Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[C:7](=[O:20])[C:6]=3[C:2]=1[CH3:1])/[C:34](=[O:40])[NH:35]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 29 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 as starting materials to obtain (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 12 (20 mg, yield 29%) as a yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[NH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=1)=[O:23])#[N:8].Cl>C(OCC)(=O)C.CN(C)C=O>[C:30]1([C:28]2[CH:29]=[C:24]([C:22]([NH:21][C:10]3[CH:11]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:13]=[CH:14][C:9]=3[C:7]3[NH:8][N:3]=[N:2][N:1]=3)=[O:23])[CH:25]=[N:26][CH:27]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(-c2ccccc2)ccc1-c1nnn[nH]1)c1cncc(-c2ccccc2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Sodium azide (38 mg) and ammonium chloride (31 mg) were added to a N,N-dimethylformamide (1.1 mL) solution of N-(2-cyano-5-phenylphenyl)-5-phenylpyridine-3-carboxamide (0.11 g) at room temperature, followed by stirring at 110° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1.0 mol/L hydrochloric acid (6.0 mL) were added thereto. The solid substance was collected by filtration to obtain 84 mg of 5-phenyl-N-(5-phenyl-2-(1H-tetrazol-5-yl)phenyl)pyridine-3-carboxamide as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), tert-butyl bromoacetate (0.88 g, 4.5 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 87%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2>C(O)C.C(O)(=O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2
Reactant: COc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(CCCBr)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.8 %

Procedure:
To a solution of the product of step 2 (160 mg) in ethanol (3 ml) and acetic acid (1 ml) were added 10% Pd—C (79 mg) was stirred under hydrogen (under a balloon) at room temperature for 24 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:2) to give 5-(3-bromopropyl)-5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepine (48 mg).
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH3:11][N:12]1[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:15][NH:14][C:13]1=[S:16]
Reactant: O=C(Cl)c1ccncc1
Reactant: CNC(=S)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cn1c(-c2ccncc2)n[nH]c1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Isonicotinoyl chloride hydrochloride (27.5 g, 154.5 mmol) and 4-methyl-3-thiosemicarbazide (16.4 g, 155.9 mmol) were mixed in pyridine (200 ml) and stirred under argon at ambient temperature overnight. After evaporation to dryness, aqueous sodium hydroxide (250 mL, 2M, 500 mmol) was added and the resulting solution was heated at 60° C. for 16 h. After cooling to room temperature, the solution was neutralized with 6N hydrochloric acid. The precipitate that formed was collected by filtration to give the title compound (pale yellow solid, 16.4 g, 55%). 1H NMR (DMSO-d6), δ (ppm): 8.78 (dd, 2H), 7.75 (dd, 2H), 3.59 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17].[CH2:44](N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:44][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:20]1)=[O:17]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCCCCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(5-hydroxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (150 mg) and triethylamine (70 μl) in tetrahydrofuran (5 ml) was added methanesulfonyl chloride (725 μl) at 0° C., and the mixture was stirred at room temperature for 2 hr. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 28% sodium methoxide-methanol solution (482 mg) was added at room temperature and the mixture was stirred at 60° C. for 3 days. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (123 mg).
Reaction SMILES: [Na].Br[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[C:6]([CH3:15])([CH3:14])[CH2:5][CH2:4]1.[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]([CH3:15])([CH3:14])[CH2:5][CH2:4][CH:3]2[O:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCCC1
Reactant: CC1(C)CCC(Br)c2cc(Br)ccc21
Agent: [Na]
Product: CC1(C)CCC(OC2CCCCC2)c2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To 9 g (89.9 mmol) of cyclohexanol was added 160 mg (7.0 mmol) of sodium metal and the mixture was stirred at 70° C. for 12 hours. After all of the sodium dissolved the reaction mixture was cooled to ambient temperature and then a solution of 1 g (3.2 mmol) of 4,6-dibromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound I) in 1 ml of cyclohexanol was added. The mixture was heated at 120° C. for 4 hours and thereafter the excess solvent distilled off under reduced pressure. The product was dissolved in Et2O (75 ml), washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 5% EtOAc-hexane) yielded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[Cl:21][S:22](O)(=[O:24])=[O:23]>CC#N.O>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1Cc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of compound 747-C (0.72 g, 2.7 mmol) in MeCN (50 mL) was added chlorosulfonic acid (3.72 g, 32.4 mmol), drop-wise, and the reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H2O, extracted with CH2Cl2, dried over Na2SO4, filtered, and dried to afford 0.976 g of compound 747-D as a brown solid. 1H-NMR (CDCl3) δ 3.26-3.43 (m, 2H,) 3.60-3.78 (m, 2H), 5.26 (t, 1H), 7.46 (d, 1H), 7.68-7.79 (m, 2H), 7.79-7.93 (m, 4H); MS: m/z 384.1 (MNa+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8][C:7]=2[CH:14]=1.[CH2:17]([NH:19][CH:20]=[O:21])[CH3:18]>C(O)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([N:19]([CH2:17][CH3:18])[CH:20]=[O:21])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: CCNC=O
Reactant: O=C1CCc2ccc(C(F)(F)F)cc2CC1
Solvent: O=CO
Product: CCN(C=O)C1CCc2ccc(C(F)(F)F)cc2CC1
Yield: 99.2 %

Procedure:
A mixture of 228.2 g of 2-trifluoromethyl-6,7,8,9-tetrahydro-[5H]-benzocyclohepten-7-one, 219 g of N-ethylformamide and 151 g of formic acid is heated under reflux for 14 hours. After concentration in vacuo, while heating on a bain-marie, the residue is taken up in 2300 ml of methylene chloride. After washing twice with 800 ml of water each time, the organic layer is dried over magnesium sulphate and, after filtration, the solvent is removed in vacuo. 283 g of 2-trifluoromethyl-7-(N-ethyl-N-formylamino)-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are obtained in the form of an oil.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:30]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:5]([NH:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:41])[F:42])[N:31]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:30]1)=[O:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H](c1cccc(F)c1)c1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cccc2NC(=O)[C@@H](N=[N+]=[N-])[C@H](c2cccc(F)c2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (134 mg, 0.42 mmol) and the product from step 4 (200 mg, 0.42 mmol) were dissolved in pyridine (4 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.04 mL, 0.46 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (5 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×15 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=683.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=2)[NH2:45])O1.CN1CCCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:45][C:44]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][CH:23]([N:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)[CH2:24][CH2:25]4)=[C:16]([CH3:33])[CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH:48]=[CH:47][CH:46]=1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1-c1cccc(N)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (93 mg), and N-methylpyrrolidone (2 mL) were added tetrakistriphenylphosphine palladium (0) (25 mg) and a 2 M aqueous sodium carbonate solution (424 μL), followed by stirring in a microwave reaction device at 100° C. for 1 hour. Water was added thereto, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-(3-aminophenyl)-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (125 mg) as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:39]([OH:41])=[O:40])[CH2:22][C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([O:30]CC4C=CC=CC=4)=[C:25]([CH3:38])[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H][H]>C(O)(C)C.[Pd]>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:39]([OH:41])=[O:40])[CH2:22][C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([OH:30])=[C:25]([CH3:38])[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc(C)c1O

Procedure:
A suspension of 600 mg (1.08 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidine-1-carboxylate and 250 mg of 10% Pd/C in 50 mL isopropanol was hydrogenated at 50° C. and 3447 hPa hydrogen pressure for 2 h. The catalyst was suction filtered, the filtrate was evaporated down i.vac., the residue was triturated with 50 mL diethyl ether, suction filtered, washed with 20 mL diethyl ether and dried at 50° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:23][NH:24][C:25](=[O:34])[CH:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27](O)=[O:28]>>[C:30]([CH:26]([C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28])[C:25]([NH:24][CH2:23][C:22]1[CH:21]=[C:20]([F:19])[CH:37]=[C:36]([F:38])[CH:35]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C)(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(C(=O)NCc2cc(F)cc(F)c2)C(C)(C)C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=506.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-tert-butyl-malonamic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:14][OH:15]
Reactant: O=C1CCOc2c(F)cccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: ON=C1CCOc2c(F)cccc21
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 8-fluorochroman-4-one (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate 8-fluorochroman-4-one oxime (4), which was reduced with Raney Nickel in EtOH at 50 PSI to yield the title amine (5) (4.69 g, 57%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[C:7]([F:11])[CH:8]=2)[C:3]1=[O:13].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C([O-])(O)=O.[Na+]>[CH2:18]([O:17][C:15](=[O:16])[NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[C:7]([F:11])[CH:8]=2)[C:3]1=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC1Cc2cc(F)c(F)cc2C1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NC1Cc2cc(F)c(F)cc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-amino-5,6-difluoroindan-1-one (Preparation 78) (165 mg, 0.90 mmol) in saturated NaHCO3 (15 mL) was added benzyl chloroformate (0.15 mL, 1.08 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was extracted with EtOAc (25 mL) and the organic phase washed with water (20 mL), brine (20 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (MeOH:DCM 1:99) to give the title compound: RT=3.50 min; m/z (ES+)=318.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]1([CH2:30][N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:29][O:28][CH2:27]1>>[CH:19]([N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][C:26]6([CH3:25])[CH2:27][O:28][CH2:29]6)[CH:35]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:15][C:16]([NH2:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC4(C)COC4)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 1-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Purification of the crude reaction mixture by reverse phase HPLC gave 400. LCMS: 478.2
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].[Na].[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]([CH2:18][CH:19]([S:31]([OH:34])(=[O:33])=[O:32])[C:20]([O:22][CH2:23][CH:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26])=[O:21])=[O:17])[CH2:12][CH3:13].CCCCC(COC(CC(S(O)(=O)=O)C(OCC(CCCC)CC)=O)=O)CC>O>[Ag:5].[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]([CH2:18][CH:19]([S:31]([OH:34])(=[O:33])=[O:32])[C:20]([O:22][CH2:23][CH:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26])=[O:21])=[O:17])[CH2:12][CH3:13]
Reactant: [Ag+]
Agent: CCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S(=O)(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na]
Solvent: O
Product: [Ag]

Procedure:
In a reaction vessel charged with a magnetic stirbar and protected from light, 5.0 g (29 mmol) of silver nitrate was dissolved in approximately 100 mL of deionized water. To the stirred solution was added, is small portions, 13.1 g (29 mmol) of sodium docusate. As the docusate was added, the solution became gradually gelatinous with attendant difficulties in stirring that were remedied by gently heating the solution. After addition of the final portion of sodium docusate, the warmed solution/suspension was stirred overnight, after which point it was rotary evaporated to yield a slightly tan mass. The mass was extracted with a chloroform-acetonitrile mixture, into which much of the material dissolved but some white solid (presumed to be NaNO3) did not. The mixture was filtered and evaporated under reduced pressure to give a soft mass of slightly off-white final product (which should be stored away from light because it is photosensitive). This material was soluble in lidocaine docusate, some organic solvents, and was relatively slow to dissolve in water, doing so to only a limited degree. The two ions have known antimicrobial and emollient properties, respectively.