Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>CN(C=O)C>[CH2:3]([O:10][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[C:17]=1[C:18]([F:20])([F:21])[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1c(Cl)ccnc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1c(OCc2ccccc2)ccnc1Cl
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 33 %

Procedure:
To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0° C., was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min. Then, intermediate compound D6 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D7 (1.1 g, 33%).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][C:47]1([OH:60])[CH2:52][CH2:51][N:50]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:49][CH2:48]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:53]([N:50]1[CH2:49][CH2:48][C:47]([CH2:46][NH:45][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])=[O:13])([OH:60])[CH2:52][CH2:51]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C(=O)NCC3(O)CCN(Cc4ccccc4)CC3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid in N,N-dimethylformamide (30 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.738 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.520 g) and 4-(aminomethyl)-1-benzylpiperidin-4-ol (1.06 g), and the mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0-95:5) to give the title compound (1.32 g, yield 76%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=S)[C:11]([C:20]([O:22]CC)=O)=[N:10]2)=[CH:4][CH:3]=1.Cl.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[NH:34][NH2:35].C(=O)([O-])[O-].[K+].[K+]>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:35][N:34]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]=4[CH3:26])[C:20](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(NN)c1C
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=S
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: Cc1cccc(-n2nc3c4cccnc4n(Cc4ccc(Cl)nc4)nc-3c2=O)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 1-[(6-chloropyridin-3-yl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (389 mg, 1.08 mmol), (2,3-dimethylphenyl)hydrazine hydrochloride (279 mg, 1.62 mmol, 1.5 equiv) and potassium carbonate (1.49 g, 10.8 mmol, 10 equiv) were combined and placed into an oil bath preheated to 70° C. for 3 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (150 mL, aqueous saturated) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (1×50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound as a deep red solid.
Reaction SMILES: [Na].[CH:2]1([S:8]([C:11]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:12]=2[C:13]([C:15]2[CH:16]=[N:17][O:18][C:19]=2[CH:20]2[CH2:22][CH2:21]2)=[O:14])(=[O:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl>C(O)C>[C:16]([CH:15]([C:19]([CH:20]1[CH2:21][CH2:22]1)=[O:18])[C:13]([C:12]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:11]=1[S:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:10])=[O:9])=[O:14])#[N:17]
Reactant: O=C(c1ccc(C(F)(F)F)cc1S(=O)(=O)C1CCCCC1)c1cnoc1C1CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(C(=O)c1ccc(C(F)(F)F)cc1S(=O)(=O)C1CCCCC1)C(=O)C1CC1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Sodium metal (0.11 g) was dissolved in absolute ethanol with stirring and was cooled to ambient temperature. 4-(2-Cyclohexylsulphonyl-4-trifluoromethybenzoyl)-5-cyclopropylisoxazole (1.5 g) in absolute ethanol was added and the resulting solution was stirred at ambient temperature for 3 hours. It was poured into ice/water, acidified to pH1 with concentrated hydrochloric acid and the resultant white suspension was allowed to warm to ambient temperature before it was extracted with ethyl acetate. The combined organic extracts were washed with water and dried (magnesium sulphate). Evaporation of the solvent gave a light-brown solid (1.3 g) of 2-cyano-1-(2-cyclohexylsulphonyl-4-trifluoromethylphenyl)-3-cyclopropylpropan-1,3-dione (compound 517) m.p. 60°-62° C.
Reaction SMILES: [CH2:1]([C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC2C=CC=CC=2)[CH:11]=1)[C@@H:4]([CH3:9])[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].[ClH:24]>CO.[Pd]>[ClH:24].[CH3:8][N:6]([CH3:7])[CH2:5][C@H:4]([CH3:9])[C@H:3]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH2:1][CH3:2]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
The product of Example 6 (2.5 g, 8 mmol) was dissolved in methanol, 5% Pd—C (250 mg) was added, and it was purged with hydrogen for three times, then the reaction was carried out with stirring at room temperature for 1 hr. The reaction solution was filtered to remove Pd—C, the residue was washed with methanol for 3 times, then the organic phases are combined and concentrated to 2 ml. After that, the concentrated hydrochloric acid (670 ml, 8 mmol) was added dropwise, then the resulted solution was concentrated and recrystallized with isopropanol and ethyl acetate to give the target 1.9 g, yield: 90%. [α]D=+ 24.3° (c=1.10, CH3OH). 1HNMR (300 MHz, CD3OD): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, br s), 2.2-2.3 (1H, m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d, J=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 222.4 (M+H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=2)[N:6]1[C:19](=[O:31])[C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH3:22])=[O:4].[OH-].[Na+].ClCCl>CO.O>[C:27]([O:26][C:24]([NH:23][C@@H:20]([CH2:21][CH3:22])[C:19]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:31])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)O
Temperature: 7.5 °C
Reaction time: 4 h

Procedure:
To the solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-trifluoromethoxyindoline-2(R/S)-carboxylic acid methyl ester (1.0 g, 2.24 mmol) in methanol (15 ml), was added sodium hydroxide (0.134 g, 3.36 mmol) in water (10 ml). The solution was stirred at 5 to 10° C. for 4 hours. The mixture was poured into dichloromethane (40 ml), and washed with cold potassium hydrogen sulphate (3×20 ml), and water (20 ml). The organic layer was dried over sodium sulphate, and evaporated to provide a white foam which was pure enough for the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:33]=[C:32]([CH:34]=O)[S:31][CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:33]=[C:32]([CH2:34][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[S:31][CH:30]=3)[S:28][C:19]=12
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C=O)c4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(CN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
Morpholine (50 μL, 0.57 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.43 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (460 mg, 2.17 mmol) is added. After stirring at 0° C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 169 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(morpholin-4-ylmethyl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 209–212° C.; MS 531.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:12]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([NH2:26])=[C:24]([CH3:25])[C:11]2=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.CO.C(OC(C)C)(C)C>>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:26][C:23]2[C:22]([CH3:27])=[C:21]([CH3:28])[C:12]3[O:13][C:14]4([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:11]=3[C:24]=2[CH3:25])=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Solvent: CO
Solvent: CC(C)OC(C)C
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Yield: 38 %

Procedure:
By using 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 38%. Melting point: 271-272° C. (Methanol-isopropyl ether).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH3:10])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>O.C(O)(=O)C>[CH2:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[N:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCNc1cc(Cl)ncn1
Solvent: O
Solvent: CC(=O)O
Product: CCNc1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-ethyl-amine (363 mg, 2.30 mmol, 1.1 eq.) and 4-(4-methylpiperazin-1-yl)-aniline (400 mg, 2.09 mmol) in water (0.8 ml) and glacial acetic acid (3.2 ml) is heated to 100° C. 3 h. After solvent evaporation, the residue is taken up in methanol, made alkaline by addition of 25% NH3 in water and concentrated. The residue is purified by MPLC (silica gel) (DCM/MeOH) to afford 395 mg of the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.25 min (purity: ˜90%, gradient J); TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: [N:1]1([C:5](=[O:23])[CH2:6][C:7]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][C:8]=2[C:9]#[N:10])[CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:5](=[O:23])[CH2:6][C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(O)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[2-(azetidin-1-yl)-2-oxoethyl]-5-(benzyloxy)benzonitrile (410 mg, 1.34 mmol) was dissolved in ethanol (2 ml) and palladium hydroxide on carbon (20%) (94 mg, 0.134 mmol) added. The mixture was stirred under an atmosphere of hydrogen gas at RT overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The reside was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 0-25% water:acetonitrile+0.05% formic acid to afford the title compound. LC/MS (m/z): 217 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CCN)OCC
Solvent: c1ccncc1
Product: CCOC(CCNC(C)=O)OCC

Procedure:
In similar manner, treat 3-aminopropanal diethylacetal with acetic anhydride in pyridine, then treat resulting 3-acetamidopropanal diethylacetal with acid to obtain 3-acetamidopropanal.
Reaction SMILES: C(OC([N:6]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])[C:7]1=[O:37])=O)C.[OH-].[Na+]>CO>[Cl:36][C:33]1[CH:34]=[C:35]2[NH:6][C:7](=[O:37])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[CH3:29])[C:30]2=[CH:31][CH:32]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(F)cccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 81.9 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.35 g, 0.65 mmol) was reacted with NaOH (2N, 5 mL, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.25 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([O:26]C)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:12].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([OH:26])=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccccc2OC)C(=O)O)cc1
Yield: 78 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 44 (1.6 g), 1 mol/L of an aqueous sodium hydroxide solution (13 mL), and methanol (150 mL), to give the captioned compound (1.2 g, 75%) as crystals.
Reaction SMILES: [SH2:1].[CH3:2][S:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:2][S:3][C:4]1[S:5][C:6]([C:10](=[S:1])[NH2:11])=[C:7]([NH2:9])[N:8]=1
Reactant: CSc1nc(N)c(C#N)s1
Reactant: S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C(N)=S)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
20 parts of hydrogen sulfide are introduced, over 6 hours, into a mixture of 51.3 parts of 2-methylmercapto-4-amino-5-cyanothiazole, 0.2 part of triethylamine and 150 parts of dimethylformamide. The reaction mixture is left to stand for 48 hours and is then poured into 500 parts of ice water, and the product is filtered off. 33 parts of 2-methylmercapto-4-amino-5-thiocarbamoylthiazole (54% of theory) of melting point 192°-195° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][C:24](OC)=[O:25].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][CH2:24][OH:25]
Reactant: COC(=O)CC1=C(C)/C(=C/c2ccc(S(C)(=O)=O)cc2)c2ccc(F)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1=C(CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 1 (2.7 g, 7 mmol) in THF (20 mL) at 0° C. there was added diisobutyl aluminum hydride (1M) in toluene (17 mL, 17 mmol) and the mixture was stirred at 0° C. for 1 hour, then quenched with methanol (10 mL). Ethyl acetate and 1N aqueous HCl were added and after collection of the organic phase the aqueous phase was extracted once more with ethyl acetate. The combined organic extracts, after washing with water three times and drying over Na2SO4, afforded on evaporation a yellow residue which was triturated with ether to afford the title compound as a yellow solid, mp: 102°-104° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C1C=CC=CC=1>[C:8]([C:10](=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:11]([O:13][CH3:14])=[O:12])#[N:9]
Reactant: O=C1CCOCC1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C#N)=C1CCOCC1

Procedure:
A 50 ml round-bottom flask equipped with a Dean-Stark distillation setup and condenser was charged with tetrahydro-4H-pyran-4-one (4.61 ml, 50 mmol), methyl cyanoacetate (5.3 ml, 60 mmol), ammonium acetate (1 g, 13 mmol), acetic acid (0.57 ml, 10 mmol) and benzene (30 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30 ml) added and the organic layer washed with water (50 ml). The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic phase was washed with sat. NaHCO3 (100 ml), brine (100 ml) dried (MgSO4), filtered and concentrated. Purified by normal phase SiO2 chromatography (10 to 60% EtOAc/hexanes) to afford methyl 2-cyano-2-(oxan-4-ylidene)acetate as a colorless oil (6.30 g, 70%, m/z: 181.1 [M+H]+ observed).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][N:8]=1)=[O:6].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O.O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:2][CH2:3][NH:4][C:5]([C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[S:9][N:8]=4)=[O:6])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Clc1ccc2c(N3CCCCC3)noc2c1
Reactant: O=C(NCCCl)c1nsc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NCCC1CCN(c2noc3cc(Cl)ccc23)CC1)c1nsc2ccccc12
Temperature: 180 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
A mixture of N-(2-chloroethyl)-1,2-benzisothiazole-3-carboxamide (2.9 g) and 1-(6-chloro-1,2-benzisoxazol-3-yl)piperidine (3.48 g) in dry N-methylpyrrolidinone (125 ml) was heated to 180° C., with stirring, under nitrogen. After 5 hr, the reaction mixture was allowed to cool to room temperature, diluted with water, basified with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica using ether as the eluent. The appropriate fractions were collected and evaporated. The residue was triturated with dichloromethane/ether to give 2.38 g (44.6%) of product, mp 132°-134° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12](O)=[O:13])[CH:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].B.O1CCCC1.O>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(CC(=O)O)CCN1C(=O)OCC
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of 10 g of 1-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine-3-acetic acid in 50 ml tetrahydrofuran is cooled to 0° and 55 ml of borane/tetrahydrofuran (1M) is added dropwise. After stirring 2 hours at 0°, 20 ml of water is added, the mixture is extracted with ethyl acetate, washed twice with water and dried over sodium sulfate. The solution is filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:1 to 7:3) to yield cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:20])([F:19])[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=1)=[O:6]>O>[F:20][C:4]([F:3])([F:19])[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=1)=[O:6]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(F)(F)F)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1csc(NC(=O)C(F)(F)F)n1
Yield: 66.9 %

Procedure:
To a solution of potassium hydroxide (4.2 g.) in water (100 ml.) was added ethyl 2-trifluoroacetamidothiazol-4-ylacetate (14.1 g.) at room temperature with stirring, and the mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was washed with ethyl acetate and adjusted to about pH 3 with 10% hydrochloric acid under ice-cooling and stirring. The precipitated solid was collected by filtration and dried over phosphorus pentoxide to give 2-trifluoroacetamidothiazol-4-ylacetic acid (8.5 g.), mp 117°-120° C.