Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]4[C:11]=3/[C:12](=[CH:23]/[C:24]3[NH:25][CH:26]=[CH:27][C:28]=3[O:29][CH3:30])/[C:13](=[O:22])[NH:14]4)[CH:8]=2)[CH:3]=[CH:2]1.O.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:19][C:18]1[C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])/[C:12]/2=[CH:23]\[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4cc[nH]c4c3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4cc[nH]c4c3)c21
Yield: 56.2 %

Procedure:
To a solution of (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (48 mg, 0.12 mmol) (from Step A above) in 2 mL of a 10% water in methanol solution and 0.5 mL THF was added zinc dust (70 mg, 1.07 mmol) followed by ammonium chloride (19 mg, 0.36 mmol). The reaction was heated at gentle reflux for 4 hours, at which time the reaction mixture was filtered through a pad of Celite® and rinsed thoroughly with ethyl acetate. The resulting solution was diluted with 5 mL water and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The resulting powder was recrystallized from EtOAc/hex to yield 25 mg (57%) of (Z)-5-amino-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8]2[O:9]CO[C:7]=2[CH:6]=1.[OH-].[K+].Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])(=O)[C:27]([O-])=[O:28]>>[O:9]1[C:8]2[CH:12]=[CH:13][C:5](/[CH:4]=[CH:3]/[CH2:2][O:1][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:6][C:7]=2[CH2:27][O:28]1
Reactant: OC/C=C/c1ccc2c(c1)OCO2
Reactant: ClCCCN1CCCC1
Reactant: O=C([O-])C(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: C(=C/c1ccc2c(c1)COO2)\COCCCN1CCCC1

Procedure:
Following the procedure described in example 2, but starting from trans-5-(3-hydroxyprop-1-en-1-yl)benzodioxolane (400 mg), potassium hydroxide (283 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (376 mg) in dimethylsufoxide (5 mL) affords 90 mg of trans-1-{3-[3-(benzodioxol-5-yl)allyloxy]-propyl}pyrrolidine, oxalate as a white solid melting at 109-111° C.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH3:23])[C:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[N:19]2)=[O:17])=[CH:11][CH:10]=1.C([Li])CCC.CCCCCC.[CH3:42][N:43]([CH3:47])[C:44](Cl)=[O:45]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]2[CH2:22][C:21]([C:44](=[O:45])[N:43]([CH3:47])[CH3:42])([CH3:23])[C:20]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[N:19]2)=[O:17])=[CH:13][CH:14]=1
Reactant: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Into a 3000 ml three necked flask equipped with a mechanical stirrer, thermometer, and addition funnel was placed 65 ml (0.47 mole) of diisopropylamine, 155 g (0.45 mole) of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide and 1000 ml of tetrahydrofuran. The atmosphere was exchanged for nitrogen and the mixture was cooled to -20° C. internal. Then 375 ml of 2.6M n-butyllithium in hexane (0.97 mole) was added at a rate to maintain the internal temperature below -10° C. The mixture was stirred for an additional 30 minutes at -20° C. and then cooled to -60° C. whereon 45 ml of dimethylcarbamoyl chloride (0.49 mole) was added in one portion. After stirring for 15 minutes the reaction was quenched with 35 ml of acetic acid and 100 ml of water. After warming to room temperature, the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Crystallization from ethyl ether gave 125 g of N,3-bis-(4-chlorophenyl)-4-dimethylcarbamoyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. Mp 194°-197° C. NMR and IR data were consistent with the structure.
Reaction SMILES: [C:1](=[S:3])=[S:2].[CH2:4]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[F:14])[CH3:5].[CH2:15](N(CC)CC)C.CI.Cl>CN(C)C=O>[CH2:4]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:1](=[S:3])[S:2][CH3:15])=[CH:9][C:8]=1[F:14])[CH3:5]
Reactant: CCN(CC)CC
Reactant: S=C=S
Reactant: CCOc1ccc(N)cc1F
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=S)SC)cc1F
Yield: 58.8 %

Procedure:
Carbon disulfide (2.0 g, 26 mmol) was added to a mixture of 4-ethoxy-3-fluoroaniline (2.7 g, 17 mmol) and triethylamine (4.0 g, 40 mmol) while stirring. The mixture was stirred at room temperature for 10 hours, N,N-dimethylformamide (30 ml) was added thereto and methyl iodide (2.2 g, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and dilute hydrochloric acid was added thereto, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=4:1) to obtain methyl 4-ethoxy-3-fluorophenyldithiocarbamate (2.5 g, 10 mmol) as crystals. m.p. 108.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCC2CCCCC2)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of the product from Example 24 (0.20 g, 0.42 mmol) and bromomethylcyclohexane (0.6 μL, 0.45 mmol) in DMF (2 mL) was added sodium hydride (60% in dispersion oil, 0.016 g, 0.42 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and warmed to room temperature. The reaction mixture was poured into a separatory funnel containing ethyl acetate (50 mL) and water (50 mL). The organic phase was collected, washed with brine, and dried. The residue was purified by chromatography (silica gel, ethyl acetate/hexane) to give the title compound (0.13 g).
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>O1CCOCC1>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@H:17]4[CH2:21][NH:20][C:19](=[O:22])[CH2:18]4)[CH3:16])=[CH:13][C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2ccccn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 130 °C
Yield: 18.1 %

Procedure:
Into a microwave-tube, a mixture of (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.275 mmol), 2-(tributylstannyl)pyridine (152.0 mg, 0.412 mmol) Bis(triphenylphosphine)palladium(II) dichloride (28.9 mg, 0.04 mmol) and dioxane (8 mL). The reaction mixture was placed in the microwave reactor and heated at 130° C. for 30 min. Quenched with saturated KF, extracted with EtOAc (3×30 ml). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH/EtOAc) to give 18.0 mg (18.1%) of (R)-4-((R)-1-((1-cyclopropyl-5-(pyridin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=7.5 Hz 1H), 8.127 (s, 1H), 8.04 (d, J=9.6 Hz 1H), 7.90-7.81 (m, 2H), 7.62 (d, J=0.9 Hz 1H), 7.60 (s, 1H), 7.324-7.283 (m, 1H), 4.856-4.815 (m, 1H), 3.742-3.695 (m, 1H), 3.41 (t, J=9.5 Hz, 1H), 3.21 (dd, J=6.3, 6.9 Hz, 1H), 2.862-2.811 (m, 1H), 2.426-2.24 (m, 2H), 1.33 (d, J=6.6 Hz, 3H), 1.266-1.016 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd C21H22N4O2:362.17; found 363.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: C1CCNCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCCCC5)n4)cc3)cc12

Procedure:
Using piperidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.6 (m, 6H); 2.98 (m, 2H); 3.55 (m, 2H); 3.84 (m, 4H); 7.19 (m, 2H); 7.49 (m, 2H); 7.93 (d, 2H, J=8 Hz); 8.20 (m, 31H); 8.44 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.14 (bs, 1H). MS (ion spray) m/z 451 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:31]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[C:11]3([CH2:31][O:10][C:8]=2[CH:9]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:12]3=[O:29]
Reactant: ClCI
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C3(COc4cc(F)c(C#N)cc43)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.50 g, 27.03 mmol) and chloroiodomethane (5.00 mL, 68.7 mmol) in tetrahydrofuran (200 mL) and N,N-dimethylformamide (50 mL) was added cesium carbonate (26.40 g, 81.02 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 20 h and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford 6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (5.27 g, 48%): mp 142-143° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.23 (m, 3H), 7.11-7.02 (m, 2H), 6.89-6.85 (m, 4H), 6.77 (d, J=9.0 Hz, 1H), 5.12-4.75 (m, 4H), 3.78 (s, 3H); MS (ES+) m/z 400.7 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1)(=O)=O.C(O)(=O)C.[Sn].Cl>O>[SH:2][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(S)cc2c1OCCO2
Temperature: 90 °C
Yield: 89.7 %

Procedure:
243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and 654 cm3 of acetic acid were introduced into a balloon flask provided with an agitator and a condenser. The mixture was heated to 90° C. and then cooled to 45° C. 389 g of tin and 1,744 cm3 of hydrochloric acid were then added. The mixture was heated to 55°-60° C., cooled and poured into water. The precipitate was dried off, washed and dried. 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 191°-192° C.; yield: 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)=[CH:3][N:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Brc1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: OCc1ccc(-c2ccnnc2)cc1
Yield: 63.7 %

Procedure:
To a solution of 4-bromopyridazine (131 mg, 0.824 mmol) in 1,2-dimethoxyethane (16.4 ml) were added 4-hydroxymethylphenylboronic acid (189 mg, 1.24 mmol), potassium carbonate (517 mg, 3.74 mmol) and water (8.2 ml), which was deaerated under reduced pressure, followed by argon substitution. Tetrakis(triphenylphosphine)palladium (73.5 mg, 0.0636 mmol) was then added, followed by heating to reflux for 5 hours under argon atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=0:1→1:4 (V/V), then methanol), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (97.7 mg) as a slightly brown solid. (Yield: 64%)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.O.O.O.O.O.O.O.O.O.[S-2:23].[Na+].[Na+].C(O[C:30](=O)[CH3:31])(=O)C>C(OCC)(=O)C.O.C(O)(=O)C>[CH3:31][C:30]1[S:23][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2cc(C(=O)O)ccc2s1
Temperature: 100 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
4-Chloro-3-nitrobenzoic acid (2.02 g, 10.00 mmol), sodium sulfide nonahydrate (7.22 g, 30.00 mmol) and water (5 ml) were suspended, and the mixture was heated at about 100° C. for 30 minutes. After being allowed to cool, the mixture was cooled by ice, and acetic anhydride (18 ml) and acetic acid (10 ml) were added to the mixture. The resulting mixture was heated under reflux for 2 hours and stirred at a room temperature for 15 hours. To the mixture, tap water and then ethyl acetate were added, and sulfur was removed by filtration. The ethyl acetate layer was washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.54 g, 80%) as a light-yellow powder.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.O1CCCC1.C([Li])CCC.[CH3:27][N:28]1[CH2:33][CH2:32]C(=O)[CH2:30][CH2:29]1>CCCCCC.O>[CH3:27][N:28]1[CH2:33][CH2:32][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:2]2)[CH2:30][CH2:29]1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (-60°) stirred solution of 2-bromobenzhydryl methyl ether in 38 ml. of tetrahydrofuran and 14 ml. of hexane is slowly added 53 ml. of 2.1 M n-butyllithium in hexane. After 2 hours, a solution of 10.7 g. of 1-methyl-4-piperidone in 15 ml. of tetrahydrofuran is added dropwise, and the suspension is stirred at -60° for 3 hours and at room temperature for 15 hours. Ice and water are added and the mixture is extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to a mixture of 4-hydroxy-4-(α-methoxy-α-phenyl-2-tolyl)-1-methylpiperidine and benzhydrol methyl ether. This oil is heated under reflux for 30 minutes if 240 ml. of acetic acid containing 60 ml. of hydrochloric acid. Dilution with water and addition of excess sodium hydroxide effects precipitation of a solid. Recrystallization from hexane provides 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], m.p. 123°-124°.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH:23](O)[CH:24]1[CH2:26][CH:25]1[C:27]#[N:28].[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[NH:36][CH:35]=[CH:34]2>ClCCCl>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:23]([C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:13]=1[F:12])[CH:24]1[CH2:26][CH:25]1[C:27]#[N:28]
Reactant: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1F
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(C(F)(F)F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
1.63 g (7.35 mmol) of indium(III) chloride and 0.85 ml (11.0 mmol) of trifluoroacetic acid were added to 1.59 g (6.13 mmol) of the compound from Example 164A and 1.90 g (7.35 mmol) of the compound from Example 87A in 100 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 763 mg (27% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1.CO[C:20]1[CH:26]=CC(O)=C[CH:21]=1>O>[C:1]([O:6][CH:12]([CH2:7][CH3:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:21][CH2:20][CH3:26])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)O
Solvent: O
Product: C=C(C)C(=O)OC(CC)CCCCCCC
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 10-liter separable flask equipped with a stirrer, a condenser and a water separator, 2700 g of tricyclo[5.2.1.02,6 ]deca-8-ol (white crystal powder), 1896 g of methacrylic acid, 2700 g of toluence, 135 g of p-toluenesulfonic acid and 0.64 g of hydroquinone monomethyl ether were placed and reacted at 115° C. with stirring for 2 hours while removing the water generated out of the system. Then, the reaction solution was taken out of the flask and then subjected to distillation to remove low boiling point components. Then, 15 g of hydroquinone monomethyl ether was added to the resulting solution and distillation under reduced pressure was conducted to isolate a distillate having a boiling point of 90°-95° C. under 0.7 mmHg. The distillate was washed with an aqueous solution of 2% KOH, washed with water, dehydrated and filtered to give tricylo[5.2.102,6 ]deca-8-yl methacrylate (hereinafter referred to as "TCD-MA") in 80% yield and 99.5% purity.
Reaction SMILES: CS(NC1C=CC=CC=1)(=O)=O.[C:12]([C:15]1[CH:25]=[CH:24][C:18]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:16]=1)(=O)[CH3:13].Cl.[NH2:36][NH:37][C:38]([NH2:40])=[O:39].N1C=CC=CC=1>C(O)C>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[S:26][C:17]1[CH:16]=[C:15]([C:12](=[N:36][NH:37][C:38]([NH2:40])=[O:39])[CH3:13])[CH:25]=[CH:24][C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: CS(=O)(=O)Nc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NNC(N)=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 101.2 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide methanesulfonanilide (1.16 g), semicarbazide hydrochloride (0.4 g), and pyridine (0.29 ml) in ethanol (15 ml) was stirred and refluxed for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtered, washed with water, and recrystallized from methanol to give a powder of 3'-(2,4-difluorophenylthio)-4'-methanesulfonamidoacetophenone semicarbazone (0.92 g).
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CSc1ncnc2cnccc12
Product: c1ccc(CNc2ncnc3cnccc23)cc1
Temperature: 10 °C
Yield: 20 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (74 mg, 0.41 mmol) (see a previous experimental), and benzylamine (1 mL) is heated to 10° C. for 2 h. On cooling the mixture is concentrated under reduced pressure and purified directly by preparative tlc on silica gel eluting with CH2Cl2, to yield 4-(benzylamino)pyrido[3,4-d]pyrimidine (21.2 mg, 20%). 1H NMR (DMSO) δ 9.21 (1H, t, J=5.8 Hz), 9.19 (1H, s), 8.63 (1H, d, J=5.8 Hz), 8.58 (1H, s), 8.20 (1H, d, J=5.1 Hz), 7.41-7.30 (4H, m), 7.26 (1H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19])=[CH:11][C:10]=1[S:22]([Cl:25])(=[O:24])=[O:23].ClC(OCC)=O.CN>O1CCCC1.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:21])[N:3]([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[S:22]([Cl:25])(=[O:24])=[O:23]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reaction time: 0.12 h

Procedure:
2.1 g of triethylamine are rapidly added dropwise to a mixture of 6.2 g 4-(4-chloro-3-chlorosulfonylphenyl)-4-oxobutanoic acid and 2.2 g of ethyl chloroformate in 20 ml of absolute tetrahydrofurane at a rate such that the internal temperature is maintained between -5° and -10° C. The mixture is stirred for about 5 to 10 minutes at -5° to 0° C. and 1.55 ml of a 4% strength solution of gaseous methylamine in tetrahydrofurane is rapidly added dropwise. Stirring is continued for 15 to 20 minutes at 10°-15° C., the reaction mixture is poured into water and extracted twice, each time with 80 ml of ethyl acetate. The organic phase is washed once with 50 ml of 0.01 N hydrochloric acid at 0° C. and once with cold bicarbonate solution, dried for one hour over Na2SO4 at 0°-10° C. while stirring with a magnetic stirrer and concentrated on a rotavapor (bath temperature ≤30° C.). The 5-(4-chloro-3-chlorosulfonylphenyl)-5-hydroxy-1-methyl-2-oxo-pyrrolidine is mostly obtained in the form of an amorphous residue. After addition of 20 ml of 40% strength aqueous methylamine solution (cooling) the mixture is stirred overnight at room temperature, concentrated and allowed to crystallize under water. Colorless crystals, melting point 112°-114° C. (from ethanol).