Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[C:10]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl.[Cu]I>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:20])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCc2ccccc21
Reactant: Cc1c(Br)cccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1CCc2ccccc2C1=O
Temperature: 150 °C
Yield: 66.1 %

Procedure:
Step 2 A mixture of 1,3-dibromo-2-methylbenzene (340 mg, 1.359 mmol), 3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.679 mmol) and potassium carbonate (94 mg, 0.679 mmol) in DMSO (2 mL) was purged with nitrogen, treated with copper (I) iodide (25.9 mg, 0.136 mmol) and heated at 150° C. for 3.5 h. The mixture was combined with that from a second reaction using 1,3-dibromo-2-methylbenzene (2.59 g, 10.36 mmol) and 3,4-dihydroisoquinolin-1(2H)-one (508 mg, 3.45 mmol), diluted with DCM and filtered through Celite. The filtrate was washed with 5% aqueous ammonium hydroxide, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one as a yellow solid (142 mg, 11%). 1H NMR (400 MHz, chloroform-d) δ 8.15 (1H, dd, J=7.70, 1.10 Hz), 7.55 (1H, dd, J=7.92, 1.10 Hz), 7.46-7.51 (1H, m), 7.37-7.42 (1H, m), 7.24-7.28 (1H, m), 7.17-7.21 (1H, m), 7.09-7.16 (1H, m), 3.95 (1H, ddd, J=12.21, 10.12, 4.73 Hz), 3.73 (1 H, ddd, J=11.94, 6.33, 5.28 Hz), 3.26 (1H, ddd, J=15.74, 10.23, 5.28 Hz), 3.06-3.14 (1H, m), 2.36 (3H, s). Mass spectrum m/z 316, 318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:17]=1[CH2:16][CH2:15][NH:14][C:13]2=[O:12]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-fluoro-1,3-dihydro-indol-2-one (30.2 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:7]=[C:6]([F:21])[C:3]=1[C:4]#N.[OH-:22].[K+].[OH2:24]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:7]=[C:6]([F:21])[C:3]=1[C:4]([OH:24])=[O:22]
Reactant: [OH-]
Reactant: O
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c(C#N)c(F)c2)CC1
Agent: [K+]
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1

Procedure:
A solution of 10 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-benzonitrile and 20 g of KOH in 40 ml of water and 160 ml of ethanol is boiled for 16 hours, cooled and worked up in the usual manner to give 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-benzoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH3:31])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:31])([O-:29])=[O:28]
Reactant: CC[N+](=O)[O-]
Reactant: O=C(O)CCCCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.154 g, 0.80 mmol) and CDI (0.261 g, 1.60 mmol) were added together and then reacted with nitroethane (0.090 g, 1.21 mmol) and DBU (0.306 g, 2.00 mmol) according to the general procedure. Purification by column chromatography gave 0.060 g (30%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 2H), 7.21 (m, 3H), 5.24 (q, J=7.2 Hz, 1H), 2.64 (t, J=7.6 Hz, 2H), 2.58 (td, J=3.2, 6.8 Hz, 2H), 1.69 (d, J=7.2 Hz, 3H), 1.68 (m, 4H), 1.37 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 200.1, 142.6, 128.7, 128.6, 126.0, 89.1, 39.3, 35.9, 31.4, 28.7, 23.3, 15.2 ppm; IR νmax (cm−1) 3026, 2933, 2858, 1732, 1559, 1453, 1362, 1030, 749, 701; HRMS (FAB) calcd for C14H19NO3 (MNa+) 272.1257, found 272.1255.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]1[N:42]([C:41]2[CH:43]=[CH:44][C:38]([F:37])=[CH:39][CH:40]=2)[C:18](=[O:20])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1)OCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of the benzoic acid (2) (180 mg, 0.55 mmol) in tetrahydrofuran (6 mL) was added 1,1′-carbonyldiimidazole (98 mg, 0.60 mmol). After a period of 2 h, 4-fluoroaniline (61 mg, 0.55 mmol) in tetrahydrofuran (1.5 mL) was added and the mixture was stirred at 75° C. overnight. The tetrahydrofuran was removed in vacuo and the residue was redissolved in ethyl acetate, washed with 10% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and concentrated to give an oily residue which was subjected to silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 20:80, ν/ν->60:40, ν/ν] to give the title quinazolinone (3) (0.11 g, 50%) as a white solid:
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)(=O)=O.[C:28]1([C:34]2[NH:35][CH:36]=CN=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:45][N:46](C=O)C>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C@@H:8]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C@H:7]([CH2:6][N:46]3[CH:45]=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:35]=[CH:36]3)[O:11][C:10]2=[O:12])=[CH:14][CH:15]=1
Reactant: COc1cccc([C@H]2[C@H](COS(C)(=O)=O)OC(=O)N2c2ccc(Cl)cc2)c1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc([C@H]2[C@H](Cn3cnc(-c4ccccc4)c3)OC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 70 °C

Procedure:
A small reaction tube fitted with a screw cap is charged with ((4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (50 mg, 0.12 mmol) and DMF (1 mL). Phenylimidazole (35 mg, 0.24 mmol) is added followed by cesium carbonate (39 mg, 0.12 mmol) and the mixture is heated to 70° C. overnight. The reaction is then cooled to room temperature, quenched with water and extracted with EtOAc. The combined organics are washed with water, dried over MgSO4, filtered, concentrated, and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 7.80-7.78 (m, 3H), 7.68 (d, J=1.2 Hz, 1H), 7.46-7.42 (m, 2H), 7.34-7.17 (m, 6H), 6.96-6.93 (m, 2H), 6.89 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 5.46 (d, J=5.2 Hz, 1H), 4.83 (ddd, J=6.0, 5.0, 5.0 Hz, 1H), 4.70-4.69 (m, 2H), 3.72 (s, 3H); HPLC-MS calculated C26H22ClN3O3 (M+H+) 460.1, found 460.1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[C:19]([CH2:21][NH:22][CH3:23])#[N:20]>>[C:19]([CH2:21][N:22]([CH3:23])[C:16](=[O:17])[CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNCC#N
Reactant: O=C(Cl)CCl
Product: CN(CC#N)C(=O)CN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-cyanomethyl-N-methylamine in an analogous manner as described in example 21.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11](=[O:12])[N:5]12)(=O)[NH2:2].[CH2:21](N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:41]1[CH2:45]OC[CH2:42]1>>[C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH2:21][CH:41]([CH3:42])[CH3:45])[C:11](=[O:12])[N:5]12)#[N:2]
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)C[C@@]1(NC(=O)OC(C)(C)C)C[C@@H]2SC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude product from 2e was dissolved in 5 ml of THF. 63 μl of triethylamine and 29 μl of trifluoroacetic anhydride were added thereto. The mixture was stirred at room temperature for 3 h and then partitioned between 60 ml of water and 60 ml of ethyl acetate. The aqueous phase was extracted twice with 50 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#N)[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])[CH3:3].[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19].[NH:26]1CCCCC1>C(O)C>[NH2:19][C:18]1[N:26]=[C:12]2[O:13][C:8]3[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:4])[CH3:3])=[CH:17][C:9]=3[C:10](=[O:16])[C:11]2=[CH:14][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)(O)c1ccc2occ(C#N)c(=O)c2c1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: CCOC(=O)c1cc2c(=O)c3cc(C(C)(C)O)ccc3oc2nc1N
Yield: 69.2 %

Procedure:
To a mixture of 6-(1-hydroxy-1-methylethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile (4.7 g), ethyl cyanoacetate (2.5 g) and ethanol (100 ml) was added piperidine (1.9 g), which was refluxed for 3 hours, then cooled. The precipitating crystals were collected by filtration. The crystals were dissolved in chloroform, which was subjected to a silica-gel (120 g) column chromatography using chloroform-acetone-formic acid (90:10:1) as the eluent. The solvent was evaporated off. To the residue was added ethanol, and sparingly soluble matter was collected by filtration, which was recrystallized from chloroform to give colorless needles (4.86 g) of ethyl 2-amino-7-(1-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate, m.p. 263°-264° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=[O:14])[CH:12]=[CH:11][C:10](=[O:13])[CH:9]=[CH:8]1.[C:15]1([CH3:21])[CH:20]=CC=C[CH:16]=1>>[CH3:16][C:15]1([CH3:21])[C:9]2[CH:8]=[C:7]([OH:14])[CH:12]=[CH:11][C:10]=2[O:13][CH:20]1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1
Reactant: C1CCNCC1
Reactant: O=C1C=CC(=O)C=C1
Product: CC1(C)c2cc(O)ccc2OC1N1CCCCC1

Procedure:
The process of Example 1 was repeated using 196.2 parts of piperidine in place of the morpholine. The product was the corresponding piperidino enamine which was reacted with benzoquinone in toluene to give 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-piperidino-benzofuran. This was converted to 2,3-dihydro-3,3-dimethyl-2-piperidino-benzofuran-5-yl methanesulphonate and then to 2,3-dihydro-3,3-dimethyl-2-ethoxy-benzofuran-5-yl methane sulphonate as in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].O.[NH2:22]N.CO.C(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:22]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Reactant: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a solution of methyl N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]carbamate (i.e. the product of Step A) (10 g, 33.78 mmol) in methanol (100 mL) was added hydrazine hydrate (1.08 mL, 33.78 mmol) and the reaction mixture was stirred at ambient temperature for 2 days. After TLC analysis (10% MeOH/CHCl3) showed completion of the reaction, the reaction mixture was filtered was filtered. The resultant solid residue was washed with methanol and dried under vacuum to give the title compound (4 g, 48% yield) as solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH2:20][OH:21])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].ClCCl.C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>C(#N)C>[CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH:20]=[O:21])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enol (3.55 g, 8.02 mmol) and dichloromethane (125 mL) in acetonitrile (25 mL) was treated with tetrapropylammonium peruthenate (0.476 g, 1.45 mmol), 4 Å molecular sieves (0.442 g), and N-methylmorpholine-N-oxide (2.78 g, 23.8 mmol), and the mixture was stirred for 0.5 h at ambient temperature. The solution was filtered through a sintered glass funnel containing a bed of silica gel about 1 inch thick using 20% ethyl acetate in hexane as the eluent. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:29][C:16]2=3)=[CH:4][CH:3]=1.[CH:34](=O)[CH3:35].[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:38].[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:34][CH3:35])[CH2:9][CH2:10][N:11]([CH2:37][CH3:38])[CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:29][C:16]2=3)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)c1cccnc1CO2
Reactant: CC=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(CCC=C1c2cc(C(C)(C)O)ccc2OCc2ncccc21)CCN(CC)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-{3-[2-(4-chloro-phenylamino)-ethylamino]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol (0.13 g, 0.27 mmol) in dichloroethane (5.0 mL) was added acetaldehyde (0.045 mL, 0.81 mmol), sodium triacetoxy borohydride (0.17 g, 0.81 mmol) and catalytic acetic acid and stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/methanol (5%). 1H-NMR (CDCL3) δ: 0.90-1.20 (6H, 2×t), 1.60 (6H, s), 2.20-2.40 (2H, m), 2.45-2.65 (6H, m), 3.20-3.40 (4H, 2×q), 5.30 (2H, br, s), 6.10 (1H, t), 6.50 (2H, dd), 6.80 (1H, d), 7.10 (2H, dd) 7.20-7.35 (2H, m), 7.45 (1H, dd),7.55 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 520 (M+1), UV retention time: 1.51 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[S:26][CH:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)[CH2:29][CH2:30]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 13.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (258 mg, 0.897 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.156 ml, 0.897 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (43.1 mg, 13.8%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:20]2C(=O)C4C(=CC=CC=4)C2=O)=[CH:15][C:14]([OH:31])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NN>C(O)C.O1CCCC1>[NH2:20][CH2:19][CH2:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:31])[CH:15]=2)[NH:10][C:9]=1[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[2-[2-(3,5-dimethylphenyl)-5-hydroxy-1H-indol-3-yl]ethyl]isoindole-1,3-dione (418 mg in a mixture of 7 mL ethanol and 7 mL tetrahydrofuran) was added 2.5 mL of 95% aqueous hydrazine and the reaction stirred at room temperature. After 12 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 89:11:1) to provide the title compound (228 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:6][CH:7]=1.O.NN>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cncc(Br)c1
Yield: 115.8 %

Procedure:
A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LVII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo, the crude product was dissolved in 1N HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL×3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3-yl)methanamine (LVIII) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found for C6H7BrN2 m/z 187 (M+H).
Reaction SMILES: O[CH2:2][C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@H:4]([OH:6])[CH3:5].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:36][O:35][CH2:34][C@@H:33]([O:32][C:17]1[CH:16]=[C:15]([C:12]2[NH:11][C:10]([C:8]3[O:9][CH2:2][C@@H:3]([C@H:4]([OH:6])[CH3:5])[N:7]=3)=[CH:14][CH:13]=2)[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])[CH:18]=1)[CH3:37]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
N-[(2S,3R)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.70 g, 3.18 mmol) synthesized in Example (114a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.78 g, 4.48 mmol) and triethylamine (1.50 mL, 10.76 mmol) were added at 0° C., followed by stirring at the same temperature for 1.5 hours under nitrogen atmosphere, followed by stirring at 50° C. overnight. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-4%) to afford the desired compound (1.30 g, yield 79%) as a white foam.
Reaction SMILES: C1([C@@H]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][NH:12][CH2:11]2)C)C=CC=CC=1.C(O)C.[ClH:20].[H][H]>[OH-].[Pd+2].[OH-].O>[ClH:20].[ClH:20].[NH2:9][C@H:10]1[C:14]2([CH2:16][CH2:15]2)[CH2:13][NH:12][CH2:11]1
Reactant: C[C@H](N[C@@H]1CNCC12CC2)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H]1CNCC12CC2
Yield: 82 %

Procedure:
An autoclave was charged with 79 mg of (S)-7-[(S)-1-phenylethyl]amino-5-azaspiro[2.4]heptane, 37 mg of 20% palladium hydroxide, 2 ml of ethanol, 1 ml of water and 0.5 ml of concentrated hydrochloric acid, and the contents were stirred overnight at room temperature in an atmosphere of hydrogen (40 kgf/cm2). After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 72 mg (82%) of the title compound in the form of colorless crystals. The thus obtained crystal compound was recrystallized from ethanol and diethyl ether and used as a sample for analyses.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[ClH:4].[CH2:5]=O.[CH2:7]1[CH2:17][C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1>O>[ClH:4].[CH3:1][NH:2][CH3:3].[ClH:4].[CH3:1][N:2]([CH2:5][CH:17]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16])[CH3:3]
Reactant: C=O
Reactant: O=C1CCCc2ccccc21
Agent: CNC
Agent: Cl
Solvent: O
Product: CN(C)CC1CCc2ccccc2C1=O

Procedure:
First, 6.83 g of a 50% by mass aqueous dimethylamine solution (dimethylamine: 75.9 mmol) was added to a 100-ml two-necked flask. Next, 8.19 g of a 35% by mass aqueous solution of hydrochloric acid (hydrochloric acid: 78.9 mmol) was added to a 100-ml dropping funnel. Subsequently, the dropping funnel was set to the two-necked flask, and then the aqueous solution of hydrochloric acid was added dropwise to the aqueous dimethylamine solution under ice-cooling. Thus, dimethylamine hydrochloride was prepared in the two-necked flask. Next, 2.78 g (92.4 mmol) of paraformaldehyde as the formaldehyde derivative and 9.0 g (61.6 mmol) of α-tetralone as the carbonyl compound were further added to the two-necked flask. Note that the volume of the mixture made of water and paraformaldehyde present in the two-necked flask was 25 mL, and the concentration of hydrochloric acid (HCl) in the mixture was 0.12 mol/L. Subsequently, a bulb condenser was set to the two-necked flask, and then the inside of the two-necked flask was replaced with nitrogen. Thereafter, the two-necked flask was immersed in an oil bath of 90° C., and heated for 4 hours with stirring. Thus, a reaction liquid was obtained. Note that the thus obtained reaction liquid was subjected to HPLC analysis for components in the reaction liquid. As a result, the conversion of α-tetralone was found to be 99%, and the yield (HPLC yield) of N,N-dimethylaminomethyl-1-tetralone hydrochloride (the Mannich base) was found to be 95%.