Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:32][NH2:33]>C(O)C>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([NH:33][CH3:32])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CN
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Solvent: CCO
Product: CN[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 80 °C

Procedure:
To a 10 mL vial was added N-[6-Chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (225 mg) and 8M methylamine in ethanol (6 mL). The vial was sealed and heated at 80° C. for 120 minutes within a microwave. The solvent was removed under vacuum and purified (SiO2, ammonia:methanol:dichloromethane, 1:2:97 as eluant) to afford the titled compound (0.033 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>>[CH3:25][C:21]1[N:22]=[CH:23][NH:24][C:20]=1[CH2:19][S:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOc1cc(Cl)nc2ccccc12
Reactant: Cc1nc[nH]c1CSCCN
Product: CCOc1cc(NCCSCc2[nH]cnc2C)nc2ccccc12
Yield: 30.3 %

Procedure:
2-Chloro-4-ethoxyquinoline (3.72 gms) and 5-(2- aminoethyl)thiomethyl-4-methylimidazole (3.1 g.) were heated together at 150°-160° C. (oil-bath temperature) for three hours. The residue, on cooling, was washed with water and dried. Purification was effected by column chromatography (silica gel column, ethyl acetate-5% methanol eluant) and crystallisation from acetone to give 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline (1.86 gms) m.p. 152.5°-153.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>C(OCC)C.O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1cccc(F)c1
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a suspension of 3.07 gm (81 mMol) lithium aluminum hydride in 115 mL diethyl ether at 0° C. were added dropwise a solution of 7.0 gm (45 mMol) 3-fluorophenylacetic acid in 26 mL tetrahydrofuran dropwise. The reaction was allowed to warm to ambient and then stirred 18 hours. The reaction mixture was quenched by the addition of 3.0 mL 2N NaOH dropwise with cooling. To this mixture was then added 9.0 mL water and the resulting suspension stirred for 1 hour at ambient. The suspension was filtered and the filter cake rinsed well with diethyl ether, The filtrate was concentrated under reduced pressure to give 6.26 gm (100%) of the title compound as a clear oil. The product was used without further purification.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19]([CH3:28])=[C:18]2[C:29]([O:31][CH3:32])=[O:30])[CH:14]=[CH:15][CH:16]=1)C.[CH3:33][N:34]([CH:36]=O)[CH3:35]>>[CH:33]1([N:34]2[CH2:36][CH2:35][N:34]([CH2:36][CH2:4][CH2:5][NH:10][C:4]3[C:7](=[O:8])[C:6](=[O:9])[C:5]=3[NH:10][C:11]3[CH:12]=[C:13]([CH:17]4[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19]([CH3:28])=[C:18]4[C:29]([O:31][CH3:32])=[O:30])[CH:14]=[CH:15][CH:16]=3)[CH2:33][CH2:35]2)[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]1
Reactant: CCOc1c(Nc2cccc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)c2)c(=O)c1=O
Reactant: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Nc2c(NCCCN3CCN(C4CCCCC4)CC3)c(=O)c2=O)c1

Procedure:
The compound of Example 1 (160 mg, 0.364 mmol) and 4-cyclohexyl-1-piperazine-1-propanamine (81.4 mg, 0.362 mmol) were stirred in 2 mL DMF at room temperature for 64 hours. The crude reaction mixture was evaporated to dryness under high vacuum (0.1 mmHg) at 50-55° C. The resulting gum was triturated with methylene chloride followed by the addition of hexanes. The titled compound precipitated out as fine creamy white crystalline solid (165 mg, 73.6%): mp 210-212° C.; 1H NMR (DMSO-d6) δ 9.52 (br. s, 1H), 8.91 (br. s, 1H), 7.54 (br. 1H), 7.27 (d, 1H, J=7.3 Hz), 7.16 (m, 2H), 6.80 (d, 1H, J=7.5 Hz), 4.88 (s, 1H), 3.61 (m, 2H), 3.55 (s, 6H), 2.45 (m, 5H), 2.30 (m, 4H), 2.26 (s, 6H), 1.69 (m, 7H), 1.53 (br. d, 1H, J=11.0 Hz), 1.11 (m, 6H); 13C NMR (DMSO-d6) δ 207.50, 207.28, 206.89, 203.73, 199.89, 194.77, 193.47, 192.12, 169.21, 167.38, 163.58, 153.67, 149.15, 145.92, 138.90, 128.87, 121.51, 116.60, 115.86, 101.11, 62.50, 54.94, 53.29, 50.57, 49.90, 48.28, 42.22, 28.32, 27.73, 26.26, 23.50, 18.29, 17.37. Anal Calcd. for C34H45N5O6•0.13 H2O: C, 65.64; H, 7.33; N, 11.26. Found: C, 65.65; H, 7.25; N, 11.09.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>ClCCl.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:8][CH:7]=1
Reactant: Fc1ccccc1
Reactant: COC(=O)CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCC(=O)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A suspension of 2.59 g (19.4.10−3 mol) of aluminum chloride in 4 ml of dichloromethane is prepared. It is cooled to −5° C. and a mixture of 0.97 ml (10.3.10−3 mol) of fluorobenzene and 1.31 ml (8.4.10−3 mol) of methyl 6-chloro-6-oxohexanoate in 3 ml of dichloromethane is added gradually, the temperature being maintained between −4 and −7° C. The temperature is then allowed to rise to 20° C. and, after 15 hours, the mixture is hydrolyzed in acidified iced water. It is extracted with dichloromethane and the organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The 2 g of crude product recovered in this way are purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (96/4) as the eluent to give 1.26 g of the expected product in the form of a white powder (yield=63%).
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:65][CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[C:66]1([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:65]=[CH:64][C:63]([O:62][CH2:61][CH2:60][CH2:59][N:48]2[CH2:47][CH2:46][CH:45]([C:43]([C:51]3[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=3)([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[OH:44])[CH2:50][CH2:49]2)=[CH:68][CH:67]=1
Reactant: ClCCCOc1ccc(-c2ccccc2)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCOc2ccc(-c3ccccc3)cc2)CC1
Yield: 68.1 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of α, α-bis(p-fluorophenyl)-4-piperidinemethanol, 2.5 g (0.01 mole) of 4-(3-chloropropoxy)-1,1'-biphenyl, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.5 g (69%) of title compound as a white solid, mp 108°-109° C.
Reaction SMILES: [NH2:1][C:2]1[N:26]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:25])=[C:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[Cl:25][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[N:26]=3)[CH:9]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1Cl
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-chlorophenyl}carbamate (5.49 g, 14.60 mmol) in N,N-dimethylacetamide (40 mL) was added cyclopropanecarbonyl chloride (1.50 mL, 16.5 mmol) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (5.61 g, 87%) as a white solid.
Reaction SMILES: [Na].[CH2:2]([N:9]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:10]1=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([OH:26])[CH:22]([OH:25])[CH2:23]Cl>CO>[CH2:2]([N:9]1[C:19]2[C:14](=[C:15]([O:20][CH2:23][CH:22]([OH:25])[CH2:21][OH:26])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:10]1=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCC(O)CCl
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Agent: [Na]
Solvent: CO
Product: O=C1CCc2c(OCC(O)CO)cccc2N1Cc1ccccc1
Yield: 36.7 %

Procedure:
0.23 g of sodium metal was dissolved in 40 ml of methanol, and 2.53 g of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 1.3 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 6 hours. After allowing the mixture to cool, the precipitated crystals were filtered, and the filtrate was concentrated to dryness. The residue thus obtained was extracted with 50 ml of chloroform, and the extract was washed with a 5% aqueous sodium hydroxide solution and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethanol to give 1.2 g of 1-benzyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 153° - 155° C.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:24]>[Cu]Br>[Br:24][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)c(F)cc1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(F)cc1Br
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To the suspension of methyl 2-amino-4-fluoro-5-methylbenzoate (2.2 g, 12 mmol) in 48% hydrobromic acid (80 mL) was added an aqueous solution (32 mL) of sodium nitrite (828 mg, 12 mmol) at 0° C., and the resulting solution was stirred for 30 min. Copper (I) bromide (1.72 g, 12 mmol) was added to the solution at 0° C. and the resulting reaction mixture was stirred at r.t for 1 h. After addition of ethyl acetate (200 mL), the reaction mixture was washed with water (200 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (10:1) to give methyl 2-bromo-4-fluoro-5-methylbenzoate (2.2 g, yield 74%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.655 (d, J=8.0 Hz, 1H), 7.257 (d, J=8.5 Hz, 1H), 3.837 (s, 3H), 2.177 (s, 3H) ppm.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-:30])=O)=[C:11]2[CH3:31])N=1.CO.[CH3:34][N:35]([CH:37]=O)C>[Pd]>[NH:35]1[CH2:37][CH2:31][CH:11]([NH:10][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:30])[CH2:12][CH2:34]1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: CN(C)C=O
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCNCC1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
Steps 3 & 4: To the solution of (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-[(5-fluoro-2-oxoindolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate (A4) (0.2 g, 0.48 mmol) in 25 mL of DMF solution was added compound 6c (0.268 g, 0.58 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. 200 mg of 5% Pd/C was added to the mixture, followed by 25 mL of MeOH. The mixture was stirred under H2 atmosphere for 30 min and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol (5 mL*2), dried under vacuum to provide the title compound (80 mg, 43.7% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.67 (s, 1H), 10.89 (s, 1H), 7.67-7.78 (m, 3H), 6.82-6.96 (m, 2H), 3.87-3.92 (m, 1H), 3.06-3.09 (d, 2H), 2.72-2.79 (t, 2H), 2.39-2.41 (ds, 6H), 1.84-1.89 (d, 6H), 1.46-1.57 (m, 2H). LC/MS: 383.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)[S:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[N:20]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)[S:22][CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCN(c2nc(-c3cccc(N)c3)cs2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (42 mg, 0.23 mmol), ethyl 1-[4-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (76 mg, 0.23 mmol) and 4-methylbenzenesulfonic acid (44 mg, 0.23 mmol) in dioxane (1 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction was concentrated under reduced pressure. The resulting residue was diluted with 30 mL ethyl acetate and washed with 30 mL saturated aqueous sodium bicarbonate and 30 mL brine. The aqueous layers were further extracted with 30 mL ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by CombiFlash (10-50% ethyl acetate/hexanes) provided 38 mg (0.08 mmol, 35% yield) of ethyl 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[NH:15][N:14]=2)=[N:4][C:5](Cl)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[NH:15][N:14]=2)=[N:4][C:5]([NH:31][C@H:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH3:30])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 145 °C
Yield: 98.1 %

Procedure:
A mixture of 3,6-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine (Method 59, 0.25 g, 0.75 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.13 g, 0.90 mmol) and DIEA (0.16 ml, 0.94 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 145° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.32 g, 98%). 1H NMR (400 MHz) δ 12.22 & 11.40 (s, 1H), 9.74 & 9.37 (s, 1H), 8.93 (d, J=7.6 Hz, 1H), 8.33 & 8.27 (s, 1H), 7.34 & 7.27 (m, 2H), 7.12 & 7.05 (m, 2H), 5.75 & 5.62 (s, 1H), 5.35 & 5.25 (m, 1H), 4.66 & 4.03 (m, 1H), 1.55 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 434. Found: [M+H]+ 435.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[O:16]1CCCC1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:8]([NH:7][CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: C1CCOC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Poly(ethoxylated fluoroalkyl acrylate)-block-polystyrene (IV). One gram of poly(acrylic acid)-block-polystyrene (2.19 mmol acrylic acid) was dissolved in 5 mL of anhydrous pyridine. DCC (6.57 mmol), DMAP (0.823 mmol), and Zonyl FSO-100 (6 g) were dissolved in tetrahydrofuran and added drop-wise to the polymer solution. The reaction mixture was stirred at room temperature for about 2.5 days. Dicyclohexylurea formed during the reaction was removed by filtration. After concentration under reduced pressure, the polymer solution was poured into excess methanol. Further purification was achieved by precipitating the polymer from tetrahydrofuran into methanol.
Reaction SMILES: COC(=O)C=CC1C2N(C3C=CC=CC=3)C=NC=2C=C(C(F)(F)F)C=1.CN1[CH2:32][CH2:31][N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29][CH2:28]1>>[C:45]1([N:43]2[C:44]3[C:36]([CH:35]=[CH:34][C:33]([N:30]4[CH2:31][CH2:32][CH2:28][CH2:29]4)=[O:55])=[CH:37][C:38]([C:51]([F:54])([F:52])[F:53])=[CH:39][C:40]=3[N:41]=[CH:42]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Agent: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: O=C(C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)N1CCCC1
Yield: 7 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford the title compound as a white solid (7.3 mg, 7%), m/z 386.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[N:16][CH:17]=2)[CH2:7]1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][NH2:35].C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:27][N:2]([CH3:1])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:35][O:34][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)=[O:21])=[N:16][CH:17]=2)[CH2:7]1
Reactant: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)O)cn2)C1
Reactant: NOC1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.4 %

Procedure:
To a mixture of crude (2E)-3-[5-({(3R)-1-[2-(dimethylamino) benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylic acid (311 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (108 mg), and HOBT (125 mg) in DMF (2.4 mL) was added WSCD (164 uL), which was stirred at room temperature for 17 hours. To the resultant was added saturated NaHCO3 aq. The mixture was extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (195 mg) as a yellow amorphous.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>C(Cl)Cl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])(=[O:4])=[O:3])[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stirring bar and N2 inlet was charged with 5.2 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate in 50 mL CH2Cl2. The flask was cooled to 0° C. and charged with 3.5 g N-Boc-piperazine and 2.9 mL (1.1 eq.) NEt3. The reaction was stirred 30 minutes at 0° C., concentrated in vacuo and partitionned between ethyl acetate/water. The combined organics were washed with 5% aqueous. citric acid, saturated aqueous sodium bicarbonate, brine, and concentrated in vacuo to yield a yellow liquid. Purification via flash chromatography on silica gel (30% ethyl acetate/hexane) yielded 7.2 g (90%) product as a clear oil.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[B:18]1[O:22]C(C)(C)[C:20]([CH3:26])(C)[O:19]1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1)=O.C[Mg+].[Br-].Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:22][B:18]1[C:17]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:15][C:16]=2[CH:20]([CH3:26])[O:19]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)cn3)cc2C=O)OC1(C)C
Agent: C[Mg+]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC1OB(O)c2ccc(Oc3ccc(C#N)cn3)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (105 mg, 0.3 mmol, 1.0 eq.) in THF (5.0 mL) at 0° C. was added MeMgBr (0.15 mL, 0.45 mmol, 1.5 eq.) drop wise. The mixture was stirred at 0° C. for 20 minutes and allowed to warm to room temperature in another 1 h. After cooling to 0° C., the clear solution was carefully treated with H2O (1 mL), followed by slow addition of HCl (10 mL, 3N). The resulting yellow suspension was allowed to ward to room temperature gradually and stirred for 2 h. The mixture was then treated with sat. NaHCO3 drop wise until PH reaching 1 and was extracted with EtOAc (3×10 mL). Combined organic extracts was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 6-(1-hydroxy-3-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile as a white solid. LCMS (m/z) 267 (M+H); 1H NMR (DMSO-d6) δ: 9.19 (s, 1H), 8.71 (dd, J=2.3, 0.6 Hz, 1H), 8.38 (dd, J=8.7, 2.4 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.28-7.35 (m, 2H), 7.20 (dd, J=7.9, 2.0 Hz, 1H), 5.26 (q, J=6.5 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H).