Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]2[CH3:29])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cc2c(-c3ccccc3)n(C)c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 67 h
Yield: 97.9 %

Procedure:
To a solution of methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (500 mg) in N,N-dimethylformamide (5.4 mL) were added cesium carbonate (1.09 g) and methyl iodide (0.168 mL), and this mixture was stirred at room temperature for 67 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (508 mg). 1H-NMR (CDCl3) δ ppm: 3.61 (3H, s), 3.89 (3H, s), 4.02 (3H, s), 4.35 (2H, s), 6.74 (1H, dd, J=2.3, 8.5 Hz), 6.84 (1H, d, J=2.3 Hz), 7.12-7.18 (1H, m), 7.28 (1H, d, J=8.5 Hz), 7.33-7.49 (5H, m), 7.59 (1H, t, J=7.8 Hz), 7.88-7.94 (1H, m).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[B-](F)(F)F.[CH2:27]([N+:34]1[CH2:35][CH2:36][CH2:37][C:38]=1OCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:34]1[CH2:35][CH2:36][CH2:37][C:38]1=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([O:20][CH3:21])=[O:19])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC1=[N+](Cc2ccccc2)CCC1
Reactant: COC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=C1CCCN1Cc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium hexamethyldisilazide solution (8.39 mL of 1M in tetrahydrofuran, 8.39 mmol) was added to dry THF and cooled to −78° C. Methyl phenylacetate (1.15 mL, 7.99 mmol) was added dropwise, and the reaction stirred for 15 minutes. A solution of 1-benzyl-5-ethoxy-3,4-dihydro-2H-pyrrolium tetrafluoroborate in 5 mL of tetrahydrofuran was added dropwise, and after one hour the reaction was allowed to warm to room temperature. The mixture was quenched with saturated NaHCO3 solution, warmed to ambient temperature and poured into water. The aqueous layer was extracted with EtOAc and the organic extract was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (25-30% EtOAc/hexane), providing methyl 2-(1-benzylpyrrolidin-2-ylidene)(phenyl)acetate. ESI+MS: 308.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31](B(O)O)=[C:30]([O:38][CH3:39])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:17]([F:26])=[C:18]([F:25])[C:19]([F:24])=[C:20]([F:23])[C:21]=4[F:22])(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1cc(Cl)c(F)cc1B(O)O
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+]
Product: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 50 °C
Yield: 85.3 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 1.7 g, 4.15 mmol), (4-chloro-5-fluoro-2-methoxyphenyl)boronic acid (INTERMEDIATE FFFFF; 1.272 g, 6.22 mmol), potassium carbonate (1.720 g, 12.45 mmol), and Pd(PPh3)4 (0.479 g, 0.415 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (15.56 ml) and water (5.19 ml) were added. The flask was fitted with a reflux condenser and heated in a 50° C. heating bath for 1 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give perfluorophenyl 1-(4-chloro-5-fluoro-2-methoxyphenyl)isoquinoline-6-sulfonate (1.89 g, 3.54 mmol, 85% yield) as a white foam. m/z (ESI) 534.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:17]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[N:4][CH:5]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)c1ccc(-c2cncc(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cccc(-c2cncc(-c3ccc(C(C)C)cc3)c2)c1
Temperature: 80 °C
Yield: 66.3 %

Procedure:
Part B. A solution of 3-bromo-5-(4-isopropyl-phenyl)-pyridine (300 mg, 1.1 mmol) and 3-carboethoxybenzeneboronic acid (180 mg, 1.1 mmol) in ethanol-toluene-water (10 mL/5 mL/3 mL) is treated with sodium carbonate (345 mg), degassed twice and treated with a catalytic quantity of tetrakis(triphenylphosphine)palladium. The mixture is heated to 80° C. with stirring until the starting material is consumed as determined by TLC. Then, the mixture is cooled, filtered and evaporated, and the residual material is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated, and the residue is separated by column chromatography to afford ethyl 3-[5-(4-isopropyl-phenyl)-pyridin-3-yl]-benzoate (252 mg, 79%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:13]([N+:15]([O-])=O)[CH:14]=1)C1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O.C(Cl)(Cl)Cl>C(O)(=O)C.[C].[Pd]>[CH3:27][S:28]([NH:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:30])=[O:29]
Reactant: COc1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Oc2ccc(O)cc2NS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 119.4 %

Procedure:
1.8 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene was dissolved in 40 ml of acetic acid. 200 mg of 5% palladium-carbon was added thereto. The mixture was subjected to hydrogenation at room temperature at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The residue was mixed with 7 ml of methylene chloride and 1.10 ml of pyridine to obtain a solution. Thereto was dropwise added 400 mg of methanesulfonyl chloride in 5 minutes at 5°-10° C. Stirring was conducted for 1 hour at the same temperature. 20 ml of water and 20 ml of chloroform were added thereto. The resulting organic layer was separated and washed with 20 ml of 2N hydrochloric acid and 200 ml of water. The organic layer was mixed with a 5% aqueous sodium hydroxide solution. The aqueous layer was separated and adjusted to pH 2 with 6N hydrochloric acid. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography [eluant: a 10 : 1 mixture of toluene and ethyl acetate] to obtain 1.29 g (yield: 81.6%) of 3-methylsulfonylamino-4-(4-methoxyphenoxy)phenol.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.O.[NH2:25]N.[C:27]([OH:30])(=[O:29])[CH3:28].COC(OC)[N:34]([CH3:36])C>>[C:27]([OH:30])(=[O:29])[CH3:28].[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]3[NH:23][CH:36]=[N:34][N:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (79 mg, about 0.23 mmol) produced above in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, hydrazine monohydrate (0.017 mL, 0.35 mmol) and acetic acid (2 mL) were added to the residue, and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and the resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (27.8 mg, 33%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1Cl
Product: Cc1ccc(C(=O)Cl)cc1Cl

Procedure:
3-Chloro-4-methylbenzoyl chloride is prepared by refluxing together 30 g. (0.175 mole) of 3-chloro-4-methyl benzoic acid and 85 ml. thionyl chloride for about 2.5 hours, after which the excess thionyl chloride is distilled off under vacuum. The aroyl chloride product, 3-chloro-4-methylbenzoyl chloride, distills over at b.p. 70°-74°C., 10.25 mm. Hg.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1>ClCCCl>[Br:1][C:12]1[C:13](=[O:16])[CH2:14][CH2:15][C:11]=1[O:10][CH3:9]
Reactant: COC1=CC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: COC1=C(Br)C(=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
N-Bromosuccinimide (24.92 g, 0.140 mol) is added, portionwise over one hour, to a stirred solution of 3-methoxycyclopent-2-enone (14.95 g, 0.133 mol) in 1,2-dichloroethane (300 ml) at 0° C. in an amber flask. The reaction is stirred at 0° C. for a further 90 minutes and then any remaining solid is removed by filtration. The filtrate is evaporated under reduced pressure, and the residue is dissolved in warm toluene (600 ml) and washed quickly with ice-cold water (2×100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure until approximately 150 ml remains. The flask is cooled in an ice bath and left for 30 minutes. The resultant precipitate is removed by filtration, washed with hexane (50 ml) and dried to give 2-bromo-3-methoxycyclopent-2-enone (17.5 g, 69%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:36][CH2:35][CH2:34][N:25]1[C:26](=[O:33])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]1=[O:23])[CH:19]([CH3:20])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)nc(C(N)C(C)C)n2Cc1ccccc1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(C(NCCCN1C(=O)c3ccccc3C1=O)C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (0.56 mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114 mg, 0.56 mmol) in dry DCM (3 mL) at room temperature, was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). After 10 min., acetic acid (34 μl, 0.56 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give crude material that was used in step 7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[C@@H:12]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH2:13][N+:14]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O1CCCC1.O>O1CCCC1>[NH2:14][CH2:13][C@H:12]([C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23])[C:11]1[CH:24]=[CH:25][CH:26]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NC[C@@H](c1cccc(OCc2ccccc2)c1)[C@H]1CCCC[C@H]1O
Reaction time: 8 h

Procedure:
A solution of 106.6 g (0.3 mol) of rac-(2S*)-2-[(R*)-3-(benzyloxy)-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added drowpise while stirring within about 3 hours to a suspension of 28.6 g (0.75 mol) of lithium aluminium hydride in 500 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 55°. The reaction mixture is stirred at 50° overnight, treated, after cooling, with 40 ml of ethanol and subsequently with 200 ml of tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The residue is crystallized from methylene chloride/isopropyl ether, there being obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-3-(benzyloxy)benzyl]cyclohexanol in the form of colourless crystals of m.p. 139°-141°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=2[F:12])[C:5]([CH2:15][CH2:16][OH:17])=[CH:4]1)C.F[C:19]1[CH:20]=[C:21]([CH2:33][CH2:34]C2C=CC=CC=2)[C:22](OC)=[C:23]2[C:27]=1NC=C2CCO>>[F:12][C:10]1[CH:9]=[C:8]([CH2:34][CH2:33][C:21]2[CH:22]=[CH:23][CH:27]=[CH:19][CH:20]=2)[C:7]([O:13][CH3:14])=[C:6]2[C:11]=1[N:3]([CH3:1])[CH:4]=[C:5]2[CH2:15][CH2:16][OH:17]
Reactant: COc1c(CCc2ccccc2)cc(F)c2[nH]cc(CCO)c12
Reactant: CCn1cc(CCO)c2c(OC)ccc(F)c21
Product: COc1c(CCc2ccccc2)cc(F)c2c1c(CCO)cn2C
Yield: 69 %

Procedure:
Following the procedure (step 2, scheme 20) used to prepare compound 20-3, compound 23-2 gave compound 23-3 in 69% yield as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm: 7.22-7.29 (m, 5H), 6.79 (s, 1H), 6.70 (d, J=12.9 Hz, 1H), 3.90 (d, J=1.92 Hz, 3H), 3.84-3.89 (m, 2H), 3.74 (s, 3H), 3.05 (d, J=6.0 Hz, 2H), 2.9-2.96 (m, 4H), 2.11 (t, J=5.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:1].[Cl:20][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: NCC(O)CO
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl
Product: COc1ccc(-c2cc(NCC(O)CO)c3ccccc3n2)cc1Cl
Product: Cl

Procedure:
The title compound, m.p. 205-210° C., and MS: m/e=358 (M+), was prepared from 4-chloro-2-(3-chloro-4-methoxy-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].Cl.[CH2:12]([OH:14])[CH3:13]>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5](=[NH:6])[O:14][CH2:12][CH3:13]
Reactant: N#CCc1ccccc1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccccc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 2-chlorobenzyl cyanide (32.4 g, 0.214 mol) in ethanol (70 ml) was cooled to 5 ° C., then HCl gas was passed through with stirring for 30 minutes and the resultant mixture was allowed to stand at room temperature for 18 hours. Evaporation of the solvent and trituration with ether gave the desired product, which was used immediately without further purification. Yield 49.0 g (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1C(OC)=O.[CH3:13][Mg]I.S(=O)(=O)(O)O.CC[O:23][CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:24]([OH:23])([CH3:25])[CH3:13]
Reactant: COC(=O)c1c(F)cccc1Cl
Reactant: CCOCC
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Product: CC(C)(O)c1c(F)cccc1Cl

Procedure:
A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs,1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:21]2[CH2:26][C@@H:25]([C:27]#[N:28])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:40]([Si](C)(C)C)=[N+:41]=[N-:42].C([Sn](CCCC)=O)CCC>>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:21]2[CH2:26][C@@H:25]([C:27]3[N:40]=[N:41][NH:42][N:28]=3)[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2nn[nH]n2)CN(C(=O)OC(C)(C)C)C1
Yield: 58.3 %

Procedure:
To tert-butyl (3S*,5R*)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-cyanopiperidine-1-carboxylate (120 mg) were added azido(trimethyl)silane (55 mg) and dibutyl(oxo)stannane (5 mg), and the mixture was stirred with heating to reflux for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (75.5 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][N:15]=2)=[O:9])[N:6]=1.[CH2:19](O)[C:20](N)([CH2:23]O)[CH2:21][OH:22].C(OC(C)C)(C)C>C(Cl)Cl.C1(N=C=N)CCCCC1.C(Cl)Cl.CN(C=O)C>[CH:16]([C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([CH3:23])[CH3:19])[S:3][CH:4]=2)=[N:15][CH:14]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(N)n2)s1
Reactant: NC(CO)(CO)CO
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CC(C)C(=O)Nc1nc(CC(=O)Nc2ncc(C(C)C)s2)cs1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of isobutyrric acid (49 μl, 0.53 mmol) in CH2Cl2 (1.5 ml), N-cyclohexylcarbodiimide, N'-methyl polystyrene (0.4 g, loading 2 mmol/g, 0.798 mmol), Nhydroxybenzotriazole (0.072 g, 0.53 mmol) and a solution of 2-(2-amino-1,3-thiazol-4-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide (0.075 g, 0.266 mmol) in CH2Cl2 /DMF (0.4 ml/0.6 ml) were added. The reaction mixture was maintained under stirring at room temperature for about 8 days. After this time, PS-Trisamine (0.44 g, loading 3.62 mmol/g, 1.596 mmol) was added, stirring was continued for about 6 hours and then the mixture was filtered. The resin was washed with CH2Cl2 (1 ml×5), the organic layers were combined and evaporated to dryness to give, after trituration with diisopropyl ether the title compound.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:34]([CH3:37])(=[O:36])=[O:35])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:33])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:26][CH:27]=2)=[CH:18][C:17]1=[O:33]
Reactant: C[C@@](CCn1ccc(-c2ccc(-n3cccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@](CCn1ccc(-c2ccc(-n3cccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of hydrochloric acid (3.0 mL, 4.0 M in 1,4-dioxane) was added dropwise to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[4-(1H-pyrazol-1-yl)phenyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (58 mg, 0.11 mmol) in dichloromethane (3.0 mL) and methanol (0.6 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether, filtered, washed with heptane, and dried under reduced pressure to provide a light yellow solid (47 mg, 98%). MS (APCI) m/z 431.3 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 1.71 (s, 3H), 2.36-2.43 (m, 1H), 2.59-2.68 (m, 1H), 3.09 (s, 3H), 3.96-4.05 (m 1H), 4.30-4.40 (m, 1H), 6.56 (dd, J=1.8, 2.3 Hz, 1H), 6.93-6.95 (m, 2H), 7.76 (d, J=1.8 Hz, 1H), 7.82-7.92 (m, 5H), 8.31 (d, J=2.3, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](Br)Br)=[C:5]([CH:12](Br)Br)[CH:4]=1.[I-].[Na+].[CH3:19][C:20]([CH3:22])=[O:21]>C(#N)C>[CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:9]=[C:22]1[C:19]([C:20](=[O:21])[C:22]3[CH:8]=[CH:3][CH:4]=[CH:5][C:19]=3[C:20]1=[O:21])=[CH:12]2
Reactant: C[Si](C)(C)c1ccc(C(Br)Br)c(C(Br)Br)c1
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(C)c1ccc2cc3c(cc2c1)C(=O)c1ccccc1C3=O
Yield: 79 %

Procedure:
A mixture of 0.1 mol of 4-trimethylsilyl-1,2-bisdibromomethylbenzene, 0.12-0.2 mol of substituted naphthoquinone, 0.6 mol of sodium iodide and 1000 ml of acetone or acetonitrile is boiled under reflux for 5 hours with stirring and under an N2 atomosphere. After cooling, the precipitate which has been deposited is filtered off and digested with water. The filtrate obtained in this way is evaporated to dryness and the residue is dissolved in CH2Cl2, washed with NaHSO3 and dried. The residue is then subjected to steam distillation and the non-volatile fractions are extracted with ether, dried and then sublimed. 8-Trimethylsilylnaphthacene-5,12-dione of melting point 168°-170° C. is obtained in a 79% yield. 2,3-Trifluoromethyl-8-methoxynaphthacene-5,12-dione is obtained in a 33% yield in an analogous manner by direct sublimation of the filtrate, melting point>280° C.