Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=2[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:42])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=2[C:24]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)OC(C)(C)C)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 7D (1.03 mg, 0.836 mmol) in CH2Cl2 (8 mL) at 0° C. under a nitrogen atmosphere, was added trifluoroacetic acid (3 mL) dropwise over two minutes. The reaction mixture was stirred at 0° C. for one hour and then stirred at room temperature for five hours. The reaction mixture was then concentrated and treated with ice cold water (50 grams). After stirring for fifteen minutes, the off-white precipitate was filtered, washed with water (5 mL) and dried to provide Intermediate 7E as a white solid: yield=500 mg (84%); HPLC: RT=2.282 (H2O/AcCN with NH4OAc, PUROSPHER® Star RP-18 (4×55) mm, 3 μm, gradient=3 min, wavelength=220 nm); MS(ES):m/z=572 [M−H+]; 1H NMR (DMSO-d6: as mixture of diastereomers) δ 10.67 (s, 1H), 9.51-9.54 (t, J=7.2 Hz, 1H), 7.5-7.6 (m, 3H), 7.5 (m, 2H), 7.1-7.3 (m, 4H), 6.771 (s, 1H), 5.29 (t, J=8.0 Hz, 1H), 3.7 (s, 3H), 2.80-2.91 (m, 1H), 2.70 (m, 1H), 2.50 (m, 1H), 2.10-2.34 (m, 3H), 1.50-1.90 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCCC2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 423.10 g/mol.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=C)[CH2:4][CH2:3]1.[O:12]=[O+][O-].O=O.S([O-])([O-])=O.[Na+].[Na+]>CO>[OH:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:9](=[O:12])[CH3:11]
Reactant: O=[O+][O-]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: O=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 10 h
Yield: 74.9 %

Procedure:
To a 500 ml reaction vessel, 70.0 g (453.8 mmol) of isopulegol and 140 ml of methanol were added and ozone generated in an oxygen stream by silent discharge was introduced into the reaction solution while the temperature of the solution was being kept between from 15° C. to 23° C. After 10 hours, disappearance of the raw material, isopulegol was confirmed by the gas chromatogram. The reaction solution obtained was cooled in an ice bath and then added into an excess amount of an aqueous sodium sulfite solution at a temperature of 30° C. or lower, followed by stirring for 2 hours. The solution was extracted with toluene. The toluene solution obtained was sequentially washed with dilute hydrochloric acid, an aqueous sodium carbonate solution, an aqueous ammonium chloride solution and brine, and was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by evaporation under a reduced pressure. The mixture obtained was crystallized by adding 350 ml of heptane, and the crystal obtained was washed with 50 ml of cold heptane followed by drying under vacuum to obtain 53.08 g (yield: 74.9%) of the titled compound as a colorless needle crystal.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH2:13])=[O:12])(O)=[O:2].Cl[C:15]1C=CC=CC=1Cl>>[CH3:15][N:13]1[C:11](=[O:12])[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:2]
Reactant: Clc1ccccc1Cl
Reactant: NC(=O)Cc1ccccc1C(=O)O
Product: CN1C(=O)Cc2ccccc2C1=O

Procedure:
A mixture of 2.28 g (11.8 mmol) of N-methyl-(2-carboxybenzeneacetamide and 24 ml of 1,2-dichlorobenzene is refluxed for 1 h and evaporated to dryness. The residue is recrystallized from EtOAc-hexane to give an off-white solid, 1.55 g (75%), mp 113-115° C.; MS (ES+) m/z 176.1 (M+H)+1.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN1C(=O)CCC1.O>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)N
Reactant: Cc1nnc2c(Cl)nc(Br)cn12
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nnc2c(NC(C)C)nc(Br)cn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1 (30.00 g; 121.2 mmol), isopropylamine (14.30 g; 242.44 mmol) and hünigbase (17.20 g; 133.33 mmol) are dissolved in 150 ml NMP and are stirred for 2 hours at 80° C. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is separated and dried over MgSO4 and evaporated to dryness.
Reaction SMILES: II.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1I.[B:12](OC)([O:15]C)[O:13]C.Cl>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[B:12]([OH:15])[OH:13]
Reactant: COB(OC)OC
Reactant: Fc1ccc(I)c(Cl)c1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)cc1Cl

Procedure:
To 1.05 g Mg in THF (20 mL) was added catalytic I2 and then a 1 mL portion of the 2-Chloro-4-fluoro-iodobenzene (10 g total, 39 mmol) was added. The mixture was stirred, slowly warmed, and an exothermic reaction began. The remainder of the 2-Chloro-4-fluoro-iodobenzene was added at a rate to maintain the exotherm and then the reaction was heated to THF reflux for 2.5 h, then cooled to 23°. The resulting mixture was added with rapid stirring to a −70° solution of trimethyl borate (4.53 mL, 40 mmol) in THF (40 mL). The reaction was stirred at <0° for 20 min and at 23° for 16 h, then poured into 2N HCl (150 mL), stirred 2 h, and the THF was removed under vacuum. The residual aqueous solution was extracted with Et2O (3×200 mL) and the combined extracts were dried (Na2SO4) and concentrated to afford a red solid. Trituration with hexane and drying afforded the title compound as a tan solid. (1.89 g, 28%). 1H-NMR CD3OD δ 7.09 (m, 1H), 7.21 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([O:12][CH2:13][C:14]([O:16]C)=O)[C:9](=[O:11])[CH3:10].Cl>C(O)(C)(C)C.CCOCC>[CH3:7][CH:8]1[C:9](=[O:11])[CH2:10][C:14](=[O:16])[CH2:13][O:12]1
Reactant: COC(=O)COC(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC1OCC(=O)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mechanically stirred solution of potassium tert-butoxide in tert-butanol (1 M, 203 mL) under a nitrogen atmosphere was treated with anhydrous ether (125 mL), cooled to 0° C., treated with the product from Example 84B (15.5 g, 97 mmol) in ether (55 mL) over 2 minutes, stirred for 10 minutes and then treated with 2M HCl (240 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×, 200 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel eluting with ethyl acetate:formic acid:water:hexane (200:1:1:200) to provide the title compound.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].I[CH2:25][CH3:26]>O>[CH2:25]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)[CH3:26]
Reactant: O=C1Nc2ccccc2Nc2ncccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ccccc2NC(=O)c2cccnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 15 g of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 150 ml DMF was heated to 50° C. To the slurry was added 7.5 g (2 equiv) of 50% sodium hydride in mineral oil dispersion, during which time the temperature rose to 65° C. The mixture was cooled to 40° C. and then 6.0 ml of iodoethane was added. The resulting mixture was stirred at room temperature overnight, then poured into 700 ml of water and extracted with 700 ml of ether. The ether phase was dried (MgSO4) and concentrated to dryness. The crude product was purified by column chromatography on basic alumina to yield 3.6 g (21% of theory) of 6,11-dihydro-11-ethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 210°-220° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[CH:3]=1.[CH:30]1([NH2:37])[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[N:5]=[C:6]([NH:36][CH:32]2[CH2:33][CH2:34][CH2:35][CH:30]([NH2:37])[CH2:31]2)[N:7]=1
Reactant: NC1CCCC(N)C1
Reactant: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC1CCCC(Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)C1

Procedure:
A mixture of Example 42b (1 g, 2.23 mmol), cyclohexane-1,3-diamine (0.509 g, 4.46 mmol) and triethylamine (0.62 mL, 4.46 mmol) in dioxane (25 mL) was heated at 60° C. for 2 hours. The reaction mixture was concentrated and used directly for the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][C:25]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C(F)(F)F)c3)CC2)cc1
Yield: 56.3 %

Procedure:
The title compound (D30) (35 mg) was prepared according sperimental procedure described in description 29 starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (40 mg, 0.13 mmol) and 4-fluoro-3-(trifluoromethyl)benzaldehyde (0.02 ml, 0.16 mmol)
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([OH:22])=[O:21])C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:27].[C:28](OCC)(=O)[CH3:29]>C(OCC)(=O)C>[ClH:27].[NH2:8][CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20]([O:22][CH2:28][CH3:29])=[O:21]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N(Cc1cc(C(=O)O)ccc1F)C(=O)OC(C)(C)C
Agent: Cl
Product: CCOC(=O)c1ccc(F)c(CN)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fluorobenzoic acid was dissolved in 10.0 mL of ethyl acetate, and 10.0 mL of a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was crystallized by addition of ethyl acetate and hexane to obtain 2.59 g of ethyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:28]([C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)(=[O:29])=[O:30])[CH2:9][CH3:10]
Reactant: CCC(N)Cc1sccc1Cl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](Cc1sccc1Cl)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Six grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Triethylamine (6.6 ml) is added in one portion followed by 7.8 g of 4-nitrobenzenesulfonyl chloride which had been previously dissolved in 10 ml of methylene chloride. After stirring for 1 hour at ambient temperature, the methylene chloride is removed under vacuum and 40 ml of methanol is added with warming to dissolve all solids. The resulting solution is poured into cold water, agitated for 30 minutes, filtered and washed with cold water, and the isolated material is dried in a vacuum oven to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-nitrobenzenesulfonamide (11.3 g) as a tan solid. MS: m/z (E1, 70EV) 375(10%). 1H NMR (200 MHz; CDCl3): δ 0.95 (3H, t, CH3), 1.7 (2H, m, CH2), 2.85 (2H, m, CH2), 3.5 (1H, m, CH), 6.65 (1H, d, CH), 7.0 (1H, d, CH), 7.9 (2H, d, Ph), 8.2 (2H, d, Ph).
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]([CH3:21])([CH3:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>CN(C=O)C>[C:3]1([S:9][C:11]([CH3:21])([CH3:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(Cl)C(=O)c1ccccc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Sc1ccccc1)C(=O)c1ccccc1
Temperature: 2 °C

Procedure:
10.88 g of a 50% suspension of sodium hydride in paraffin mineral oil are fed into 100 ml of DMF, followed slowly by 25.11 g of thiophenol. When dissolution is complete (65° C.), the solution is cooled to 2° C. and 36.5 g of 2-chloro-2-methylpropiophenone are fed in over 30 minutes maintaining the temperature below 10° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.ClC1C=CC(O[CH2:18][C:19]#[N:20])=CC=1.CC([O-])(C)C.[K+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:18][C:19]#[N:20])[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CC#N)n1
Temperature: -12.5 °C
Reaction time: 3 h

Procedure:
Under argon and in an anhydrous medium, 15 g (97.3 mmol) of 2-methoxy-5-nitropyridine and 17.9 g (107 mmol) of 4-chlorophenoxyacetonitrile are dissolved in 300 ml of anhydrous tetrahydrofuran; the solution is added by transfer to a solution of 24 g (214 mmol) of potassium tert-butylate in 220 ml of anhydrous tetrahydrofuran maintained at a temperature below −10° C. The reaction mixture is stirred for three hours at a temperature of from −10 to −15° C. An aqueous 5% hydrochloric acid solution (170 ml) is added dropwise to the reaction mixture, maintaining the temperature at −10° C. The mixture is extracted with ethyl acetate. After drying over magnesium sulphate and evaporation, the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 2:1). After washing with a petroleum ether/diethyl ether mixture (2:1), the title compound is obtained in the form of a brown product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12][C:13]1[CH:18]=[C:17](/[C:19](/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[C:34]#[N:35])=[N:20]\S(C(C)(C)C)=O)[CH:16]=[CH:15][N:14]=1>>[Br:12][C:13]1[CH:18]=[C:17]([C:19]2([C:2]3[CH:3]=[C:4]([CH3:11])[C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=3)[C:27]3[C:28](=[C:29]([F:33])[CH:30]=[CH:31][CH:32]=3)[C:34]([NH2:35])=[N:20]2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1ccnc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1c(C)cc(Br)cc1C
Product: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1C

Procedure:
The title compound was synthesized as described in Example 24i starting from 5-bromo-2-methoxy-1,3-dimethylbenzene (190 mg, 0.88 mmol) and (E)-N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) to give the title compound which was used without further purification (400 mg, quant.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(#N)C>[Br:19][C:16]1[CH:15]=[N:14][C:13]2[N:18]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:17]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ncc(Br)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(Br)cnc3n2)cc1
Temperature: 110 °C
Yield: 28.5 %

Procedure:
748 mg (corresponding to 3.5 mmol) of 2-bromo-4′-hydroxyacetophenone and 605 mg (corresponding to 3.5 mmol) of 2-amino-5-bromopyrimidine were dissolved in 30 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 15 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure. The resulting crude product was recrystallized from N,N-dimethylformamide, to obtain 289 mg (corresponding to 0.997 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyrimidine (FIG. 6, Step 2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO.[Br:17]Br>Br.O>[Br:17][CH2:13][C:12]([C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])=[O:14]
Reactant: CC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Reactant: BrBr
Agent: Br
Solvent: O
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(2,5-dimethyl-4-nitrophenyl)ethanone (300 mg, 1.55 mmol) in HBr (48%) (5 mL)/methanol (2.4 mL) was added bromine (250 mg, 1.55 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine and concentrated. The residue was purified with silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2-bromo-1-(2,5-dimethyl-4-nitrophenyl)ethanone as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13](=[O:31])[CH:12]=1>>[CH3:10][C:11]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13](=[O:31])[C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCCn1c(=O)cc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=S(=O)(O)O
Product: CCCn1c(=O)c([N+](=O)[O-])c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To concentrated sulfuric acid (2.0 ml) were added in ice bath fuming nitric acid (0.2 ml), 6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 21) (200.0 mg) and the resulting mixture was stirred for three hours in ice bath. The reaction mixture was poured into ice water, and the precipitated solids were collected by filtration to afford 6-methyl-5-nitro-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (219.0 mg).
Reaction SMILES: [Cl:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:21]1([C@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Cl:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:29][C@@H:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:28])=[O:6]
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)C1CC1(F)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)C1CC1(F)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-2-fluorocyclopropanecarboxylic acid (112 g, 809 mmol) in THF (2.0 L) was added 1,1′-carbonyldiimidazole (170 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 1 hour and then (R)-(+)-1-phenylethylamine (117.5 g, 971 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was extracted with ethyl acetate. The organic extract was washed with 2N aqueous HCl, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography on silica gel (solvent gradient: 15-33% ethyl acetate in petroleum ether) to yield 2-chloro-2-fluoro-N—((R)-1-phenylethyl)cyclopropanecarboxamide as a white solid (149 g, 50% yield over three steps).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].Br[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:12]([N:3]1[C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=2[S:1][C:2]1=[NH:10])[CH2:13][CH2:14][CH3:15]
Reactant: Nc1nc2c(s1)CCOC2
Reactant: CCCCBr
Solvent: CN(C)C=O
Product: CCCCn1c2c(sc1=N)CCOC2
Temperature: 25 °C
Yield: 101.3 %

Procedure:
A mixture of Example 96A (290 mg, 1.86 mmol) and 1-bromobutane (220 μL, 2.0 mmol) in DMF (400 μL) was heated at 95° C. for 16 hr, cooled to room temperature and quenched with 5 mL of aqueous 1M NaHCO3 solution. The aqueous layer was extracted with dichloromethane (3×5 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 0.4 g of the crude product of the title compound. LC/MS (ESI+) m/z 213 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[Cl:14])=[N+:2]=[N-:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:14][C:5]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:8]=[CH:9][C:4]=1[N:1]1[C:24]([NH2:25])=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=[N:2]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-trifluoromethyl-benzene (1.00 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.797 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.366 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (20 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (1.20 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 15% ethylacetate in hexane, to afford the title compound as a white solid (0.324 g, 30% yield). M.p. 130.0-130.7° C.