Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2[CH:16]=O)[CH2:2][CH2:3][CH3:4].C(OC1C=C2C(=CC=1)NC(C)=C2/C=[CH:32]/[C:33]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:34])C>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2/[CH:16]=[CH:32]/[C:33]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Reactant: CCCCOc1ccc2[nH]c(C)c(C=O)c2c1
Product: CCCCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Yield: 57 %

Procedure:
5-Butoxy-2-methylindole-3-carboxaldehyde 409d (250 mg, 1.08 mmol) was reacted in a similar manner to that for 402a to yield a bright yellow powder (206 mg, 57%): mp 227-228° C. TLC Rf 0.33 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.39 (s, 1H), 8.81-8.80 (m, 2H), 8.08-8.06 (d, 1H, J=15.3 Hz), 7.93-7.92 (m, 2H), 7.41 (d, 1H, J=12.3 Hz), 7.34-7.31 (d, 1H, J=15.24 Hz), 7.30-7.28 (d, 1H, J=8.64 Hz), 6.84-6.82 (dd, 1H, J1=8.64 Hz, J2=2.34 Hz), 4.08-4.06 (t, 2H, J=6.48 Hz), 2.57 (s, 3H), 1.76-1.71 (m, 2H), 1.52-1.45 (m, 2H), 0.97-0.94 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, d6-DMSO) δ 188.2, 154.6, 150.6, 145.74, 145.19, 139.6, 131.0, 126.6, 121.4, 112.90, 112.25, 111.44, 109.3, 104.3, 64.8, 31.0, 18.9, 13.8, 12.2. Elemental analysis calculated for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.39; H, 6.55; N, 8.37.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][N:15]1[CH2:16][CH2:17][CH:12]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH2:13][CH2:14]1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(I)nn2C1CCN(Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.45 mmol), 1H-2-imidazolecarbaldehyde (0.42 g, 4.34 mmol), sodium triacetoxyborohydride (0.61 g, 2.90 mmol) and glacial acetic acid (0.26 g, 4.36 mmol) were mixed with 1,2-dichloroethane (20 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.57 g, 92%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.17 (m, 4H), 2.92 (m, 2H), 3.55 (s, 2H), 4.57 (m, 1H), 6.92 (s, 2H), 8.14 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]=[CH2:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]1[O:27][CH2:21]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-1-phenyl-3-butene (1.43 g, 5.08 mmoles) in 20 mL of CH2C12 was added 3-chloroperoxybenzoic acid (2.19 g, 60%, 7.62 mmoles) in several portions, and the mixture was stirred at room temperature for 30 hrs. After addition of EtOAc (60 mL), the mixture was washed with saturated NaHCO3 and brine, and the organic layer was dried over Na2SO4. Evaporation of the solvent afforded an oily residue. The crude product was purified by column chromatography on silica gel with elution by 2:8 EtOAc-hexane to give pure 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[C:24]1([CH2:23][N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
A suspension of 13.95 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 600 ml. dry dimethylformamide is stirred under nitrogen as 3.70 g. ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 9.30 g. benzyl chloride (8.5 ml.) in 20 ml. dry dimethylformamide is added during ca. 10 min. Stirring is continued for 5 hours and then 120 ml. gl. acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed with water, and dried. The crude product is dissolved in 1.4 l. boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 125 ml. and chilled. The crystalline solid is collected, washed with acetone, and again recrystallized from methanol to afford 11.76 g. title compound, m.p. 228°, NMR (dDMSO): δ 5.53 (singlet, N-CH2C6H5), 7.12 (doublet, J-3Hz, 9H), 7.23 (doublet, 8Hz, 5 or 6H), 7.63 (doublet, J=3Hz, 8H), 7.77 (doublet, J=9Hz, 5 or 6H) p.p.m.; λmax95%EtOH 235 (ε 26,900), 260 (ε 28,620), 317 (ε 9,640), 345 sh (ε 7,520) nm; λmin95%EtOH 243 (ε 26,020), 281 (ε 2,430) nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=1.[F:31][C:32]1([F:47])[CH2:37][CH2:36][N:35]([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>C(Cl)Cl.CCN(CC)CC>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:41]2[CH2:40][CH2:39][C:38]([C:44]([NH2:46])=[O:45])([N:35]3[CH2:34][CH2:33][C:32]([F:31])([F:47])[CH2:37][CH2:36]3)[CH2:43][CH2:42]2)=[O:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=1
Reactant: NC(=O)C1(N2CCC(F)(F)CC2)CCNCC1
Reactant: CS(=O)(=O)CCCOc1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCOc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(N4CCC(F)(F)CC4)CC3)sc2-c2ccc(F)cc2Cl)cc1
Reaction time: 3 h
Yield: 119.1 %

Procedure:
0.3 g of the compound obtained in stage 22A), 0.3 g of 4,4-difluoro-1,4′-bipiperidine-4′-carboxamide (described in Preparation 5, page 23, of Application WO 2008/068423), 0.45 ml of Et3N and 0.25 g of TBTU are added in order to 10 ml of CH2Cl2. After 3 hours at AT, the mixture is concentrated to dryness and the residue is taken up in AcOEt, washed with water, dried and concentrated to dryness. After purifying by chromatography on silica (elution gradient: CH2Cl2 up to CH2Cl2/MeOH 98/2), the compound obtained is dissolved in CH2Cl2, ethereal hydrochloric acid is added down to a pH of 1 and then the mixture is concentrated to dryness. 0.28 g of the expected compound is obtained.
Reaction SMILES: [CH:1]1([C@@H:4]2[CH2:9][CH2:8][N:7](C(OCC3C=CC=CC=3)=O)[CH2:6][C@H:5]2[NH:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C@@H:4]2[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[NH:20][P:21](=[O:22])([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])[CH2:2][CH2:3]1
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CC1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1C1CC1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of trans-benzyl 4-cyclopropyl-3-(diethoxyphosphorylamino)piperidine-1-carboxylate (1.84 g, 4.48 mmol) and 10% Pd/C (0.48 g, 0.45 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-cyclopropylpiperidin-3-ylphosphoramidate (1.24 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:17]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C:18]=1[CH2:19][CH2:20][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:25]([C:17]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:22]([OH:24])=[O:23])=[O:26])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: O=C1OC(=O)C2=C1CCC2
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 5-ethyl-2-imino-3-(4-iodobenzyl)-1,3,4-thiadiazoline (17.3 g) in chloroform (200 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (7.5 g), and they were stirred at room temperature for one hour. The reaction mixture was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was dispersed in diethyl ether and collected by filtration, whereby 23.8 g of the title compound was obtained.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[I-:11].[Na+].COC(C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:11][CH2:2][O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: [I-]
Reactant: CCC(CC)C(=O)OCCl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCC(CC)C(=O)OCI

Procedure:
2-Ethyl butyric acid chloromethyl ester (700 g) was dissolved in acetone (3 L). To this solution was added sodium iodide (1.0 kg). The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC). The solution was then cooled to ambient temperature where tert-butyl methyl ether (7 L) and 5% aqueous sodium thiosulfate (4 L) were added. The phases were separated and the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L). The organic layer was dried over magnesium sulfate (350 g), filtered, and the filter cake was washed with tert-butyl methyl ether (2×0.7 L). The filtrate was evaporated to a small volume (ca. 2 L) to give 2-ethyl butyric acid iodomethyl ester, as a solution in tert-butyl methyl ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[O:3]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)OC(C=Cc2ccc(F)cc2)=CC1=O
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) and 4-fluorobenzaldehyde (1.6 g, 13.2 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 50° C. for four hours. After the reaction solution was cooled to room temperature and diluted with saturated aqueous sodium chloride (200 mL) and water (200 mL), the aqueous solution was extracted with diethyl ether (2×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a dark yellow crystalline solid. The crude product was recrystallized from hexane to give light yellow crystals (1.8 g, 45% yield), m.p. 55°-57° C.
Reaction SMILES: [CH3:1][N:2]([CH2:26][C:27](=[O:33])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][C:24]#[N:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[OH:34][Li].O.OO>CO>[CH3:1][N:2]([CH2:26][C:27](=[O:33])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][C:24]([NH2:25])=[O:34])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:7][CH2:8]1
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (80 mg, 0.17 mmol, 1.00 equiv) in methanol (5 mL) and cooled to 0° C. Then LiOH.H2O (22 mg, 0.52 mmol, 3.00 equiv) and H2O2 (30%, 0.3 mL) were added at 0° C. and the resulting solution was stirred for 2 h at the same temperature. The reaction was quenched by the addition of saturated aqueous Na2SO3 and extracted DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (82.5 mg) as a white solid. MS (ES): m/z 486 [M+H]+; 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.32-5.22 (1H, m), 3.58 (2H, t), 3.45 (2H, t), 3.35 (2H, s), 3.20-3.09 (1H, m), 3.03-2.95 (1H, m), 2.73-2.65 (2H, m), 2.37 (3H, s), 2.33-2.19 (5H, m), 2.03-1.88 (6H, m), 1.66 (2H, m), 1.69-1.52 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3ccnc(Cl)c3)c2)cc(C)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2,6-dimethylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=353.2, 355.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1>CC(O)C.C([O-])(=O)C.[NH2+]1CCCCC1>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (549 mg) in 2-propanol (5 mL) were added a solution of 4-[(trans-2-hydroxycyclohexyl)amino]thiazol-2(5H)-one (520 mg) in 2-propanol (5 mL) and piperidinium acetate (240 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (557 mg).
Reaction SMILES: [F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](OCC)=[O:4].[NH2:16][NH2:17].O>CCO>[F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([NH:16][NH2:17])=[O:4]
Reactant: CCOC(=O)C(F)(F)Cc1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C(F)(F)Cc1ccccn1
Reaction time: 1 h

Procedure:
The product of Example 66 (0.18 g, 0.84 mmol) was dissolved in 5 mL of EtOH. To the solution was added NH2NH2.H2O (0.084 g, 1.7 mmol). The reaction was complete in 1 hour. The solvent was removed under vacuum. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH2:24][CH2:25]OS(C)(=O)=O)[C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CO.[Na]>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH2:24][CH2:25][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2]
Reactant: CCn1c(=O)n(CC)c2cc(-c3cnn(CCOS(C)(=O)=O)c3-c3cccc(C)c3)ccc21
Reactant: C1COCCN1
Agent: [Na]
Solvent: CO
Product: CCn1c(=O)n(CC)c2cc(-c3cnn(CCN4CCOCC4)c3-c3cccc(C)c3)ccc21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
[4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-acetic acid ethyl ester is prepared according to the procedures outlined in Example 334. [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-acetic acid ethyl ester (388 mg) is diluted with tetrahydrofuran (3 mL) and methanol (4 mL). Lithium borohydride (39 mg) is added and the mixture is stirred at 23° C. for 20 hours. The reaction mixture is diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried with sodium sulfate and concentrated. Chromatography on silica gel gave 3-Diethyl-5-[1-(2-hydroxy-ethyl)-5-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one. 3-Diethyl-5-[-(2-hydroxy-ethyl)-5-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one (86.5 mg) is diluted with pyridine, (1 mL) cooled to 0° C., and treated with methanesulfonyl chloride (0.02 mL). The reaction mixture is allowed to stir for 20 hours then is treated with water and extracted with dichloromethane. The organic layer is dried with sodium sulfate and concentrated to give Methanesulfonic acid 2-[4-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-ethyl ester. Methanesulfonic acid 2-[4-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-ethyl ester (104 mg) is diluted with morpholine (0.15 mL) and methanol (0.9 mL). The reaction is heated to 65° C. for 5 hours then allowed to stand at 23° C. for 20 hours. The reaction mixture is diluted with saturated sodium bacarbonate and extracted with ethyl acetate. Chromatography on silica gel gave 1,3-Diethyl-5-[1-(2-morpholin-4-yl-ethyl)-5-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29])[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:29])([F:30])[F:31])/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)c(Cl)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (550 mg, 2.226 mmol) in toluene 25 mL was added 3-chloro-4-(trifluoromethyl)benzaldehyde 90 (464.2 mg, 2.226 mmol). PTSA (846.7 mg, 4.452 mmol) was added to the reaction, and stirred at 120° C. for 6 h, then diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 91 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid compound (E)-2-(3-chloro-4-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][OH:14])[CH2:7][CH2:6]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:7][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCC(CO)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 80.9 %

Procedure:
(RS)-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanol (939 mg, 4.88 mmol), p-toluenesulfonyl chloride (934 mg, 4.9 mmol), triethylamine (1.12 ml, 7.88 mmol) and N,N-dimethyl aminopyridine (10 mg) in CH2Cl2 (10 ml) was stirred together at ambient temperature for 24 hr. Acidification with 1N HCl (pH 1-2), extraction of the aqueous phase with CH2Cl2 (2×20 ml), drying (Na2SO4) filtration and evaporation afforded the crude product which wag chomatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-n-Hexane (1:3) to afford the title compound as a colourless oil (1.37 g, 3.95 mmol, 81%), MS m/e=346.1 (M+).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH3:17])=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=[N:13]2)=[CH:8][CH:7]=1.[C:21]1(C)C=CC=C[CH:22]=1>>[CH2:21]([O:19][C:18]([C:15]1[CH:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=2)[C:16]=1[CH3:17])=[O:20])[CH3:22]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C

Procedure:
Toluene (40 ml) and thionyl chloride (8.0 ml) were added to 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (20.50 g) described in reference Example 13, stirred under reflux and the solvent was evaporated in vacuo. Pyridine (20 ml) and ethanol (40 ml) were added to the residue, and the mixture was stirred again under reflux and then the solvent was evaporated in vacuo. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting solid was washed with n-hexane to give 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (15.83 g).