Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][C:4]2([CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[N:7]([C:13](=[O:23])[C@H:14]([CH:20]([CH3:22])[CH3:21])[NH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:6]2)[CH2:3]1.[CH3:25][O:26][C:27]([NH:29][C@H:30]([C:34]([N:36]1[CH2:62][CH2:61][CH2:60][C@H:37]1[C:38]([O:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56](=[O:59])[CH2:57]Br)=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)=[O:43])=[O:39])=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28]>>[F:24][C:2]1([F:1])[CH2:5][C:4]2([CH2:9][C@@H:8]([C:10]([O:12][CH2:57][C:56]([C:53]3[CH:54]=[CH:55][C:50]([C:47]4[CH:46]=[CH:45][C:44]([C:42](=[O:43])[CH2:41][O:40][C:38]([C@@H:37]5[CH2:60][CH2:61][CH2:62][N:36]5[C:34](=[O:35])[C@@H:30]([NH:29][C:27]([O:26][CH3:25])=[O:28])[CH:31]([CH3:33])[CH3:32])=[O:39])=[CH:49][CH:48]=4)=[CH:51][CH:52]=3)=[O:59])=[O:11])[N:7]([C:13](=[O:23])[C@@H:14]([NH:15][C:16]([O:18][CH3:19])=[O:17])[CH:20]([CH3:21])[CH3:22])[CH2:6]2)[CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)O)CC(F)(F)C2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)CBr)cc2)cc1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)COC(=O)[C@@H]3CC4(CN3C(=O)[C@@H](NC(=O)OC)C(C)C)CC(F)(F)C4)cc2)cc1)C(C)C
Yield: 76 %

Procedure:
This compound was prepared in an analogous fashion to 117 (Example 17) from (7S)-2,2-difluoro-6-{N-[(methyloxy)carbonyl]-L-valyl}-6-azaspiro[3.4]octane-7-carboxylic acid (156) (59 mg, 0.17 mmol) and 2-[4′-(bromoacetyl)-4-biphenylyl]-2-oxoethyl N-[(methyloxy)carbonyl]-L-valyl-L-prolinate (70) (95 mg, 0.16 mmol) to afford the title compound as a white solid (104 mg, 75% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[S:23][CH2:22][CH2:21][C:19]=2[N:20]=1>C(O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:18]3[S:23][CH2:22][CH2:21][C:19]=3[N:20]=[C:15]([Cl:14])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
454 mg piperazine-1-carboxylic acid tert-butyl ester in 5 mL ethanol was added to 0.5 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine in 5 mL dichlormethane. The reaction was stirred 2 h at RT, 3 h at 60° C. and over night at RT. The solvents were removed and water was added to the residue. The precipitate was filtered and dried to give 0.83 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][NH:13][CH2:12][CH:9]3[O:8][C:7]4[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[O:11][CH2:10]3)[CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: BrCCCOc1ccc2cccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3cccnc3c1)CO2
Temperature: 80 °C
Yield: 28.2 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine (2.7 g, 14 mmole), 7-(3-bromopropoxy)quinoline (3.86 g, 14 mmole), and diisopropylethylamine (6.5 g, 50 mmole) were combined in 100 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 200 g of silica gel using 4% methanolchloroform as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue recrystallized from 50 ml of ethanol with the addition of 8 ml of 4N isopropanolic HCl to give 1.5 g of the title compound as a yellow solid dihydrochloride monohydrate, m.p. 135°-142° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (20 g, 79 mmol) and phosphoryl chloride (36.0 mL, 395 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (17.35 g, 81%). NMR (DMSO-d6) δ 7.71 (s, 1H), 7.73 (s, 1H), 7.88 (d, 2H, J=8.1 Hz), 8.05 (d, 2H, J=8.1 Hz) ppm.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[C:1]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A three liter flask equipped with a stirrer, theremometer, nitrogen inlet, Barrett trap and condenser was used. Myristic acid (commercially available from Emery Chemicals, 97 percent purity, 685 grams, 3.0 moles), aniline (300 ml., 3.2 moles) and 120 ml xylene were charged to the flask. The mixture was stirred and heated for approximately 61/2 hours at a temperature of from about 170° C.-220° C. The reaction was conducted in a nitrogen atmosphere. The reaction mixture was then cooled to 140° C. and poured into a 4 liter beaker. About 1.8 liters of denatured alcohol were slowly added to the reaction solution. After standing overnight, the slurry of semi-solid myristanilide was collected by filtration. The filter cake was washed thoroughly with two portions of denatured alcohol and then air dried at about 22° C. The resultant white crystalline solid weighed 706 grams and had a melting point of 83.5° C.-84.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH:18]([CH2:34][O:35][CH3:36])[C:17]1=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:38])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH:18]([CH2:34][O:35][CH3:36])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-[3-methoxymethyl-4(2-nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 60, (5.6 g, 10.4 mmol) in anhydrous THF (10 mL) is added 1.0M borane-tetrahydrofuran complex (31.2 mL) at −20° C. The reaction mixture is stirred at this temperature overnight. Methanol (3 mL) is added to the reaction mixture at −20° C. and allowed to stir for twenty minutes. Additional methanol (6 mL) is and the reaction mixture is allowed to warm to the room temperature. The solvent is removed in vacuo and the product purified over silica (EtOAc/Hexane, 1:1) to afford 3.5 g (64% yield) of the desired product. 1H NMR (CDCl3, δ): 8.05 (m, 1H), 7.75 (m,3H), 7.62 (m, 4H), 7.50 (m, 2H), 7.30 (dd, J=8.4, 2.1 Hz, 1H), 3.94 (t, J=6.3 Hz, 1H), 3.66 (s, 3H), 3.58 (t, J=6.8 Hz, 1H), 3.30–2.95 (m, 7H), 2.82 (s, 3H), 2.79 (m, 2H), 2.40 (dt, J=12.7, 4.3 Hz, 1H); 13C NMR, δ 171.8, 148.0, 136.0, 134.1, 133.7, 132.4, 132.0, 131.5, 128.1, 127.9, 127.7, 126.3, 125.8, 124.5, 69.5, 68.7, 58.7, 53.8, 52.8, 51.6, 46.6, 42.8, 35.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H][H]>CO>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([OH:8])[CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCC(=O)CC(=O)OC
Solvent: CO
Product: CCC(O)CC(=O)OC
Reaction time: 48 h

Procedure:
A solution of methyl-3-oxo-pentanoate (31) (20 g) noyori hydrogenation with RuCl2 [(S)-BINAP] (60 mg), in methanol was added. The flask was charged with hydrogen gas (5 atm) at 100° C. The resulting suspension was vigorously stirred for 48 hours. The reaction mixture was diluted with methanol and the combined organic layers were filtered through a Celite pad. The combined organic phases were evaporated in a rotary evaporator to yield the product (S) isomer of methyl-3-hydroxy-pentanoate (32). The methyl-3-hydroxy-pentanoate (secondary alcohol-32) was protected with TBDMSCl in the presence of imidazole in dichloro methane. The reaction mixture was stirred for 24 hours at room temperature. This reaction was quenched with aqueous saturated sodium bicarbonate and extracted with dichloro methane. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the TBS protected product (33). A stirred solution of ester was reduced with di-isobutyl aluminum hydride in dichloro methane at −78° C. for 5 hours. This reaction mixture was quenched with saturated aqueous sodium potassium tartarate. The combined organic and aqueous layers were filtered and organic layer was separated by separating funnel. The aqueous layer was extracted with dichloro methane. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the product primary alcohol (34) as a pale yellow liquid. The primary alcohol was protected with methane sulfonyl chloride in the presence of TEA in dichloromethane. The reaction mixture was stirred for 4 hours at 0° C. This reaction was quenched with aqueous saturated sodium bicarbonate and extracted with dichloro methane. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the methane sulfonyl protected product (35). The methane sulfonyl protected primary alcohol was stirred at 70° C. with NaN3 in DMF for 16 hours. A stirred solution of TBS protected secondary alcohol. This reaction was quenched with pre cooled ice water and extracted with diethyl ether. The combined organic phases were dried over Na2SO4. The combined organic phases were evaporated in a rotary evaporator to yield the azido product as a colorless liquid (36). This was deprotected with TBAF in tetrahydrofuran at room temperature. This reaction was quenched with saturated ammonium chloride solution and extracted with diethyl ether; the combined organic phases were dried over Na2SO4 and evaporated on rotary evaporator to yield the product 1-azido-3-pentanol (36A) as a colorless liquid.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[CH3:15][C:16]1([CH3:28])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[O:17]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([CH2:3][C:4]1([N:26]2[CH:27]=[C:23]([B:18]3[O:17][C:16]([CH3:28])([CH3:15])[C:20]([CH3:22])([CH3:21])[O:19]3)[CH:24]=[N:25]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.2 %

Procedure:
In a 5 L flask, tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (Preparation F, Step A; 94.2 g, 485 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (85.6 g, 441 mmol) were dissolved in acetonitrile (882 mL). To this was then added DBU (33.0 mL, 220 mmol). The resulting clear orange brown mixture was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated down to remove solvents and afforded a dark reddish-orange oil. Solid crystals formed within a few hours at ambient temperature. This was isolated by washing with cold Et2O and cold EtOAc (carefully to prevent dissolution) to afford 110 g (64% yield) of the title compound. The recrystallization was repeated to give another 13.7 g (8% yield). Additional compound was isolated by purification of the filtrate from the above recrystallization. This was purified by silica chromatography eluting with a 20-50% EtOAc/Hexanes gradient to afford an additional 22.7 g (13%) of the title compound. MS (apci) m/z=289.2 (M+H-Boc).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([CH3:24])=[N:6][C:7]2[N:8]([N:11]=[C:12]([CH3:23])[C:13]=2[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:9]=1[OH:10].S(Cl)(Cl)=O>C1C=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]=[C:15]([CH3:22])[C:14]=1[C:13]1[C:12]([CH3:23])=[N:11][N:8]2[C:9]3[O:10][CH2:2][CH2:3][C:4]=3[C:5]([CH3:24])=[N:6][C:7]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(O)c(CCO)c(C)nc23)c(C)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCO4)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A solution of 6-(2-hydroxyethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (500 mg, 1.54 mmol) and thionyl chloride (0.26 mL) in benzene (30 mL) was heated under reflux for two hours. After cooling to room temperature, the resulting crystals were collected by filtration. A suspension of the resulting crystals in 2% sodium carbonate was stirred at room temperature for two hours. The crystals were collected by filtration and purified by silica gel column chromatography (50-70% ethyl acetate/hexane), to give the title compound (310 mg) as pale brown crystals.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]3[NH2:37])[CH2:25]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]3[NH:37][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][CH:5]=3)=[O:3])[CH2:25]2)=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 38.3 %

Procedure:
1-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea was synthesized as described in General Procedure G, using 1-isocyanato-4-(trifluoromethoxy)benzene (15.31 mg, 0.075 mmol) and (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (24 mg, 0.075 mmol) to give 15 mg (30% yield) of the title compound as a yellow solid. Anal. Calcd. for C25H30F3N5O4 m/z 521.5, found: 522.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.77 (d, J=8.80 Hz, 2H), 7.22 (d, J=8.80 Hz, 2H), 6.99 (d, J=8.25 Hz, 2H), 6.67 (d, J=8.80 Hz, 2H), 3.67 (br. s., 1H), 3.63-3.56 (m, 1H), 3.56-3.49 (m, 1H), 3.29 (br. s., 3H), 3.07-2.96 (m, 1H), 2.11-2.20 (m, 2H), 1.99-1.58 (m, 7H), 1.43 (d, J=12.65 Hz, 1H), 1.30-1.12 (m, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][CH2:20][C@H:21]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])[CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:21]([CH2:20][O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](COCc2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
p-Toluenesulfonyl chloride (1.4 g. 7.4 mmol) was added in one portion to a cold (ice/water bath) stirred solution of 4 (2.0 g, 6.16 mmol) in anhydrous pyridine (25 ml). The reaction was allowed to warm up to room temperature and stirred for 6 hrs until no starting material was found by HPLC analysis. Ethyl acetate (100 ml) and 10% citric acid (enough to neutralize pyridine) were added. The organic phase was washed with saturated NaCl, saturated NaHCO3 and dried over MgSO4. The crude tosylate 9 (2.9 g) was used in the next step without additional purification. 1H NMR (CDCl3): δ 7.80 (d, J=8.1 Hz, 2H). 7.40-7.25 (m, 7H), 4.41 (d, J=3.6 Hz, 2H), 4.25 (m, 1H), 4.11 (m, 1H), 3.98 (m, 1H), 3.45 (m, 2H), 2.45 (s, 3H), 1.96 (m, 1H), 1.12 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.036 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18].CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:17](=[O:18])[C:16]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:15]=1[F:14])=[O:21]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 2,5-dichloro-3-trifluoromethyl aniline (0.6 g) in 10 ml of dry benzene was added dropwise a solution of 2,6-difluorobenzoylisocyanate (0.5 g) in 5 ml of dry benzene under water-cooling and the solution was stirred for one hour at room temperature. 50 ml of n-hexane was added to the above solution and the precipitated crystal was filtered. The crystal was washed with n-hexane to obtain the desired product 0.9 g. (m.p. 205°-207.5° C.)
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][C:26](=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:28][CH2:27][C:26]([NH:25][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[O:29])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)Nc1c(C)cccc1C
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-bis-(1,1-Dimethylethyl)-4-mercaptophenol(1.19 g, 0.005 mole), N-(2,6-dimethylphenyl)-2-propenamide (0.87 g, 0.005 mole) and triethylamine (0.5 ml) in methanol (100 ml) were stirred at room temperature under argon for 12 hours. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica. The solvents were removed and the product recrystallized from ethyl acetate/hexane, filtered and dried in vacuo to yield the title compound, m.p. ca. 142.5°-144° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=S)[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O.Cl>[OH-].[K+].CO.O>[C:1]1([N:7]2[C:12](=[O:24])[C:11]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][NH:9][C:8]2=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]nc(Cc2c(F)cccc2F)c(=S)n1-c1ccccc1
Reactant: OO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]nc(Cc2c(F)cccc2F)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
4-Phenyl-6-(2,6-difluorobenzyl)-5-thioxo-2H-(1,2,4)triazin-3-one (1.00 g, 3.02 mmol) was dissolved in a solution of KOH (643 mg) in MeOH (12 mL) and water (6 mL). A solution of H2O2 (1.2 mL, 30% in water) in water (5 mL) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with conc. HCl (1.1 mL) and a white solid precipitated. Filtered and washed with water to give a white solid (816 mg, 85.8%): MS (CI) m/z 380.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(Br)CC
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A mixture of 5.0 g (32 mmole) of 2-methyl-3-nitrophenol, 4.8 ml (ca. 32 mmole) of ethyl 2-bromobutanoate, and 4.5 g (32 mmole) of potassium carbonate in 50 ml of dimethylformamide was stirred for 18 hours at room temperature. The mixture was then poured over ice, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 8.0 g of the title compound as an analytically pure solid. Structure assignment was supported by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][N:25]([CH3:26])[CH3:27])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 56.6 %

Procedure:
Following general procedure F, {6-bromo-4-[6-((dimethylamino)methyl)pyridin-3-ylamino]quinolin-3-yl}(cyclopropyl)methanone (37 mg, 0.087 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.131 mmol) to afford the desired product (25 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.37 (s, 1H), 8.75 (s, 1H), 8.32 (dd, J=8.8, 2.1 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.96 (dd, J=8.4, 2.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.47 (s, 2H), 4.58 (s, 2H), 2.95 (s, 6H), 2.83-2.74 (m, 1H), 1.19-1.07 (m, 4H); ESI MS m/z 507 [C27H24Cl2N4O2+H]+; HPLC 98.9% (AUC), tR=10.66 min.