Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[N-].[BrH:14].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:14][CH2:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=CC(=O)Cc1ccc(I)cc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CBr)Cc1ccc(I)cc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
1-Diazo-3-(4-iodophenyl)propan-2-one (13) (1.27 g, 4.43 mmol) was dissolved in acetic acid (20 mL) and cooled to 0° C. To this was added 47% hydrobromic acid (1.55 mL, 13.3 mmol) and stirred for an hour after warming to room temperature. After neutralization by adding saturated aqueous solution of sodium bicarbonate, the product was extracted with ethyl acetate (×3) and the organic layer was washed sequentially with saturated aqueous solution of sodium bicarbonate (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═7/1) to give 1-bromo-3-(4-iodophenyl)propan-2-one (16) as a colorless solid (1.42 g, 4.18 mmol, 94.4%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:4])[CH3:5]
Reactant: c1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Product: CC(O)(c1ccccc1)C(F)(F)F

Procedure:
1,1,1-Trifluoro-2-phenylpropan-2-ol was prepared from benzene and 1,1,1-trifluoroacetone by an AlCl3 -catalyzed Friedel-Crafts reaction.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)#[N:7].CI>CCCCCC.O1CCCC1>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]([P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[CH3:1])=[CH:21][CH:22]=1)#[N:7]
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOP(=O)(OCC)C(C)c1ccc(C#N)cc1
Temperature: -40 °C
Reaction time: 0.42 h

Procedure:
18.7 ml of a 1.6M solution of n-butyllithium in n-hexane are added dropwise with stirring at -50° C. to a solution of 7.5 g of diethyl 4-cyanobenzylphosphonate in 60 ml of tetrahydrofuran, the mixture is subsequently stirred at -40° C. for 25 minutes and 4.7 g of methyl iodide in 20 ml of tetrahydrofuran are then added dropwise at -40° C. After stirring overnight at ambient temperature, the mixture is evaporated down, the residue is taken up in ethyl acetate and washed with water, and the organic phase is dried and evaporated down. After purification by column chromatography on Silica gel (petroleum ether/2-propanol=6:1 to 2:1, v/v), 5.7 g of the title compound are obtained as a colourless oil. Rf value: 0.52 (Silica gel, petroleum ether/2-propanol=3:1, v/v).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Mg]Cl)(C)C.[Cl-].[Li+].[F:13][CH:14]([F:20])[C:15](OCC)=[O:16]>C1COCC1.C(OCC)(=O)C>[F:13][CH:14]([F:20])[C:15]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:16]
Reactant: c1cscn1
Reactant: CCOC(=O)C(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1nccs1)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
This procedure is based on literature, see: Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958. Thiazole (5.7 mL, 80 mmol) in THF (100 mL) was added to a stirred, cooled (0° C.) solution of isopropylmagnesium chloride-lithium chloride (1.18 M in THF, 74.9 mL, 88 mmol) in THF (75 mL) then the mixture was stirred at room temperature for 1 hour. Then the solution was cooled to −20° C. and ethyl difluoroacetate (9.29 ml, 88 mmol) was added. The mixture was stirred for 10 minutes at −20° C., then 10 minutes at room temperature. The mixture was diluted with ethyl acetate (200 mL), washed with aqueous ammonium chloride (saturated, 200 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chromatography on silica gel, 0-90% ethyl acetate in hexanes) to give 2,2-difluoro-1-(1,3-thiazol-2-yl)ethanone (12 g, 73.6 mmol, 92% yield) as a yellow oil. MS ESI: [M+H]+ m/z 164.0.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([CH3:10])[CH2:5][CH2:4]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[Cl:11][C:12]1[N:17]=[C:16]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:10])[C@H:7]([OH:9])[CH2:8]2)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a reactor was added (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (16.0 kg), 2,4-dichloropyrimidine-5-carboxamide (19.0 kg), K2CO3 (14.9 kg) and THF (160 L) at 25° C. The batch was cooled to 0° C., and water (160 L) was added. The batch was stirred for an additional 1 h at 0° C., warmed to 25° C. and held for 16 h. Water (288 L) was added to the batch while keeping the batch at 25° C., and the batch was cooled to 15° C. and agitated for an additional 4 hs. The batch was filtered, rinsed twice with water (2×80 L), and dried in a vacuum oven at 40° C. with nitrogen bleed for 24 h to give 2-chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as white powder (23.3 kg, 86% yield). 1H NMR (DMSO-d6) δ 0.93 (d, J=5.7 Hz, 3H), 0.97-1.29 (m, 4H), 1.63-1.68 (m, 1H), 1.75-1.88 (m, 1H), 2.09-2.13 (m, 1H), 3.00-3.08 (m, 1H), 3.80-3.95 (m, 1H), 4.65 (d, J=5.1 Hz, 1H), 7.69 (br. s., 1H), 8.20 (br. s., 1H), 8.53 (s, 1H), 9.22 (d, J=7.5 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[O:15][CH3:16])CC.[C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27]O)=[CH:20][CH:19]=1.C[CH:36]([O:38]C(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>>[C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:4]([O:38][CH3:36])[C:3]([OH:2])=[O:17])=[C:9]([O:15][CH3:16])[CH:10]=2)=[CH:20][CH:19]=1
Reactant: CCC(Cc1ccc(O)cc1OC)C(=O)OC
Reactant: OCCCOc1ccc(-c2ccccc2)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Product: COc1cc(OCCCOc2ccc(-c3ccccc3)cc2)ccc1CC(OC)C(=O)O

Procedure:
A mixture solution of 2-(4-hydroxy-2-methoxy-benzyl)-butyric acid methyl ester from Step C and 3-(biphenyl-4-yloxy)-propan-1-ol was reacted under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product, which afforded the title compound via the Standard hydrolysis procedure C (NaOH). MS(ES) for C26H28O6 [M+NH4]+: 454.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:29]O>CO>[CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15]3[CH:16]=[C:17]([OH:19])[O:18][N:29]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)CC(=O)OC(C)(C)C)c2C1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCCN(CCC)C1CCc2cccc(-c3cc(O)on3)c2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Di-n-propylamino-8-(t-butoxycarbonylacetyl)-1,2,3,4-tetrahydronaphthalene (prepared as in Example 6) (1.0 g, 3.3 mmol) was taken up in 25 ml methanol. Ten equivalents of hydroxylamine hydrochloride (8.3 g, 33 mmol) were added and the reaction stirred at room temperature for 48 hours. The solution was filtered to remove unused hydroxylamine hydrochloride. The mixture was then concentrated and three crystallizations were performed from methanol/ethylacetate. The title compound (30 mg) was recovered.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]([C:12]1[CH:21]=[C:20]([F:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10].O>C(COC)OC>[F:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([C:9]([OH:11])=[CH:10][C:3](=[O:5])[CH3:4])[CH:21]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2cc(C(C)=O)cc(F)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2cc(C(O)=CC(C)=O)cc(F)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of sodium hydride (0.048 mol) and ethyl acetate (4.22 g, 0.048 mol) in dry dimethoxyethane (10 ml) under nitrogen, was treated over 30 minutes at room temperature with a solution of 2-acetyl-4-fluoro-6-methoxynaphthalene (5.33 g, 0.024 mol) in dry dimethoxyethane (25 ml). The reaction mixture was then stirred at 50° C. for 31/2 hours. After cooling it was treated with water (50 ml) then dilute hydrochloric acid (50 ml) and the orange precipitate collected by filtration, washed with petrol and dried. Recrystallisation from methanol/ether gave 3.2 g product m.p. 107°-8° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: BrCc1ccccc1
Product: O=C1C(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
Prepare by the method of Example 17.2 using 1-benzyl-2-oxopyrrolidine and benzyl bromide to give the title compound: Rf=0.46 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:23])[CH:11]=[N+:12]([O-])[C:13]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]2=[O:24])=[CH:4][CH:3]=1.C[O-:28].[Na+:29]>C(OC(=O)C)(=O)C>[CH2:20]([O:19][C:17]([C:13]1[NH:12][C:11](=[O:28])[C:10]([O-:23])=[C:9]2[C:14]=1[CH2:15][CH2:16][N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]2=[O:24])=[O:18])[CH3:21].[Na+:29]
Reactant: C[O-]
Reactant: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1[nH]c(=O)c([O-])c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate 2-oxide (2.3 gm, 6.38 mmol) in neat acetic anhydride (24 mL) was stirred under nitrogen at 100° C. for 1 hour. The reaction was concentrated to an oil under reduced pressure and dry methanol (20 mL) was added followed by a methanolic sodium methoxide solution (30% by wt) (4.54 mL, 25.2 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to an oil under reduced pressure and crystallized from a small amount of methanol (˜5 mL). The crystals were collected by filtration, washed an additional 10 mL of methanol and dried in vacuo to give the desired product.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](O)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].N1C=CC=CC=1.[F:27]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([F:27])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoic acid (9) (1.7 g, 6.1 mmol) in DCM (20 mL) was added pyridine (0.53 g, 6.7 mmol), followed by 2,4,6-trifluoro-1,3,5-triazine (0.86 g, 6.4 mmol) dropwise. The reaction mixture was stirred for 4 h and TLC indicated completion of the reaction. The reaction mixture was washed with 10% aqueous citric acid and brine, dried over Na2SO4, and concentrated to provide the title compound (1.7 g, 100%) as red oil. 1H NMR (300 MHz, DMSO) δ ppm 0.86 (t, J=6.7 Hz, 3H), 1.16-1.38 (m, 4H), 1.57 (m, 2H), 3.03 (m, 1H), 3.87 (m, 2H), 4.91 (s, 2H), 7.41 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:22]([OH:21])[CH2:23][CH2:24][CH2:25][CH2:19][CH2:18][CH2:17][CH2:16][CH2:16][CH2:17][CH2:18][CH2:19][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1
Reactant: [Li]CCCC
Reactant: CC1(C)COC(c2ccc(Br)cc2Cl)=N1
Reactant: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(O)c1ccc(C2=NC(C)(C)CO2)c(Cl)c1
Reaction time: 3.5 h

Procedure:
A solution of the product of Example 4 (4 mmoles) in tetrahydrofuran (150 ml) was cooled to ca. -75° C. under an atmosphere of argon. n-Butyllithium (2 ml, 2.04M in hexane) was added by syringe over 15 min. while maintaining the reaction temperature below -70° C., and the solution then stirred for 3.5 hours. A cold solution (ca. -8° C.) of octadecyl aldehyde (4 mmoles) in tetrahydrofuran (100 ml) was canulated by syringe to the above solution over 25 min., keeping the temperature below -60° C. The reaction temperature rose to 25° C. during the next 2 hours, after which the reaction was quenched with water (10 ml) and stirred overnight. After removing the tetrahydrofuran under a nitrogen stream, water (75 ml) was added and the product extracted into ethyl acetate. The combined extract was dried over sodium sulfate, filtered and stripped under reduced pressure to give 1.7 g of an oil. The product was purified by chromatography on silica gel to give 0.85 g of the title compound, m.p. ca. 74°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=[O:21].C(O)(=O)C>C1COCC1.CCCCCC>[N+:23]([C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:22][C:19]=1[CH:20]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[OH:21])([O-:25])=[O:24]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Clc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To 16.75 g of 1,3-dichlorobenzene dissolved in 250 ml of THF are added dropwise, at −70° C., 68 ml of a 1.6M solution in hexane of n-butyllithium. After one hour at −70° C., 10 g of 5-chloro-2-nitrobenzaldehyde dissolved in THF are introduced and the mixture is left for 3 hours at this temperature. The resulting mixture is hydrolysed by addition of 5 ml of acetic acid and is allowed to warm to room temperature. The resulting mixture is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 7.975 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[N:19]=[C:5]2[N:6]([CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:20].[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:1][C:2]1[N:19]=[C:5]2[N:6]([CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH3:23])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:20]
Reactant: CI
Reactant: Cc1nc2n(CC(O)c3ccccc3)cccc-2c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(Cn1cccc2c(C)c(C)nc1-2)c1ccccc1
Yield: 65 %

Procedure:
A solution of 2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine (as the base) (266 mg, 1.0 mmol) in 25 ml dry THF was deaerated and treated with 55% NaH dispersion in oil (48 mg, 1.1 mmol) for 30 min. Methyl iodide (62 μl, 1.0 mmol) was added and allowed to react for 50 min. The solvent was evaporated and the residue partitioned between 100 ml CH2Cl2 and 20 ml 5% NaOH. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed (silica, CH2Cl2 saturated with NH3). Pure fractions were pooled and evaporated leaving a gum which partly crystallized. Trituation with diethyl ether furnished 207 mg (65%) pure title compound.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:19][C:16]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]2[NH:9][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C1CCCCC1Br
Product: Cc1cc(C(=O)O)c2[nH]c3c(c2c1)CCCC3
Yield: 55 %

Procedure:
Under the conditions of Example 60, 2-bromocyclohexanone is reacted with the methyl ester of 2-amino-5-methylbenzoic acid; after recrystallization from cyclohexane, the methyl ester of 3-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is obtained in a 55% yield, m.p. 111° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[C:16]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:26](=[O:27])[CH2:25][CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution containing 1.0 eq each of 1-(3-nitropyridin-4-yl)piperazine, N-Boc-beta-alanine, HOAT and EDC in DCM, at a concentration of 0.1 M, was stirred for 16 hours. The solution was diluted with EtOAc and was washed with H2O, Na2CO3(sat), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl 3-(4-(3-nitropyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (93%). LCMS (m/z): 379.9 (MH+); LC Rt=1.92 min.
Reaction SMILES: ClC(=C)[CH2:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].C(C1C=C(SC2C=C(C)C(O)=C(C(C)(C)C)C=2)C=C(C)C=1[OH:30])(C)(C)C.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+].[Cl:62][CH2:63][CH2:64]Cl>>[Cl:62][CH2:63][C:64](=[O:30])[CH2:3][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6]
Reactant: C=C(Cl)CC(C#N)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: ClCCCl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: N#CC(CC(=O)CCl)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A 265 g. portion of 4-chloro-2,2-diphenyl-4-pentenenitrile and 3.84 g. of bis(3-t-butyl-4-hydroxy-5-methylphenyl) sulfide were dissolved in 1 liter of 1,2-dichloroethane and heated to the reflux temperature, about 75°-80° C. To the mixture was added dropwise a solution of 276.9 g. of 3-chloroperbenzoic acid dissolved in 2.5 liters of 1,2-dichloroethane. The resulting solution was heated for 24 hours, and was then cooled to ambient temperature. Sodium sulfite solution was added until starch-iodide paper showed a negative test for peracid. The reaction mixture was then made basic by the addition of 135 g. of sodium bicarbonate in saturated aqueous solution, and the organic layer was then separated, washed with water and dried over sodium sulfate. The solvent was then evaporated away under vacuum to obtain 294.5 g. of crude product, which was crystallized from ethanol to obtain 194.3 g. of the product named in the heading, m.p. 102°-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C[O-].[Na+].[C:12](O)(=[O:14])C>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:14][CH3:12]
Reactant: CC(=O)O
Reactant: N#Cc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 6 h

Procedure:
2-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in methanol (50 ml). Sodium methoxide (0.26 g, 4.8 mmol) was added to the solution, and reaction was conducted for 6 hours at room temperature. After the reaction was completed, acetic acid (0.32 g, 5.3 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (50 ml) was added to the concentrated residue, and diethyl ether insoluble products were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-pyridinecarboximidate as a pale yellow oil in a yield of 7.5 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(F)c1

Procedure:
Into a 2000-mL round-bottom flask maintained with a nitrogen atmosphere, was placed a solution of methyl 3-fluoro-4-nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl acetate:methanol=1:1 (1000 mL). Then Pd/C (10 g, 10 wt %, Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred fo(16 h under a hydrogen atmosphere at 30°C. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the deisred product methyl 4-amino-3-fluorobenzoate.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(Cl)Cl>CN(C=O)C.O>[N:1]1([C:10]2[N:11]=[C:12]([Cl:17])[CH:13]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)nc(-n2cnc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Clc1cc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
The obtained 2-(benzimidazol-1-yl)-4,6-dichloropyrimidine (2.08 g, 7.85 mmol) dissolved in DMF(30 ml) was cooled to −5° C., added with anhydrous potassium carbonate (3.0 g, 22 mmol) and morpholine (0.68 g. 7.85 mmol) and stirred for 30 minutes. The reaction mixture was further stirred at room temperature overnight and condensed under reduced pressure. The residue was added with methylene chloride and water and shaken for mixing. The organic layer was separated out and washed with water, dried over anhydrous magnesium sulfate and condensed. The obtained residue was purified by silica gel column chromatography to obtain 1.90 g (yield 77%) of 2-(benzimidazol-1-yl)-4-chloro-6-morpholinopyrimidine with melting point of 178° C.-181° C.