Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[FH:7].[O:8]1[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9]1.O.CCCCCCC>CCOCC>[F:7][C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][OH:8]
Reactant: CCCCCC[C@@H]1CO1
Reactant: F
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC[C@H](F)CO
Reaction time: 1 h

Procedure:
To 30 ml of hydrogen fluoride pyridine solution which was cooled with ice, 8.5 g of (R)-1,2-epoxyoctane in 20 ml of ether was added dropwise. The mixture was stirred for one hour at the same temperature and brought to room temperature. 100 ml of water was added to the mixture. After extracting it with 50 ml of ether twice, the obtained organic layer was washed with an alkali solution and then with water, dried over magnesium sulfate and concentrated. The concentrate was distilled under reduced pressure and 4.9 g of distillate was obtained at 126°-129° C./80 mmHg. 3.7 g of (S)-2-fluorooctane-1-ol was obtained by recrystallization from 40 ml of heptane. Its melting point was 33°-35° C., [α]D26 -13.14 (c1.7, benzene) of optical rotation was shown.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].C([O:18][N:19]=O)CCC>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:19][OH:18])[C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc2c(cc1Br)C(=O)CC2
Reactant: CCCCON=O
Product: COc1cc2c(cc1Br)C(=O)C(=NO)C2

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-5-methoxy-indan-1-one and n-butylnitrite to give 6-Bromo-5-methoxy-indan-1,2-dione 2-oxime. LC-MS: m/e 270 (MH+).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])[C@H:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=CC=1)([O-])=O.[CH3:32][NH2:33]>C(Cl)Cl.C(O)C>[CH3:32][NH:33][C:11](=[O:31])[C@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (5.0 g, 11.9 mmol) in DCM at 0° C. was slowly added a/solution of 8M methylamine (1.5 ml, 11.9 mmol) in ethanol. The reaction immediately turned bright yellow and was stirred for 0.5 h. The reaction was diluted with DCM (50 ml), washed with 10% sodium carbonate (1×50 ml), brine (2×50 ml) and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a white residue which was crystallised from ethyl acetate/hexane to give N-benzyloxycarbonyl-L-phenylalanine methylamide (3.0 g, 81%) as a white crystalline solid.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[BH4-].[Na+].Cl.[OH-].[Na+]>CO>[OH:12][CH:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)[C:7]1[S:6][C:5]([NH:1][C:2]([NH2:4])=[NH:3])=[N:9][C:8]=1[CH3:10]
Reactant: Cc1ccnc(C(=O)c2sc(NC(=N)N)nc2C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccnc(C(O)c2sc(NC(=N)N)nc2C)c1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a suspension of 2-guanidino-4-methyl-5-(4-methylpyridin-2-ylcarbonyl)thiazole (0.1 g) in methanol (3 ml) was added sodium borohydride. (48.4 mg), and the mixture was stirred for 2 hours. The mixture was poured into 1N hydrochloric acid. The pH was adjusted to 12 with 4N aqueous sodium hydroxide, and the mixture was stirred for 15 minutes. The precipitate was collected by filtration, washed with water and dried to give N-(5-(hydroxy-(4-methylpyridin-2-yl)methyl)-4-methylthiazol-2-yl)guanidine (92 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[CH3:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: CS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and commercially available 3-methanesulfonyl-phenylboronic acid (0.22 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.45 g, 86%). MS (ISP) 523.0 [(M+H)+]; mp 183.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1

Procedure:
A solution of 6-methoxy-1,2,3,4-tetrahydroisoquinoline, Sall and Grunewald, J. Med. Chem. 1987, 30, 2208-2216 (1.1 mmol), ethyl chloroacetate (1.17 mmol), and K2CO3 (1.17 mmol) in CH3CN (10 mL) is stirred for 18 h. The mixture is partitioned between EtOAc and H2O. The organic phase is concentrated to an oil, which is purified by chromatography (silica gel, gradient, 20-80% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42].O>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([C:48](=[O:49])[C:47]1[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(C(=O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.5 %

Procedure:
First, 59 g (109 mmol) of 2,3,4,6-tetra-O-benzyl glucose, from Sigma Chemical Company, was dissolved in 200 ml of pyridine and 22.3 g (120 mmol) of p-nitrobenzoyl chloride was added. The mixture was stirred at room temperature for 72 hours, poured into 750 ml of water, and the solid was isolated by filtration and recrystallized from 95% ethanol to produce 68.8 g (91%) of 2, 3, 4, 6-tetra-O-benzyl-1-p-nitrobenzoyl glucose.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])[CH:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A solution of N-Methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (300 mg, 1.46 mmol) in DMF (5 mL) was cooled to in an ice bath and sodium hydride (73 mg of 60% dispersion, 1.83 mmol) added in one portion. The mixture was stirred for 5 minutes then triisopropylsilyl chloride (353 mg, 1.83 mmol) added dropwise. The reaction was then stirred for 14 hrs during which time the temperature reached rt. The reaction was then quenched by pouring into a mixture of ice and 25% ammonium chloride solution (50 mL). The resulting mixture was then extracted with EtOAc (2×20 mL) and the combined extracts washed with water (10 mL) and brine (10 mL) then dried over magnesium sulfate. Subsequent filtration and concentration afforded a yellow oil. This crude oil was considered sufficiently pure to carry forward directly. Yield=92%
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[NH:22][C:23](=[O:25])[CH3:24].C1(O[Na])C=CC=CC=1.O.O.O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([NH:22][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[CH:10]=[C:9]([NH:11][CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:25])[CH3:24]
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccs1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Nc2cc(NCc3cccs3)c(C(N)=O)cn2)c1
Reaction time: 3 h
Yield: 12.7 %

Procedure:
A mixture of 6-chloro-4-(thiophen-2-ylmethylamino)nicotinamide (100 mg, 0.373 mmol), 3′-aminoacetanilide (65 mg, 0.433 mmol), PhONa trihydrate (80 mg, 0.471 mmol), xantphos (30 mg, 0.051 mmol) and Pd2 dba3 (20 mg, 0.021 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. Water and EtOAc were added. The mixture was filtered. The organic phase was separated, washed with aq. 1N NaOH, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give the titled compound (18 mg). MS 382.3 (M+H); UV 251.0 nm; t 0.465 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[Cl-].[Li+].[C:17]([N:20]1[CH2:28][CH2:27][CH:23]([C:24](Cl)=[O:25])[CH2:22][CH2:21]1)(=[O:19])[CH3:18].O>C1COCC1.CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:24]([CH:23]1[CH2:22][CH2:21][N:20]([C:17](=[O:19])[CH3:18])[CH2:28][CH2:27]1)=[O:25]
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2-Chloro-4-fluoro-1-iodobenzol (5 g, 19 mmol) was solved in THF (3 mL) and at −10° C. isopropyl magnesium chloride-lithium chloride (2M in THF) was added dropwise and the mixture stirred for 30 minutes at 0° C. At −10° C. 1-acetyl-isonipecotoyl chloride was added (3.3 g, 18 mmol) solved in THF (2 mL) and the mixture stirred for 10 minutes to −10° C. and 4 h to 0° C. Water was added and the reaction extracted with dichloromethane. Chromatography with Heptane/EtOAc (2:1) gave the desired compound as a clear orange liquid (1.8 g, 33% yield). (m/e): 284.3 (M+H+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[C:14](=O)[CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:10]1=O)[CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[F-].[K+]>O1CCOCC1.CCOCC>[CH2:16]([N:12]1[CH2:13][CH2:14][N:9]([C@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[CH2:10][CH2:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1[C@@H]1CN2CCC1CC2
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: c1ccc(CN2CCN([C@@H]3CN4CCC3CC4)CC2)cc1
Temperature: 0 °C
Yield: 81.2 %

Procedure:
To a solution of 1-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzyl-2,6-piperazinedione (1.90 g, 6.00 mmol) in 1,4-dioxane (40 mL) was added LiAlH4 (911 mg, 24.0 mmol) at room temperature under nitrogen atmosphere. The resulting suspension was stirred under reflux for 3.5 h, then cooled to 0° C. The mixture was diluted with Et2O (80 mL), then treated carefully with Na2SO410 H2O (9.1 g) and anhydrous KF (1 g). After the resulting white suspension was stirred vigorously at room temperature for 30 min, the white precipitate was removed by filtration through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (NH gel, 200-350 mesh, 40 g, EtOAc) to give a product (1.39 g , 81%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.[ClH:29].O1CCOCC1>C(O)(C)C>[ClH:29].[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2[nH]ncc12
Yield: 100 %

Procedure:
Under nitrogen, the 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (60 mg, 0.156 mmol) obtained in Example 725 was dissolved in isopropyl alcohol (2 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (2 ml), and the resulting mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2, 100/4). Then, a 4N-hydrochloric acid/1,4-dioxane solution was added thereto and the solvent was distilled off under reduced pressure to obtain 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole monohydrochloride (55 mg, yield 100%) as a hygroscopic light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.N([O-])=O.[Na+].NC(N)=O.[I-:21].[K+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1[I:21]
Reactant: [I-]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a stirred suspension of 2,6-dichloro-4-nitroaniline (200 g) in glacial acetic acid (1.3 1) at 16° was added dropwise a solution of sodium nitrite (93.84 g) in concentrated sulphuric acid (500 ml), keeping the reaction mixture below 22°. The reaction mixture was stirred and kept below this temperature for 0.5 hour, then poured slowly onto crushed ice/water (2.5 liters) containing urea (31.71 g), keeping the mixture below 23°. Potassium iodide (225.77 g) in water (600 ml) was slowly added with stirring and the mixture stirred at room temperature for 3 hours. The product was filtered off, washed with water then triturated with hot ethanol to give 3,5-dichloro-4-iodonitrobenzene (263.4 g, 86%) as a buff solid, m.p. 147°-150°.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]3[C:19]([C:20]([N:22]4[CH2:28][CH2:27][C:26](=[O:29])[NH:25][CH2:24][CH2:23]4)=[O:21])=[CH:18][C:17]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:14]32)=[CH:9][C:8]=1[O:35][CH3:36])([CH3:5])[CH3:4].I[CH2:38][CH2:39][CH2:40][CH3:41].[NH4+].[Cl-]>CN(C=O)C>[CH2:38]([N:25]1[C:26](=[O:29])[CH2:27][CH2:28][N:22]([C:20]([C:19]2[N:13]3[CH2:12][CH2:11][C:10]4[C:15]([C:14]3=[C:17]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:18]=2)=[CH:16][C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[C:8]([O:35][CH3:36])[CH:9]=4)=[O:21])[CH2:23][CH2:24]1)[CH2:39][CH2:40][CH3:41]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)cc(C(=O)N3CCNC(=O)CC3)n1CC2
Reactant: CCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C(=O)c2cc(-c3cccs3)c3n2CCc2cc(OC)c(OC(C)C)cc2-3)CCC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (160 mg, 60% dispersion in oil) was added to a solution of the product of example 13 (767 mg) in DMF (24 ml). After stirring for 5 min at room temperature, 1-iodobutane (1.46 ml) was added and stirring was continued for 18 h at 60° C. The reaction mixture was poured in a sat. aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in dichloromethane/methanol [100/0→90/0 (v/v)] as eluent.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].[CH:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=O.C(C1(C(OC)=O)CCC1)=O>>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:7][CH2:8][C@H:9]([O:12][C:13]2[C:18]3[C:19]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C@H:32]5[CH2:33][CH2:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][CH2:37]5)[CH2:28][CH2:29]4)=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: CC(=O)OC[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](COC(C)=O)CC5)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using (cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexyl)methyl acetate (EXAMPLE 46, Step 3) and methyl trans-4-formylcyclohexanecarboxylate (JP 490-48639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[C:6]([C:14]#[N:15])=[CH:5]2.C[O-].[Na+].[Na].[NH3:20]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2=[CH:8][C:7]3[C:12](=[NH:13])[NH:15][C:14](=[NH:20])[C:6]=3[CH:5]=[C:4]2[CH:3]=1
Reactant: N#Cc1cc2ccc(Br)cc2cc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: N=C1NC(=N)c2cc3cc(Br)ccc3cc21

Procedure:
Under nitrogen, 44.1 g (0.172 mol) of 6-bromo-2,3-dicyanonaphthalene was added to a solution of sodium methoxide in methanol prepared by adding 1.92 g (84 m mols) of metallic sodium to 270 ml of absolute methanol, and anhydrous ammonia gas was slowly bubbled into the resulting mixture for about 1 hour. The mixture was refluxed for about 3 hours, while bubbling therethrough anhydrous ammonia gas. After cooling, the yellow solid precipitated was filtered and the residue was sufficiently washed with methanol and dried under reduced pressure to obtain 45 g of 6-bromo-1,3-diiminobenz[f]isoindoline as a yellow solid IR spectrum of this 6-bromo-1,3-diiminobenz[f]isoindoline is shown in FIG. 4. The 6-bromo-1,3-diiminobenz[f]isoindoline was used in the subsequent reaction without further purification.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]([CH3:13])[C:7]=2[CH:14]=1.C(OC(C)C)(=[O:17])C>C(#N)C.C(OCC)(=O)C>[OH2:17].[BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]([CH3:13])[C:7]=2[CH:14]=1.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]([CH3:13])[C:7]=2[CH:14]=1.[BrH:1]
Reactant: CC(=O)OC(C)C
Agent: Br
Agent: C[C@H]1CNCCc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O
Reaction time: 8 h

Procedure:
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide salt hemihydrate was prepared by the dropwise addition of one equivalent of aqueous HBr (˜48%) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in isopropyl acetate, acetonitrile, or ethyl acetate with vigorous stirring. The product readily precipitated from the reaction in isopropyl acetate. In acetonitrile the solvent was evaporated to near dryness to obtain a solid. In ethyl acetate, seeds were added and the reaction was allowed to stir unstoppered to initiate crystallization. The reaction was then closed and stirring was continued to afford a yellow suspension. The suspension was filtered and the solid was washed with cold ethyl acetate. The resulting white solid was under nitrogen at ˜38° C., and held overnight at 25° C./75% RH. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide salt hemihydrate had an extrapolated dehydration onset temperature by TGA of about 72.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC([C:45]1[CH:50]=[CH:49][C:48](CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=[CH:47][CH:46]=1)=N)(C)(C)C.C1(CS(Cl)(=O)=O)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH2:32][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Agent: O=S(=O)(Cl)Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)Cc4ccccc4)c(=O)n32)cc1
Yield: 44 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and alpha-toluene sulfonyl chloride (26.7 mg, 0.14 mmol) yielded 35.6 mg (44%) of 36a. MS (ESI) 581.1 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=O.[BH4-].[Na+].Cl>C(O)C.ClCCl.C1C=CC=CC=1>[CH3:1][NH:2][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: CN
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Methylamine gas was bubbled through the benzene solution(60 ml) of 10.7 g(100 mmol) of 2-pyridinecarboxaldehyde for 2 hours. Benzene was distilledoff under a reduced pressure and the residue was taken up in 40 ml of ethanol. To the resulting solution was added 5.7 g of NaBH4 in three portions and the resulting mixture was stirred at room temperature for 8 hours. To the reaction mixture was added 0.5N hydrochloric acid with care not to allow the pH below 6. 300 ml of dichloromethane was added thereto and the resulting solution was washed three times with 1M NaHCO3 solution of pH 10. The organic layer was concentrated under a reduced pressure to give 10.4 g of the title compound(yield: 85%).