Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:22][C@H:23]1[CH2:27][C:26](=[O:28])[N:25]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:37].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:30]([O:29][N:25]1[C:26](=[O:28])[CH2:27][C@H:23]([NH:22][S:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])[C:24]1=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: N[C@H]1CC(=O)N(OCc2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Yield: 35 %

Procedure:
4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl chloride (256 mg; 0.78 mmol), (3S)-3-Amino-1-benzyloxy-pyrrolidine-2,5-dione hydrochloric acid (112 mg; 0.44 mmol), Et3N (230 ul; 1.65 mmol) and DMAP (43 mg; 0.35 mmol) was dissolved in DMF (2 ml). The mixture was heated in a microwave oven at 200 W for 2×10 seconds, allowed to cool to room temperature and then heated for another 10 seconds at 200 W. Evaporation of solvent and the residue was partitioned between EtOAc and 5% KHSO4, separation. Organic phase were washed with H2O and brine, the combined waterphases was extracted twice with warm DCM. Organic phases were combined and evaporated directly onto Si-60 gel. Purified by flash chromatography on 20 g of Si-60 gel using a gradient solvent system of 100% iso-Hexane to 100% EtOAc. Fractions containing the product was evaporated to give the title compound as a slightly yellow solid. Obtained 78 mg (35% yield). Purity by H-nmr was 90%, considered pure enough to use in next step.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCCC[CH2:35][NH:36][C:37](=[O:39])[CH3:38]>>[C:37]([NH:36][CH2:35][CH2:12][CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])(=[O:39])[CH3:38]
Reactant: CC(=O)NCCCCN
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CC(=O)NCCCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-(4-aminobutyl)acetamide instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 372 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.36 (1H, s) 8.11 (1H, t, J=5.56 Hz) 8.02 (1H, d, J=5.47 Hz) 7.77 (2H, d, J=5.47 Hz) 7.48 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.51, 2.54 Hz) 6.82 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.51, 1.95 Hz) 3.19-3.27 (2H, m) 2.96-3.07 (2H, m) 1.77 (3H, s) 1.44-1.59 (2H, m) 1.39 (2H, dd, J=8.40, 6.83 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O=S(Cl)Cl.[CH3:15][NH2:16].C1COCC1>O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:16][CH3:15])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cccc(O)c1
Reaction time: 4 h

Procedure:
To a solution of 3-hydroxybenzoic acid (10 g, 72 mmol, 1.0 eq.) in 100 mL of anhydrous dioxane was added SOCl2 (6.5 mL, 72 mmol, 1.0 eq.). The solution was heated to reflux and stirred for 4 h. The solvent was removed and the crude was dissolved in anhydrous THF (100 mL). A solution of 2 M CH3NH2 in THF (7.2 mL, 144 mmol, 2.0 eq.) was added upon which a white suspension was formed. The solvent was evaporated and the residue was dissolved in MTBE, washed with sat. NH4Cl (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-100% EtOAc in hexanes) yielded 3-hydroxy-N-methyl-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[O:12][C:10]2=O)=[CH:5][CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(C2CC(=O)OC2=O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(C2CC(=O)N(c3ccncc3)C2=O)cc1
Reaction time: 6.5 h

Procedure:
The starting material is prepared as follows: The mixture of 57.9 g of 2-(p-methoxyphenyl)-succinic anhydride, 26.3 g of 4- aminopyridine and 500 ml of xylene is refluxed on a water separator while stirring for 6.5 hours. The hot solution is decanted off, cooled, filtered and the residue recrystallized from ethanol, to yield the 3-(p-methoxyphenyl)-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 179°-180°; its 3,4-dimethoxy-analog melts at 172°-174°.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2Cl)=[C:7]([CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].CS(C)=[O:25].Cl>O1CCOCC1>[Cl:19][C:15]1[N:14]=[N:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=2[CH3:20])=[C:17]([OH:25])[CH:16]=1
Reactant: CS(C)=O
Reactant: CC(=O)Oc1ccc(Oc2nnc(Cl)cc2Cl)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,4-dioxane (1.4 mL) was dissolved 173 mg (0.553 mmol) of 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate obtained in Example 630(3), 0.7 mL (2.1 mmol) of 3 mol/L sodium hydroxide solution and dimethylsulfoxide (2.8 mL) were added to the solution and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added 4 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (developed by dichloromethane:methanol=36:1) to obtain 66.8 mg of 6-chloro-3-(4-hydroxy-2-methylphenoxy)-4-pyridazinol.
Reaction SMILES: [SH2:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]>COCCOCCOC>[CH2:13]([SH:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C=CCCCCCCCCCC
Reactant: S
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCS

Procedure:
Under the conditions of Example 3, with an input of 38 liters per hour of hydrogen sulphide, 67.7 mmoles of dodecene-1 dissolved in diglyme at a concentration of 0.564 mole per liter were irradiated at 11° C. After 3 minutes of irradiation, 48.2 mmoles of n-dodecyl mercaptan were formed.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.C(=O)=O.CC(C)=O>>[Cl:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: OB(O)c1ccc(O)c(Cl)c1
Temperature: -78 °C
Yield: 26.7 %

Procedure:
A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g, 24.1 mmol) and purged with N2(g). Anhydrous THF (100 mL) added with stirring and the vessel cooled to −78° C. (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at −78° C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At about 0° C. 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in ethyl acetate (50 mL). Distilled H2O (50 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (50 mL×2). The organic portions were combined and washed with sat. Na2CO3 (aq). The aqueous layer was separated and treated with 2M HCl (aq) until the pH was about 4. This was then extracted with ethyl acetate (50 mL×2). The organic portions were then dried over MgSO4 and solvent removed. The resultant brown residues were taken up in a minimum of ethyl acetate (2-3 mL) and added to dropwise to hexane (50 mL) with stirring. The brown ppt was filtered to give the title compound as a brown solid (1.11 g, 27%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[NH:38][N:39]=[CH:40][C:33]=12>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:32]2[N:37]=[CH:36][N:35]=[C:34]3[NH:38][N:39]=[CH:40][C:33]=23)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.6 %

Procedure:
DIPEA (0.419 mL, 2.41 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (250 mg, 0.80 mmol) and 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (124 mg, 0.80 mmol) in butan-1-ol (5 mL). The resulting solution was stirred at 60° C. for 6 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness and triturated with diethyl ether to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidine-4-carboxamide (112 mg, 32.5%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[Na])(C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: Ic1ccccc1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1C
Product: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
1.00 g (4.46 mmols) of N,N-di(4-methoxyphenyl)amine (31a), 1.00 a (4.90 mmols) of iodobenzene (32a), 0502 g (5.23 mmols) of t-BuONa and 0.010 g (0.044 mmols) of PdG(CH3COO)2 were dissolved in anhydrous xylene, and while refluxing the solution in an atmosphere of nitrogen, 1.0 ml of 0.237 M of P(But)3 was further dropped, followed by refluxing for 4 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O[O:22][S:23]([O-:25])=O.[K+].OS([O-])(=O)=O.[K+].CO.[CH2:35]1COCC1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:14]=[CH:15][C:16]([S:23]([CH3:35])(=[O:25])=[O:22])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Reaction time: 4 h
Yield: 54 %

Procedure:
A solution of 1.5 g (5 mmol) of 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene (Step 3) in 46 mL of methanol/THF (1:1) was slowly treated with 5.2 g (8.4 mmol) of Oxone® [2 KHSO5.KHSO4.K2SO4 ] in 23 mL of water. After stirring for 4 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried (MgSO4), and reconcentrated. Recrystallization from ethyl acetate/hexane provided 960 mg (54%) of 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (41 in Synthetic Scheme X when R5 =SO2CH3, R10 =F, and R1, R2, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid: mp 138°-139° C.; NMR (CDCl3) δ 2.09 (m, J=7 Hz, 2H), 2.91 (t, J=7 Hz, 4H), 3.04 (s, 3H), 6.88-6.96 (m, 2H), 7.06-7.14 (m, 2H), 7.32 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H). MS (EI) m/e (rel intensity) 316 (100), 237 (41), 161 (13); HRMS. Calc'd for C18H17FO2S: 316.0933. Found: 316.0943. Anal. Calc'd for C18H17FO2S: C, 68.33; H, 5.42; F, 6.00; S, 10.13. Found: C, 68.08; H, 5.45; F, 6.42; S, 9.98.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[ClH:16].[F:12][C:8]1([F:11])[O:7][C:6]2=[CH:5][CH:4]=[C:3]([NH2:13])[C:2]([NH2:1])=[C:10]2[O:9]1
Reactant: Nc1c([N+](=O)[O-])ccc2c1OC(F)(F)O2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1N)OC(F)(F)O2
Yield: 97 %

Procedure:
30 g of 4-amino-2,2-difluoro-5-nitro-1,3-benzodioxole in 300 ml of methanol are hydrogenated over 0.5 g of 10% strength palladium-on-charcoal in a circulatory hydrogenation apparatus under atmospheric pressure at room temperature, 2.5 equivalents of methanolic hydrogen chloride solution are added, the mixture is filtered, the solution is concentrated in vacuo and isopropanol and ether are added to the residue to give 35 g (97%) of 2,2-difluoro-1,3-benzodioxole-4,5-diamine dihydrochloride of m.p. 232°-233° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:10]([NH:1][C:2]4[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=4)=[O:11])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cl
Reactant: N#Cc1ccc(N)cn1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccc(C#N)nc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 5-aminopyridine-2-carbonitrile (Aldrich, Cat. #538906), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=470.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:26][CH2:27][C:28]1([CH3:31])[CH2:30][O:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:27][C:28]4([CH3:31])[CH2:30][O:29]4)[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:26][CH2:27][C:28]([OH:29])([CH3:31])[CH2:30][N:24]1[CH:25]=[C:21]([C:19]([NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)=[O:20])[N:22]=[CH:23]1
Reactant: CC1(CCl)CO1
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(CC(C)(O)CCl)cn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(CC2(C)CO2)cn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (120 mg, 0.338 mmol), 2-(chloromethyl)-2-methyloxirane (2.88 g, 27.1 mmol and Y(NO3)3×6H2O (3.6 mg, 0.0093 mmol) was stirred under MW at 120° C. for 30 min. After evaporation of oxirane the residue was purified by flash chromatography on silica gel using CH2Cl2-MeOH as a gradient eluent (100:0-99:1) to obtain N-{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-[(2-methyloxiran-2-yl)methyl]-1H-imidazole-4-carboxamide as a major product and 1-(3-chloro-2-hydroxy-2-methylpropyl)-N—{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide as a minor product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc4c(c3)OCO4)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reaction time: 12 h
Yield: 79 %

Procedure:
To a solution of 2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (300 mg) in THF (3 ml) were added methanol (3 ml) and 8N-aqueous sodium hydroxide solution (0.16 ml) at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure, and 1N-hydrochloric acid was added to the residue. The aqueous layer of the mixture was acidified, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (230 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](=[O:47])[NH:40][S:41]([CH:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([O:30]CC)=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](=[O:47])[NH:40][S:41]([CH:44]([CH3:46])[CH3:45])(=[O:42])=[O:43])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[N:25]([CH2:26][CH3:27])[N:24]=[CH:23][C:22]=4[C:28]([OH:30])=[O:29])=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cnn(CC)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1ncc(C(=O)O)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
Ethyl 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-ethyl-1H-pyrazole-4-carboxylate was dissolved in THF (14 mL) and methanol (14 mL) then sodium hydroxide (15 mL, 15.00 mmol) (1.0N aqueous) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 16.5 hrs. The reaction was concentrated in vacuo using a rotary evaporator (bath temp equal to less than 26 C) then partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic extracts combined, washed with brine and dried over magnesium sulfate. The organic solution was filtered and solvents removed in vacuo to give amorphous amber-orange solid (902 mg) after drying at room temperature in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:29](B1OC(C)(C)C(C)(C)O1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[CH2:29]([C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1Cc1ccccc1
Yield: 41.9 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[B+3].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[NH3:19]>>[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]#[N:19])=[CH:10][CH:9]=1.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1
Reactant: N
Agent: CCOC(=O)c1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [B+3]
Product: N#Cc1ccc(O)cc1
Reaction time: 0 h

Procedure:
A reaction tube having an inside diameter of 5 cm was filled with a thorough mixture of 195 g of alumina and 195 g of a supported catalyst composed of 3.94% by weight of boron phosphate (P2O5 /B2O3 mole ratio=1) deposited on the same silica carrier as in Example 1. Ethyl p-hydroxybenzoate, ammonia and steam were introduced into the reaction tube at a rate of 75 g/hr, 268.8 g/hr and 40.7 g/hr, respectively, and reacted in the vapor phase at 395° C. The mole ratio of ammonia, steam and ethyl p-hydroxybenzoate was 35:5:1 in the gaseous mixture, and the contact time was 5 seconds. When the reaction was carried out for 308 hours, 15.75 kg of p-hydroxybenzonitrile was obtained from 23.1 kg of ethyl p-hydroxybenzoate. The yield was 95.1% by weight. Gas-chromatographic analysis showed that only 2.5% by weight of phenol was formed as a by-product. The amount of p-hydroxybenzonitrile obtained per part by weight of the supported catalyst was more than 40.3 parts by weight.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccncc2)n1
Yield: 53.7 %

Procedure:
A solution of thioisonicotinamide (5.0 g) and ethyl bromopyruvate (7.22 g) in ethanol (90 ml) was heated for 5 hours under reflux and concentrated. To the residue were added sodium bicarbonate solution and ethyl acetate, and the organic layer was separated, washed with water and sodium chloride solution, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give pale yellow solid of ethyl 2-(4-pyridyl)-4-thiazolecarboxylate (4.55 g).