Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.251 mL, 0.251 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 132-(2); 44.0 mg, 0.084 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature for two hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the target compound as a colorless oil (40.2 mg, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13](/[CH:14]=[N:20]/[OH:19])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C=O
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(OCc2ccccc2)cc1/C=N/O
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
A mixture of 5-(benzyloxy)-2-methylbenzaldehyde (15.9 g), hydroxyl ammonium chloride (5.37 g), sodium bicarbonate (6.49 g), and ethanol (150 mL) was stirred at room temperature for 6 hours. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (16.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])[N:12]=1.CI.[CH3:31]CN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH3:31])[CH2:20][CH2:21]2)=[O:14])[N:12]=1
Reactant: O=C(NC1CCNCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CN1CCC(NC(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-carboxamide (Example 37) (80 mg, 0.2 mmol) in CH2Cl2 (6 mL) was added CH3I (28.4 mg, 0.2 mmol) and Et3N (0.031 mL, 0.22 mmol). The reaction mixture was heated at reflux for 5 h, cooled to rt, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (2M NH3 in methanol:EtOAc=1:10) to afford the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-methyl-4-piperidinyl)-1H-imidazole-4-carboxamide (24 mg, 28% yield): LC-MS m/z 429.1 (MH+), retention time 2.27 min (method 1); Rf=0.31 (EtOAc: 2M NH3 in MeOH=9:1).
Reaction SMILES: [Na].Cl.[OH:3][CH:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[NH2:6].[C:15]([CH:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N+:28]([O-:30])=[O:29])[C:19]1=[O:31])(=O)[CH3:16]>CO>[N+:28]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:26](=[O:27])[C:18](=[C:15]([NH:6][C@@H:5]1[C@@H:7]([OH:8])[C@H:9]([OH:10])[C@@H:11]([CH2:13][OH:14])[O:12][CH:4]1[OH:3])[CH3:16])[C:19]2=[O:31])([O-:30])=[O:29]
Reactant: CC(=O)C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CC(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Sodium (126 mg, 5.47 mmol) was added to abs. methanol (50 ml) and the reaction mixture was stirred for 5 min. D-glucosamine hydrochloride (1.18 g, 5.47 mmol) was added to the resulting clear solution and the reaction mixture was stirred at room temperature for another 5 min. 2-acetyl-4-nitroindane-1,3-dion (1.91 g, 8.21 mmol) was added and the reaction mixture was stirred under reflux for 5 hours. The solution was cooled and the product was filtered off. The solid was washed with MeOH (10 ml), ether (50 ml) and dried, affording 2-Deoxy-2-[1-(4-nitro-1,3-dioxoindan-2-ylidene)ethylamino]-D-glucopyranose (22) 1.10 g, 55%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][C:14]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)C1C=CC=CC=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>CO.[Pd]>[C:18]1([C:14]2[N:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH2:16][CH2:17][NH:8][CH2:9]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: c1ccc(CN2CCc3c(ccnc3-c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nccc3c2CCNC3)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-benzyl-5-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine, 2 TFA (0.48 g, 0.908 mmol) in MeOH (10 mL) was added Pd/C (0.193 g, 0.182 mmol). The mixture was flushed with N2, then was purged with H2 and stirred at rt under 1 atm. After stirring the reaction for 3 h it was filtered through a pad of CELITE®. The organic solution was concentrated under reduced pressure to give 5-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine, 2 TFA (0.398 g, 0.908 mmol, 100% yield) as a light-brown oil which crystallized under vacuum. The residue was used in the next step with no additional purification. LC/MS: m/z 211.00 (M+H)+, 0.270 min (method 7). 1H NMR (500 MHz, MeOD) δ ppm 8.66 (d, 1H) 7.74 (d, J=5.49 Hz, 1H) 7.57-7.67 (m, 5H) 4.69 (s, 2H) 3.54 (t, J=6.10 Hz, 2H) 3.11 (t, J=6.10 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C(Cl)Cl>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]2[NH:1][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=Nc1cccnc1N2
Temperature: 200 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
A mixture of 15.0 g (0.0647 mole) of 2-amino-5-chlorobenzophenone and 9.1 g (0.068 mole) of 3-amino-2-chloropyridine was heated at 200° C. (in an oil bath) for 0.75 hr under nitrogen atmosphere. The mixture was cooled and methylene chloride added. The mixture was stirred for 1 hr then allowed to stand overnight. Brown solid precipitate weighing 8.7 g was separated by filtration. The filtrate was evaporated under reduced pressure. The residue was combined with the brown solid and partitioned with aqueous sodium hydroxide and methylene chloride and crude product isolated as in Example 1, except the crystallizing solvent was ethanol. Recrystallization from ethanol and drying over night at 82° C./0.1 mm Hg gave 3.0 g product; m.p. 156.5°-158.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].I.[CH3:17][N:18]1[CH2:22][C:21](=[O:23])[N:20]=[C:19]1SC.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:19]2[N:18]([CH3:17])[CH2:22][C:21](=[O:23])[N:20]=2)[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: CSC1=NC(=O)CN1C
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCNC2=NC(=O)CN2C)c1

Procedure:
2-(4-(Dimethylaminomethyl)pyrid-2-ylmethylthio)ethylamine (2.25 g), 1-methyl-2-methylthio-imidazolin-4-one hydroiodide (2.71 g) and triethylamine (2.18 g) were refluxed in ethanol (50 ml) for 6 hours.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:17]2[S:16][N:15]=[C:14](Cl)[C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[C:17]=2[S:16][N:15]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(Cl)nsc12
Reactant: NCCCN
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCN)nsc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-tert-butyl-3-chlorobenzo[d]isothiazole-7-sulfonamide (260 mg, 0.85 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 3h. The dark brown reaction mixture was then poured over water (10 mL), extracted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-7-sulfonamide (271 mg) as a pale yellow solid. 1H NMR (300 MHz, CD3OD): 8.17 (dd, 1H), 8.01 (dd, 1H), 7.55 (t, 1H), 3.58 (t, 2H), 2.81 (t, 2H), 1.86-1.95 (m, 2H), 1.17 ppm (s, 9H). MW=342 confirmed by LC-MS, tr=7.95 min (Method Y) MH+=343.
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.CCOC(C)=O>[CH2:4]([N:11]1[CH:16]=[C:15]([F:17])[CH2:14][CH2:13][CH:12]1[CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c[n+]1Cc1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCC(F)=CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 62 %

Procedure:
NaBH4 (5.56 mmol, 0.21 g) was added to a solution of 1-benzyl-2-((tert-butoxycarbonylamino)methyl)-5-fluoropyridinium bromide (1.40 mmol, 0.60 g) in MeOH at 0° C. The resulting mixture was stirred at 0° C. for 40 min. An aliquot was checked by analytical HPLC and some of the starting material remained. Additional NaBH4 (5.56 mmol, 0.21 g) was added at 0° C. and the resulting mixture was stirred for extra 40 min. The reaction mixture was diluted with EtOAc and washed with brine. EtOAc layer was separated, dried with MgSO4 and concentrated in vacuo to give desired tert-butyl (1-benzyl-5-fluoro-1,2,3,4-tetrahydropyridin-2-yl)methylcarbamate in 62% yield which was used for next step without further purification. MS (ESI) 321 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reaction time: 0.17 h

Procedure:
10% w/w palladium on charcoal (250 mg) was added to a solution of the product from step (i) (5.37 g) in ethanol (100 ml) and the mixture hydrogenated at room temperature and pressure until the theoretical amount of hydrogen had been taken up. Charcoal was added, the mixture stirred for 10 minutes then filtered through diatomaceous earth and the filtrate evaporated to dryness. The solid residue, on recrystallisation from ethyl acetate/hexane gave 4-(N-tertiary-butyloxycarbonylaminomethyl)aniline, 4.20 g: m.p. 80°-81° C.; NMR (d6DMSO) δ 7.10(1H,bt), 6.88(2H,d), 6.49(2H,d), 4.92(2H,s), 3.92(2H,d), 1.38(9H,s); m/e 223(M+H)+ ; calculated for C12H18N2O2 : C, 64.8; H, 8.2; N, 12.6. found: C, 65.4; H, 8.3; N, 13.0%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[C:20]3[CH:19]=[C:18]4[C:21]([CH3:29])([CH3:28])[C:22]5[C:27]([C:17]4=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:5]=[C:4](Br)[N:3]=1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[C:6]([N:8]3[C:20]4[CH:19]=[C:18]5[C:21]([CH3:29])([CH3:28])[C:22]6[C:27]([C:17]5=[CH:16][C:15]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[CH:5]=[C:4]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)[N:3]=2)[CH:34]=[N:33][CH:32]=1
Reactant: OB(O)c1cncnc1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(Br)nc(Br)c4)c3cc21
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: [Na+]
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(-c5cncnc5)nc(-c5cncnc5)c4)c3cc21

Procedure:
15 g (29 mmol) of 10-(2,6-dibromopyridin-4-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene and 7.9 g of 5-pyrimidineboronic acid (63.7 mmol) are suspended in 300 ml of ethylene glycol dimethyl ether. 65 ml of a 2 M Na2CO3 solution are added to the reaction mixture. 1.67 g (1.45 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 12 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 8.5 g, 57% of theory.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.[C:23](Cl)(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[C:23]([O:15][CH2:14][C:3]1[CH:4]=[C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[O:6][C:2]=1[CH3:1])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1cc([Si](CC)(CC)CC)oc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyl-2-triethylsilyl-4-furanmethanol (208 mg. 0.92 mmol) and triethylamine (121 mg, 1.20 mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon was added lauroyl chloride 302 mg, 1.38 mmol). This solution was allowed to warm gradually to room temperature and quenched with a 10% aqueous HCl solution. The organics were extracted into hexanes and the combined fractions were washed with a saturated aqueous solution of sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31]OS(C)(=O)=O)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][NH:40][CH3:41].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31][N:40]([CH3:41])[CH3:39])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(COS(C)(=O)=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)CC(C)(O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Yield: 23.1 %

Procedure:
Methanesulfonic acid 2-[4-(4-benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-2-hydroxy-propyl ester (64 mg, 0.120 mmol) is combined with dimethylamine (300 μL, 2M in THF, 0.600 mmol), diisoproylethylamine (63 μL, 0.360 mmol), and acetonitrile (1 mL). The mixture is heated to reflux for 16 h. Concentrate the crude mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (13.4 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CCOCC>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:8][CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol LIV (23.1 g, 0.175 mol) in pyridine (150 mL) at 0° C. was added tosyl chloride (44.5 g, 0.23 mol) in portions. The mixture was stirred for 7 h at 0° C. and was placed in a refrigerator for 18 h. Et2O (150 mL) was added and the mixture was washed with 1 N aqueous HCl (5×150 mL). The organic layer was washed with aqueous NaHCO3 (150 mL) and water (150 mL). The organic phase was dried over Na2SO4, filtered, concentrated and dried under vacuum. The crude product was purified by column chromatography on silica gel (1:1 Et2O:hexane) to afford (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate LV (42.1 g, 0.15 mol, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:3]([CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH2:27])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: O=C(Cc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(Cc1ncc(C(F)(F)F)cc1Cl)c1ccccc1

Procedure:
5.6 g (0.0187 mol) of 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1-phenylethanone are diluted in 50 mL of methanol. 50 g of molecular sieves 3 Å, 14.4 g (0.187 mol) of ammonium acetate and 2.45 g (0.037 mol) of sodium cyanoborohydride are then consequently added. The pH is adjusted to 5-6 with acetic acid (1 mL). After of 4 days of reaction at room temperature, the medium is filtered and 1M aqueous sodium hydroxide is added until pH=12. 150 mL of ethyl acetate are added, after separation, the aqueous phase is extracted twice with 150 mL of ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:4]([CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]1[C:17](O)=[O:18].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:20])[CH:4]([CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]1[C:17]([Cl:23])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C=C(c2ccccc2)C(F)(F)F)C1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(c2ccccc2)C(F)(F)F)C1C(=O)Cl
Yield: 92.5 %

Procedure:
7.1 g (0.025 mol) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid were dissolved in 100 ml of carbon tetrachloride, and 9 g of thionyl chloride were slowly added dropwise at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. The oil which remained was freed from last residues of solvent by brief incipient distillation at a bath temperature of 40° C./2 mm Hg. 7 g (92.7% of theory) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid chloride were obtained. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[C:8](I)[C:7](=[O:22])[C:6]=2[CH:23]=1.CO[C:26]1[C:27](OC)=[C:28](B([O-])[O-])[C:29](OC)=[N:30][CH:31]=1.[Li+].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[C:8]([C:28]3[CH:29]=[N:30][CH:31]=[CH:26][CH:27]=3)[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: COc1cnc(OC)c(B([O-])[O-])c1OC
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccc(F)cc3c(=O)c2I)cc1
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(-c2oc3ccc(F)cc3c(=O)c2-c2cccnc2)cc1

Procedure:
The title compound was prepared from 6-fluoro-3-iodo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one and lithium trimethoxy-3-pyridinylboronate by the same method as described in Step 5 of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH2:14][C:13](=O)[C:12]=3[CH:19]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CCCO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=CCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepin-5-one (1 g) dissolved in ethanol (50 ml) was added under ice cooling sodium borohydride (0.3 g). The resulting mixture was stirred at room temperature for 30 minutes, was mixed with water and was concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with water and was then concentrated. To the residue dissolved in bis(2-methoxyethyl)ether (20 ml) was added hydrochloric acid (5 ml), and the resulting mixture was stirred with heating at 75° C. for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, was then dried with anhydrous magnesium sulfate and was evaporated to remove the solvent. The precipitate was collected by filtration using hexane to obtain 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (0.78 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 98 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (1.28 g, 5 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h, then all of the solvent was removed to give 1.479 g (98%) of 1-acetamido-3,5-bis(trifluoromethyl)benzene as white needles. 1H NMR (CDCl3): δ2.229 (s, 3H); 7.589 (s, 1H); 8.048 (s, 2H).