Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[NH2:8].[NH2:16][C:17]1[C:22]([CH:23]=O)=[CH:21][C:20]([I:25])=[CH:19][N:18]=1.S([O-])(O)=O.[Na+].O>CN(C=O)C>[NH2:16][C:17]1[C:22]([C:23]2[NH:1][C:2]3[CH:3]=[C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][C:10]4=[O:15])[CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:21][C:20]([I:25])=[CH:19][N:18]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1N
Reactant: Nc1ncc(I)cc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(I)cc1-c1nc2ccc(N3CCOCC3=O)cc2[nH]1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
22.4 320 mg (1.544 mmol) of 4-(3,4-diaminophenyl)morpholin-3-one are dissolved in 4 ml of DMF, and 382.99 mg (1.544 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 0.913 ml (4.633 mmol) of 38-40% sodium hydrogensulfite solution are added at room temperature. The mixture is stirred at 150° C. for 18 hours. The batch is cooled to room temperature, poured into 20 ml of water, the precipitate which deposits in the process is separated off and washed well with about 10 ml of water. The precipitate is triturated with about 25 ml of acetonitrile, and the undissolved crystals are separated off and dried, giving 4-[2-(2-amino-5-iodopyridin-3-yl)-3H-benzimidazol-5-yl]morpholin-3-one; HPLC-MS [M+H]+ 436.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>ClCCl>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To a suspension of potassium carbonate (7.06 g, 50 mmol, 1.50 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (9.98 g, 34.05 mmol) in dichloromethane (50 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (13.8 g, 37.8 mmol, 1.10 equiv.) in dichloromethane (50 mL) at room temperature. After 3 h at this temperature, the solids were filtered off and water was added to the filtrate. The mixture was extracted with dichloromethane and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diethyl ether to yield the title compound (10.1 g, 52%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C([CH:8]([C:22]([O-:24])=O)[C:9]([C:19]([O-:21])=O)([OH:18])[C:10](CC)(CC)[C:11]([O-:13])=O)C>CO>[CH2:1]([NH:5][C:11](=[O:13])[CH2:10][C:9]([CH2:8][C:22]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:24])([C:19]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:21])[OH:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Reactant: CC(C)CN
Solvent: CO
Product: CC(C)CNC(=O)CC(O)(CC(=O)NCC(C)C)C(=O)NCC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
N,N′,N″-tri-iso-butylcitramide was prepared by the reaction of iso-butylamine with triethylcitrate. To a round-bottomed flask were added-triethylcitrate (30.001 g; 1 eq), iso-butylamine (24.034 g; 3.03 eq) and methanol (40 mL). The clear light yellow solution stirred for 2 days at room temperature and then additional isobutylamine (3.06 eq) was added. After stirring overnight, a wet white solid was observed. Methanol was removed in vacuo and the solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with no detectable odor (31.09 g; 80.3% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[C:8]([CH3:10])[CH:7]=1)#[N:6]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1cc(N)cc(C#N)c1
Agent: Br
Product: Cc1cc(C#N)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 48.9 %

Procedure:
3-amino-5-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure similar to the one described in Example 3.03 to give 8-(1-(3-cyano-5-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 48%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[CH2:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[O:27][CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:14][O:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10]1
Reactant: CCOC(=O)c1ccc(OCC2CC(F)CN2C(=O)OC(C)(C)C)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(OCC2CC(F)CN2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of ethyl 4-[1-(tert-butoxycarbonyl)4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate (482.2 mg, 1.213 mmol) in CH2Cl2 (10.0 mL) was added TFA (1.9 mL) at 0° C., and the mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1 N NaOH and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 348.7 mg (97%) ethyl 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoate as a brownish oil. 1H-NMR (400 MHz, CDCl3) δ 1.39 (t, J=6.8 Hz, 3H), 1.97 (ddt, J=1.5, 5.4, 14.7 Hz, 1H), 2.27 (dddd, J=5.9, 8.8, 14.7, 32.7 Hz, 1H), 3.02 (ddd, J=3.9, 13.1, 35.2 Hz, 1H), 3.36 (dd, J=12.7, 21.5 Hz, 1H), 3.65 (m, 1H), 3.90 (s, 3H), 4.09 (m, 1H), 4.35 (q, J=6.8 Hz, 2H), 5.17, 5.31 (br m each, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.65 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 298 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:18][NH:19][O:20][CH3:21])#[N:14]>>[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:18][N:19]([O:20][CH3:21])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)#[N:14]
Reactant: CONCc1ccc(F)c(C#N)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)c(C#N)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-cyano-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (97% yield): mp 119–120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.75 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.36 (1H, s, CH), 7.17 (1H, t, aromatic), 7.58–7.64 (2H, m, aromatics). Anal. calcd for C16H15F2NO5: C, 57.48; H, 4.52; N, 8.38. Found: C, 57.39; H, 4.61; N, 8.32.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:6]=1.O>O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:8]=1
Reactant: Clc1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The synthesis method shall be explained concretely following the order below. 50% dimethylamine aqueous solution (2.9 ml) was added to a solution of 4,6-dichloro-2-(4-phenylpiperazin-1-yl)pyrimidine (1.01 g, 3.26 mmol) in tetrahydrofuran (10 ml) solution, and this was agitated overnight at room temperature. Water was added and extraction was carried out 2 times with ethyl acetate. After washing the organic layer in saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure, and a 4-chloro-6-dimethylamino-2-(4-phenylpiperazin-1-yl)pyrimidine powder was obtained. This powder was used in the next reaction without separation and refinement. Morpholine (6.0 ml) was added to this powder, and this was agitated at 100 degrees Celsius overnight. After cooling, water was added and extraction was carried out 2 times with dichloromethane. The organic layer was washed with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. The residue was washed with ether, and 810 mg (two step yield: 70%) of coarse crystals of 6-dimethylamino-4-morpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 2 are shown below.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8].[CH3:16][NH:17][CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:16][N:17]([CH2:18][C:19]#[N:20])[S:7]([CH2:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: CNCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(CC#N)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
In this example 36.1 g of 3-trifluoromethylbenzylsulfonyl chloride was added cautiously to a solution containing 29.8 g of the hydrochloride salt of methylaminoacetonitrile and 38.7 g of potassium carbonate in 130 ml of water at room temperature. The reaction mixture was maintained at about 70° C. for about four hours. The mixture was allowed to cool and then extracted with ethyl ether. The ethyl ether extract was dried over magnesium sulfate and evaporated to dryness. The residue was vacuum filtered through silica gel using 3% vol. tetrahydrofuran: chloroform as eluent. 29 g of the title compound was obtained as a waxy white solid.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[CH3:6][O:7][C:8]([CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:9]>ClCCl>[CH3:6][O:7][C:8](=[O:9])[CH:10]=[C:3]1[CH2:2][O:1][CH2:4]1
Reactant: O=C1COC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=C1COC1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
Oxetan-3-one (commercially available) (50 mg, 0.69 mmol) was solved in 1 ml dichloromethane and cooled to 0-5° C. (Methoxycarbonylmethylene) triphenylphosphorane (255 mg, 0.76 mmol) was added and the mixture stirred for 15 minutes. The mixture was directly purified with column chromatography on silica gel using heptane:ethyl acetate 100:0->0:100. The product fractions were concentrated to give 57 mg (64% yield) of a white solid.
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:9]=[N:10][NH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:9]=[N:10][NH:11][CH:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCC2)c2c[nH]nn2)cc1
Reaction time: 2 h
Yield: 31.7 %

Procedure:
7.1 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred with 24 ml of thionyl chloride for 1 hour at 0°. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 32 ml of triethylamine for 2 hours, diluted with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 2.1 g of 4-[1-cyclopentylidene-1-(1,2,3-triazolyl)methyl]benzonitrile as the free base, 108°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][SH:13]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[S:13][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Product: CCOC(=O)c1cc2ccc(Br)cc2s1

Procedure:
4-Bromo-2-fluorobenzaldehyde and ethyl thioglycolate were treated in a manner similar to Reference Example 31-(1) to give 6-bromo-2-ethoxycarbonylbenzo[b]thiophene as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(O)(=O)C.S([O-])([O-])(=O)=O.[Ca+2]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:13]([CH2:12][O:11][CH3:10])=[CH:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COCC(=O)CC(=O)OC
Reactant: COc1ccccc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Product: COCC(=CC(=O)OC)Nc1ccccc1OC
Yield: 73.5 %

Procedure:
A mixture of 100 g of o-anisidine, 190 g of methyl γ-methoxyacetoacetate, 2.3 ml of acetic acid, 203 g of calcium sulfate and 800 ml of absolute ethanol was refluxed for 16 hours. The residue after filtration and concentration of the filtrate under reduced pressure was taken up in ethyl acetate, the solution was extracted several times with 2 N NaOH and 5% strength citric acid solution and dried over Na2SO4, and the solvent was removed in a rotary evaporator. 150 g of crude product were obtained and were employed without further purification in the following stage.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:18](O)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1COCC1>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:18]([SH:43])=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Sc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-ol (257 mg) was dissolved in THF, and Lawesson's reagent (200 mg) was added to the solution, followed by stirring the mixture at 60° C. for 8 hours. Then Lawesson's reagent (110 mg) was further added and the mixture was stirred at 60° C. for 8 hours. Water was added to the mixture and then the mixture was extracted with dichloromethane. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium: sulfate and the residue was purified by (ethanol:ethyl acetate=10:1) to obtain 103 mg of 3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-thiol. Yield: 39%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc(Cl)ccc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) and from 3-amino-2-benzoyl-5-chloro-1-(ethoxycarbonyl)indole (step 1) and acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cn1
Product: O=C(CCl)Nc1ccc(Cl)cn1
Yield: 20 %

Procedure:
The sub-titled compound (0.33 g, 20%) was prepared by a similar procedure to that used to prepare Example 14f using 2-amino-5-chloropyridine in place of 2-amino-pyridine and adding the chloroacetyl chloride at room temperature rather than at 0° C.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[NH2:13][S:14]([C:17]1[CH:18]=[C:19]([C:23](=[S:25])[NH2:24])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH3:12][C:2]1[S:25][C:23]([C:19]2[CH:18]=[C:17]([S:14]([NH2:13])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=2)=[N:24][C:3]=1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccncc1C(=O)C(C)Br
Reactant: NC(=S)c1cccc(S(N)(=O)=O)c1
Product: Cc1ccncc1-c1nc(-c2cccc(S(N)(=O)=O)c2)sc1C
Yield: 65.2 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)propan-1-one hydrobromate (520 mg) and 3-(aminosulfonyl)benzenecarbothioamide (361 mg), the title compound (376 mg) was obtained as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([NH:22][C:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:15]([O:19][C:20]([NH:22][C:23]1([C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.4 %

Procedure:
To a solution of ethyl 4-aminocinnamate (1.00 g, 5.23 mmol) and 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid (1.24 g, 5.75 mmol) in N,N-dimethylformamide (10 ml) were added 1-hydroxybenzotriazole monohydrate (1.44 g, 9.41 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g, 9.41 mmol) under ice-cooling, and the mixture was stirred at room temperature for 21 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and hexane:diethyl ether (2:3) solution was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane:diethyl ether (2:3) solution. The obtained solid was dried in vacuo to give ethyl (E)-3-{4-[(1-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]phenyl}acrylate (943 mg, yield 46%).
Reaction SMILES: C([S:4][CH2:5][N:6]1[C:18](=[O:19])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([O:16]C)=[O:15])[N:8]2[C:7]1=[O:20])(=O)C>C(OCC)(=O)C.CCCCCC>[SH:4][CH2:5][N:6]1[C:18](=[O:19])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:20]
Reactant: COC(=O)C1CCCn2c(=O)n(CSC(C)=O)c(=O)n21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCn2c(=O)n(CS)c(=O)n21
Yield: 29 %

Procedure:
In a manner analogous to that described in Example 32, from methyl 2-acetylthiomethyl-2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate there was obtained in 29% yield 2,3,5,6,7,8-hexahydro-2-mercaptomethyl-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 157.5°-158.5° C. (from ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][NH:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:17]([N:8]1[C:7](=[O:10])[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:9]1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc2s[nH]c(=O)c2c1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)n1sc2ccc(C)cc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6t (98% yield) was synthesized from 5-methyl-benzo[d]isothiazol-3-one and n-butyl isocyanate as a white solid. IR(KBr) 3268, 1708, 1650, 1534 cm−1; 1H-NMR (CDCl3) δ0.96 (t, J=7.3 Hz, 3H), 1.38-1.48 (m, 2H), 1.60-1.67 (m, 2H), 2.46 (s, 3H), 3.41-3.47.(t, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 8.88 (br s, 1H); ESIMS m/e 265 (M++1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1ccnc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2nccc(I)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (1.5 g, 6.12 mmol) was dissolved in dry DMF (51.0 mL), cooled to 0° C. and NaH (0.245 g, 60% in oil, 6.12 mmol) was added. After 15 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (1.080 mL, 6.12 mmol) was added and the mixture was warmed to room temperature over 2 hours then poured into ice water (350 mL) to give a solid which was filtered off. The filtrate was combined with dichloromethane and evaporated onto silica gel. Silica gel chromatography eluted with 0-5% MeOH in DCM gave 7-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:30]2[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCC(O)CC2)n(C)c(=O)c1OCc1ccccc1

Procedure:
A solution of 5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.725 g, 2 mmol) and 4-hydroxypiperidine (1 g, 10 mmol) in THF (20 mL) was stirred for 16 h at ambient temperature. Then, the reaction mixture was taken up in EtOAC (100 mL), washed with 1N aq HCl (2×10 mL) and brine (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated to give the desired product as a pale yellow paste (0.608 g, 79%) which was used in the subsequent reaction without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.46 (d, J=7.0 Hz, 2H), 7.36–7.28 (m, 3H), 5.14 (s, 2H), 4.30 (q, J=7.0 Hz, 2H), 3.92–3.87 (m, 1H), 3.50 (s, 3H), 3.44–3.39 (m, 2H), 3.01–2.95 (m, 2H), 2.79 (br s, 1H), 2.02–1.98 (m, 2H), 1.71–1.64 (m, 2H), 1.28 (t, J=7.0 Hz, 3H). LRMS (M+H) calcd for C20H26N3O5: 388.44. found: 388.20