Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2].[Na+].Cl[C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=2>CN(C=O)C>[C:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:21]2[S:22][C:23]3[C:28]([N:29]=2)=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=3)=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc2nc(Cl)sc2n1
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccc(C)nc3s2)cc1
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To sodium 4-{[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenolate (170 mg, 0.63 mmol) was added 2-chloro-5-methyl[1,3]thiazolo[5,4-b]pyridine (117 mg, 0.63 mmol) and DMF (6.3 mL). The solution was stirred for 16 h, filtered, and purified by preparative reverse phase HPLC to provide the desired product (140 mg, 56%). 1H NMR (400 MHz, CDCl3): 7.81 (d, J=8.2, 1H), 7.46-7.39 (m, 2H), 7.33-7.28 (m, 2H), 7.18 (d, J=8.3, 1H), 4.79 (s, 0.5H), 4.24 (s, 0.5H), 3.82-3.72 (m, 2.5H), 3.60-3.53 (m, 1.5H), 3.30 (ddd, J=13.3, 10.3, 2.1, 1H), 3.02 (dd, J=9.5, 2.1, 0.5H), 2.85 (dd, J=9.7, 2.2, 0.5H), 2.78 (d, J=9.7, 0.5H), 2.61 (s, 3H), 2.57 (dd, J=9.5, 1.2, 0.5H), 2.08 (s, 1.5H), 2.03-1.96 (m, 2H), 1.91 (d, J=9.8, 0.5H), 1.81 (d, J=9.7, 0.5H), 1.67 (d, J=10.0, 0.5H). MS (ESI): mass calcd. for C21H22N4O2S, 394.15; m/z found, 395.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14](F)[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([NH:32][CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19]
Reactant: N#Cc1cnc2cnc(F)cc2c1NCc1ccc(F)c(Cl)c1
Reactant: NCCN1CCOCC1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1NCc1ccc(F)c(Cl)c1
Yield: 48 %

Procedure:
Following the procedure described above in Example 34, 4-[(3-chloro-4-fluorobenzyl)amino]-6-fluoro-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.14 g, 48%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.4 (m, 4 H) 2.6 (m, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 5.0 (d, J=7.1 Hz, 2 H) 6.5 (m, 1 H) 7.0 (s, 1 H) 7.3 (m, 1 H) 7.4 (m, 1 H) 7.5 (dd, J=6.9, 1.9 Hz, 1 H) 8.1 (s, 1 H) 8.5 (m, 1 H) 8.8 (s, 1 H).
Reaction SMILES: C([N:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)CCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCC.CCCCCC.N>C(O)C>[NH2:17][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH2:42])[CH:36]=1
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C#N)c1
Agent: N
Solvent: CCO
Solvent: CCCCCC
Product: NCc1cccc(CN)c1
Reaction time: 4 h
Yield: 290.7 %

Procedure:
1-(Dihexadecyl)aminomethyl-3-cyanobenzene (1,814 g.) was placed in an autoclave (15 gal.) with a mixture of hexane (1.98 l.), ethanol (17.82 l.) and ammonia (3,627 g.). Said mixture was prepared in advance by saturating the ethanol-hexane mixture with ammonia gas. The saturated mixture was refrigerated until it was ready for use. Raney nickel (3,689 g., wet weight) was added. The Raney nickel W2 is weighed as a wet slurry, the form in which it is obtained from W. R. Grace as Raney nickel No. 28. This differs from the standard W2 Raney nickel in that it is slurried in water rather than benzene. For the present process, the difference is inconsequential. The mixture was contacted with hydrogen gas maintained at a pressure of 50 psig. for four hours at room temperature. After the uptake of hydrogen ceased, the mixture was filtered and the filtrate concentrated to an oil by vacuum distillation. The oil was dissolved in methylene chloride (4.0 l.) and washed once with water (2.0 l.) and three times with a saturated sodium chloride solution (1.0 l.). The clear methylene chloride solution was then dried over magnesium sulfate (454 g.), filtered and concentrated to an oil again to yield 1-dihexadecyl)aminomethyl-3-aminomethylbenzene (1,236 g., 68% yield). The purity of the product was determined by thin layer chromatography. The dihydrochloride salt was prepared by dissolving the 1-(dihexadecyl)aminomethyl-3-aminomethylbenzene (1,236 g.) in ethanol (5.0 l.) and ethanol (5.0 l.) containing dissolved hydrogen chloride gas (800 g.) was added. The mixture was stirred for one hour at room temperature and the solvent removed by vacuum distillation. Ether (8.0 l.) was added to the residue until a clear solution was obtained. Cooling with a dry ice/acetone bath followed by the slow addition of acetonitrile effected the precipitation of 1-(dihexadecyl)aminomethyl-3-aminomethylbenzene diamine dihydrochloride as a fine white crystalline material. The overall yield for the two processes was 62.5%.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([C:11]1[S:10][C:9]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3)sc2c1
Yield: 52 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and benzoyl chloride were converted to the title compound by the procedure of Example 1 in 52% yield, after crystallization from methanol.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].NC(N)=N.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([O:22][CH3:23])[CH:16]=1>[OH-].[Na+]>[Br:14][C:15]1[C:21]([N+:6]([O-:9])=[O:7])=[CH:20][C:18]([NH2:19])=[C:17]([O:22][CH3:23])[CH:16]=1
Reactant: COc1cc(Br)ccc1N
Reactant: O=[N+]([O-])O
Agent: N=C(N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1cc(Br)c([N+](=O)[O-])cc1N
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
85% Sulfuric acid was made by adding 98% sulfuric acid (13 mL) cautiously to ice (2 g). Guanidine nitrate (1.221 g, 10.00 mmol) was added portionwise over a period of 10 minutes to a cooled (0-5° C.) mixture of 4-bromo-2-methoxyaniline (2.020 g, 10 mmol) in 85% sulfuric acid (15.68 mL, 250.00 mmol). The resulting dark blue mixture was stirred at 0-5° C. for 0.75 h and was then poured very slowly into a well-stirred mixture of 50% aq NaOH (40 mL) and ice (120 g). An orange precipitate was collected by filtration, washed with water (4×50 mL) and air dried. This material was dissolved into diethyl ether (100 mL) and filtered through a silica plug. The resulting solution was diluted with isohexane and purified by evaporative crystallisation from diethyl ether/isohexane to give the title compound (1.821 g, 74%) as an orange crystalline solid; 1H NMR: 3.90 (3H, s), 5.52 (2H, s), 7.14 (1H, s), 7.32 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)(=[O:36])=[O:37])=[CH:39][CH:40]=3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (200 mg, 0.504 mmol), 4-[(4-methyl-1-piperazinyl)sulfonyl]phenylboronic acid (186 mg, 0.655 mmol), PdCl2 (dppf) (29 mg, 0.0355 mmol), and aq. K2CO3 (2M, 3 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H2O, and the aqueous phase extracted with CH2Cl2 (9×). The combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/MeOH (100:0 to 99.75:0.25), followed by chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), and recrystallization from CH2Cl2/MeOH/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (93 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]([O:26]CC)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[NH3:29].CO>>[NH2:29][C:24](=[O:26])[CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CCOC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC(N)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)-piperidine-1-carboxylate (0.971 g, 2.36 mmol) was dissolved in 7 M NH3/MeOH (20 mL), and stirred overnight at room temperature. The solvent was removed under reduced pressure to give (R)-tert-butyl 3-((R)-(2-amino-2-oxoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (902 mg, 100%), which was used for the next step without further purification. MS ESI+ve m/z 383 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(C)[C:10](S(O)(=O)=O)=[CH:11][CH:12]=[CH:13][CH:14]=1.CC(CCC)=C.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:11]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:10][CH2:9][CH2:14][CH2:13][CH3:12]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Oc1ccc(S)cc1
Agent: C=C(C)CCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCSc1ccc(O)cc1
Temperature: 60 °C

Procedure:
A 4-(hexylthio)phenol was prepared as follows. In a one liter flask equipped with thermometer, stirring rod and water condenser was added 126 grams of 4-mercaptophenol and 7 grams of toluenesulfonic acid. The flask contents were heated to 60° C. and 93 grams of 2-methyl-1-pentene were added over a fifty minute period. The flask contents were neutralized with 9 grams of Na2CO3 in aqueous solution and decanted. The reaction product was stripped to a pot temperature of 80° C. at 20 millimeters of mercury. It weighed 216 grams.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[NH:24]C(=O)OC(C)(C)C)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(1-benzylpiperidin-4-ylcarbamoyl)-6-fluorophenylcarbamate (67.0 g, 157 mmol) in dichloromethane (700 mL) at 0° C. was added trifluoroacetic acid (100 mL). The ice bath was removed and the reaction stirred at room temperature overnight. The reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate (2×), which were washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give 47.6 g (93%) as a white solid which was used without purification. Mass spec.: 328.33 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]3[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]3[CH:3]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc3nc(C)cn3c(NCCNc3ccc([N+](=O)[O-])c(N)n3)n2)cc1OC

Procedure:
In analogy to the procedure described for Example 7, 57 mg (39% of theory) of the product are obtained starting from 120 mg (0.32 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 31A) by coupling with 69 mg (0.38 mmol) of (3,4-dimethoxyphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:10][O:9]C(C)(C)[O:7][C@H:6]1[CH:13]=[CH2:14])C=C.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[OH:9][CH2:10][C@H:5]1[C@@H:6]([OH:7])[CH:13]=[CH:14][CH2:1][O:4]1
Reactant: C=CCO[C@H]1COC(C)(C)O[C@H]1C=C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@@H]1OCC=C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (50 mg, 0.29 mmol) in MeOH (5 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The mixture was stirred for 30 min at ambient temperature. Aqueous saturated NaHCO3 (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated NaHCO3 (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([NH:22][C:23]([CH2:25]Br)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:16]1([NH:22][C:23]([CH2:25][O:11][C:10](=[O:12])[C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(CBr)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 15 ml of DMF were dissolved 2.8 g of N-t-butoxycarbonyl-(S)-proline and 2.8 g of phenylcarbamoyl methyl bromide. To the solution was added 1.1 g of sodium hydrogencarbonate. The mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (using chloroform as an eluent), giving the title compound as a colorless oil. Yield 3.5 g.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)(=[O:6])[CH2:4][CH3:5]>CO>[OH:6][CH:3]([C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]([CH3:17])([CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5]
Reactant: CCC(=O)c1ccc(OC(C)(C)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)c1ccc(OC(C)(C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (10.6 g., 0.279 mole) was added to a stirred solution of 114.5 g. (0.458 mole) of methyl 2-(p-propionylphenoxy)-2-methylpropionate in 500 ml. of methanol, held at 5°C. in an ice bath. After the exothermic reaction had slowed, the ice bath was removed and the reaction mixture stirred for one hour at room temperature. The solvent was removed in vacuo, and the residue partitioned between ether and water containing acetic acid in slight excess of that needed to make the aqueous layer acidic. The ether layer was separated, washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. There was thus obtained 113 g. of methyl 2-[p-(1-hydroxypropyl)phenoxy]-2-methylpropionate as a pale straw-colored oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:12]=1.I.CS[C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[NH:30]>C(O)C>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[NH:30])[CH:3]=3)[NH:7][CH:6]=2)=[CH:12][CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 67.6 %

Procedure:
A solution of compound 98 (0.415 g, 1.215 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.693 g, 2.430 mmol) at room temperature and the resulting solution was stirred for 24 h. The solvent was evaporated and crude was diluted with sat. NaHCO3 solution (25 mL) and CH2Cl2 (50 mL). The organic layer was separated and aqueous layer was extracted with CH2Cl2 (2×25 mL). The combined organic layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude product was purified by column chromatography on silica gel (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 99 (0.37 g, 68%) as a foam. 1H NMR (DMSO-d6) δ: 0.85 (t, 1H, J=7.2 Hz), 1.20-1.26 (m, 1H), 1.40 (s, 9H), 1.77-1.87 (m, 2H), 2.22-2.40 (m, 2H), 2.72 (s, 3H), 4.06-4.16 (m, 1H), 6.06 (s, 1H), 6.28 (brs, 1H), 6.66 (d, 1H, J=8.4 Hz), 7.10 (t, 1H, J=4.2 Hz), 7.22 (s, 1H), 7.25-7.32 (m, 2H), 7.60 (d, 1H, J=4.8 Hz), 7.72 (d, 1H, J=3.3 Hz), 10.94 (s, 1H); ESI-MS m/z (%): 451 (MH+, 100).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2/[CH:33]=[CH:34]\[CH3:35])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:46][O:47][CH3:48].O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:32][CH2:46][O:47][CH3:48])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:25])[F:26])=[CH:19][C:18]=2/[CH:33]=[CH:34]\[CH3:35])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCOCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.6 %

Procedure:
(Z)-2-(4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-(prop-1-en-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40 mg, 0.0796 mmol) was dried with a vacuum pump, and dissolved in dichloromethane (796 μL). Under ice-cold conditions, diisopropylethylamine (42 μL, 0.239 mmol) and chloromethylmethylether (6.6 μL, 0.0876 mmol) were added sequentially, and the mixture was stirred at room temperature for 20 hours. Further, under ice-cold conditions, diisopropylethylamine (84 μL, 0.478 mmol) and chloromethylmethylether (26 μL, 0.350 mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (32 mg (yield 73%)) was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[F:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:33][C:34]1[CH:39]=[C:38]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
3-Bromo-5-nitro-1-trityl-1H-indazole 3BI (15.64 g, 32.3 mmol), 2-fluoro-4-pyridine boronic acid 2BV (5.0 g, 35.5 mmol), K3PO4 (17.1 g, 80.7 mmol) and Pd(dppf)Cl2 (2.64 g, 3.23 mmol) was mixed in dioxane/H2O (240 mL/60 mL) at rt and heated at 80° C. overnight. The reaction mixture was cooled to rt and concentrated to a small volume. The residue was partitioned between ethyl acetate (200 mL) and brine (150 mL). The organic layer was washed with brine, dried (MgSO4) and filtered. The resulting filtrate was concentrated and the residue was purified on silica gel column eluting with hexanes, 5% ethyl acetate in hexanes, 10% ethyl acetate in hexanes sequentially to yield a yellow solid 3BV (3.33 g, 64%).
Reaction SMILES: Br[C:2]([F:19])([F:18])[C:3]([F:17])([F:16])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.Cl>CS(C)=O.[Cu]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]([F:19])([F:18])[C:3]([F:17])([F:16])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])=[CH:23][CH:22]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OC(F)(F)C(F)(F)Br
Reactant: Clc1ccc(I)cc1
Agent: [Cu]
Agent: Cl
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OC(F)(F)C(F)(F)c1ccc(Cl)cc1
Temperature: 160 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
Under a dry argon atmosphere a stirred mixture of 4-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3-methoxynitrobenzene (5.0 g, 0.014 mole), 4-chloroiodobenzene (3.4 g, 0.014 mole), and copper powder (4.6 g, 0.072 mole, 200 mesh) in dimethyl sulfoxide (75 mL) was heated at about 160° C. for approximately three hours. The reaction mixture was allowed to cool to room temperature and stirred for an additional 18 hours. The cool mixture was poured into 200 mL of 2N hydrochloric acid, the resultant mixture was extracted with three 100 mL portions of methylene chloride. The extracts were combined and washed in succession with 2N hydrochloric acid, an aqueous, saturated, sodium chloride solution, and 2N aqueous sodium hydroxide. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving an oil. This oil was purified by column chromatography on silica gel, eluting with n-heptane:toluene (90:10), to yield 1.4 g of 4-[2-(4-chlorophenyl)-1,1,2,2-tetrafluoroethoxy]-3-methoxynitrobenzene as an oil.