Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]O)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:27][CH2:28]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
DIAD (19.73 mL, 100.18 mmol) was added dropwise to 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (28 g, 77.06 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (14.53 g, 100.18 mmol) and triphenylphosphine (26.3 g, 100.18 mmol) in THF (250 mL). The resulting solution was stirred at ambient temperature for 3 days. The reaction mixture was evaporated to dryness and re-dissolved in DCM (1 L), and the solution was washed sequentially with 2M NaOH (300 mL×2) and saturated brine (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 75% EtOAc in isohexane followed by a gradient of 0 to 3% MeOH in DCM. Fractions containing the desired product were evaporated to dryness then re-dissolved in DCM (500 mL) and the solution washed with 2M NaOH (300 mL×2) followed by brine (250 mL), then dried over MgSO4, filtered and evaporated. The residue was further purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 6-[4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (18.21 g, 50.1%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:28])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([Cl:28])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 66.6 %

Procedure:
(1R)-1-(4-Bromophenyl)-2-(4-morpholinyl)ethanol (48.5 g, 0.17 mol) was dissolved in 200 mL CH2Cl2 at room temperature with magnetic stirring and triethylamine (52 mL. 0.37 mol, 2.2 equiv) was added. The resulting solution was cooled to 0° C. and treated with methanesulfonyl chloride (16 mL, 0.20 mol, 1.2 equiv) through an addition funnel. After the addition, the reaction mixture was maintained at 40° C. for 48 h with magnetic stirring. The reaction mixture was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude brown oil was purified by silica gel chromatography (800 g silica gel 60, 230-400 mesh, 5% EtOAc/CH2Cl2 as eluent). Concentration of the pure fractions yielded the title compound as a yellow oil (34.5 g, 67%). MS (ES) m/e 304 [M+H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:11][CH:12]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Oc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
To a mixture of 4-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N,N-dimethylformamide (30 mL) was added sodium hydride (730 mg, 15 mmol, 50% in oil) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was then stirred for 5 hours at 110° C. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water twice, and then washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=15:1) to obtain the title compound (2.6 g, 75%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:34][CH2:33][C:18]2=[C:19]([C:26](=[O:32])[C:27](OCC)=[O:28])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:17]2[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:34][CH2:33][C:18]2=[C:19]([CH:26]([OH:32])[CH2:27][OH:28])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:17]2[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=O)c1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(O)c1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2
Reaction time: 1 h
Yield: 168.5 %

Procedure:
(Chart D, Step 2): A dry round bottom flask is charged with THF (100 mL) and 1M LAH in THF (65.13 mL, 65.13 mmol). A solution of ethyl 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-2-oxoacetate (6.13 g, 16.28 mmol) in THF (75 mL) is slowly added to the reaction via syringe. The addition is exothermic. The reaction mixture is heated to reflux for 5 hours then reaction is quenched with a very slow and sequential addition of a) 2.47 mL H2O, b) 2.22 mL of 5N aq. NaOH, and c) 8.64 mL H2O. The resulting heterogeneous solution is stirred vigorously with excess ethyl acetate for one hour and filtered through a pad of celite. The filtrate is concentrated to give 9.23 g of 1-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1,2-ethanediol as a crude yellow solid. A 2 L round bottom is charged with a solution of the crude diol in dichloromethane (541 mL). A semi-dropwise addition of TFA (14.46 mL, 188 mmol) is followed by the slow addition of triethylsilane (9.1 mL, 57 mmol) and the mixture is first refluxed for two hours, then stirred at ambient temperature for 18 hours. The resulting brown solution is concentrated in vacuo, diluted with dichloromethane, basified with sat. aq. Na2CO3 and vigorously stirred while cooling to 10° C. The mixture is transferred to a round bottom, volatiles are removed in vacuo at 50° C. The residue is partitioned between water and dichloromethane. The organics are combined, dried with Na2SO4, filtered and concentrated to give 5.57 g of an orange oil. Purification of the crude on silica gel using a gradient of 35%-50% ethyl acetate/heptane as the eluent gives 3.52 g of 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanol as a tan oil. IR (liq.) 2933, 2873, 2816, 1469, 1453, 1427, 1376, 1364, 1347, 1325, 1185, 1046, 1015, 733, 699 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5](C(C)(C)C)=[C:6]([C:9]2[C:10]([OH:21])=[C:11]([CH3:20])[C:12]([Cl:19])=[CH:13][C:14]=2C(C)(C)C)[C:7]=1[OH:8].C1(C)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:20][C:11]1[C:12]([Cl:19])=[CH:13][CH:14]=[C:9]([C:6]2[C:7]([OH:8])=[C:2]([CH3:1])[C:3]([Cl:26])=[CH:4][CH:5]=2)[C:10]=1[OH:21]
Reactant: Cc1c(Cl)cc(C(C)(C)C)c(-c2c(C(C)(C)C)cc(Cl)c(C)c2O)c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Cl)ccc(-c2ccc(Cl)c(C)c2O)c1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
The optically active 6,6′-dimethyl-5,5′-dichloro-3,3′-di(t-butyl)-2,2′-biphenol obtained in Example 6 (110 mg, optical purity: >99% ee, 0.28 mmol), toluene (5 ml) and trifluoromethanesulfonic acid (45 mg, 0.5 mmol) were mixed followed by stirring the entire volume for 1 hour at 5° C. Water (1 ml) and chloroform were then added to the reaction mixture followed by extraction and liquid separation. The organic phase was then washed with water and dried with anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. N-hexane (10 ml) was added to the remaining slurry followed by stirring at room temperature, washing and filtering to obtain optically active 6,6′-dimethyl-5,5′-dichloro-2,2′-biphenol (70 mg, yield: 82%, optical purity: >99% ee).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:55]([C:58]1[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=1[NH2:60])([CH3:57])[CH3:56]>>[Br:1][C:63]1[CH:62]=[CH:61][C:59]([NH2:60])=[C:58]([CH:55]([CH3:57])[CH3:56])[CH:64]=1
Reactant: CC(C)c1ccccc1N
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)c1cc(Br)ccc1N
Yield: 55.5 %

Procedure:
In a manner analogous to example 9a, the process is carried out by a reaction of 89 g (185 mmol) of tetra-n-butylammonium tribromide with 25 g (185 mmol) of 2-isopropylaniline. 22 g of 4-bromo-2-isopropyl-phenylamine are obtained (yield=57%).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH3:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[C:21]([S:28][CH3:29])[N:20]=1.C(=O)([O-])O.[Na+]>O>[CH3:18][C:19]1[C:24]([C:25]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:26])=[CH:23][N:22]=[C:21]([S:28][CH3:29])[N:20]=1
Reactant: CSc1ncc(C(=O)O)c(C)n1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To 40 ml of N,N-dimethylformamide were dissolved 4.00 g (20 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 4.00 g (22 mmol) of 4-methyl-2-(methylthio)pyrimidine-5-carboxylic acid, followed by the addition of 3.70 g (44 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, the addition of “Florisil” and filtering. The solution was concentrated under reduced pressure to obtain 5.30 g (yield: 92%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-(methylthio)-pyrimidine-5-carboxylate.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[CH2:10]1[CH:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]2[CH2:13][CH2:12][N:11]1[CH2:29][CH2:30][CH2:31][OH:32].C(OCC)(=O)C>C(Cl)Cl>[C:3](=[O:4])([O:32][CH2:31][CH2:30][CH2:29][N:11]1[CH2:12][CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[CH:15]2[CH2:10]1)[NH2:5]
Reactant: OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
0.2 ml of trichloroacetyl isocyanate were added to a solution of 400 mg of 3-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)propanol (prepared as described in Example 16) in 20 ml of methylene chloride, whilst ice-cooling, 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. The resulting residue was dissolved in 22 ml of methanol, 9.0 g of silica gel were added to the solution and the mixture was stirred at room temperature for 15 hours. At the end of this time, the mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with ethyl acetate, to give, after recrystallization from ethyl acetate, 260 mg (yield 59%) of the title compound as crystals, melting at 160°-161° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[Cl:14][C:15]([F:20])([F:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:16](=[O:17])[C:15]([Cl:14])([F:20])[F:19])=[C:7]([CH3:12])[CH:6]=1
Reactant: O=C(Cl)C(F)(F)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(NC(=O)C(F)(F)Cl)c(C)c1

Procedure:
According to general procedures outlined above, 3-methyl-4-aminophenyl N-methylcarbamate (2.3g., 0.0128 mole) was reacted with chlorodifluoroacetyl chloride (2.1g., 0.014 mole) in the presence of triethylamine (1.4g., 0.014 mole) and benzene. The product was a light tan solid (1.6g., m.p. 156°-58.5° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:5][CH:4]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:5][CH:4]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: COCCOCCOCCOCCOCc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCc1ccc(CN=[N+]=[N-])cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-(4-(chloromethyl)phenyl)-2,5,8,11,14-pentaoxapentadecane (1.50 g, 4.33 mmol) in DMF (10 mL) was added NaN3 (337.9 mg, 5.20 mmol). The reaction mixture was stirred overnight at 110° C. The solvent was subsequently evaporated. The residue was then suspended in ethyl acetate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired azide (1.53 g, 4.33 mmol, 90%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.37 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.2 Hz), 4.58 (s, 2H), 4.33 (s, 2H), 3.69−3.58 (m, 14H), 3.56−3.52 (m, 2H), 3.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6, 134.7, 128.3, 128.2, 72.9, 72.0, 70.7, 70.6, 70.5, 69.7, 68.0, 59.1, 54.6; MS (ESI) m/z calcd for C17H27N3O5 [M+H]+ 353.2 found [M+H2O]+ 371.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[C:10]1([CH2:16][CH2:17][NH2:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: NCCc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(NCCc2ccccc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (815 mg, 5.0 mmol), (2-phenylethyl)amine (665 mg, 5.5 mmol) and triethylamine (1.0 g, 10 mmol) in CH3OH (20 mL) was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to flash chromatography on SiO2 (eluent: 1/1 EtOAc/petroleum ether) to afford the title compound (1.0 g, 81%) as light yellow solid. LC-MS (ES) m/z=249 [M+H]+.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]1[CH:46]=[C:47]([NH2:51])[CH:48]=[N:49][CH:50]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:51][C:47]3[CH:48]=[N:49][CH:50]=[C:45]([F:44])[CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1cncc(F)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cncc(F)c3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-fluoro-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=374.2 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](CC(N)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O[C:32]([C:34]([F:37])([F:36])[F:35])=O.N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1.O(CC(F)(F)F)S(C(F)(F)F)(=O)=O>C(N(CC)CC)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:32][C:34]([F:37])([F:36])[F:35])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(F)(F)F)C3)ccc1-2

Procedure:
Following the procedure of 319, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235, trifluoroethyl triflate and triethylamine were reacted to give 422 isolated as a white solid (105 mg, 52%). LCMS: RT=12.34 min, [M+H]+=450. 1H NMR δ (ppm) (CDCl3): 8.32 (1 H, d, J=8.18 Hz), 7.90 (1 H, s), 7.10 (1 H, dd, J=8.21, 1.86 Hz), 6.98 (1 H, d, J=1.83 Hz), 5.93-5.84 (1 H, m), 4.39 (2 H, t, J=5.05 Hz), 3.90 (2 H, t, J=7.29 Hz), 3.82-3.73 (1 H, m), 3.42-3.33 (4 H, m), 3.04 (2 H, q, J=9.39 Hz), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[NH:8][C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[N:8]([CH3:27])[C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)n1c(=O)[nH]c2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)n1c(=O)n(C)c2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.9 %

Procedure:
A solution of 1-(1-ethylpropyl)-6-methyl-4-(2,4,6-trimethylphenoxy)-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (100 mg, 0.28 mmol) in 5 ml of dry THF was treated with lithium bis(trimethylsilyl)amide (0.31 ml, 1 M in THF, 0.31 mmol) at −78° C. After 20 min, the mixture was quenched with 1 ml of methyl iodide and stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 110 mg of an off-white solid which was recrystallized from isopropyl ether to give white crystals. Mp 152–154° C.; 1H NMR (CDCl3) δ 6.91 (s, 2H), 6.57 (s, 1H), 4.18 (m, 1H), 3.73 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 2.12 (s, 6H), 1.9–2.1 (m, 2H), 1.7–1.9 (m, 2H), 0.88 (t, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[OH-].[Li+]>CO.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1ncc(C(=O)[O-])c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1ncc(C(=O)O)c(N)n1
Temperature: 60 °C

Procedure:
4-Amino-2-methylmercaptopyrimidine-5-carboxylate (1.5 g, 7 mmol) was suspended in the solution of lithium hydroxide (340 mg, 14 mmol) in methanol (10 mL) and water (5 mL) and stirred at 60° C. over night. Solid was filtered out and filtrate was collected. Solvent was removed under reduce pressure. Residue was dissolved in water and was neutralized by acetic acid till pH˜5. White solid thus formed was filtered out and dried in vacuo (0.72 g, 55%).
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[C:18]#[N:19]>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([C:18](=[NH:13])[NH2:19])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: [NH4+]
Reactant: N#Cc1ccc(F)c(F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)c1ccc(F)c(F)c1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
3.6 mL (7.2 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 384 mg (7.17 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (7.1 mmol) of 3,4-difluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was poured into 100 mL of chloroform containing 200 g of silicagel and filtered off. The residue was washed with 200 mL of methanol and distillation was conducted to give 370 mg (2.36 mmol) of the title compound in a yield of 33%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([NH2:9])=[O:8].C(O)C.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:15][OH:16])[C:7]([NH2:9])=[O:8]
Reactant: NO
Reactant: NC(=O)C(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)C(=NO)c1cccs1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A mixture of 15.5 g of 2-thienylglyoxylamide, 75 ml of water, 75 ml of ethanol, 10.4 g of hydroxylamine hydrochloride and 24.6 g of sodium acetate is stirred at 40° C. for 5 h, the volatile fractions are stripped off in vacuo, and the residue is taken up in water. The product is extracted with ethyl acetate, and the organic phase is dried and concentrated. The residue is recrystallized from a little ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[N:23]1C=CC=CC=1.ClC(OC(C)C)=O.N>C(#N)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([C:7](=[O:8])[NH2:23])[CH:10]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)O)cc1
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(N)=O)cc1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
5-Chloro-N-methyl-N-(p-toluenesulfonyl)anthranilic acid (5.00 g (14.7 mmol)) and pyridine (1.33 ml (16.4 mmol)) were dissolved in 70.0 ml of acetonitrile. To this, under cooling with ice and with stirring, isopropyl chloroformate (2.00 g (16.3 mmol)) was added dropwise. After 30 minutes' stirring under ice-cooling, ammonia gas (ca. 1.25 g (73.4 mmol)) was bubbled into the reaction mixture. The resulting mixture was stirred under cooling with ice for 30 minutes and at room temperature for 20 hours, and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dilute sodium hydroxide solution and water, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give crude crystals. Diethyl ether was added to these crystals, followed by filtration and washing, to give 1.70 g (34%) of the title compound.