Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8](O)[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]C.C[CH2:17][O:18]CC.[C:21](=[S:23])=[S:22].CI>C1COCC1>[CH3:17][O:18][C:21](=[S:23])[S:22][CH:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(O)c1cccnc1Br
Reactant: CCOCC
Reactant: S=C=S
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=S)SC(c1cccnc1Br)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 76.6 %

Procedure:
To a cold solution (−40° C.) of 1-(2-bromo-pyridin-3-yl)-2,2-dimethyl-propan-1-ol (8.18 g, 33.5 mmol) (Romero, D. L. et al. J. Med. Chem. 1994, 37, 999-1014) in dry THF (310 mL) was added dropwise a solution of 1.6 M MeLi in Et2O (23.1 mL, 36.9 mmol). The solution was warmed to room temperature and stirred 15 min before the addition of carbon disulfide (2.22 mL, 36.9 mmol). The solution was stirred 50 min and then MeI (2.50 mL, 40.2 mmol) was added. The mixture was stirred 1.5 h and was quenched with a saturated solution of NaHCO3 (100 mL). The solution was extracted with Et2O (3×120 mL). The combined organic portions were dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/hexanes) to afford 8.58 g (81%) of Dithiocarbonic acid [1-(2-bromo-pyridin-3-yl)-2,2-dimethyl-propyl]ester methyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.09 (s, 9H), 2.55 (s, 3H), 6.50 (s, 1H), 7.26 (dd, 1H, J=4.7, 7.7 Hz), 7.60 (dd, 1H, J=2.0, 7.7 Hz), 8.30 (dd, 1H, J=1.9, 4.7 Hz).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.[CH2:12](I)[CH3:13]>CS(C)=O.O>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([CH2:10][O:11][CH2:12][CH3:13])[CH:5]=1
Reactant: OCc1cncc(Br)c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a mixture of powdered KOH (5.96 g, 106.4 mmol) in anhydrous DMSO (20 mL) was added under argon a solution of (5-bromopyridin-3-yl)methanol (example 26c) (5 g, 26.6 mmol) in anhydrous DMSO (20 mL), followed by EtI (2.6 mL, 31.9 mmol). The reaction mixture was stirred at room temperature for 1 hour then diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated to give 5.6 g of 3-bromo-5-(ethoxymethyl)pyridine as a dark brown oil in 97% yield. 1H NMR (400 MHz, CDCl3): 1.27 (t, 3H), 3.57-3.59 (q, 2H), 4.50 (s, 2H,), 8.48 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: C(B1O[C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])O1)(C)=C.C(=O)([O-])[O-].[K+].[K+].ClC1C=[C:22]([C:35]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:36]=2)[C:23]([NH:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:24]C=1>O1CCOCC1.O>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][N:42]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=2)[C:37]2[N:36]=[C:35]([C:22]3[C:23]([NH:26][C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[N:24][CH:11]=[C:9]([C:6]([CH3:7])=[CH2:8])[CH:10]=3)[N:40]=[C:39]([CH3:41])[N:38]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Yield: 91.5 %

Procedure:
A mixture of isopropenylboronic acid pinacol ester (0.119 mL, 0.633 mmol, Aldrich, St. Louis, Mo.), potassium carbonate (0.175 g, 1.267 mmol), (Amphos)2PdCl2 (0.022 g, 0.032 mmol) and 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 155, 0.185 g, 0.317 mmol) in 4:1 dioxane/water (2.5 mL) was heated in a sealed tube for 24 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol, 92% yield) as an orange solid. m/z (ESI, +ve ion) 590 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.71 (br. s., 1H); 8.94 (s, 1H); 8.44 (d, J=2.5 Hz, 1H); 8.27 (d, J=2.3 Hz, 1H); 7.91 (br. s., 1H); 7.22 range (m, 4H); 6.86 range (m, 4H); 6.73 (d, J=9.0 Hz, 1H); 5.33 (s, 1H); 5.01 (s, 1H); 4.89 (s, 2H); 4.82 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 2.59 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]([C:14](=[O:21])[CH:15]([NH:17][C:18]([NH2:20])=[O:19])[CH3:16])[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3].[OH2:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26](S(O)(=O)=O)=[CH:25][CH:24]=1>CO>[OH:22][NH:6][C:7]([C@H:8]([C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]([NH:6][N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14](=[O:21])[CH:15]([NH:17][C:18]([NH2:20])=[O:19])[CH3:16])=[O:13])[CH2:9]/[CH:10]=[CH:33]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)C(C)NC(N)=O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C(C)NC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.232 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2(RS)-ureidopropionyl)valerohydrazide in 5 ml of methanol was treated with 0.03 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.168 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2(RS)-ureidopropionyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>C1COCC1.[Zn]>[OH:7][C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)CBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCCC1
Yield: 95.2 %

Procedure:
To a solution of cyclohexanone (9.52 g, 97.0 mmol), a zinc powder (7.6 g, 116.4 mmol) and a small amount of iodine in THF (100 ml) was added dropwise ethyl bromoacetate (11.8 ml, 106.7 mmol) under a nitrogen atmosphere, and the mixture was heated under reflux for 5 hrs. 10% Sulfuric acid (100 ml) was carefully added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the title compound (17.2 g, 94%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O.O1CCOCC1>[C:35]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1)(=[O:37])[CH3:36]
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)n1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g) in dimethylformamide (150 cc), acetyl chloride (1.95 cc) in dioxane (50 cc) and sodium hydride (1.3 g as a 50% dispersion in vaseline oil). The mixture is stirred for 15 hours at a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar), firstly with dichloromethane as eluant and then with ethyl acetate as eluant, then recrystallization from boiling acetonitrile (45 cc), 2-{3-[4-(1-acetyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (1.3 g) is obtained, m.p. 163° C.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10](=O)OCC2C=CC=CC=2)[CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=C(S(C)=O)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1>C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=[C:10]([NH:9][C@H:5]4[CH2:6][CH2:7][CH2:8][C@@H:3]([C:1]#[N:2])[CH2:4]4)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:53]=[CH:54][C:55]([CH3:56])=[CH:57][CH:58]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1
Reactant: N#C[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](C#N)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 45 °C
Reaction time: 2.25 h

Procedure:
Benzyl N-[(1S,3R)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman's catalyst (50% wet by weight). The suspension was degassed with hydrogen for 2 min then placed under static hydrogen atmosphere. After 135 min, TLC showed no remaining starting material. The suspension was filtered through celite, washed with THF and degassed with nitrogen followed by the addition of iPr2NEt (0.21 mL, 1.23 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (0.48 g, 1.02 mmol). The mixture was allowed to stir overnight at 45° C. then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using 0-60% EtOAc/hexanes gradient to afford 293 mg of a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.I[CH2:15][CH3:16].[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:3]([CH2:15][CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NC(=O)c1c(N)[nH]c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A solution of 2-aminoindole-3-carboxamide (Reference compound 18-1, 0.40 g, 2.3 mmol) in anhydrous N,N-dimethylformamide (2 mL) and a solution of iodoethane (0.20 mL, 2.5 mmol) in anhydrous N,N-dimethylformamide (2 mL) were successively added to a suspension of sodium hydride (purity 60%, 0.10 g, 2.5 mmol) in anhydrous N,N-dimethylformamide (10 mL) under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water (30 mL), and the whole was extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.22 g) as a brown solid (yield 49%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-ylamine (4.47 g, 16.0 mmol) in THF (50 ml) was added a solution of K2CO3 (4.31 g, 31 mmol) in H2O (35 ml). After 10 minutes, ethyl chloroformate (2.97 ml, 31 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (62 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with cone. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (50 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 2.68 g (57%) of the title compound as a colorless oil. ES-MS m/e: 301.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:26])N(OC)C)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[C:30]([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:26])[CH3:30])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of 4-[3-chloro-5-(methoxy-methyl-carbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester from step (b) above (1.0 g, 2.6 mmol) in anhydrous THF (20 mL) was added MeMgBr (2.6 mL, 3M solution in Et2O, 7.8 mmol, Aldrich) with stirring at 0° C. The reaction mixture was stirred at room temperature for 4 h and poured into satd. aq. NaHCO3 solution (20 mL). After the addition of EtOAc (50 mL), the mixture was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (70% EtOAc in hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 340 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][NH2:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:4]([NH:1][C:2]([NH:24][O:23][CH:20]1[CH2:21][CH2:22][N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:26])([F:6])[F:25])[CH:9]=2)(=[O:15])=[O:16])[CH2:18][CH2:19]1)=[O:3])[CH3:5]
Reactant: CCN=C=O
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.6 %

Procedure:
Isocyanatoethane (53.0 mg, 0.74 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (200 mg, 0.62 mmol) and pyridine (98 mg, 1.23 mmol) in CH2Cl2 (4 ml) and stirred at room temperature for 17 hours. The resulting precipitation was collected, washed with aqueous 1 N HCl solution (10 ml×3), aqueous NaHCO3 solution (10 ml×3), ether (10 ml×2) to give 1-ethyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea (156 mg, 64%) as a white solid: LCMS: 396 [M+1]+. 1H NMR (DMSO-d6) δ: 0.98 (m, 3H), 1.73 (m, 2H), 1.86 (m, 2H), 2.85 (m, 2H), 3.00 (m, 2H), 3.18 (n, 2H), 3.60 (m, 1H), 6.65 (m, 1H), 7.91 (m, 2H), 8.01 (m, 2H), 8.82 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.[CH2:11](N(CC)CC)C.Cl[C:19]1[N:28]=[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:40])[CH:25]=2)[N:20]=1>CC(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:9][CH2:10][N:1]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]4[O:37][CH2:38][O:39][C:33]=4[CH:32]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:40])[CH:25]=3)[N:20]=2)[CH2:2][CH2:3]1)=[O:6])[CH3:11]
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: COC(=O)C1CCNCC1
Reactant: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Yield: 97.3 %

Procedure:
3.61 g of methyl isonipecotate, 2.32 g of triethylamine and 5 ml of 2-propanol were added to 1 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline prepared in Example 92. The obtained mixture was refluxed for 100 minutes. The mixture thus obtained was extracted with chloroform twice. The organic layers were combined, washed with water, dried over magnesium sulfate and freed from the solvent by distillation. The residue was recrystallized (from ethanol/water) to give 1.31 g of the title compound.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40].C(OCC)(=O)C>O1CCCC1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:26]4)=[O:23])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=CS(C)(=O)=O
Reactant: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and methylvinylsulfone (0.016 g, 0.15 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at ambient temperature for 16 h. Ethyl acetate (10 mL) was added to the reaction mixture and everything subsequently washed with water. The organic phase was dried over sodium sulfate, filtered and the filtrate evaporated. The residue was subjected to column chromatography (basic silica gel, ethyl acetate) to yield the title compound (0.026 g, 41%) as an off-white solid; MS: m/e=508.8 (M+H+).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OC(CCl)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-nitrophenol to give white title compound, m.p. 60°-63° C.
Reaction SMILES: [H-].[Na+].CO.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12](Cl)[N:13]=1)[C:9]#[N:10].C[CH2:16][O:17]C(C)=O.CCCCCC>CN1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:17][CH3:16])[N:13]=1)[C:9]#[N:10]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(C#N)cc(Cl)n1
Reaction time: 0.5 h

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with thermometer pocket fitted with an nitrogen inlet and a rubber septum, NaH (0.112 g, 1.0 eq.), methanol (0.11 mL, 1.0 eq.), suspended in N-methylpyrrolidine (5 mL). The reaction mixture was stir at 25-30 C for 30 minutes. To this reaction mixture 2,6-dichloroisonicotinonitrile was added at 0-5 C. The progress of the reaction was followed by TLC analysis on silica gel with 10% EtOAc-hexane as mobile phase which shows that starting material was consumed after 2 hours staring at 0-5 C. Reaction was quenched by water, precipitate was observed that was filter by filter paper and wash with hexane to give required compound (0.51 g, crude). Reaction was stirred for 20 min with water solid was separated and compound was collected by filtration on a Buchner funnel and washed with of hexane (30 mL); Yield: 0.51 g crude 2-chloro-6-methoxyisonicotinonitrile.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][N:11]1[CH2:25][CH3:26])(=[O:9])[NH2:8]>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:12][N+:11]1([CH2:25][CH3:26])[CH3:6])(=[O:9])[NH2:8]
Reactant: CCN1C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(N)=O
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: CC[N+]1(C)C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(N)=O
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.43 ml of methyl fluorosulfonate was added, whilst ice-cooling, to a solution of 1.44 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)-1-ethylpyrrolidine dissolved in 30 ml of dry methylene chloride and the mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed repeatedly by decantation with diethyl ether and dried under reduced pressure to afford 2.0 g of the title compound as an oil.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16][C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:37][C:18]1[CH:19]=[C:20]([F:36])[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]=1[O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3OCc3ccccc3)c(N)cc2F)c1=O
Temperature: 45 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a mixture of 0.55 g of an iron powder, 3 ml of acetic acid and 0.3 ml of water was added a solution of 0.548 g of 4-benzyloxy-3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}pyridine in 0.5 ml of acetic acid and 3 ml of ethyl acetate dropwise. After completion of the addition, the mixture was stirred for 3 hour at 40-50° C. The mixture was poured into water, then, the mixture was filtrated through Celite, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 0.438 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-benzyloxypyridine.