Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:13]=[C:12]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:10][C:8]=1[NH2:9])=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](O)=[O:41])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](=[O:41])[NH:9][C:8]3[CH:10]=[CH:11][C:12]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][C:7]=3[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23
Reactant: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 2-(2-methoxycarbonylethyl)-4-tert-butoxycarbonylaminomethylaniline (3.4 g), (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (2.80 g, 9.5 mmol), triethylamine (2.43 g, 24 mmol), and Bop-Cl (2.42 g, 9.5 mmol) in dichloromethane (40 mL) was stirred for 2 h at room temperature and diluted with ethyl acetate (800 mL). The mixture was washed with 5% potassium hydrogen sulfate, water, 1/15 phosphate buffer (pH 7.5), water, and brine, successively, dried over magnesium sulfate, and concentrated. The residue was recrystallized from acetone-ethyl acetate to give 3.22 g of the title compound. The mother liquid was concentrated and the residue was purified by silica gel column chromatography with ethyl acetate to 1% AcOH/ethyl acetate to give additionally 0.8 g of the title compound (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:14][CH:11]1[CH2:13][CH2:12]1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC1CC1
Product: Clc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedures B and D from 2-chlorobenzoyl chloride and cyclopropylamine.
Reaction SMILES: C([O:3][CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)C.C(O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)C.C(OCC)(=O)C.Cl>[NH:22]1[C:4](=[O:3])[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][N:21]=[CH:20]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc[nH]c1=O
Temperature: 25 °C

Procedure:
Diethyl ethoxymethylenemalonate (10.1 mL, 50 mmole) and formamidine acetate (10.4 g, 100 mmole) were refluxed in ethanol (10 mL) for 24 hours. The reaction mixture was allowed to cool to room temperature overnight, and suspended in ethyl acetate (30 mL) and 1.0N HCl (20 mL). The suspension was filtered, and the filter cake was washed with 1.0N HCl, followed by water, then ethyl acetate, and air dried affording the title compound as an tan:solid (3.33 g, 40% yield). Rf=0.21 (silica gel, 10% methanol in dichloromethane); m.p. 187-188° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]1[C:19](=[O:20])[CH2:18][NH:17][C:16](=[O:21])[CH:15]=[C:10]12)[CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]1[C:19](=[O:20])[CH2:18][NH:17][C:16](=[O:21])[CH:15]=[C:10]12)(=[O:1])[CH2:3][CH3:4]
Reactant: CCC(O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
124-2. A solution of 9-(1-hydroxypropyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (231 mg, 0.78 mmol) in DCM (40 mL) was treated with Dess-Martin periodinane (365 mg, 0.86 mmol) and the mixture was stirred at RT for 2 h. The reaction mixture was then poured onto a saturated aq. solution of NaHCO3 and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH 95:5) gave the title compound (225 mg). UPLC-MS: MS 285.2 (M+H+); UPLC rt 0.68 min.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:2][O:16]2)=[CH:13][CH:14]=1
Reactant: C[S+](C)C
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(C2(c3ccccc3)CO2)cc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
To a stirring solution of trimethylsulfonium iodide (5.27 g, 19.15 mmol) in THF (20 mL) was added sodium hydride (0.957 g, 23.94 mmol) and the reaction mixture was stirred at 55° C. for 6 h. A solution of (4-bromophenyl)(phenyl)methanone 50 (5.0 g, 19.15 mmol) in THF (10 mL) was added and the mixture was stirred an additional 16 h at 55° C. The reaction mixture was quenched with water, diluted with ether and layer separated. The organic layer was dried over Na2SO4, filtered and concentrated to afford 2-(4-bromophenyl)-2-phenyloxirane 51 (quantitative yield) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1O)[C:32]([O:34][CH3:35])=[O:33].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][C:38]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:29]([Cl:28])[CH:30]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl 3-chloro-4-hydroxybenzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White foam (81%). MS (Turbo Spray): m/z=559.1 [M+H].
Reaction SMILES: C1(P(CC2C(CP(C3C=CC=CC=3)C3C=CC=CC=3)C3CC2CC3)C2C=CC=CC=2)C=CC=CC=1.[CH:36]1[CH:37]=[CH:38][C:39]([CH:42]2[N:49]=[C:48]3[N:44]([CH2:45][CH2:46][S:47]3)[CH2:43]2)=[CH:40][CH:41]=1>[Rh].PP>[CH:36]1[CH:41]=[CH:40][C:39]([C@@H:42]2[N:49]=[C:48]3[N:44]([CH2:45][CH2:46][S:47]3)[CH2:43]2)=[CH:38][CH:37]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Agent: [Rh]
Agent: PP
Agent: c1ccc(P(CC2C3CCC(C3)C2CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1

Procedure:
The utility of the compound of this invention: chiral-2,3-Bis(diphenylphosphinomethyl)bicyclo[2.2.1]heptane is as an intermediate in the manufacture of a chiral rhodium-diphosphine catalyst which is useful in the reduction of a tetramisole precursor to give a significant excess of the desired S-(-) isomer, levamisole. The chiral rhodium-diphosphine catalyst and the process of using the catalyst in the reduction of the tetramisole precursor is also novel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C@H:22]3[CH2:26][O:25]C(C)(C)[O:23]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C@H:22]([OH:23])[CH2:26][OH:25])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC1(C)OC[C@H](c2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)O1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc([C@H](O)CO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-propionamide (8.85 g, 17.4 mmol) in tetrahydrofuran (50 mL) was treated with a 1N aqueous hydrochloric acid solution (50 mL). The resulting milky reaction mixture was stirred at 25° C., and within 15 min, the milky reaction mixture became clear. The stirring was continued at 25° C. for 16 h. The reaction was concentrated in vacuo, and the residue was extracted with methylene chloride (1×100 mL then 2×50 mL). Each organic extract was washed with a saturated aqueous sodium bicarbonate solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/1 ethyl acetate/hexanes then 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1(S),2-dihydroxy-ethyl)-pyrazin-2-yl]-propionamide (7.15 g, 88%) as a colorless foam: (ES)+-HRMS m/e calcd for C21H26ClN3O5S (M+H)+ 468.1355, found 468.1360.
Reaction SMILES: [H][H].[CH3:3][N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([N+:16]([O-])=O)=[C:13]([NH2:15])[CH:14]=1>C(O)C.[Pd]>[CH3:20][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][C:10]=1[F:19]
Reactant: CN(C)CCCOc1cc(N)c([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCOc1cc(N)c(N)cc1F
Yield: 90.6 %

Procedure:
In a 25 ml autoclave, dissolve 350 mg of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitrophenylamine, obtained in the previous stage, in 20 ml of ethanol, add 40 mg of 10% palladium-on-charcoal and then subject to an initial hydrogen pressure of 1 bar at 20° C. for 16 hours. After cooling, the volume of hydrogen absorbed is 123 ml. After filtration of the catalyst and then concentration to dryness under reduced pressure, we obtain 280 mg of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine, in the form of a viscous black oil, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.B>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(CO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of 2-(4-bromophenyl)propanoic acid (2 g, crude) in tetrahydrofuran (50 mL) was added a solution of borane in tetrahydrofuran (1 mmol/L, 13 mL, 13 mmol) at 0° C. The mixture solution was stirred for 3 hours at 0° C., then worm to room temperature, and quenched by water. The solvent was removed, purified by column chromatography (silica-gel, petroleum:ethyl acetate=5:1) to give 2-(4-bromophenyl)propan-1-ol as a colorless oil (1.8 g, 96%). 1H NMR (300 MHz, CDCl3): δ 1.7.38-7.46 (m, 2H), 7.10-7.13 (m, 2H), 3.72-3.78 (m, 2H), 2.84-2.98 (m, 1H), 1.23-1.27 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:35][C:36]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][Si](C)(C)C)=[CH:43][C:37]=1[CH2:38][NH:39][C:40](=[O:42])[CH3:41]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[C:14]([C:13]1[CH:16]=[C:9]([C:48]#[C:47][C:44]2[CH:45]=[CH:46][C:36]([F:35])=[C:37]([CH:43]=2)[CH2:38][NH:39][C:40](=[O:42])[CH3:41])[CH:10]=[N:11][CH:12]=1)#[N:15]
Reactant: CC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1F
Reactant: N#Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 60 °C
Yield: 41.6 %

Procedure:
Add zinc (II) bromide (313 mg, 1.20 mmol), triethylamine (0.67 mL, 4.80 mmol), 5-bromonicotinonitrile (183 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.050 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (2.0 mL) in tetrahydrofuran to a solution of N-(2-fluoro-5-trimethylsilanylethynylbenzyl) -acetamide, (prepared as described in PREPARATION 31), (289 mg, 1.10 mmol) in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. Heat to 60° C. for 5 h, cool to room temperature, and filter through diatomaceous earth. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 50:50 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (122 mg, 42%).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39](=[O:43])(=[O:42])[NH:40][CH3:41])[CH:20]=1.N1C=CC=CC=1C1C=CC=CN=1>CN1C(=O)CCC1.ClCCl.[Cu-]=O>[C:27]([O:26][C:25]([NH:24][CH2:23][C:22]1[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39]([N:40]([C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH3:41])(=[O:43])=[O:42])=[O:31])([CH3:30])([CH3:28])[CH3:29]
Reactant: CNS(=O)(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OC
Agent: O=[Cu-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCOc2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OC
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of methyl 5-bromo-8-methoxy-1,6-naphthyridine-7-carboxylate (2.4 mmol), tert-butyl 4-fluoro-2-(4-(N-methylsulfamoyl)butoxy)benzylcarbamate (Example 19; 2.6 mmol), 2,2′-bipyridine (3.1 mmol) and copper (I) oxide (3.1 mmol) in NMP (30 ml) was stirred at 120° C. under nitrogen atmosphere for 10 hours. The reaction mixture was diluted with dichloromethane and filtered off. The filtrate was washed with 10% 2-[2-(bis(carboxylatomethyl)amino)ethyl-(carboxylatomethyl)amino]acetate (EDTA) disodium salt solution, saturated NaHCO3 solution and brine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (83 mg, 86%), MS (ISP) m/z=386.4 [(M+H)+], mp 230.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH2:18]CC)[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:21])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[F:62][CH2:63][CH2:64][C:65]([CH3:69])([NH2:68])[CH2:66][NH2:67].C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(#N)C>[NH2:68][C:65]([CH3:69])([CH2:64][CH2:63][F:62])[CH2:66][NH:67][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:7][C:8]([CH3:21])=[CH:9][C:10]=12)=[O:16]
Reactant: CCCc1nn2c(OCc3c(F)cccc3F)cc(C)cc2c1C(=O)O
Reactant: CC(N)(CN)CCF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC(C)(N)CCF)c2c1
Reaction time: 0.33 h

Procedure:
200 mg (0.45 mmol, about 75% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-methyl-2-propylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged together with 274 mg (0.72 mmol) of HATU and 0.42 ml (2.41 mmol) of N,N-diisopropylethylamine in 2.8 ml of DMF, and the mixture was stirred for 20 min. A solution of 330 mg (1.27 mmol assuming a purity of about 75%) of rac-4-fluoro-2-methylbutane-1,2-diamine dihydrochloride from Example 86A in 1.4 ml of DMF and 0.63 ml (3.61 mmol) of N,N-diisopropylethylamine was added to the first reaction mixture and the mixture was stirred at RT for 1 h. The reaction solution was admixed with acetonitrile, water and TFA and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined and concentrated. Subsequently, the residue was taken up in dichloromethane and a little methanol, and washed twice with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. 75 mg of the target compound were obtained (37% of theory, 98% purity).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[Cl:15].Cl>O>[Cl:15][C:7]1[CH:8]=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=[CH:11][C:6]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(=O)c1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A solution of sodium nitrite (1.63 g) in water (4.3 ml) was added dropwise to a solution of 4'-amino-3'-chloroacetophenone (2.5 g) and concentrated hydrochloric acid (5.5 ml) in water (5.5 ml) at 0° to 3° C., and the solution was stirred for 15 minutes at 0° C. The resulting solution was added portionwise to a mixture of sodium nitrite (7.3 g) and cuprous oxide (0.76 g) in water (32 ml) at -5° to 0° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature, and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (60 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure to give pale yellow crystals of 3'-chloro-4'-nitroacetophenone (2.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[CH2:9].[H-].[Na+].[C:18]1([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH2:9])=[CH:30][CH:31]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(Cn1ccnc1)c1ccccc1O
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cn1ccnc1)c1ccccc1OCc1ccc(-c2ccccc2)cc1

Procedure:
2-(2-Hydroxyphenyl)-3-(imidazol-1-yl)-1-propene (400 mg, 2.0 mmole) was dissolved in dimethylformamide (5 ml) and sodium hydride (60% dispersion in oil)(110 mg, 2.75 mmole) was added to the solution with stirring and ice-cooling. After stirring for additional 30 minutes, 4-phenylbenzylchloride (490 mg, 2.42 mmole) was added and the mixture was stirred overnight at room temperature. Then, the mixture was poured into water (50 ml) and extracted with diethyl ether (75 ml×2). The extract was washed with water (50 ml×2) and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was subjected to chromatography on a silica gel column and eluted with methylene chloride/methanol to obtain the title compound (0.41 g, 55.9%), m.p. 90°-92° C. (recrystallized from ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=S)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[NH:3][C:2]([CH3:14])([CH3:1])[CH2:8][C:7]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: CC1(C)CC(=S)Nc2ccccc2N1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1NC(C)(C)C2
Temperature: 130 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A disposable tube was charged with 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (600 mg, 2.91 mmol) and a stirbar. nBuOH (30 mL) was added, followed by acetohydrazide (431 mg, 5.82 mmol), and the solution was stirred at 130° C. overnight. The solution was concentrated with celite and purified by silica gel chromatography (eluting with methylene chloride/methanol/ammonium hydroxide) to yield 1,5,5-trimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white amorphous solid (0.153 g, 0.67 mmol, 23%).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH2:13][C:14]([N-:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:12]>>[CH2:17]([NH:16][C:14](/[C:13](=[CH:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)/[C:11]#[N:12])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Reactant: O=CC=Cc1ccccc1
Product: N#C/C(=C\C=C\c1ccccc1)C(=O)NCc1ccccc1

Procedure:
The compound was prepared as described in Example 3 by adding cinnamaldehyde (0.048 ml, 0.38 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.066 g, 0.38 mmol). After refluxing for 1 h and recrystallization from ethanol a white solid was obtained (0.074 g, 68%). The product gave the following analytical data:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:2])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[C:13](=[O:24])[NH:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1
Yield: 41.7 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4,6-dichloro-2-[2-(4-methoxy-phenyl)-propionylamino]-benzoic acid methyl ester (1.44 g, 3.77 mmol) and LiHMDS (11.0 mmol, 1M solution in THF). After normal workup, the pure objective compound (0.55 g, 42%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.52 (s, 3H, CH3), 3.67 (s, 3H, CO2CH3), 6.89 (d, J=8.9 Hz, 2H, ArH), 6.99-7.08 (m, 3H, ArH), 7.23 (d, J=1.9 Hz, 1H, ArH), 11.25 (s, 1H, NH); m.p. 210-212° C.; MS(EI) m/e 349 [M+], 162, 134; HRMS m/e cacld. for C17H13NO3Cl2 349.0272, found 349.0278.