Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:7]1[C:8]2[CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][C:14]=2[C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:31][N:30]=4)=[CH:33][C:34]3=[O:38])=[N:23][C:6]1=2
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.15 g, 0.40 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100 mg, 0.42 mmol), and Cs2CO3 (0.14 g, 0.43 mmol) were suspended in DMSO (2.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol) and copper iodide (98 mg, 0.51 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 21 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2(30 mL) and washed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (32 mg, 15%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 9.15 (dd, J=1.0, 1.0 Hz, 1H), 8.39-8.34 (m, 2H), 8.05-8.03 (m, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.11 (dd, J=7.0, 1.5 Hz, 1H), 3.72 (s, 3H), 3.70 (t, J=5.5 Hz, 2H), 3.61-3.58 (m, 2H), 3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44-1.43 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]3[C:26](=O)[NH:25][C:24]([CH3:28])=[N:23][C:22]=3[CH2:29][CH2:30][CH3:31])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:26]1[C:21]([CH2:20][C:18]2[CH:17]=[CH:16][C:10]3/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:32][C:6]=4[O:7][CH2:8][C:9]=3[CH:19]=2)=[C:22]([CH2:29][CH2:30][CH3:31])[N:23]=[C:24]([CH3:28])[N:25]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Product: CCCc1nc(C)nc(Cl)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
[step 3] (E)-2-{3-fluoro-8-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (960 mg, 2.23 mmol) obtained in step 2 was dissolved in phosphorus oxychloride (2.5 mL, 26.8 mmol), and the mixture was stirred at 100° C. for 2 hr. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 v/v) to give (E)-2-{8-[(4-chloro-2-methyl-6-propylpyrimidin-5-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (970 mg, 97%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](O)=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: O=C(O)Cc1cccc(F)c1F
Product: Fc1cccc(CCNC2CC2)c1F

Procedure:
Synthesized according to typical procedures C and D from (2,3-difluorophenyl)-acetic acid and cyclopropylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[S:26]>CO.C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH:11][C:25]([NH:24][C:18]2[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])=[S:26])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cc(N)c(NC)cc1F
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F

Procedure:
Prepared analogously to example 131d from 5-amino-2-fluoro-4-methylamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene in methanol and acetonitrile.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.[N+:13]([O-])([O-:15])=[O:14].[Na+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][C:5](=[O:12])[C:6]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=C1CCCOc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
40.5 g (0.25 mole) of 2,3-dihydro-1-benzoxepin-5(4H)-one are introduced at -10° C. into 400 ml of concentrated sulfuric acid while stirring. Coarsely crystalline sodium nitrate is slowly introduced at -5° C. to 0° C. whilst stirring vigorously. The mixture is then stirred at 0° C. for about 1 hour, during which the sodium nitrate slowly dissolves. The mixture is stirred into ice/water and, after about 30 minutes, filtered with suction and washed thoroughly with water. The residue on the filter is taken up in ethyl acetate, and the solution is separated from the water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is crystallized in ethyl acetate/cyclohexane.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:23]=[CH:22][C:9](/[CH:10]=[C:11]2\[CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[N:19][C:20]\2=3)=[CH:8][C:7]=1[O:24][CH3:25])(=O)C>Cl>[OH:5][C:6]1[CH:23]=[CH:22][C:9](/[CH:10]=[C:11]2\[CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[N:19][C:20]\2=3)=[CH:8][C:7]=1[O:24][CH3:25]
Reactant: COc1cc(/C=C2\CCCc3cc(C)cnc32)ccc1OC(C)=O
Agent: Cl
Product: COc1cc(/C=C2\CCCc3cc(C)cnc32)ccc1O

Procedure:
A mixture of E-5,6,7,8-tetrahydro-8-(4-acetoxy-3-methoxybenzylidene)-3-methylquinoline HCl (prepared according to Example 8) (3.0 g) and 2N HCl (50 ml) were heated for 1 hour on a steam bath. After cooling the yellow crystals were removed by filtration, washed with diethyl ether and then dried to give the title compound as the hydrochloride salt (2.5 g). m.p. 257°-60° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].CCN(C(C)C)C(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][C:28]2[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=2)=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][C:28]2[S:32][C:31]([S:33](=[O:35])(=[O:34])[NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])=[CH:30][CH:29]=2)=[O:25])=[CH:22][CH:23]=1
Reactant: CC(C)(CN)CO
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2 equivalents of 3-Amino-2,2-dimethyl-propan-1-ol (1.0 g, 10 mmol) in DMF in the presence of 2 equivalents of DIEA (1.7 ml, 10 mMol) is added a solution of sulfonylchloride (1b) (1.75 g, 5 mMol, 1 equivalent) in DMF. The reaction mixture is stirred for 12 h at room temperature. DCM is added and any excess of amine is extracted into 0.1N HCl solution. The organic phase is washed with brine and dried over MgSO4. 4-Chloro-N-[5-(3-hydroxy-2,2-dimethyl-propylsulfamoyl)-thiophen-2-ylmethyl]-benzamide (compound of formula XII) is obtained after evaporation of the solvent. LC-MS analysis and NMR analysis showed that the compound was pure enough to carry on the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Cl>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1ccccn1
Agent: Cl
Product: O=C1CCN(Cc2ccccn2)CC1

Procedure:
1-(2-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 2-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([Cl:15])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:13]#[N:14].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([Cl:15])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:10]=[C:9]2[C:13]#[N:14]
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1c[nH]c2c(Br)cc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c2cc(Cl)cc(Br)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Sodium hydride (0.081 g, 2.020 mmol) (60% in oil) was added slowly to a 0° C. solution of 7-bromo-5-chloro-1H-indole-3-carbonitrile (0.43 g, 1.683 mmol) in THF (10 mL). Bubbling occurred, and the reaction was stirred at 0° C. for 30 min, then 2-(Trimethylsilyl)ethoxymethyl chloride (0.418 mL, 2.356 mmol) was added. After stirring 30 min at ambient temperature, the reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried with MgSO4 and evaporated, and the residue was purified by chromatography on SiO2 with 5% ethyl acetate/hexanes to give 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (620 mg, 1.607 mmol, 95% yield) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.71 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 5.82 (s, 2H), 3.52 (app T, J=8.1 Hz, 2H), 0.90 (app t, J=8.2 Hz, 2H), −0.05 (s, 9H). LC/MS (HPLC method 4): tR=4.07 min, 385.4(MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CN1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of benzyl piperidin-4-ylmethylcarbamate (Tetrahedron Lett. 1990, 31, 6903, 6.9 g, 27.8 mmol) in N,N-dimethylformamide (60 mL) were added triethylamine (9.7 mL, 69.5 mmol) and 1-bromo-3,3-dimethylbutan-2-one (7.9 g, 41.7 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and quenched with water (60 mL) followed by extraction with ethyl acetate-toluene mixture (3×30 mL). Concentration and purification by column chromatography on silica gel eluting with ethyl acetate/hexane (2:1) gave the title compound (9.6 g, 100%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:25]([CH3:27])=[CH:24][N:23]=[C:22]([NH2:28])[C:21]=2[N:20]=[C:19]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:22]1[C:21]2[N:20]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:26]=2[C:25]([CH3:27])=[CH:24][N:23]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNC(=O)N[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 147-164, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 437.2668.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Cl[C:15]([C:25]1[CH:26]=[N:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:29][CH:30]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[CH3:34][C:31]([C:28]1[N:27]=[CH:26][C:25]([CH:15]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:30][N:29]=1)([CH3:32])[CH3:33]
Reactant: CCOC(=O)C(Cl)(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1)C(C)(C)C
Temperature: 25 °C
Yield: 88.3 %

Procedure:
Tri-n-Butyl tin hydride (1.3 cm3) was added to a solution of ethyl (RS)-2-chloro-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (1.4 g) and a catalytic amount of 2,2'-azobisisobutyronitrile in dry toluene (10 cm3). The mixture was heated to the reflux temperature for a period of 11/2 hours, after which it was cooled to the ambient temperature, poured into water, and extracted into ethyl acetate. After concentration by evaporation of the solvent under reduced pressure, the residue was subjected to column chromatography on silica gel using hexane followed by ethyl acetate as eluent to give ethyl (RS)-2-[2-(1,1-dimethyl-ethyl)pyrimidin-5-yl]-3,3-dimethylbutanoate (1.1 g) as a pale yellow liquid, the spectral data of which were identical to those obtained for the sample generated in Example 9.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([C:10]3[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=3)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>C(O)C>[CH:30]1([NH:33][CH:24]=[C:18]([C:17](=[O:28])[C:13]2[CH:14]=[C:15]([F:16])[C:10]([CH:7]3[CH2:8][CH2:9][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6]3)=[CH:11][C:12]=2[F:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Reaction time: 1.5 h
Yield: 83 %

Procedure:
A solution of 20.5 g (50 mmol) of 4-(1,4-dioxaspiro[4.4]non-7-yl)-α-(ethoxymethylene)-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester in 200 ml of ethanol was cooled to 10° and treated dropwise with 3.4 g (60 mmol) of cyclopropylamine maintaining the temperature below 15° with an ice bath. After the addition was complete, the reaction was stirred at 5°-15° for 1.5 hours and then at room temperature for 1 hour. The resulting suspension was chilled to 5° and the solid removed by filtration, washed with ethanol, then hexane. The combined filtrate and washings were evaporated in vacuo and the residue was recrystallized from hexane to give 17.5 g of the title compound.
Reaction SMILES: [OH-].[Li+].O1CCCC1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1)[CH:13]=O.C(OP([CH:32]1[CH2:40][CH2:39][C@@H:38]2[N:34]([C@H:35]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[CH2:36][CH2:37]2)[C:33]1=[O:48])(=O)OCC)C>O.C(O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([C@H:35]2[N:34]3[C@H:38]([CH2:39][CH2:40]/[C:32](=[CH:13]\[C:12]4[CH:15]=[CH:16][C:17]([N:18]5[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]5)=[C:10]([O:9][CH3:8])[CH:11]=4)/[C:33]3=[O:48])[CH2:37][CH2:36]2)=[CH:46][CH:45]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(Cl)cc3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C2\CC[C@@H]3CC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
Lithium hydroxide (355 mg) was added to a solution mixture of tetrahydrofuran (8 mL)-ethanol (30 mL) of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (875 mg) and [(3S,8aR)-3-(4-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonic acid diethyl ester (2.5 g). The resulting reaction solution was stirred under light-shielded conditions at room temperature for 5 hr and then poured into iced-water. The resulting mixture was extracted with ethyl acetate. The extract solution was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to give 1.43 g of the title compound as a colorless solid. The physical property values of this compound were as follows:
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:9]=[C:8]2[NH2:17]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)C
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCn1nc2c(N)nc3c(c2c1CC(C)C)CCCC3
Reaction time: 24 h
Yield: 64 %

Procedure:
A solution of 1-(2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.8 g, 3 mmol), prepared as described in Example 1, in trifluoroacetic acid (10 mL) was treated with platinum (IV) oxide (0.5 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours on a Parr apparatus. The reaction mixture was diluted with chloroform (20 mL) and methanol (10 mL) and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure. The residue was suspended in 6 M aqueous hydrochloric acid (5 mL), stirred for 30 minutes, and treated with 50% aqueous sodium hydroxide to adjust the mixture to pH 13. A precipitate formed and was isolated by filtration, washed with water, and dried. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) to yield 0.55 g of 1-(2-methylpropyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an off-white powder, mp 167-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>CO.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(Br)cc1N

Procedure:
A mixture of 4-bromo-2-nitroaniline (1 g; 4.6 mmol) and SnCl2.2H2O (6.2 g; 27.6 mmol) in MeOH (30 mL) with 5-6 drops of conc. HCl was heated at reflux for 5 hrs., concentrated, suspended in sat'd NaHCO3 (aq.) and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO4), and concentrated to provide the product of sufficient purity to carry on.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=O)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:3])[N:26]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:16])=[O:17])=[CH:23][CH:22]=1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reactant: NCCc1ccccn1
Product: COC(=O)C1CN(CCc2ccccn2)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that the compound of Example 3 and 2-(2-aminoethyl)pyridine were used to prepare an oil (yield 74%).
Reaction SMILES: O.[CH3:2][C:3]1[C:4]([CH2:15][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C(N)(N)=[O:27].OO.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>C(O)C.O>[CH3:2][C:3]1[C:4]([CH2:15][S:16]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:27])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:13])([F:12])[F:14]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: NC(N)=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 11 °C
Reaction time: 2 h
Yield: 120.7 %

Procedure:
40 g (0.1077 mole) 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole hydrate was suspended in 240 ml of ethanol and 0.264 g (1.077 mmole) vanadium(V) oxytriisopropoxide dissolved in 1 ml of ethanol were added at room temperature (20-25° C.). The suspension was cooled to 10-12° C. and 12.14 g (0.129 mole) hydrogen peroxide urea adduct were added. The reaction was carried out at 10-15° C. for two hours and then at 5-10° C. until the reaction was completed. At the end of the reaction (3-6 hours, depending upon the temperature), 6 g of sodium thiosulphate pentahydrate in a solution of 40 ml water and 120 ml ethanol were added at 5-10° C., the mixture was stirred for one hour at 10-15° C. and 0.5 ml of 30% aqueous solution of sodium hydroxide were added to achieve a pH of about 10. The suspension was heated to 50-55° C., hot filtered and then gradually cooled to room temperature in one hour and then to 5-10° C. in half to one hour and agitated at that temperature for another one hour. The product was filtered off to obtain 48 g of wet lansoprazole.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([S:15]([OH:18])(=O)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].CN(C)C(=O)C.C(N(CC)CC)C.P(Cl)(Cl)([Cl:34])=O>S1(CCCC1)(=O)=O.C(#N)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([S:15]([Cl:34])(=[O:18])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)O)cc1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O=S1(=O)CCCC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1OC(C)=O
Temperature: 70 °C
Yield: 74 %

Procedure:
To a solution of the crude, 3,4-diacetoxy benzene sulphonic acid (0.83 g) in a mixture of sulpholane (1.5 ml) and acetonitrile (1.5 ml) was added at room temperature successively N,N-dimethylacetamide (75 μl), triethylamine (0.85 ml) and phosphorus oxychloride (1.1 ml). The reaction mixture was thereafter heated for 15 minutes at 70° C., cooled, poured onto water and extracted with CH2Cl2. The extract was dried over magnesium sulphate, concentrated and chromatographed on silica gel (50 g). Elution with CH2Cl2 gave 0.65 g (74%) of the title compound as a white solid. NMR in CDCl3 : 2.33(s,6H); 7.29(d,1H); 7.90(s,1H); 7.95(dd,1H).