Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si:16]([CH3:28])([CH3:27])[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH2:24][C:23]([CH3:26])=[CH:22]2>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][Si:16]([CH3:27])([CH3:28])[C:17]2[CH:18]=[CH:19][CH2:20][C:21]3[C:25]=2[CH:24]=[C:23]([CH3:26])[CH:22]=3)[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CC1=Cc2cccc([Si](C)(C)Cl)c2C1
Reactant: Cc1cc(C)cc(N)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=CC2=C([Si](C)(C)Nc3cc(C)cc(C)c3)C=CCC2=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4.54 g (37.5 mmol) of 3,5-dimethylaniline in 110 mL of THF 15.0 mL (37.5 mmol) of 2.5 M nBuLi in hexanes was added at 0° C. This mixture was additionally stirred for 4 hours at room temperature, then cooled to −40° C., and a solution of 8.35 g (37.5 mmol) of chloro(dimethyl)(2-methyl-1H-inden-7-yl)silane in 70 mL of THF was added in one portion. The resulting mixture was stirred for 12 hours at room temperature and then evaporated to dryness. To the residue 100 mL of ether was added, and the obtained suspension was stirred for 20 minutes, and then filtered through glass frit (G3). The precipitate was additionally washed with 2×100 mL of ether. The combined filtrate was evaporated to dryness, and the residue was washed with 3×7 mL of cold hexanes and then dried in vacuum. Yield 7.26 g (63%) of white solid. 1H NMR (C6D6): δ 7.50 (dd, J=6.5 Hz, J=2.1 Hz, 1H, 6-H in indenyl), 7.24-7.30 (m, 2H, 4,5-H in indenyl), 6.35 (m, 2H, 3-H in indenyl and 4-H in 3,5-Me2C6H3), 6.27 (s, 2H, 2,6-H in 3,5-Me2C6H3), 3.27 (s, 2H, 1,1′-H in indenyl), 3.24 (s, 1H, NH), 2.08 (s, 6H, 3,5-Me in 3,5-Me2C6H3), 1.83 (s, 3H, 2-Me in indenyl), 0.45 (s, 6H, SiMe2). Anal. Calc. for C20H25NSi: C, 78.12; H, 8.19; N, 4.55%. Found: C, 78.41; H, 8.00; N, 4.38%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Br)[CH:5]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16](B2OC(C)(C)C(C)(C)O2)[C:15]([CH3:28])=[N:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:16]1[C:15]([CH3:28])=[N:14][N:13]([CH3:12])[C:17]=1[CH3:18]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccncc1-c1c(C)nn(C)c1C
Temperature: 80 °C
Yield: 40.2 %

Procedure:
To a microwave reactor tube was added 2-bromo-isonicotinic acid methyl ester (150 mg, 0.69 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (197 mg, 0.83 mmol) and Pd2(PtBu3)2(14 mg, 0.028 mmol) and 1,4-dioxane (2 mL). The mixture was degassed and then 2M aqueous K3PO4 (0.46 mL, 1.4 mmol) was added. The mixture was heated in a microwave reactor at 80° C. for 1 hour. The cooled mixture was partitioned between CHCl3 and water. The organic layer was isolated and the product purified by SiO2 chromatography (0-15% MeOH in EtOAc) to give 2-(1,3,5-trimethyl-1H-pyrazol-4-yl-isonicotinic acid methyl ester (68 mg, 21%) as a yellow gum. MS(ESI) m/z 246 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>>[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:18])=[CH:13][CH:12]=1
Reactant: NC1CCc2ccccc21
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)NC2CCc3ccccc32)cc1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (5.0 g, 37.6 mmole) and p-toluoyl chloride (5.2 g, 33.8 mmole) as in Ex. 52; 4.8 g (19.1 mmole, 57%), mp: 140° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[N:4]=[C:5]([O:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 160 °C

Procedure:
A mixture of (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1.61 g, 4.74 mmol) and ethyl hydrazinecarboxylate (1.482 g, 14.23 mmol) in NMP (8 mL) was heated at 160° C. overnight. The reaction mixture was diluted with EtOAc and washed with water (2×). The aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound as a pale oil, which was used without further purification. ESI-MS m/z [M+H-tert-butyl]+ 342.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[C:14]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)[C:13]=1[CH3:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[C:14]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)[C:13]=2[CH3:31])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(Br)c3)c2C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A screwcap vial was charged with a solution of 5-bromopyridin-3-amine (273 mg, 1.58 mmol) in dry DMF (8 mL) under nitrogen. To this stirring solution was slowly added sodium hydride (63.0 mg, 1.58 mmol), followed 5 min later by 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (400 mg, 1.31 mmol). The reaction mixture was then stirred at rt for 6 h. Additional portions of sodium hydride (1.2 equivalents) were added after 2 and 4 h of stirring. Upon completion, the reaction was quenched with 10% aq. sodium carbonate and the product was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, and cond. The resulting crude residue was purified by flash-chromatography (silica gel, 0-60% EtOAc in hexanes) and subsequently by recrystallization in MeOH. This afforded N-(5-bromopyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=441.0 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH3:65])[CH2:45]2)[CH:7]([CH3:67])[CH2:6][CH2:5][C:4]1=[O:68])[CH3:2].[N-:69]=[N+:70]=[N-:71].[Na+].O>CN(C=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:69]=[N+:70]=[N-:71])[CH:46]([O:63][CH2:64][CH3:65])[CH2:45]2)[CH:7]([CH3:67])[CH2:6][CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 80 °C

Procedure:
To a stirred solution of 17-ethyl-1-hydroxy-12-[2'-[4"-(2"'-nitrobenzenesulfonyloxy)-3"-ethoxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (87 mg, Example 47) in dry DMF (1 ml) is added sodium azide (16.7 mg) in one portion. The reaction is heated at 80° C. under nitrogen atmosphere for 3 h. The reaction mixture is cooled, poured into water (5 ml) and extracted with ethyl acetate. Normal work-up followed by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][S:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:29])=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][S:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:29])=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(SCc2ccccc2OCc2ccccc2)cc1

Procedure:
4-[2-benzyloxybenzylthio]benzoic acid (6.3 g) and oxalyl chloride (2.26 g) were stirred in dichloromethane (100 ml) for 18 hours. The solvent was evaporated to give 4-[2-benzyloxybenzylthio]benzoylchloride which was dissolved in dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([C:30]1[S:34][C:33]([NH2:35])=[N:32][N:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C:30]1[S:34][C:33]([NH:35][C:18]([C:17]2[CH:21]=[CH:22][C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[CH:15][CH:16]=2)=[O:19])=[N:32][N:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1nnc(Cc2ccccc2)s1
Product: CC(C)(C)OC(=O)C1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1

Procedure:
This compound is obtained according to Preparation 11.5. 85 mg of tert-butyl 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexanecarboxylate are obtained from 4-(4-tert-butoxycarbonylcyclohexyl)benzoic acid and 5-benzyl-1,3,4-thiadiazol-2-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([N:17]([CH3:31])[CH2:18][CH2:19][CH2:20]/[C:21](/[CH3:30])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:29])=[CH:26]/[CH:27]=[O:28])[CH:15]=[CH2:16]>C1COCC1.CCCCCC>[CH2:14]([N:17]([CH3:31])[CH2:18][CH2:19][CH2:20]/[C:21](/[CH3:30])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:29])=[CH:26]/[CH:27]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1)[OH:28])[CH:15]=[CH2:16]
Reactant: C=CCN(C)CCC/C(C)=C/CC/C(C)=C/C=O
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCN(C)CCC/C(C)=C/CC/C(C)=C/C(O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A solution of 6.4 g of 1,4-dibromobenzene in 50 ml of absolute THF is cooled -78° C. and treated within 30 min. with 15.3 ml of 1.6M butyllithium in hexane. After 1 hr. 3.0 g of (2E,6E)-10-(allyl-methyl-amino)-3,7-dimethyl-deca-2,6-dienal (Ex. 57.1.A) in 12 ml of THF are added dropwise. After 1 1/2 hr. at -78° C. the bath is removed until the suspension has dissolved. Subsequently, 4.5 ml of acetic acid in 6 ml of ether are added dropwise at -78° C. Then, the mixture is poured into saturated ammonium chloride solution/ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and 10% sodium chloride solution, dried and evaporated. After silica gel chromatography with methylene chloride/methanol (95:5) there are obtained 1.14 g of (2E,6E)-(RS)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-deca-2,6-dien-1-ol. This is dissolved in ethanol with 0.29 g of fumaric acid, evaporated and converted with ethyl acetate/ether into 0.91 g of (2E,6E)-(RS)-10-(allyl-methyl-amino)-1-(4-brom-phenyl)-3,7-dimethyl-deca-2,6-dien-1-ol.fumarate (1:1), MS: m/e 406 (M+H+, 1Br).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.Cl.[CH:17]([NH:20][NH2:21])([CH3:19])[CH3:18]>CCO>[CH:17]([N:20]1[C:6]([CH:4]2[CH2:5][C:2](=[CH2:1])[CH2:3]2)=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:21]1)([CH3:19])[CH3:18]
Reactant: C=C1CC(C(=O)CC(=O)C(=O)OCC)C1
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Product: C=C1CC(c2cc(C(=O)OCC)nn2C(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 8b (6.29 g, 29.9 mmol) was dissolved in dry EtOH (65 mL, denaturated with 5% of MeOH) and isopropyl hydrazine hydrochloride (3.97 g, 35.9 mmol) was added. The reaction mixture was stirred for 3 h at rt. The solvent was removed and to the oily residue were added EA (100 mL), water (50 mL) and sat. NaHCO3 (50 mL) sequentially. The layers were separated and the aq. phase was re-extracted with EA (50 mL). The combined organic phases were washed with brine (70 mL) and dried over anh. Na2SO4. The solvent was removed under vacuum and the residue was dried under reduced pressure. Yield: 7.23 g (contains 3.4% of EtOAc by NMR, recalculated pure yield: 6.98 g, 94%). Crude product 8c is 98% pure by HPLC and NMR. 1H-NMR (CDCl3), δ (ppm): 6.62 (s, 1H), 4.88-4.82 (m, 2H), 4.42-4.32 (m, 3H), 3.56-3.45 (m, 1H), 3.17-3.07 (m, 2H), 2.88-2.79 (m, 2H), 1.49 (d, J=8.0 Hz, 6H), 1.37 (t, J=8.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (0.850 g, 3.4 mmol), Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in 1, 2 dichloroethane (10 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[C:3]1=[N:9]O.C(=O)([O-])[O-:12].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:9][C:3]1=[O:12]
Reactant: C[C@@H]1CCC[C@H](C)C1=NO
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)C(=O)N1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Into 40 ml of xylene were added 3.1 g of cis-2,6-dimethylcyclohexanone oxime and 12 g of polyphosphoric acid, the mixture was stirred for 10 hours at 100° C. The reaction mixture was cooled to near room temperature, poured into ice-water. Sodium carbonate was added to the mixture, and the mixture was extracted with ethyl acetate three times. The organic layers was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.5 g of cis-3,7-dimethylhexahydro-1H-azepine-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:8]>C(OCC)(=O)C.CO>[CH3:8][N:7]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:6][CH2:5][O:4][C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[CH3:1]
Reactant: Cc1ccccc1OCCN(C)CCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1OCCN(C)CCc1ccc(N)cc1

Procedure:
The title compound is prepared as described in Example 7, except that N-[2-(2-methylphenoxy)ethyl]-N-methyl-2-(4-nitrophenyl)ethylamine (Example 3) is used as starting material to obtain a yield of 82% of the base (oil), Rf=0.35 (ethyl acetate/methanol=9:1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:23][OH:24])=[CH:17][C:16]=3[F:25])=[O:11])=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([F:25])[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=3)[N:14]([CH2:29][CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:13]=2)=[O:11])=[CH:26][CH:27]=1
Reactant: BrCCCOC1CCCCO1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CO)cc2c1O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCOC2CCCCO2)c2c(F)cc(CO)cc2c1=O
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 24 %

Procedure:
To a suspension of NaH (60% dispersion in oil, 11.1 mg) in 2.5 mL anhydrous DMF is added N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Preparation No. 7 (100 mg). After stirring the reaction mixture at room temperature for 15-20 min., 2-(3-bromopropoxy)tetrahydro-2H-pyran (89.4 mg) is added. The reaction is stirred at room temperature for 3 days. The reaction mixture is treated with saturated aqueous NaHCO3, then extracted with CH2Cl2 (3×). The combined organic layers are washed with 15% K2CO3 and H2O (2×), dried over Na2SO4, and condensed to obtain a yellow residue. The residue is chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 34.0 mg (24%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:21](OC)=[O:22])[CH:15]=[CH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[NH2:26][OH:27].C(O)(=O)C>CO>[CH2:1]([NH:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:21]([NH:26][OH:27])=[O:22])[CH:15]=[CH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Reactant: NO
Agent: [K]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NO)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 13 h
Yield: 36 %

Procedure:
To a vial containing methyl 6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH) and the resulting mixture was shaken at rt for 13 h. The solution was quenched with acetic acid (0.200 mL, 3.52 mmol) before being concentrated. To the resulting residue was added DMSO (1.2 mL) and it was purified via prep-HPLC to yield N6-benzyl-N2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5 H)-dicarboxamide (0.0113 g, 36.0%). LC-MS: (FA) ES+ 327; 1H NMR (Methanol-d4, 400 MHz) δ 7.86 (d, J=7.8 Hz, 1 H), 7.70 (d, J=8.0 Hz, 1 H), 7.25-7.19 (m, 5 H), 4.68 (s, 2 H), 4.39 (s, 2 H), 3.79 (t, J=6.0 Hz, 2 H), 3.03 (t, J=6.0 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[O:15])[N:5]2[CH:16]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:15])[NH:5][CH:16]=1
Reactant: Cc1cn2c(n1)Cc1ccccc1NC2=O
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: Cc1c[nH]c(Cc2ccccc2NC(=O)N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 16 g of 2-methyl-11H-imidazo[1,2-c][1,3]benzodiazepine-5-(6H)-one, 9.58 g of N-methylpiperazine and 160 ml of methylene chloride is stirred at room temperature overnight. The mixture is decolorized with charcoal and evaporated to dryness. The residue is crystallized from methanol-ether to give 1-[2-(4-methyl-2-imidazolylmethyl)phenylcarbamoyl]-4-methylpiperazine, m.p. 177°-179°.
Reaction SMILES: C([C:3]([N:17]1CCOCC1)([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:4][CH:5](C)[C:6](OC)=[O:7])#N.C(C(N1CCOCC1)(C1CCNCC1)CCC(OCC)=O)#[N:24]>>[N:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH2:4][CH2:5][C:6](=[O:7])[NH:24][N:17]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCC(C#N)(C1CCNCC1)N1CCOCC1
Reactant: COC(=O)C(C)CC(C#N)(c1ccncc1)N1CCOCC1
Product: O=C1CCC(c2ccncc2)=NN1

Procedure:
Following the procedure described in Example 1 but using in place of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate a molar equivalent quantity of ethyl 4-cyano-4-(4-morpholinyl)-4-(4-piperidinyl)butanoate [McEvoy et al., J. Org. Chem. 44, 4597 (4600)(1979)], it is contemplated that there can be obtained 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[C:5]([CH2:18][CH3:19])[C:4]=1[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1.N.C([N:33](C(C)C)CC)(C)C>C(O)(C)C>[NH2:33][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[C:5]([CH2:18][CH3:19])[C:4]=1[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CC(C)O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 92.9 %

Procedure:
The bromide of Example 137 (444 mg, 0.900 mmol) was added to a saturated solution of ammonia in isopropanol (25 ml) and diisopropylethylamine (173 μl, 1.00 mmol) at room temperature. The reaction was stirred for 5 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to provide the title compound (359 mg) as a white solid, m.p. 112-114° C.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[C:22]([CH3:28])[CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: CSc1ccc(O)cc1C
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1C
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methyl-phenol (85 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methyl-phenoxy)-nicotinamide (118 mg) as an off-white foam.