using N-(2,3-dihydro-1H-inden-2-yl)methanesulfonamide and 5-chlorovaleryl chloride according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals having a melting point of 71 to 72° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[N+:13]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[NH2:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#N)cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C#N)cc1N

Procedure:
2-t-Butyl-5-cyano-1-nitrobenzene [prepared as described in step (i) above] was reduced in a similar manner to that described in Preparation 5 to give the title compound as crystals, melting at 94.5°-95° C. (from hexane-ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 4-chloro-3-nitropyridine (Kruger J, Mann F. G, J. Chem. Soc., 1955, 2755) (700 mg, 4.41 mmol) in ethanol (10 ml) was added 4-methoxyaniline (1.087 g, 8.82 mmol), followed by sodium acetate (362 mg, 4.41 mmol). The mixture was heated under reflux for 16 hours, cooled to room temperature and diluted with water (30 ml). The resulting precipitate was collected by filtration, washed with water (×3) and dried in vacuo to afford the title compound (800 mg, 74%); MS (ES+) m/e 309 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: OC(c1ccccc1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
To a solution of (4-bromophenyl)(phenyl)methanone (200 g, 0.766 mole) in THF (600 mL) and methanol (400 mL) was added in portions pulverized sodium borohydride (29 g, 0.766 mole) while maintaining the internal temperature between 3° C. and 10° C. After stirring for an additional 15 minutes, acetone (125 mL) was added and the mixture stirred for a subsequent 10 minutes. The solution was concentrated and the residue partitioned between water (250 mL) and ethyl acetate (1.0 L). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was pumped on by high vacuum for 18 hours to give the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2)(=[O:3])[NH2:2].[OH-].[K+]>O1CCCC1.C(O)CO.O>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2[nH]c(C(N)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a suspension of methyl 2-carbamoyl-1H-indole-5-carboxylate (300 mg, 1.38 mmol) in tetrahydrofuran (4.5 mL) and ethylene glycol (4.5 mL) was added potassium hydroxide (3.16 g, 56.4 mmol). The mixture was heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and diluted with water. The tetrahydrofuran was removed under reduced pressure. The solids were filtered off and the filtrate was acidified to pH 4 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give 2-carbamoyl-1H-indole-5-carboxylic acid (230 mg, 82%). 1H NMR (400 MHz, DMSO-d6, δ): 12.53 (br. s., 1 H), 11.88 (br. s., 1 H), 8.28 (s, 1 H), 8.04 (br. s., 1 H), 7.77 (d, J=8.6 Hz, 1 H), 7.46 (m, J=8.6 Hz, 2 H), 7.25 (s, 1 H).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([O:8]C)=[O:7])#[N:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>Cl>[C:3]([C:5](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([O:11][CH3:10])[CH:13]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: COC(=O)CC#N
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=C(C#N)C(=O)O)cc1OC
Temperature: 85 °C
Yield: 55.7 %

Procedure:
To 150 ml of an aqueous solution of 9.19 g of sodium hydroxide, 20.50 g of methyl cyanoacetate was added and, under stirring, 25.38 g of 3,4-dimethoxybenzaldehyde was further added, followed by heating at 85° C. for 40 hours under stirring. After completion of the reaction, the reaction mixture was added to 50 ml of 12 N hydrochloric acid to recover the resultant solid. The solid was repeated twice to recrystallize from ethanol to obtain 19.84 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.F[C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)[O:43][CH2:42]1.CO[C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:19]([O:43][CH3:42])[CH2:18][O:21]2)[N:6]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Agent: CO[C@@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 21) gave tert-Butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate.
Reaction SMILES: [CH2:1]([N:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Br-:21].[CH2:1]([N+:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCBr
Reactant: CCCCCCCCCCCCCCN(C)C
Solvent: CC#N
Product: CCCCCCCCCCCCCC[N+](C)(C)CCCCCC
Product: [Br-]
Temperature: 85 °C
Reaction time: 4 h

Procedure:
The following are added successively at room temperature with stirring to a flask of contents 1 dm3 which is equipped with a stirrer, a reflux condenser and a contact thermometer and is surrounded at its bottom by an electrically heatable jacket which is controlled by the contact thermometer: 145.3 g (0.6 mol) of N-tetradecyl-N,N-dimethylamine, 249.3 g (6.07 mol) of acetonitrile and 104.0 g (0.63 mol) of 1-bromohexane. While stirring is continued, the mixture is heated to a temperature of 85° C. and kept at this temperature for 4 hours, then it is cooled to room temperature, a sample is taken and the residual amine content in this is determined. On the basis of this determination, the amine conversion is 99%. The contents of the flask are then added to a rotary evaporator and the liquid constituents, essentially acetonitrile, are distilled off in a water bath at a temperature rising from 50° to 80° C. and a pressure falling from 9.6 to 1.8 kPa at 320 revolutions per minute during the course of 4 hours. The N-tetradecyl-N-hexyl-N,N-dimethylammonium bromide (1) thus obtained is then dried at room temperature under a pressure of 40 Pa generated by an oil vacuum pump and used for the viscosity determinations described below. The product is analysed, the following values being determined:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C:17]1=[O:22].[O:23]1[C:27]2([CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1.[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH:30]2[CH2:31][CH2:32][C:27]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:28][CH2:29]2)[CH2:18][C:17]1=[O:22]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(C2CCC3(CC2)OCCO3)CC1=O

Procedure:
26.18 g Sodium triacetoxyborohydride are added at 5° C. to a solution of 10.0 g 4-methyl-3-oxo-piperazine, 13.51 g 1,4-dioxa-spiro[4,5]decan-8-one, 5.65 ml acetic acid and 200 ml dichloromethane. After 23 hours stirring at ambient temperature 100 ml dichloromethane and 100 ml 4N sodium hydroxide solution are added. The phases are separated and the organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([C:8]2[N:9]=[C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:35]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36]1>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:40]([C:37]3[CH:38]=[CH:39][O:35][CH:36]=3)(=[O:42])=[O:41])[C:3]=2[F:34])[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (280 mg, 0.556 mmol) in pyridine (3 mL) was added 3-furansulfonyl chloride (139 mg, 0.833 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to the title compound (310 mg). MS (ESI): 634.1 [M+1]+.
Reaction SMILES: C1C2[C:10]3=CC4C=CC(C(O)=O)=CC=4[N:9]3[CH2:8]C=CC=2C=CC=1.[Cl:22][C:23]1[C:28]([C:29]([N:31]2[CH2:36][CH2:35]O[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.[CH2:37]1COCC1>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>[Cl:22][C:23]1[C:28]([C:29]([N:31]2[CH:36]3[CH2:35][CH2:37][CH:32]2[CH2:33][N:9]([CH3:10])[CH2:8]3)=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: C1CCOC1
Reactant: O=C(c1cccnc1Cl)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN1CC2CCC(C1)N2C(=O)c1cccnc1Cl
Temperature: 160 °C
Yield: 44 %

Procedure:
7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[3-(4-morpholinylcarbonyl)-2-pyridinyl]-, 1,1-dimethylethyl ester. To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester (100 mg, 0.136 mmol) dissolved in THF (2 mL) was added 4-[(2-chloropyridin-3-yl)carbonyl]morpholine (47 mg, 0.21 mmol), TEA (0.029 mL), and tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol). This mixture was capped under nitrogen and heated in a microwave at 160° C. for 2 hr. The reaction mixture was filtered purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: % A=10% acetonitrile, 90% water, 0.1% TFA; % B=90% acetonitrile, 10% water, 0.1% TFA; Initial % B=30; Final % B=100; Gradient=12 min; Runtime=20 min; Flow rate=40 ml/min; Column=Waters Sunfire 30×100 mm S5. This afforded the title compound (38 mg, 44%) as a yellow paste. MS m/z 634 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCSc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCSc2ccccc2)CC1
Yield: 27 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.5 g) as starting compound and 4-phenylthiobutyl bromide (2.48 g) were reacted and treated in the same manner as in Example 168 to give 0.84 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-phenylthiobutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9]O>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1cccc(Br)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(Br)[n+]1[O-]
Temperature: 90 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
2-Bromo-6-methylpyridine (36 g, 0.2 mol) was dissolved in acetic acid (700 ml), hydrogen peroxide (30%, 62 ml, 0.6 mol) was added and the mixture was stirred at 90° C. for 24 hours. After cooling to room temperature, the mixture was diluted with water (700 ml) and extracted with DCM (4×). The combined organic phases were washed with water, dried (sodium sulfate) and concentrated under reduced pressure to give 36 g of a red-brown liquid (0.19 mol, 94%) MS (APCI) m/z=188.0 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:4].Cl.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21]N2CCCCC2)=[CH:19][CH:18]=1.C(O[CH2:33][CH3:34])C>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:34]2[CH2:33][CH2:6][N:5]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=3)=[O:4])[CH2:3][CH2:2]2)=[CH:28][CH:29]=1
Reactant: CCOCC
Reactant: Fc1ccc(CN2CCCCC2)cc1
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1cccc([N+](=O)[O-])c1

Procedure:
The title compound is prepared from 2-chloro-N-(3-nitrophenyl)-acetamide and 4-(4-fluoro-benzyl-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 118-120° C. (diethylether)
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:33]=[N:34][NH:35][N:23]=3)[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
Heat a mixture of 3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-N-(3-cyano-phenyl)-benzamide, sodium azide (1.12 g, 17.3 mmol), and ammonium chloride in dimethylformamide at 110 C for 24 hours. Cool to room temperature and dilute with water. Filter and wash several times with water. Dry filtered material and dissolve in hot acetone. Purify the resulting solution via chromatography, eluting with hexanes:acetone with 1% acetic acid to afford the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.52 (sextet, 2H), 2.58 (s, 3H), 2.62 (t, 2H), 5.37 (s, 2H), 6.76 (d, 1H), 7.57 (d, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.74 (d, 1H), 7.82 (d, 1H), 7.97 (m, 2H), 8.09 (m, 1H), 8.59 (s, 1H), 10.56 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 470 (100).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[C:7]([N+:21]([O-])=O)=[C:8]([CH:18]=[CH:19][CH:20]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10].[H][H]>[Ni].CO>[NH2:21][C:7]1[C:6]([O:5][CH3:4])=[CH:20][CH:19]=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: [H][H]
Reactant: COc1cccc(C(=O)N2CCCC2CO)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cccc(C(=O)N2CCCC2CO)c1N
Reaction time: 2 h
Yield: 96 %

Procedure:
Hydrazine hydrate (4.37 g, 136.4 mmol) was added dropwise to a solution of 92 (6.37 g, 22.7 mmol) in gently refluxing methanol (100 mL) over Raney nickel (2.4 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded a brown glass (5.49 g, 21.8 mmol) as a single spot by TLC.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6](I)[CH3:7].[CH3:9][C:10]([O-])(C)C.[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:9]([C:2]([CH2:6][CH3:7])([C:1]#[N:5])[C:3]#[N:4])[CH3:10]
Reactant: CCI
Reactant: CC(C)(C)[O-]
Reactant: N#CCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: CCC(C#N)(C#N)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Malononitrile (15.2 g) was mixed with TBAB (3.0 g, 4 mol %) and ethyl iodide (36.8 mL, 2 equiv.). After stirring for 30 minutes at room temperature, the mixture was cooled in an ice bath, KOtBu (51.6 g, 2 equiv.) was added portionwise, the ice bath was removed, and the mixture was stirred for 30 minutes at room temperature. Extraction with DCM/H2O, drying over Na2SO4 and evaporation under reduced pressure gave 40 grams of crude material, which was purified by flash chromatography eluting with DCM. This yielded 20.4 grams of an orange oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=7.5 Hz, 6H), 2.00 (q, J=7.5 Hz, 4H).