Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[N:18]1([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[CH:29]=O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[N:18]1([C:24]2[CH:31]=[C:28]([CH:29]=[CH:3][C:1]#[N:2])[CH:27]=[N:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=Cc1cncc(N2CCOCC2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=Cc1cncc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) cooled at 0° C. was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction was cooled to 0° C. and a solution of 5-morpholin-4-ylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was stirred at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (2E & Z)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc dust (30 g) was added in portions to a 5° C. solution of 2-nitro-4-trifluoromethyl-benzonitrile (3.0 g, 14 mmol) in glacial acetic acid (260 mL). The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 1 hour. The reaction mixture was filtered through a celite plug, and the celite layer was washed with glacial acetic acid. The combined filtrate and washings were concentrated to afford 2-amino-4-trifluoromethyl-benzonitrile as an oily, orange solid which was used in subsequent reactions without additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]CC=C)=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl[C:33]1[CH:38]=CC=C[C:34]=1Cl>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:38][CH:33]=[CH2:34])[C:21]([OH:24])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=CCOc1ccc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc1C(=O)OC
Reactant: Clc1ccccc1Cl
Product: C=CCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OC)c1O

Procedure:
A solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(4-allyloxy-3-methoxycarbonylphenyl)thiazole in 25 ml of o-dichlorobenzene was refluxed for 15 hours with heating. After the completion of a reaction, the solvent was removed by distillation. The residue was recrystallized from diisopropyl ether to obtain 1 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[N:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([NH:24][C:14]([C:12]2[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: NN1CCCCC1
Product: Cc1ccc(C(=O)NN2CCCCC2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid (Example 49 e) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (D): 330.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH2:22]([C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:41]=[CH:42][C:35]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:36][CH:37]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCCCc1ccc(C#N)cc1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A mixture of 0.82 g of N-methyl-N-phenylsulfonyl-2-chlorobenzohydrazonoyl chloride, 0.70 g of 4-tridecylbenzonitrile, 0.4 g of anhydrous aluminium chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.70 g of the given compound (melting point: 55.0°-57.0° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:14]=1[C:21](=O)[CH3:22]>CCO.O.O>[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:14]=1[C:21](=[N:2][OH:3])[CH3:22]
Reactant: CC(=O)c1c(O)cc(C)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1c(O)cc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of hydroxylamine hydrochloride (470 mg, 6.76 mmol) and sodium acetate trihydrate (590 mg, 4.34 mmol) dissolved in 20 ml of a mixture of EtOH/H2O (7/3) was added to a solution of 1-(2,6-dihydroxy-4-methylphenyl)ethanone (Intermediate 16, 940 mg) in 15 ml of a mixture of EtOH/H2O (7/3). After refluxing and stirring under N2 for 2 hours, additional hydroxylamine hydrochloride (159 mg, 2.29 mmol) and sodium acetate trihydrate (199 mg) dissolved in 5 ml of water were added. The reaction mixture was heated at reflux overnight. After cooling down to room temperature, the volatiles were removed. Water was added and the solid afforded was filtered, washed with water and dried giving 829 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4].[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1>O1CCOCC1>[F:20][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]([NH:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1)=[O:19])(=[O:15])=[O:16])[C:3]([F:6])([F:5])[F:4]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Reactant: COc1nc(C)nc(N)n1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)(F)C(F)(F)F)n1
Temperature: 20 °C

Procedure:
3.2 g of 2-pentafluoroethoxyphenylsulfonyl isocyanate and 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are stirred in 40 ml of dioxane for 3 hours at 90°-100° C. The solution is then cooled to 20° C., filtered, and concentrated to about 1/4 of its volume. After addition of ether, 3.3 g of N-(2-pentafluoroethoxyphenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea crystallise from the residue. Melting point: 157°-159° C.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S([CH2:12][N+:13]#[C-:14])(=O)=O)=CC=1.[F:16][C:17]([F:25])([F:24])/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21].CCOCC.CS(C)=O>CCOCC.CCOC(C)=O>[F:16][C:17]([F:25])([F:24])[C:18]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:12][NH:13][CH:14]=1
Reactant: COC(=O)/C=C/C(F)(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
In a round-bottomed flask was added sodium hydride (3.24 mmol, 78 mg) in Et2O (5 mL). A mixture of p-toluenesulfonylmethyl isocyanide (3.24 mmol, 634 mg) and (E)-methyl 4,4,4-trifluorobut-2-enoate (3.24 mmol, 500 mg) were added in a 2:1 mixture of Et2O/DMSO (22.5 mL). The reaction mixture was stirred for a further 30 min then quenched with H2O (10 mL) and extracted with Et2O (×3). The Et2O layers were combined and washed with brine, dried over MgSO4, filtered and the solvent removed to give a yellow/orange solid. Purification by flash chromatography (1:4 EtOAc:Hept) the desired product (154 mg, 0.80 mmol, 24.6%). 1H NMR (400 MHz, CD3OD) δ 3.79 (s, 3H) 7.20 (s, 1H) 7.50 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]I.[H-].[Na+]>O1CCCC1>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH3:23])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(4-Benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine (0.1 g, 0.31 mmol), methyl iodide (22 μL, 0.35 mmol) and sodium hydride (60% dispersion in mineral oil, 15 mg, 0.35 mmol) were combined in tetrahydrofuran (2 ml) and stirred at room temperature for 18 hours. The reaction was quenched by the addition of water and brine and the mixture extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2–5% methanol/dichloromethane, to give the title compound. The hydrochloride salt was obtained by treatment with ethereal hydrogen chloride and crystallisation from ethanol/diethyl ether (77 mg, 74%). NMR of hydrochloride salt:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:33])([F:32])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]([F:33])([F:32])[F:19])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=463.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.CC([O:16][C:17](OC(OC(C)(C)C)=O)=[O:18])(C)C.[Li]CCCC.C(=O)=O>C1COCC1.CN(C)C1C=CN=CC=1>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[C:17]([OH:18])=[O:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
4-(trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[C:17]([CH:22]=O)=[N:18][CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:22][C:17]1[C:16]([F:15])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: O=Cc1ncccc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CN(CCCCNCc1ncccc1F)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of (4-amino-butyl)-methyl-carbamic acid tert-butyl ester (0.202 g, 1.00 mmol), 3-fluoro-pyridine-2-carbaldehyde (0.125 g, 1.00 mmol) and K2CO3 (0.138 g, 1.00) in MeOH (5 mL) was stirred for 16 h. The mixture was filtered through a celite cake and NaBH4 (0.050 g, 1.3 mmol) was added to the filtrate, and the mixture was stirred for 30 min. Saturated aqueous NaHCO3 (20 mL) was added, and MeOH was removed. The aqueous residue was extracted with CH2Cl2 (3×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (50:2:1 CH2Cl2/MeOH/NH4OH), affording {4-[(3-fluoro-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a colorless oil (0.230 g, 74%). 1H NMR (CDCl3) δ 1.42 (s, 9H), 1.48-1.54 (m, 4H), 2.61-2.68 (m, 2H), 2.80 (s, 3H), 3.14-3.22 (m, 2H), 3.96 (s, 2H), 7.11-7.20 (m, 1H), 7.30-7.36 (m, 1H), 8.33-8.38 (m, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[N:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccncc1
Reactant: BrCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccncc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3 g of 4-pyridylacetonitrile hydrochloride in 50 ml of DMF is cooled to 0° C., 2.6 g of 60% sodium hydride in oil are added portionwise and the mixture is left stirring at RT for 1 hour 30 minutes. The reaction mixture is cooled on an ice bath, 2.7 ml of 1,5-dibromopentane are added dropwise and this mixture is left stirring at RT for 48 hours. The reaction mixture is poured into saturated NH4CO solution and extracted with ether, the organic phase is washed three times with water and dried over MgSO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and, then with a DCM/MeOH mixture (98/2; v/v). 2.5 g of the expected product are obtained; m.p.=79° C.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[S:4][CH:3]=1.[CH3:28][O-:29].[Na+].[I-].[Na+]>CO.[Cu]=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:8]3[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]4[S:4][CH:3]=[C:2]([O:29][CH3:28])[C:6]=4[N:7]=3)[CH2:16][CH2:17]2)=[CH:22][CH:23]=1
Reactant: NCCCc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c(Br)csc12
Reactant: C[O-]
Agent: O=[Cu]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1csc2c(CCCN)nc(N3CCN(c4ccc(Cl)cc4)CC3)nc12
Temperature: 160 °C
Yield: 12.9 %

Procedure:
2.00 g (4.28 mmol) of {7-bromo-2-[4-(4-chlorophenyl)piperazin-1-yl]thieno[3,2-d]pyrimidin-4-yl}propylamine (VII) is placed in 15 mL of methanol and cooled to some extent. First 0.995 g (18.42 mmol) of sodium methoxide, then 0.187 g (2.36 mmol) of copper (II) oxide, and 0.040 g (0.27 mmol) of sodium iodide are added. The reaction mixture is heated to 160° C. in the microwave for 0.75 hours. Then it is suction filtered through silica gel and the mother liquor is concentrated by evaporation. The residue is dissolved and any insoluble matter is removed by suction filtering. Further purification is carried out by preparative HPLC. 0.23 g of product VIII (20%) is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13].[CH2:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26])[CH:15]([CH3:17])[CH3:16]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[CH3:26])[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)c(F)c1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(Br)c(F)c2)c(C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3,5-difluorobenzene-1-sulfonyl chloride (1462 mg, 5.02 mmol) in pyridine (10 mL) at 20° C. was added N-isobutyl-2,4-dimethylaniline (889 mg, 5.01 mmol) and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was then evaporated in vacuo and redissolved in ethyl acetate. The organic phase was washed with saturated sodium carbonate (25 mL), dried using a hydrophobic frit and evaporated in vacuo to give the required product as a yellow oil, 2.06 g. LCMS [LCMS2] Rt 1.57 min, m/z (ES+) 432/434 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][CH:28]=2)=[C:23]([F:37])[C:22]=1[O:38][CH3:39]>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][CH:28]=2)=[C:23]([F:37])[C:22]=1[O:38][CH3:39]
Reactant: COc1ccc(CN)cc1
Reactant: COc1c(Cl)ccc(-c2ccnc(C)c2C(=O)Cl)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2c(-c3ccc(Cl)c(OC)c3F)ccnc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a stirred solution of (4-methoxyphenyl)methanamine (0.437 g, 3.18 mmol) in CH2Cl2 (25 mL) was added DIEA (0.556 mL, 3.18 mmol) and the reaction mixture was stirred at 0° C. for 15 min. 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinoyl chloride (1 g, 3.18 mmol) (prepared by treatment of carboxylic acid with thionyl chloride) dissolved in 10 mL of DCM was then added to the reaction mixture and the reaction was stirred at rt for 10 h. The reaction was quenched by addition of water (50 mL) and the solution was extracted with DCM (2×50 mL). The combined organic layers were washed with brine solution 50 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate in hexanes as eluant to yield 4-(4-chloro-2-fluoro-3-methoxyphenyl)-N-(4-methoxybenzyl)-2-methylnicotinamide (800 mg, 1.109 mmol, 35% yield) as a brown oil. LC/MS (ESI) m/e 415.1 [(M+H)+, calcd for C22H21ClFN2O3 415.1]; LC/MS retention time (method D): tR=0.78 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8]1)=[O:6].[CH:32](O)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([C:23]([O:25][CH:26]([CH3:32])[CH3:27])=[O:24])=[CH:8]1)=[O:6]
Reactant: CC(C)O
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21
Product: CC(C)OC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21

Procedure:
Ethyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding isopropyl ester using CU and isopropanol, and then oxidized as described previously in Step D of Example 63 to give the title compound; 1H-NMR (DMSO-d6): δ 10.83 (1H, s), 7.76 (1H, d), 7.71 (1H, app t), 7.64 (1H, s), 7.52-7.61 (2H, m), 7.40 (1H, m), 7.08 (1H, app t), 6.98 (1H, app t), 5.05 (1H, sept), 1.52 (6H, s), 1.18 (6H, d); MS (ESI): 439 (MH+).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.C([C:16]([CH2:21][OH:22])(CO)CC)O.[C:23]([O:28][CH3:29])(=[O:27])[C:24]([CH3:26])=[CH2:25].C1(=O)C=CC(=O)C=C1.C(OCCO)(=O)C(C)=C>>[NH2:8][C:9]([O:22][CH2:21][CH3:16])=[O:10].[C:23]([O:28][CH3:29])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: CCC(CO)(CO)CO
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCO
Agent: O=C1C=CC(=O)C=C1
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A U.V. curable urethane composition is prepared by heating 104.4 grams (0.6 moles) of tolylene diisocyanate to 70° C. and, while maintaining this temperature adding dropwise over 2 hours a homogeneous solution, also heated to 70° C., consisting of 26.8 grams of trimethylolpropane, 79.0 grams of methyl methacrylate and 0.02 grams p-benzoquinone. At the end of the reaction period, the product is maintained at 70° C. for an additional 6 hours. There is, thereafter, added dropwise 57.2 grams of 2-hydroxyethyl methacrylate over a period of one-half hour, after which the reaction is continued for an additional 10 hours, followed by the addition of 43 grams methyl methacrylate, to obtain a methyl methacrylate solution of a light yellow, transparent photopolymerizable prepolymer containing approximately 1.8% by weight of isocyanate groups.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][O:7][C:8]=1[CH3:9])(=O)[CH3:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[C:16]1([NH:22][N:23]=[C:1]([C:4]2[C:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:6][O:7][C:8]=2[CH3:9])[CH3:2])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1c(-c2ccccc2)noc1C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CC(=NNc1ccccc1)c1c(-c2ccccc2)noc1C

Procedure:
A mixture of 80.4 g. (0.4 mole) of 4-acetyl-5-methyl-3-phenyl isoxazole, 39.4 ml. (0.4 mole) of phenyl hydrazine and 500 mg. toluenesulfonic acid in 400 ml. ethanol is stirred at room temperature for 48 hours. The resulting solid is filtered and washed with cold ether to give 1-(5-methyl-3-phenyl-4-isoxazolyl)-1-ethanone phenyl hydrazone; m.p. 129°-133° C.