Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][CH:13]([CH3:14])[N:9]3[C:10]=2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]3)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=O>CN(C)P(=O)(N(C)C)N(C)C>[N:20]1([C:2]2[C:11]3[CH2:12][CH:13]([CH3:14])[N:9]4[C:10]=3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]4)=[CH:4][C:3]=2[F:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=C1CCCN1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 39.8 %

Procedure:
A mixture of 56 g of 9-chloro-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid, 71 g of pyrrolidone and 60 ml of hexamethylphosphoric triamide in a stainless steel autoclave was reacted at 150° C. for 8 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure and the residue was recrystallized repeatedly from dimethylformamide to give 25 g of 9-(1-pyrrolidinyl)-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. not lower than 300° C., pale yellow rhombic crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)/[CH:5]=[N:13]/[C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1cc(Cl)cc([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2cc(Cl)cc([N+](=O)[O-])c2)cc1
Yield: 1085.6 %

Procedure:
To a solution of 3-chloro-5-nitrobenzaldehyde (371 mg, 0.1 mmol) in ethanol (6 mL) was added methyl 4-aminobenzoate (302 mg, 2.0 mmol). After a while, solids precipitated from the resulting clear yellow solution. The precipitated solid was filtered and 346 mg of (E)-methyl 4-(3-chloro-5-nitrobenzylideneamino)benzoate as a yellow solid was obtained. Yield=54%.
Reaction SMILES: C(O[C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:9][CH:6]1[CH2:7]2)(=O)C.N.[Na]>CCOCC>[C:10]1([CH:5]2[CH:6]3[CH2:9][CH:8]2[CH2:7]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC1(c2ccccc2)C2CC1C2
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: c1ccc(C2C3CC2C3)cc1
Temperature: -78 °C
Yield: 0.1 %

Procedure:
A solution of 2-phenylbicyclo[1.1.1]pentan-2-yl acetate (2.7 g, 13.4 mol) in 50 mL of anhydrous ether was placed in a three-necked flask. The flask was cooled to −78° C., and 150 mL of liquid ammonia was added. To the stirring mixture was added sodium (0.62 g, 27.0 mmol) in small pieces over a period of 10 minutes. Stirring was continued until the blue color was discharged. The reaction was quenched by the addition of saturated aqueous ammonia chloride solution (5 mL), and the solvent was allowed to evaporate overnight. Pentane (40 mL) was added to the residue, and the solution was washed with 30 mL saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The crude product was purified by column chromatography (100% pentane) to give the desired compound as a colorless liquid (1.8 g, 12.5 mmol, yield: 93%). 1H NMR (300 MHz, CDCl3) δ ppm 7.40-7.21 (m, 5H), 3.48 (d, J=6.9 Hz, 1H), 2.81 (s, 2H), 2.20 (dd, J1=9.9 Hz, J2=2.7 Hz, 1H), 2.00 (d, J=2.1 Hz, 1H), 1:94-1.85 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)#[N:2].[N-:42]=[N+:43]=[N-:44].[Na+].[Cl-].[NH4+].O>CS(C)=O>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][C:32]([C:29]2[N:21]3[C:20]([CH2:19][N:18]([C:16]([C:13]4[CH:12]=[CH:11][C:10]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH2:3][C:1]5[NH:44][N:43]=[N:42][N:2]=5)=[CH:15][CH:14]=4)=[O:17])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH2:22]3)=[CH:31][CH:30]=2)=[O:33])[CH:37]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3Cc3nnn[nH]3)cc1)C2
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 0.537 g (0.001 mol) of 10-{[2′-(cyanomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 17, 0.32 g (0.005 mole) of sodium azide and 0.26 g (0.005 mole) of ammonium chloride in 20 mL of dimethyl sulfoxide was heated with stirring at 50° C. for three hours. The reaction mixure was poured into 100 mL of water, and the precipitated crude product was subjected to chromatographic purification giving 0.46 g of title compound, m.p. 164-167° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl>C1COCC1>[O:4]=[C:3]([CH2:5][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCc1cccc(Cl)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1cccc(Cl)c1
Yield: 63.7 %

Procedure:
Ethyl acetoacetate (78.6 g, 0.6 mole) was added to a slurry of sodium hydride (20.8 g of 75% dispersion in oil, 0.65 mole) in dry THF at 0° C. under nitrogen followed by addition of n-butyl lithium (390 ml, 1.6 M in hexane, 0.63 mole) by the method given in Description 1(a). 3-Chlorobenzyl chloride (100 g, 0.62 mole) was added and after work-up and purification by vacuum distillation the required product was obtained as a very pale yellowish green oil (97.3 g, 64%), δ(CDCl3) 7.3-6.9 (4H, m), 4.18 (2H, q, J=7 Hz), 3.42 (2H, s), 2.88 (4H, s), and 1.27 (3H, t, J=7 Hz).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][C:28]1[C:29]2[C:33]([CH:34]=[CH:35][CH:36]=1)=[N:32][N:31]([C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1)[CH:30]=2)(C(C)(C)C)(C)C>C1COCC1.CCOC(C)=O>[OH:26][CH2:27][C:28]1[C:29]2[C:33]([CH:34]=[CH:35][CH:36]=1)=[N:32][N:31]([C:37]1[CH:38]=[CH:39][C:40]([C:41]#[N:42])=[CH:43][CH:44]=1)[CH:30]=2
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2nn(-c3ccc(C#N)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2cc3c(CO)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
TBAF (1.3 eq., 1M in THF) was added dropwise to a solution of (C4) in dry THF (0.1 M) and allowed to stir at RT for 1 h. The reaction mixture was diluted with EtOAc and washed with 1N HCl (2×), sat. aq. NaHCO3, brine and dried (Na2SO4). Evaporation of the solvent yielded (100%) the title compound. 1H NMR (300 MHz, DMSO-d6, 300K) δ 9.33 (1H, s), 8.36 (2H, d, 8.5 Hz), 8.11 (2H, d, J=8.2 Hz*−), 7.62 (1H, d, J=8.5 Hz), 7.36 (1H, t, J=7.3 Hz), 7.12 (1H, d, J=6.6 Hz), 5.36 (1H, bt, J=5.4 Hz), 4.84 (2H, d, J=5.2 Hz). MS (ES+) C15H11N3O required: 249, found: 250 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([NH:26][CH:27]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=1)[C:28]([NH:30][CH2:31][CH:32]([OH:39])[CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][CH3:36])=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:26][CH:27]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=1)[C:28]([NH:30][CH2:31][C:32](=[O:39])[CH2:33][C:34]([CH3:37])([CH3:38])[CH2:35][CH3:36])=[O:29])(=[O:25])[CH3:24]
Reactant: CCC(C)(C)CC(O)CNC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (2.94 g, 6.92 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)-N-(2-hydroxy-4,4-dimethylhexyl)propanamide (1.43 g, 3.46 mmol) in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% acetone/methylene chloride afforded 2-(acetylamino)-3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH:10]1([CH2:16][CH2:17]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH:10]1([CH2:16][CH2:17][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrCCC1CCCCC1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(CCC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Imidazole-4-carboxaldehyde (4.8 g, 50 mmol) was added portionwise to a suspension of sodium hydride (2.20 g, 60% dispersion in mineral oil, 55 mmol) in tetrahydrofuran (150 ml), and the mixture was then stirred at room temperature for 1 hour. 2-Cyclohexylethyl bromide (8.6 ml, 55 mmol) was added, and the mixture was heated under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was partitioned between water (500 ml) and dichlorornethane (500 ml). The layers were separated, and the organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of toluene:ethyl acetate (100:0 to 96:4) to afford the title compound, 1.78 g. 1H-NMR (CDCl3, 400 MHz) δ: 0.98 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H), 4.00 (t, 2H), 7.4 (s, 1H), 7.60 (s, 1H), 9.80 (s, 1H). LRMS: m/z (TSP+) 207.2 [MH+].
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19](=[O:33])[CH:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)C(OC)=O>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][CH2:20][C:19]([NH2:18])=[O:33])=[CH:31][CH:30]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(N)cc1)C(N)=O
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: NC(=O)CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 23.2 %

Procedure:
Following general procedure A1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.060 g, 0.23 mmol) was reacted with methyl 3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.050 g, 0.23 mmol) to afford the title compound (0.021 g, 23%) as a light brown solid. The intended product (methyl 3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-oxopropanoate) was very minor and not isolated. MW=392.88. 1H NMR (DMSO-d6; 500 MHz) δ 8.78 (s, 1H), 8.30-8.21 (m, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.29 (s, 1H), 7.21 (d, J=8.5 Hz, 2H), 6.75 (s, 1H), 2.94-2.84 (m, 4H), 2.80 (t, J=7.5 Hz, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C.C(N(C(C)C)C(C)C)C.O>O1CCCC1>[C:35]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:34])[CH2:36][OH:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CO)Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), 2-chloro-2-oxoethyl acetate (273 mg, 2.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (518 mg, 4.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (140 mg, 57%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[C:4]([Cl:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>O1CCOCC1>[Cl:18][C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1)Oc1ccccc1
Yield: 68.5 %

Procedure:
To a mixture of 5-(4-amino-2-chlorophenyl)--3-(2-furanyl)-1,2,4-oxadiazole (0.75 g) and 0.56 g of potassium carbonate in 30 ml of dioxane is added 0.94 g of phenyl chloroformate. The resulting mixture is heated at reflux for 2 hours and concentrated to dryness. 50 ml of water is added to the residue and the resulting mixture is extracted three times with 300 ml of chloroform. The residue is recrystallized from benzene to yield 0.75 g of the title compound, melting point 184°-185.5°C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([NH:19][C:20]([C:22]2[N:23]([CH3:30])[CH:24]=[C:25]([N+:27]([O-])=O)[CH:26]=2)=[O:21])[S:12][C:13]=1[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:8]>CO.[Pd]>[NH2:27][C:25]1[CH:26]=[C:22]([C:20]([NH:19][C:11]2[S:12][C:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:31])=[O:8])[N:10]=2)=[O:21])[N:23]([CH3:30])[CH:24]=1
Reactant: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)NCCCN(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)CCc1sc(NC(=O)c2cc(N)cn2C)nc1C(=O)NCCCN(C)C
Reaction time: 3 h

Procedure:
N-[3-(Dimethylamino)propyl]-5-isopentyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxamide (265 mg, 0.588 mmol; see step (v) above) was suspended in methanol (25 mL) to which Pd/C-10% (300 mg) was added at 0° C. under a nitrogen with stirring. The reaction mixture was hydrogenated for 3 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr and methanol was removed under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([OH:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].CC1C=[CH:19][C:20](S(O)(=O)=O)=[CH:21][CH:22]=1.C1(=O)CCC1>C1(C)C=CC=CC=1>[C:19]12([O:14][C:11]3[CH:12]=[CH:13][C:8]([C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]4)=[CH:9][C:10]=3[O:15]1)[CH2:20][CH2:21][CH2:22]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Agent: O=C1CCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Yield: 461 %

Procedure:
To a solution of 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (1.0 g, 4.8 mmol) in toluene (30 mL) was added TsOH (0.10 g, 0.50 mmol) and cyclobutanone (0.70 g, 10 mmol). The reaction mixture was heated at reflux for 2 h before being concentrated under vacuum. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 15:1) to give methyl 1-(spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-5-yl)cyclopropanecarboxylate (0.6 g, 50%). 1H NMR (CDCl3 300 MHz) δ 6.78-6.65 (m, 3 H), 3.62 (s, 3 H), 2.64-2.58 (m, 4 H), 1.89-1.78 (m, 2 H), 1.56-1.54 (m, 2 H), 1.53-1.12(m, 2 H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].S(=O)(=O)(O)O.[I:22](O)(=O)(=O)=O.II>C(O)(=O)C.O>[I:22][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:3]2
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Yield: 483.7 %

Procedure:
Intermediate 1 (1.75 g, 7.32 mmol) was dissolved in glacial acetic acid (30 ml) and then treated with concentrated sulfuric acid (0.8 ml) followed by water (2.8 ml) with stirring. This mixture was then treated with periodic acid (0.23 eq., 0.38 g, 1.67 mmol) then iodine (0.43 eq., 800 mg, 3.15 mmol), and the whole mix was stirred at 60° C. for 3-4 h. The reaction mixture was allowed to cool and then partitioned between ethyl acetate and 10% aqueous sodium metabisulfite. The organic layer was separated and dried over sodium sulphate and evaporated in vacuo to give the title compound as a yellow oil (2.95 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH2:8]Cl>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH2:8][C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CC#N)cc1C
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 6.8 g of 90% sodium cyanide dissolved in 6.5 ml of distilled water while being subjected to heating was added a solution of 15.5 g of 3,4-dimethylbenzyl chloride in 20 ml of dry ethanol; and the resultant mixture was heated at the boiling temperature for 10 hours and then cooled to room temperature. This solution was added to 50 ml of distilled water and extracted twice with 150 ml of ethyl ether. The organic solvent was removed to obtain 11.5 g(yield 79%) of 3,4-dimethylbenzyl cyanide, which was dissolved in 50 ml of dry tetrahydrofuran. The organic solution was slowly added to a dispersion of 6.0 g of LiALH4 suspended in 150 ml of dry tetrahydrofuran; and the mixture was heated at the boiling point for 14 hours. This reaction mixture was cooled to room temperature; and 16 ml of 1N NaOH and 8 ml of distilled water were slowly added thereto. Thereafter, this reaction mixture was filtered through a Celite layer to obtain solids, which were dissolved in a mixture of 250 ml of ethyl ether and 250 ml of ethyl alcohol and filtered. After the filtrate was basified with 5N NaOH aqueous solution and extracted with dichloromethane(200 ml×2), the solvent was evaporated and distilled under reduced pressure to provide 5.6 g(yield 48%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:17])[C:15]=1Cl)[C:5]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[F-:18].[K+].S1(CCCC1)(=O)=O>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:17])[C:15]=1[F:18])[C:5]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6]
Reactant: [F-]
Reactant: CC(C)(C)COC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)COC(=O)c1cc(Cl)c(F)c(Cl)c1
Reaction time: 6 h
Yield: 63.3 %

Procedure:
The reaction was conducted in the same manner as in Example 1 for 6 hours by using 8.9 g (30 mmol) of neopentyl 3,4,5-trichlorobenzoate instead of neopentyl 2,3,4,5-tetrachlorobenzoate in Example 1, 2.6 g (45 mmol) of spray-dried potassium fluoride, 1.3 g (3 mmol) of tetraphenyl phosphonium bromide and 9 g of anhydrous sulfolane. The post-treatment was conducted in the same manner, followed by distillation under reduced pressure to obtain 5.3 g of neopentyl 3,5-dichloro-4-fluorobenzoate. Further, the distillation residue was subjected to silica gel column chromatography and eluted with benzene to obtain 2.0 g of neopentyl 3,5-dichloro-4-fluorobenzoate as slightly yellow plates. The combined yield was 87%. The physical properties are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O>CC#N>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1nc(Br)c2cc(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 12.9 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (1 mmol, 293 mg), N-bromosuccinimide (1.2 mmol, 214 mg) and anhydrous MeCN (10 mL) was stirred at ambient temperature for 4 days before silica gel was added and the mixture was concentrated in vacuo. The residue was added on top of a chromatography column filled with silica gel. Elution with hexanes:ethyl acetate=75:25 gave the title compound as an off-white solid (48 mg); MS-(+)-ion: M+1, 79Br/81Br=372.4 and 374.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.Cl.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[I:28])[CH2:17][CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([I:28])=[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6](=[O:1])[CH3:5])[CH2:16][CH2:17]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2I)CC1
Reactant: C1COCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cc(Cl)ccc2I)CC1
Reaction time: 8 h

Procedure:
Add a 4N HCl dioxane solution (604 μL, 2.42 mmol) to a solution of 4-(5-chloro -2-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (prepared according to preparation 70, 170 mg, 0.40 mmol) in CH2Cl2 (6 mL) at room temperature under argon, and stir the mixture overnight. Add triethylamine (450 μL, 3.20 mmol), DMAP (catalytic amount) and acetyl chloride (56 μL, 0.80 mmol), and stir the mixture overnight. Quench the reaction by addition of Et2O, wash with 1N NaOH and water, dry over MgSO4 and concentrate to afford 1-[4-(5-chloro-2-iodo-phenyl)-piperidin-1-yl]-ethanone. Purify the crude product by flash chromatography on silica gel, eluent hexane/EtOAc 3:2 (65% yield). Follow a procedure similar to preparation 49 substituting 1-[4-(5-chloro-2-iodo-phenyl)-piperidin-1-yl]-ethanone for 1-(5-chloro-2-iodo-phenyl)-pyrrolidine to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-cyclohexyl-4-(2-methoxycarbonyl-vinyl)-piperidine-1-carboxylic acid tert-butyl ester, 8, (2.64 g, 7.5 mmole) in methanol (30 ml) is added 10% palladium on carbon (120 mg) under argon. The mixture is purged with hydrogen and then stirred for two hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture is filtered through a short pad of Celite and the filtrate concentrated under reduced pressure. The crude product is purified over silica to afford 2.57 g (97% yield) of the desired compound.