Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=O)c1ccc(O)nc1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)nc1C
Temperature: 150 °C

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([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)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)(=O)=O)=CC=1>>[CH:54]1([CH2:53][N:31]2[C:30]3[CH2:29][CH2:28][CH:27]([CH2:26][C:3]4[N:4]=[CH:5][N:6]([C:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:2]=4[CH3:1])[C:39](=[O:40])[C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CC2CCc3c(c4ccccc4n3CC3CCCC3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
Using the procedures described above for Intermediate 10, 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) was treated with sodium hydride (73% dispersion in oil; 38 mg) and was then stirred with cyclopentanemethanol (p-toluenesulphonate) (292 mg) for 24 h. Work up and FCC as described above gave the title compound (283 mg), m.p. 177°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[C:4]([F:25])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23]([CH3:24])=[O:34])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[C:4]([F:25])[CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.16 mmol) of the compound from Example 6 were introduced into 2 ml of dichloromethane at 0° C., 40.7 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29 mg (46% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=O)[O:10][N:9]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].CN(C)C=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[N:12]=1
Reactant: Cc1ccc(-c2noc(=O)[nH]2)cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(Cl)n2)cc1[N+](=O)[O-]

Procedure:
To a solution of 3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one (106) (12 g, 54.26 mmol) in POCl3 (120 mL) was added N,N-dimethylformamide (12 mL). The resulted solution was heated to reflux for 72 hours then concentrated under vacuum. The residue was dissolved in water (250 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine (3×250 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (PE/EA=10:1) to afford 5-chloro-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (107) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.64 (dd, J=1.5, 8.4 Hz, 1H), 8.18 (dd, J=1.5, 7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 2.70 (s, 3H). MS m/z 240.7 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[NH:1][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CC(=O)Cc1ccc(Cl)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Cc1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(3-Amino-4-chloro-phenyl)-propan-2-one (Intermediate D) (0.5 g, 2.73 mmol) in DCM (2 ml) and pyridine (1 ml) is added drop wise methanesulfonyl chloride (0.34 g, 0.23 ml, 3.0 mmol) at 0° C. (ice-bath). The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The solvents are removed in vacuo and the residue is dissolved in EtOAc and washed with water, the organic portion is dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica eluting with EtOAc affords the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 200 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 1) (2.28 g, 8.05 mmol) and 6-chloronicotinonitrile (2.231 g, 16.10 mmol) was added NMP (20 mL) and the mixture treated with DIPEA (4.22 mL, 24.16 mmol). The mixture was split between 2 flasks and each flask was flushed with nitrogen, sealed and stirred under microwave irradiation at 200° C. for 2 h. The reaction mixtures were combined and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×4) and the combined organic layers were washed with water (×3), then brine and were dried (MgSO4) filtered and concentrated in vacuo. The brown solid residue was purified by chromatography (EtOAc in Hexanes gradient) to give 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (1.940 g, 5.04 mmol, 62.5% yield) as a pale yellow foam. LCMS (HpH, 2 min), Rt=1.02 min, MH+=386 (1 Br).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:34]([C:31]2([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:32][CH2:33]2)=[O:35])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)[C@H]2CN[C@H](C(=O)NC3(C#N)CC3)C2)cc1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(N4CCCCC4)CC3)C2)cc1
Yield: 40 %

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-tosylpyrrolidine-2-carboxamide 7G with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)-4-tosylpyrrolidine-2-carboxamide as a light yellow solid (40%). MS ISP (m/e): 485.4 (100) [(M+H)]+.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=2)=[O:28])=[CH:15][CH:14]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Agent: Cl
Product: Cc1ccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2)cc1
Yield: 71.1 %

Procedure:
In a manner similar to that described in Example 163, 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and para-tolyl isocyanate (0.047 mL, 0.377 mmol) were reacted to give the title compound as a white solid (64 mg, 71%). 1H NMR (DMSO-d6) δ: 8.42 (s, 2H), 8.34 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.29-7.34 (m, 4H), 7.17 (d, J=5.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.95-7.02 (m, 2H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.9 Hz, 2H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2O.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: COc1cccc2c1CCCC2O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1CCCC2n1cncc1C(=O)OC(C)C

Procedure:
To a suspension of 5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol (0.150 g, 0.842 mmol) and isopropyl 4-imidazolecarboxylate (0.087 g, 0.564 mmol), which can be prepared as described in Example 1, in THF (5 mL) at 0° C. is added triphenylphosphine (0.221 g, 0.842 mmol) followed by diisopropyl azodicarboxylate (94%, 0.181 g, 0.842 mmol). After 1 hour the mixture is diluted with ethyl acetate and extracted twice with 1M aqueous HCl. The aqueous phase is basified to a pH of ca. 9 with 2M aqueous NaOH and is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to give a colorless residue, which is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 99:1) to give 3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 315.1 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.44 (d, J=6.3 Hz, 3 H), 1.45 (d, J=6.0 Hz, 3 H), 1.62-1.72 (m, 1 H), 1.90-1.97 (m, 1 H), 2.26-2.34 (m, 2 H), 2.66-2.74 (m, 1 H), 2.95-3.02 (m, 1 H), 3.92 (s, 3 H), 5.30-5.40 (m, 1 H), 6.53 (t, J=4.7 Hz, 1 H), 6.74 (d, J=8.0 Hz, 1 H), 7.02 (d, J=8.0 Hz, 1 H), 7.27 (t, J=8.0 Hz, 1 H), 8.32 (s, 1 H), 8.56 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](Cl)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=4[N+:19]([O-:21])=[O:20])=[CH:6][CH:7]=3)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(N)cc2)s1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A suspension of the product of Example 430B (0.500 g, 1.541 mmol) and 9-fluorenylmethoxycarbonyl chloride (0.478 g, 1.849 mmol) in methylene chloride (10 mL) under a nitrogen atmosphere was treated with pyridine (0.25 mL, 3.083 mmol), and the resulting solution stirred for 18 hours at room temperature. The reaction was diluted with methylene chloride (50 mL) and washed with 1N aqueous HCl (50 mL) then water (50 mL). The organic was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with methylene chloride afforded the title compound as a bright yellow solid (0.842 g, quantitative). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.23 (t, J=7.17 Hz, 3 H) 4.24 (q, J=7.23 Hz, 2 H) 4.35 (t, J=6.43 Hz, 1 H) 4.57 (d, J=6.25 Hz, 2 H) 7.29-7.50 (m, 4 H) 7.69 (s, 4 H) 7.77 (d, J=7.35 Hz, 2 H) 7.92 (d, J=7.35 Hz, 2 H) 8.11 (s, 1 H) 10.15 (s, 1 H); MS (ESI+) m/z 564 (M+NH4)+, 569 (M+Na)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1Cl>>[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1[N:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=S(=O)(c1ccc2ccccc2n1)C1CCNCC1
Product: O=S(=O)(c1ccc2ccccc2n1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 15.8 %

Procedure:
Using the procedure from Example 7A, Step 7E, 2-(piperidin-4-ylsulfonyl)quinoline (150 mg, 0.51 mmol) was reacted with 3,4,5-trichloropyridine (182 mg, 1.0 mmol) to afford the title compound (34 mg), an off-white solid, in 16% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=S)=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:18][NH2:19])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (1.50 g, 0.00485 mol) and a 1 M solution of hydrazine in tetrahydrofuran (6.3 mL, 0.0063 mol) were heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. Additional 3 mL of a 1M solution of hydrazine in tetrahydrofuran was added and the stirring at reflux was continued for another 6 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated to yield N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.54 g, 0.0050 mol) as a tan solid. TLC (ethyl acetate/heptane 1:3) Rf 0.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[C:22](=O)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36].B.C1COCC1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH:15]=[C:16]([CH:19]3[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CCN1CCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCC1=O
Agent: B
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN1CCCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-(1-ethyl-2-oxoazepan-5-yl)-3,4-dihydro-2(1H)-quinazolinone (EXAMPLE 78) (9.7 mg, 0.018 mmol) in THF (0.2 mL) under N2 atmosphere was added BH3.THF (88 μL, 1.0M solution in THF). The reaction was stirred at RT overnight. The solvent was removed in vacuo, and the residue was dissolved in CH2Cl2. The resulting solution was washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the residue was re-dissolved in CH2Cl2 (0.5 mL) then cooled down to 0° C. To this was added Et3SiH (3 μL, 0.036 mmol) followed by BF3.Et2O (2.5 μL, 0.04 mmol), and the mixture was slowly warmed to RT over 2 hours. It was quenched with saturated solution of NaHCO3, then extracted with CH2Cl2 three times. The combined extracts were washed with brine and dried over Na2SO4. The crude residue was purified by preparative TLC eluting with 5% 2M NH3 in MeOH(CH2Cl2 to obtain 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-ethylazepan-5-yl)-3,4-dihydro-2(1H)-quinazolinone. 1H NMR (CDCl3, 500 MHz): selected data δ 1.03 (t, J=7.1 Hz, 3H), 1.6-1.87 (m, 6H), 2.52 (q, J=7.1 Hz, 2H), 2.56-2.73 (m, 5H). MS(ES) 530 (M+H); LC 1: 2.36 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 12a using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3) and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) as starting materials; MS (EI) 302.0 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:8])[CH3:7].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].O>CCOCC>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])=[O:20])([CH3:8])[CH3:7]
Reactant: CC(C)c1ccccc1Br
Reactant: CCN(CC)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
n-Butyllithium (2.5M, 100 mL) was added with stirring under nitrogen at 0°-5° C. during ten minutes to a solution of 2-isopropylbromobenzene in anhydrous ether (500 mL). The mixture was allowed to warm to room temperature, stirred at room temperature for six hours, and cooled to -60° C. A solution of diethylcarbamyl chloride (34 g) in anhydrous ether (50 mL) was added during 20 minutes while maintaining the temperature below -50° C. The temperature was allowed to rise to room temperature during one hour. Water (100 mL) was added. The ether layer was washed with saturated aqueous sodium chloride (200 mL), dried over magnesium sulfate and stripped of ether. Distillation of the residue (80°-90° C./0.1 mm Hg) gave 2-isopropyl-N,N-diethylbenzamide (44 g, 80% yield).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[CH:25]=[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[CH:25]=[C:13]2[C:14]([C@@H:18]3[CH2:4][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.64 g, 41.0 mmol) in dimethyl sulfoxide (30 mi.') was added trimethylsulfoxonium iodide (9.01 g, 41.0 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methylpyrazolo[1,5-a]pyridin-4-yl)acrylate (7.86 g, 34.1 mmol) in dimethyl sulfoxide (120 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (5.10 g, yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][N:23]=1.ClC1C=C[C:35]([NH:38]C(=O)C2C=CC(C(F)(F)F)=NC=2C)=CC=1C1C=CC(C(O)=O)=CN=1.Cl.CN>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:27])[NH:38][CH3:35])=[CH:24][N:23]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cn2)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)[O-])cn2)c1
Agent: CN
Agent: Cl
Product: CNC(=O)c1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
120 mg of 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate was hydrolyzed via Procedure M. 112 mg of 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinic acid was coupled to Methylamine Hydrochloride via Procedure G and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(methylcarbamoyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 449 (M)+.