Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)([Cl:19])=O.[CH2:22](O)[CH3:23]>>[Cl:19][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:22][CH3:23])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCO
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a mixture of 2-hydroxynicotinic acid (13.91 g., 0.1 mole) and phosphorus pentachloride (42 g., 0.2 mole) was added phosphorus oxychloride (25 ml., excess) and then stirred at room temperature for 30 minutes. This was then heated at 120° C. for 2 hours. The reaction mixture was then concentrated in vacuo until a red viscous mass was obtained. The latter was cooled in an ice water bath and 45 ml. absolute ethanol was added first slowly and then rapidly. It was then refluxed for 30 min. and cooled. Most of the excess ethanol was removed under vacuo and the remaining mass was diluted with water (90 ml.). The aqueous solution was neutralized with 10% sodium carbonate solution and then extracted with 2×100 ml. portions of dichloromethane. The organic layer was washed with 2N NaOH solution followed by water and brine. It was dried and then concentrated to give a pale yellow liquid which was purified by distillation under reduced pressure (20 mm. Hg, b.p. 140°-44° C.) to give ethyl 2-chloronicotinate in 60-65% yield. A fore-run at 80°-110° C. (5-10%) was discarded which consisted mainly of ethyl 2-ethoxynicotinate.
Reaction SMILES: CN(C1C=CC=CN=1)C.[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CN(C)C=[O:28]>>[CH:19]1([NH:18][C:17](=[O:28])[NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An equimolecular mixture (10-2M) of L-N-Boc-NG -nitroarginine and N-B-hydroxyethyl morpholine is dissolved in 30 ml of anhydrous dimethyl formamide (DMF), then 3×10-3M of dimethylaminopyridine (DMAP) is added. The solution is cooled to 0 degrees C. and 10-2M of dicyclohexyl carbodiimide (DDC) is added. It is stirred at 0 degrees C. for 10 minutes, then the stirring is continued at room temperature for 24 hours. The precipitate of dicyclohexyl urea formed is filtered and the solvent eliminated. The residue is recovered by ethyl acetate, then washed once with water and once with saturated NaCl. The elimination of the solvent leaves a viscous product which is chromatographed on a silica column (eluant CHCl3/MeOH9595 then 90:10); the compound (4) is obtained in the form of an oil which crystalizes.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].N12CCCN=C1CCCC[CH2:28]2.CI>C(#N)C>[CH3:28][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (208 mg, 0.54 mmol) is suspended in acetonitrile (5 mL). 1,8-Diazabicyclo[5,4,0]undec-7-ene (0.096 mL, 0.64 mmol) is added and followed by the addition of methyl iodide (0.073 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica, eluent: DCM, MeOH) to provide 171 mg of the title compound. Yield: 79%; m/z 403 [M+H].
Reaction SMILES: BrCCBr.[Li+].[Br-].[C:7]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>C(O)(C)(C)C.C1COCC1.[Zn]>[C:36]([C:33]1[CH:34]=[CH:35][C:30](/[CH:29]=[CH:28]/[C:25]2[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]\[C:17]3[CH:16]=[CH:15][C:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)=[CH:31][CH:32]=1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(/C=C\c2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1

Procedure:
272 g of zinc dust in 270 ml of tert.-butanol are boiled with 24.9 ml of 1,2-dibromoethane until evolution of gas ceases. 55.5 g of CuBr and 66.9 g of LiBr in 200 ml of THF are then carefully added at 50° C. When the exothermic reaction has died down, 272 g of E-4-(carbo-tert.-butoxy)-4'-(4-carbo-tert.-butoxy-styryl)-tolan in 1.7 l of THF and 560 ml of tert.-butanol are added and the reaction mixture is heated under reflux for 4 days. The resulting reaction mixture is then evaporated to dryness, taken up in CH2Cl2 and filtered and the filtrate is washed with dilute HCl, dried and concentrated by evaporation.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]1[OH:8].[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](Cl)=[CH:12][C:11]=1[Cl:20].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:9][C:10]1[C:11]([Cl:20])=[CH:12][C:13]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]2[OH:8])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: N[C@@H]1CC[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1CC[C@@H](O)[C@H]1O

Procedure:
(±)-(1R*,2S*,3R*)-3-Amino-1,2-cyclopentanediol (7.10 g, 50.0 mmol), 1,2,4-trichloro-5-nitrobenzene (11.67 g, 50.0 mmol as 97%, Aldrich), triethylamine (10 mL) and t-butanol (50 mL) were refluxed under nitrogen for 7 hours. Volatiles were removed in vacuo and the black residue chromatographed on silica gel. Title compound was eluted with methanol:chloroform/1:24 as an orange solid (6.45 g, 42%). Crystallization of such a sample from ethanol-water gave title compound as yellow needles, m.p. 137°-140° C.; 1H-NMR (DMSO-d6) δ: 8.26 and 7.49 (both s, 1 each, 2 aromatic CH), 8.06 (d, J=7.0 Hz, 1, NH), 5.04 (d, J=6.1 Hz, 1, OH), 4.65 (d, J=4.1 Hz, 1, OH), 4.0-3.7 (m, 3,2 OCH and NCH), 2.2-2.1, 2.0-1.8, 1.7-1.3 (all m, 4, 4 CH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[O-2].[Ca+2]>>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:22]([CH:19]3[CH2:21][CH2:20]3)[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]=12
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [Ca+2]
Agent: [O-2]
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Reaction time: 1 h

Procedure:
The process according to claim 3, wherein 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is heated with cyclopropylamine in the presence of 0.5 to 2 mol of calcium oxide in an inert solvent to a temperature of 130° to 150° C. over a period of 5 to 8 hours, the reaction mixture is then cooled to a temperature below 40° C. and filtered, the filter cake is washed with an inert solvent and the combined filtrates are concentrated, the residue is then diluted with an inert solvent and this solution is added to a solution or suspension of a base in an inert solvent, heated at 120° to 150° C., the reaction mixture is then kept at a temperature of 120° to 150° C. for 30 to 90 minutes, the reaction medium is then distilled off as much as possible and the residue is hydrolysed at a temperature of 20° to 90° C., the hydrolysed residue is cooled down and mixed with an inert solvent and an organic acid and the mixture is stirred at a temperature of 5° to 50° C. for 30 to 90 minutes, the product is then present as a suspension which is isolated and washed with an inert solvent, followed by water and an alcohol to give nevirapine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=O)[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16].C(#N)C.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: ClCCl
Product: CC1(C)CC(C)(C)c2cc(Br)cc(CNC3CC3)c2O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (U.S. Pat. No. 6,252,090, 2.4 g, 8.4 mmol) in dichloromethane (10 mL) and acetonitrile (9 mL) was treated with cyclopropyl amine (1.45 mL, 21 mmol). After 5 minutes, acetic acid (1 mL) was added followed by sodium cyanoborohydride (1.33 g, 21 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The volatiles were distilled off in vacuo, the residue was diluted with water and extracted with ethyl acetate (×2). The combined organic extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230–400 mesh) afforded the title compound (1.4 g, 50%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][Cl:5].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Cl-:5].[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)=CCCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 80.5 %

Procedure:
A stirred solution of 52.3 g (0.5 mole) of 3-methyl-2-butenyl chloride and 144.1 g (0.55 mole) of triphenylphosphine in 400 ml of toluene was heated at 100° C. for 18 hours. The white solid formed was collected by filtration to give 147.6 g of (3-methyl-2-butenyl)triphenylphosphonium chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:8]=[C:9]([CH3:18])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+]>CO.O>[CH3:18][C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)c(C)cn1Cc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cn2cc(C)c(-c3ccc(C)cc3)c2C(=O)O)cc1

Procedure:
A reaction mixture of 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (550 mg, 1.58 mmol) and NaOH (1.26 g, 32 mmol) in MeOH (45 mL) and H2O (15 mL) was refluxed for 1 h. After removal of the solvent, aqueous 1N NaOH (100 mL) was added and extraction performed with EtOAc (2×20 mL). After drying of the combined organic phases over Na2SO4, filtration and removal of the solvent, the desired product 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid was obtained, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (181 mg, described in Example 114) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (161 mg, 51%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.42 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 8.02-8.09 (m, 2H) and 9.21 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.4 (s, 3F).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].B1([O-])O[O:17]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])[C:1]([OH:17])=[O:2])#[N:9]
Reactant: CC[C@@H](C)Oc1ccc(C=O)cc1C#N
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC[C@@H](C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 50 °C
Yield: 93.9 %

Procedure:
To a solution of 5-formyl-2-{[(1R)-1-methylpropyl]oxy}benzonitrile (D37) (310 mg, 1.53 mmol) in acetic acid (30 ml) was added sodium perborate tetrahydrate (471 mg, 3.05 mmol), the reaction mixture was heated at 50° C. over the weekend. The reaction mixture was concentrated in vacuo and water (˜50 ml) added, EtOAc (˜30 ml) was added and the layers partitioned, the aqueous layer was extracted twice more with EtOAc (˜30 ml) and the combined organics evaporated to dryness under reduced pressure to give the title compound (315 mg) as an off-white solid. MS (ES): C12H13NO2 requires 219; found 220 (MH+).
Reaction SMILES: S([O:5][CH2:6][C@@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)(=O)C.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[SH:33].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33][C:6](=[O:5])[C@@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Reactant: Sc1ccc2ccccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)Sc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-Boc-D-phenylalaninol mesylate (0.3 g, 0.9 mmol), dimethylformamide (10 mL), 2-napthalenethiol (0.22 g, 1.39 mmol), diisopropylethylamine (1.39 mmol) and sodium iodide (0.14 g, 0.93 mmol) was kept at 80° C. for 18 hr, cooled to room temperature and methylene chloride (25 ml) was added. This mixture was washed with water (2×10 mL), 1 M sodium hydroxide (3×10 mL) and brine (2×15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate adsorbed onto silica gel and applied to a column prepacked with silica gel. The title compound (121 mg) was eluted with hexane:ethyl acetate (90:10, v:v) to afford a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[CH2:9]=[O:10].C(N(CC)CC)C>CC(C)=O>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][OH:10])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc[nH]n1
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccn(CO)n1
Temperature: 130 °C
Reaction time: 7 h
Yield: 87.5 %

Procedure:
The mixture of 1.15 g of 3-i-propyl-1H-pyrazole, 0.94 g of paraformaldehyde and 0.14 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 1.28 g of 3-i-propyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:26][CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][CH:12]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH:1]=[O:3])[CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:15][CH:16]=1)[CH3:9]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(=O)O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.18 ml) was added dropwise formic acid (0.09 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling a solution of methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g) in THF (15 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([N:24]2[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Cc1cn(-c2ccc(Cl)nn2)cn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 180 °C

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline (128 mg, 0.5 mmol), 3-chloro-6-(4-methylimidazol-1-yl)pyridazine (78 mg, 0.4 mmol) in DMSO (1.5 mL) was added DIPEA (0.25 mL, 1.5 mmol). The resulting mixture was sealed and heated at 180° C. for 1.5 h under microwave irradiation. The resulting mixture was then poured into H2O (30 mL) and the aqueous layer was extracted with 10% CH2Cl2/Et2O (80 mL×4). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column (dry loading) using EtOAc then 3% MeOH/EtOAc as the eluent to yield 6-fluoro-1-(1-(6-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)piperidin-4-yl)indoline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[C:13](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC.N1C2C(=CC=CC=2)C=C1>O.CN(C)C=O>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(=O)OC
Product: Cn1cc(CC#N)c2ccccc21
Temperature: 124 °C
Reaction time: 10 h
Yield: 158.1 %

Procedure:
A 500 mL, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with indole-3-acetonitrile (10.0 g, 0.064 mol), potassium carbonate (5.0 g, 36 mmol), N,N-dimethylformamide (60 mL) and dimethyl carbonate (11.0 mL, 0.13 mol). The resulting mixture was heated to 124±1° C. The progress of the reaction was monitored by HPLC. After 10 h at this temperature, the presence of the starting indole could not be detected. The reaction mixture was then cooled to zero to −5° C. Water (140 mL) was added which resulted in the formation of a precipitate. The mixture was stirred at −5° C. for 1 hour, then the solid was collected by filtration, washed with water (150 mL), and dried under high vacuum at 45° C. for 24 h to give 1-methylindole-3-acetonitrile (I and II, 9.69 g, 89%) as a brown solid.
Reaction SMILES: [N:1]1([NH:7][C:8](=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[N:1]1([N:7]=[CH:8][C:27]2[CH:30]=[CH:31][C:24]([C:23]([F:33])([F:32])[F:22])=[CH:25][CH:26]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C=NN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Tert-butyl piperazin-1-yl-carbamate (403 mg, 2.0 mmol) was suspended in methylene chloride (4 ml), to which trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 5 minutes. To which 4-(trifluoromethyl)benzaldehyde (0.3 ml, 2.2 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=9/1) to afford piperazin-1-yl-(4-trifluoromethylbenzylidene)-amine (432 mg, yield 84%) as a colorless crystalline powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])=[O:11])=[CH:6][CH:5]=1.[CH2:19](I)[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:21]([O:18][CH2:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:11])[CH:20]=[CH2:19]
Reactant: C=CCI
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Sodium hydride (61.5 mg, 1.41 mmol) (55% in paraffin liquid) was added to a solution of 200 mg (0.704 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone in N,N-dimethylformamide (2 ml) synthesized in the same manner as in step (i) of Reference Example 8, and the mixture was stirred at room temperature for 30 min. Thereafter, allyl iodide was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 155 mg (yield 68%) of the title compound.