Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:29])[NH:25][CH:26]5C[CH2:27]5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24](=[O:29])[NH:25][CH2:26][CH3:27])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:30][CH:31]=1
Reactant: O=C(Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)NC1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 50 °C
Reaction time: 10 h
Yield: 77.6 %

Procedure:
A suspension of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-[(cyclopropylcarbamoyl)methyl]indoline (0.04 g) obtained in Example 154 and active manganese dioxide (0.04 g) in chloroform (30 ml) was vigorously stirred at 50° C. for 10 hr. Then the reaction mixtures were filtered through celite and the residue was washed with chloroform. After concentrating the filtrate under reduced pressure, the residue was recrystallized from chloroform/hexane to give the title compound (0.03 g) as a white powder (yield: 81.9%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]1[CH2:17][NH:18]C(=O)OCC1C=CC=CC=1)(=[O:5])=[O:4]>CN(C=O)C.[Pd]>[NH2:18][CH2:17][C:7]1[N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:4])=[O:5])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=1
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl (1-(N,N-dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)methylcarbamate (235 mg, 0.56 mmol) was dissolved in anhydrous DMF (5 mL) and Pd on carbon (about 5 mg, catalytic) was added. The vessel containing the solution was purged with H2, and the vessel was sealed. A H2 balloon was attached. Another 10 mg of Pd on carbon was added after 8 h, and the suspension was stirred at room temperature for 48 hours (total). The suspension was filtered through Celite, washing with EtOAc (30 mL), and the washes were concentrated to give crude 2-(aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH2:1]([C:3]1([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH3:10])[CH3:2].[OH:18]O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCSC1(CC)CCCCC1CC
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCCCS(=O)C1(CC)CCCCC1CC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of n-hexyl 1,2-diethylcyclohexyl sulphide (6.5 g., 25 mmoles), glacial acetic acid (50 ml.) and hydrogen peroxide (2.7 ml. of 100 vols.) was stirred at room temperature for 20 hours. The mixture was poured into an excess of 2N sodium hydroxide and extracted with methylene chloride. The extract was washed with water and dried (MgSO4). The solvent was removed and the residual oil (6 g.) was eluted with chloroform from a silica column (Merck Kieselgel 7734). n-Hexyl 1,2-diethylcyclohexyl sulphoxide was obtained as a viscous liquid (Found: S= 11.7%. C16H32OS requires S= 11.8%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[C:11](=[O:15])[CH2:12][O:13][CH3:14].[CH2:16]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O-])=O)=[CH:26][C:25]=1[O:33][CH3:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[OH-].[K+].Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:16]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]2[O:1][C:2]3[C:3]([C:11](=[O:15])[C:12]=2[O:13][CH3:14])=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=3)=[CH:26][C:25]=1[O:33][CH3:34])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(=O)[O-])ccc1OCc1ccccc1
Reactant: COCC(=O)c1c(O)cc(OC)cc1O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(OCc4ccccc4)c(OC)c3)oc2c1
Yield: 62.7 %

Procedure:
A mixture of 0.67 g of 2',6'-dihydroxy-2,4'-dimethoxyacetophenone, 3.5 g of bis-[4-(benzyloxy)-3-methoxybenzoic] anhydride and 1 g of sodium 4-(benzyloxy)-3-methoxybenzoate was heated at 180°-185° C. under reduced pressure for 3 hours. After cooling, 12 ml of 10% solution of potassium hydroxide in ethanol were added, and the mixture was refluxed under nitrogen for 30 minutes. To the cooled mixture were added 20 ml of 1 N-hydrochloric acid and 100 ml of chloroform, followed by shaking. The organic phase was separated and concentrated under reduced pressure. The residue was chromatographed on silica gel with chloroform. After recrystallization from ethyl acetate/hexane, there was obtained 0.86 g (60% yield) of 4'-(benzyloxy)-5-hydroxy-3,3',7-trimethoxyflavone as yellow crystals: m.p. 156°-157° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:6]=1)(=O)=O.[I:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1>>[I:25][C:26]1[N:27]=[CH:28][N:29]([C:5]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[N:6]=2)[CH:30]=1
Reactant: Ic1c[nH]cn1
Reactant: CS(=O)(=O)c1nc(-c2cccc(C(F)(F)F)c2)cc(C(F)(F)F)n1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)c1

Procedure:
The title compound was prepared 2-methanesulfonyl-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example A.15) (1.1 g, 3 mmol) and commercially available 4-iodo-imidazole (0.70 g, 4 mmol) according to the general procedure IVa. Obtained as a white solid (0.96 g, 66%). MS (ISP) 485.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]CS([O-])(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+]=[N-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOCCCS(=O)(=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCN
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To 146 g of [2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate was dissolved in 500 ml DMF, was added 134 g of sodium azide. The reaction mixture was stirred at 70° C. for 20 h, and then concentrated under reduced pressure. The resulting residue was dissolved in 1,200 ml water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine. The reaction mixture was stirred at RT for 2 h, after which was added 200 ml water. The reaction mixture was stirred at RT for 18 h and concentrated to 500 ml under reduced pressure. Then the resulting precipitate was filtered off. The filtrate was further concentrated under reduced pressure to remove THF, and washed with MC. The aq layer was concentrated to obtain 86.2 g of compd 42 as a liquid. 1H NMR (400 MHz; CDCl3) δ 4.96 (br s, 1H), 3.54-3.48 (m, 4H), 3.34 (q, 2H), 2.88 (t, 2H), 1.48-1.46 (m, 11H).
Reaction SMILES: [CH2:1]([Li])CCC.C(N(C(C)C)CC)(C)C.[CH2:15]([O:17][C:18]([C:20]1([C@H:23]2[CH2:27][N:26]([C@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[C:25](=[O:36])[CH2:24]2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].CI.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([O:17][C:18]([C:20]1([C@H:23]2[CH2:27][N:26]([C@H:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:29])[C:25](=[O:36])[C@@H:24]2[CH3:1])[CH2:21][CH2:22]1)=[O:19])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
The following reaction was carried out under a nitrogen atmosphere. At −78° C., n-butyl lithium (5.39 ml, 1.68 N, n-hexane solution, 9.06 mmol) was added dropwise to a tetrahydrofuran solution (40 ml) of diisopropylethylamine (1.37 ml, 9.75 mmol), and the mixture was warmed to 0C and stirred for 30 minutes. At −78° C., to this was further added dropwise a tetrahydrofuran solution (20 ml) of (4S)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-2-pyrrolidone (2.10 g, 6.97 mmol). After an additional 15 minutes of stirring, methyl iodide (2.17 ml, 34.8 mmol) was added dropwise thereto, and the mixture was stirred for 30 minutes while warming to 0° C. After completing the reaction, this was cooled in an ice bath and mixed with a saturated ammonium chloride aqueous solution (150 ml) and then tetrahydrofuran was evaporated. The resulting residue was extracted with chloroform (150 ml×3), and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting residue was purified by a silica gel column chromatography (silica gel, 160 ml; ethyl acetate:hexane=2:3), to thereby obtain 1.90 g (87%) of the title compound.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)([O-:5])=[O:4].Cl[CH2:12][C:13]([CH3:18])([N:15]([CH3:17])[CH3:16])[CH3:14].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][N:15]([CH3:17])[C:13]([CH3:18])([CH3:14])[CH2:12][N:8]1[CH:9]=[CH:10][C:6]([N+:3]([O-:5])=[O:4])=[N:7]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CN(C)C(C)(C)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(C)(C)Cn1ccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (156 mg) was added to a solution of 3-nitro-1H-pyrazole (196 mg) in anhydrous DMF (2 mL) under cooling with ice, and the mixture was stirred at room temperature for 15 minutes. A solution of 1-chloro-N,N,2-trimethylpropan-2-amine in DMF (0.52 mL) was added to the resultant mixture, and the mixture was stirred at room temperature for about 24 hours. A saturated aqueous ammonium chloride solution (25 mL) and ethyl acetate (25 mL) were added to the reaction mixture and stirred under cooling with ice. The organic layer was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (neutral spherical silica gel, ethyl acetate:hexane=1:1) to give N,N,2-trimethyl-1-(3-nitro-1H-pyrazol-1-yl)propan-2-amine as yellow powder crystals (90.9 mg, yield: 25%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=4[F:26])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:34]1(OC(N(C)C)=[N+](C)C)[C:38]2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN>CN(C)C=O.O1CCCC1>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:25]=[CH:24][C:20]([C:21]([NH:34][CH3:38])=[O:22])=[CH:19][C:18]=4[F:26])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzoic acid (E272) (164 mg, 0.36 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (438 mg, 1.15 mmol) in dimethylformamide (2 ml) was treated with diisopropyl ethylamine (0.40 ml, 2.3 mmol) followed by a 2M methylamine solution in tetrahydrofuran (2 ml). The reaction was stirred at room temperature for 4 hours, applied to a SCX ion exchange column (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol, and the basic fractions concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound. MS (ES+) m/e 369 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH2:20][CH3:21])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH2:22]([NH:29][C:30](=[O:48])[N:31]([CH3:47])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH2:20][CH3:21])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([N:31]([CH3:47])[C:30]([NH:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:48])[CH:37]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\CC)C(=O)OCC)ccc1I
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2OCCCC)c1
Temperature: 92.5 °C
Yield: 79 %

Procedure:
3 mg (0.013 mmol) of palladium acetate and then 9 mg (0.026 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 523 mg (1.3 mmol) of ethyl 2-[1-(3-butoxy-4-iodophenyl)meth-(E)-ylidene]butyrate (prepared as described in Example 22a), 494 mg (1.7 mmol) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]urea (prepared according to Example 35b) and 1.3 mL of aqueous 2M potassium phosphate solution in 6.5 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 2 hours. The reaction medium is hydrolyzed with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the brown oil obtained (1.3 g) is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 537 mg (79%) of ethyl 2-[1-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate are obtained.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:15])([CH3:14])[S:4]1)[OH:2].[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:15])([CH3:14])[S:4]1)=[O:19]
Reactant: CC1(C)SC(=NO)N=C1C1CCCCC1
Reactant: CN=C=O
Product: CNC(=O)ON=C1N=C(C2CCCCC2)C(C)(C)S1

Procedure:
2-oxo-4-cyclohexyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-cyclohexyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 158°-160° C. The 2-oxo-4-cyclohexyl-5,5-dimethyl-3-thiazoline-oxime starting material melts at 159°-162° C.
Reaction SMILES: Cl.Cl.[C:3]1([NH2:10])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:11][CH:12]1[CH2:17][CH2:16][O:15][C:13]1=O>Cl>[NH:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:10]=[C:11]1[CH:12]([CH3:13])[CH2:17][CH2:16][OH:15]
Reactant: Nc1ccccc1N
Reactant: CC1CCOC1=O
Agent: Cl
Product: CC(CCO)c1nc2ccccc2[nH]1
Yield: 126.9 %

Procedure:
Following the general procedure described in A. R. Friedman, D. S. Payne and A. R. Day, J. Heterocyclic Chemistry, 3:257-259(1966), a mixture of 9 g of 1,2-phenylenediamine dihydrochloride and 7 g of 2-methylbutyrolactone in 60 mL of 4N hydrochloric acid was heated to reflux for 4 days, 1 teaspoon of decolorizing carbon added, and after another 15 min reflux, filtered hot. The filtrate was concentrated under reduced pressure to near dryness, the residue made basic (pH=8) with ammonium hydroxide and extracted into 3×100 mL of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. After drying under vacuum, 12 g of 3-(1H-benzimidazol-2-yl)-butan-1-ol was obtained as a resin.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].C([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])(OC(C)(C)C)=O>>[NH2:28][C@H:29]([C:31]([C:2]1([NH2:1])[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:32])[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1C(=O)C(N)N=C(N2CCCCC2)c2ccccc21
Product: C[C@H](N)C(=O)C1(N)N=C(N2CCCCC2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3-amino-1,3-dihydro-1-methyl-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one (Example 4-A) and N-Boc Alanine (Novabiochem), the title compound was prepared as a white foam.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:6][CH2:7][OH:8])[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.ClCCl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][CH2:7][CH2:6][O:5][C:2]2([CH3:1])[CH2:4][CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(OCCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCOC2(C)CC2)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To the crude 2-(1-methylcyclopropoxy)ethanol from the previous step (0.32 g) in a mixture of 4.6N sodium hydroxide (6.3 mL, 2.52 mmol) and tetrahydrofuran (3 mL) was added 4-methylbenzene-1-sulfonyl chloride (2.1 g, 11.2 mmol) in dichloromethane (6 mL) at 0-5° C. The solution was stirred for 3 h at 0-5° C., and then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain crude product (100 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 80.9 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (52 mg) was obtained.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.[CH3:21][N:22]1[CH2:28][C:27]2[CH:29]=[C:30](/[CH:33]=[CH:34]/[C:35](O)=O)C=N[C:26]=2[NH:25][C:24](=O)[CH2:23]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:25]([CH3:26])[CH2:24][C:23]2[N:22]([CH3:21])[C:28]3[C:34]([CH:35]=2)=[CH:33][CH:30]=[CH:29][CH:27]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCC1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(CN2CCCC2)c1
Yield: 82 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-pyrrolidin-1-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (223 mg, 82%) was prepared as a light, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.2 (br s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.52-7.39 (m, 3H), 7.24-7.01 (m, 4H), 6.41-6.16 (m, 1H), 5.05-4.85 (m, 2H), 4.29 (s, 2H), 3.74-3.68 (m, 3H), 3.10-3.00 (m, 6H), 2.10-1.82 (m, 5H); MS (ESI) m/e 404 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([CH:13]=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16].[ClH:17]>>[CH3:15][NH:16][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:17].[CH3:15][NH:16][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CC1(c2ccccc2)CCCCC1
Reactant: CN
Agent: Cl
Product: CNCC1(c2ccccc2)CCCCC1

Procedure:
The title compound was synthesized from 1-phenylcyclohexane-carbaldehyde (126 mg, 0.67 mmol) and methyl amine (370 μL, 0.73 mmol, 2.0 M in THF) according to General Procedure H, followed by HCl salt formation. The HCl salt was recrystallized from CH3CN to give pure N-methyl(1-phenylcyclohexyl)methanamine hydrochloride (8 mg, 6%) as colorless crystals. HPLC Rt=7.76 min; 1H NMR (400 mHz, MeOH-d4) 7.43-7.38 (m, 4H), 7.28-7.25 (m, 1H), 3.11 (s, 2H), 2.50 (s, 3H), 2.25-2.22 (m, 2H), 1.67-1.23 (m, 8H); LC-MS 6.37 min, (M+1)+ 204 @ 6.62 min.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1F
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methylamino]phenoxy]acetate (150 mg, 0.34 mmol, 1.0 eq) in THF (8 mL) was added NaOH (1M in water, 3.0 mL, 3.0 mmol) at room temperature. The reaction was stirred for 2 h, then the THF was removed in vacuo and the aqueous layer acidified to pH 4 by addition of 1M HCl. The resultant precipitate was collected by filtration and dried in vacuo to give the title compound (I(h)) (120 mg, 85%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([NH:14][NH2:15])=[O:13].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=1)[C:22](O)=O)[CH3:18]>>[CH2:28]([C:26]1[CH:25]=[C:21]([C:22]2[O:13][C:12]([C:7]3[S:8][C:9]([CH3:11])=[C:10]4[C:6]=3[CH2:5][C@H:4]3[C:2]([CH3:16])([CH3:1])[C@H:3]34)=[N:14][N:15]=2)[CH:20]=[C:19]([CH2:17][CH3:18])[N:27]=1)[CH3:29]
Reactant: Cc1sc(C(=O)NN)c2c1C1C(C2)C1(C)C
Reactant: CCc1cc(C(=O)O)cc(CC)n1
Product: CCc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(CC)n1

Procedure:
2,6-Diethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine is synthesized from 1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid hydrazide and 2,6-diethyl-isonicotinic acid in analogy to Example 5; LC-MS: tR=0.96 min, [M+1]=380.34.