Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:7]=[CH:8][N:9]3[CH:13]=[CH:12][S:11][C:10]=23)[N:3]=[CH:2]1.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl-].[Na+]>C1COCC1>[S:1]1[CH:5]=[C:4]([C:6]2[N:7]=[CH:8][N:9]3[CH:13]=[C:12]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[S:11][C:10]=23)[N:3]=[CH:2]1
Reactant: c1nc(-c2ncn3ccsc23)cs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(-c3cscn3)c2s1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g of 7-(thiazol-4-yl)imidazo[5,1-b]thiazole in 45 ml of THF was cooled to −70° C. in an argon atmosphere. Tri-n-butylstannyl chloride (1.58 ml) was added thereto. A 1 N lithiumbis(trimethylsilyl)amide/THF solution (11.2 ml) was added dropwise at the same temperature. The mixture was stirred for 30 min. The temperature of the mixture was raised to −30° C. over a period of one hr. A saturated aqueous sodium chloride solution was added thereto, followed by extraction twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (294 mg) was obtained from the fraction of Rf=0.5.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=O)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH:11]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1NCc1ccccc1
Yield: 71 %

Procedure:
24.7 g of 1-benzyl-3-carboethoxy-4-pyrrolidone and 10.7 g of benzylamine were added to 100 ml of benzene, and then dehydrated with Dean-Stark distillation apparatus. The residual benzene was evaporated. The residue was dissolved in 200 ml of tetrahydrofuran, and then a small amount of methyl orange was added. To this was added methanol saturated with hydrogen chloride to adjust the pH to about 4, and then 7 g of sodium cyanoborohydride was added thereto. A solution of methanol saturated with hydrogen chloride was added dropwise to the reaction solution with stirring until the pink-color of the solution did not disappear. The reaction solution was basified with 15% aqueous caustic soda solution, and then the reaction mixture was diluted with ether, after which the aqueous layer was separated the aqueous layer was removed by addition of ether. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and then subjected to silica gel column chromatography (hexane:ethyl acetate, 5:1 (v/v)) to obtain 24 g of the desired compound (yield: 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH3:21]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:18]1[CH2:19][CH2:20][CH3:21]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: CCCC(OC)(OC)OC
Solvent: CC(=O)O
Product: CCCC1=Nc2ccccc2CC(c2sccc2C)N1C

Procedure:
A solution of 5.0 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, 18.02 ml trimethyl orthobutyrate and 6.8 ml of glacial acetic acid was refluxed for 8 hours under a nitrogen atmosphere. The solution was concentrated at 40° C. on a rotary evaporator and the residual oil was acidified with 10% hydrochloric acid solution (60 ml) and extracted with diethyl ether (3×70 ml). The acidic aqueous phase was basified with 10% sodium hydroxide solution (100 ml) and extracted with diethyl ether (3×100 ml). The ethereal phase was dried over sodium sulfate/magnesium sulfate, filtered and concentrated to an oil. Purification was accomplished by HPLC (Water's Associates Prep LC/System 500A, silica gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of the appropriate fractions yielded 4,5-dihydro-3-methyl-4-(3-methyl-2-thienyl)-2-(1-propyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C.CCOC(C)=O>[N:34]1([C:32](=[O:33])[CH2:31][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:22][C:21]4([CH3:24])[CH2:23][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]4)=[O:15])=[CH:12][CH:13]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NCC(=O)N3CCOCC3)cc2)C1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (0.5 g, 1.34 mmol) in dry DMF (40 ml) was added sodium hydride (80 mg, 3.33 mmol in 60% mineral oil) and the mixture was stirred for 30 min. 2-Chloro-1-morpholin-4-yl-ethanone (264 mg, 1.61 mmol) was added and the stirring was continued for an additional 1 hr. at 50° C. The reaction was quenched by addition of water (50 ml) and extracted with diethyl ether (2×25 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (20 ml) and TFA (10 ml) was added. The resulting mixture was stirred for 4 hrs. at room temperature and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using first EtOAc (500 ml) followed by 4% TEA in EtOAc as eluents. Semi-pure fractions were collected and evaporated to dryness affording 0.4 g as an oil which was dissolved in EtOAc (25 ml) and washed with water (2×25 ml), dried (Na2SO4), filtered and evaporated in vacuo affording 180 mg (34%) of the title compound as a oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53](Cl)=[O:54].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=3)=[O:54])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added pyridine-2-carbonyl chloride (0.089 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 708 [M+H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[CH3:25][N:26]([CH2:34][CH2:35][CH:36]=[O:37])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].[Cl-].[NH4+]>O1CCCC1>[OH:37][CH:36]([C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)[CH2:35][CH2:34][N:26]([CH3:25])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(CCC(O)c1ncccn1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To 2-(tributylstannyl)pyrimidine (690 mg, 1.87 mmol) dissolved in dry tetrahydrofuran (10 ml) cooled to −78° C. was added 2.4M n-butyl lithium in hexanes (0.8 ml, 1.87 mmol) under nitrogen. After stirring for a further 0.5 h, methyl(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester in dry tetrahydrofuran (10 ml) was added rapidly at −78° C. The reaction mixture was allowed to warm to ambient, treated with aqueous saturated ammonium chloride solution and extracted with ethyl acetate which was washed with brine and dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue eluted down a flash chromatography column using initially 10% ethyl acetate/dichloromethane, then 10% methanol/dichloromethane to give 260 mg (43%) of the subtitle compound as a viscous yellow oil.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:18]([CH3:25])[N:19]=[CH:20][C:21]=2[N+:22]([O-])=O)[O:4][CH2:3]1.BrC1SC(NC(=O)OC(C)(C)C)=C(C(=O)NC2C=NN(C)C=2[C@@H]2CC[C@@H](NC(OC(C)(C)C)=O)[C@@H](F)CO2)N=1.C(OC([NH:72][C:73]1[S:77][C:76]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[C:79]=2[F:85])=[N:75][C:74]=1[C:86](O)=[O:87])=O)(C)(C)C>>[NH2:72][C:73]1[S:77][C:76]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[C:79]=2[F:85])=[N:75][C:74]=1[C:86]([NH:22][C:21]1[CH:20]=[N:19][N:18]([CH3:25])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@@H:2]([F:1])[CH2:3][O:4]1)=[O:87]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccc(F)c2F)nc1C(=O)O
Agent: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (Intermediate 88), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2,3-difluorophenyl)thiazole-4-carboxylic acid (Example 25) gave 181 as the hydrochloride salt as a pale pink solid (30 mg, 38% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 9.42 (s, 1H), 8.54-8.41 (m, 4H), 7.96-7.89 (m, 1H), 7.67 (s, 1H), 7.50-7.39 (m, 3H), 5.28 (m, 1H), 4.84 (d, J=10.4 Hz, 1H), 4.33-4.17 (m, 1H), 4.11-3.99 (m, 1H), 3.78 (s, 3H), 3.74-3.52 (m, 1H), 2.16-1.81 (m, 4H). LCMS (ES+) m/z 467 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:12][C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (17.6 g), benzyl chloride (20.0 g) and anhydrous K2CO3 (13.2 g) in acetone (100 ml) is stirred under reflux for 22 hours. The reaction mixture is filtered and the precipitate washed with acetone. The acetone extract is concentrated in vacuo and the residue short path distilled (160°-170° C.; 50μ) to give 22.9 grams of an orange liquid which crystallized on standing.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][N:3]=1.CO.[Li+].[OH-].O>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(c1)sc1c(C(N)=O)cnc(N)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC(=O)c1cnc(N)c2c1sc1cc(C(=O)O)ccc12
Reaction time: 18 h

Procedure:
A suspension of methyl methyl 1-amino-4-(aminocarbonyl)[1]benzothieno[3,2-c]pyridine-7-carboxylate (Example 22, Step 2) dissolved in THF and MeOH was treated with a solution of LiOH in H2O (2.5 equiv). The reaction media became cloudy so H2O, MeOH and THF were added until a clear solution ensued. After 18 h, analysis showed consumption of all the starting material. A large proportion of the volatiles were removed under reduced pressure. The remaining solution was treated with 1 N HCl. The precipitate was filtered off to obtain the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C@@:9]3([CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[NH2:18])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH:31]=2)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C@@:9]3([CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[NH:18][C:28]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[N:40]([CH3:41])[N:39]=[N:38][N:37]=4)[CH:31]=3)=[O:27])[CH2:8]2)=[CH:19][CH:20]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: N[C@@H]1CCCC[C@@]12CCCN(Cc1ccc(F)cc1)C2
Solvent: C1CCOC1
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@@]23CCCN(Cc2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A solution of (6S,7R)-2-(4-fluorobenzyl)-2-aza-spiro[5.5]undec-7-ylamine (90 mg, 0.32 mmol) in tetrahydrofuran (2 mL) was treated with [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (123 mg, 0.42 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the resulting solid was purified by chromatography on silica gel, eluting with 0.2:1.8:98 ammonium hydroxide/methanol/dichloromethane, to give the desired product (80 mg). 1H NMR (300 MHz, CDCl3) δ8.27 (bs, 1H), 7.94 (d, J=9 Hz, 1H), 7.82 (bs, 1H), 7.39 (t, J=8 Hz, 1H), 7.26-7.19 (m, 3H), 6.98-6.91 (m, 2H), 6.21 (bs, 1H), 4.17 (s, 3H), 3.98 (bs, 1H), 3.35 (m, 2H), 2.50-2.15 (m, 3H), 1.85 (m, 2H), 1.65-1.20 (m, 11H). Mass spec (ES+) m+/z 478.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)=[CH:15][CH:14]=2)[N:11]=[C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])[CH2:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[N:11]=[C:10]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccc(C3=CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 205.6 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (435.0 mg, 0.72 mmol) prepared in Example 423 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 400.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: O=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[S:29]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=S)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 14.1 mmol of diethyl 3-oxopentanedioate in 15 mL of toluene under argon add 49.4 mmol of sodium bicarbonate and 15.1 mmol of Lawesson's reagent. Stir for 1 h at room temperature then heat under reflux for 5 h. Cool, filter, and concentrate in vacuo. Purify the residue by silica gel chromatography using ethyl acetate/hexanes eluant to yield the title compound.
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][C:9]([OH:11])=O)[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:9](=[O:11])[CH2:8][CH:7]3[CH2:6][S:5][C:4]4[S:12][CH:13]=[CH:14][C:3]=4[C:2]3=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)CC1CSc2sccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: O=C1CC2CSc3sccc3C2=NN1c1ccc(Cl)cc1
Yield: 73.3 %

Procedure:
A mixture of 4.0 g of 4-oxo-5,6-dihydro-4H-thieno-[2,3-b]thiopyran-5-acetic acid and 3.3 g of 4-chlorophenylhydrazine in 70 ml of ethanol is refluxed under heating for 6.5 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in 50 ml of acetic acid and the solution is refluxed under heating for 2 hours. Then, the resultant mixture is concentrated under reduced pressure, the residue is subjected to chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 4.3 g of 2-(4-chlorophenyl)-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one as pale brown crystals, melting at 162°-164° C.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1>CC(C)=O>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[CH:4][C:5](=[O:6])[CH:8]=[CH:2][C:3]2[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=2)=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(C)=O
Product: COc1cc(C=CC(=O)C=Cc2ccc(O)c(OC)c2)ccc1O

Procedure:
From vanillin and acetone in a 2:1 molar rate in acid medium, in temperatures that changes between 25 and 60° C., under ultrasonic irradiation conditions in a range from 25 to 40 KHz for a period of 1 to 3 hours further putting the reacted mixture into water/ice until producing the raw product, which dissolves in a solution of sodium hydroxide or potassium hydroxide (between 10-30%) being filtered; the filtrated is treated with hydrochloric acid or sulphuric acid from a concentration between 10-30%, the obtained product being filtered again, finally it is washed with distillated water until obtaining a neutral pH, this operation being repeated until the total purification of the product, not being necessary to perform a new purification of the compound using other procedures such as recrystallization or chromatographic column (the purity was determined by means of the HPLC technique):
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:38](=[O:39])[CH2:37][N:36]([CH3:41])[CH3:35])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)CC(=O)O
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CN(C)CC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and N,N-dimethylglycine hydrochloride (16.7 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:25])=[CH:8][C:9]=1[N:10]([CH:20]([CH2:23][OH:24])[CH2:21][OH:22])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C=O.[C:28]([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:25])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:23][O:24][CH2:28][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Temperature: 80 °C
Reaction time: 0.23 h

Procedure:
A mixture of 5-bromo-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (18 mg, 0.041 mmol), paraformaldehyde (6 mg) and boron trifluoride-diethyl etherate (15 μl, 0.12 mmol) in dry dioxane (0.6 mL) was stirred at 80° C. for 14 min. It was cooled and added to ice and NaHCO3 solution mixture, extracted with ethyl acetate, washed with brine, dried and evaporated. Pure 5-bromo-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:ethyl acetate-9:1 as eluent) (15 mg; 81%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])(=O)C.C(O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)C.O>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]
Reactant: CC(=O)OCCCCSc1cccc(C#N)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NCc1cccc(SCCCCO)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
Lithium aluminum hydride (0.20 g) was suspended in tetrahydrofuran (15 mL). To the mixture was added 3-(4-acetoxy-butylsulfanyl)benzonitrile (0.75 g) under ice-cooling. The mixture was stirred at 60° C. for 2 hours, and the mixture was cooled under ice-cooling. To the reaction mixture were added dropwise ethanol and water successively, and then added diethyl ether. To the reaction mixture was added anhydrous sodium sulfate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(C=O)c1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 g of 5-Bromo-2-hydroxy-3-methoxy-benzaldehyde is dissolved in 200 ml of DMF and 4.78 g of potassium carbonate and 2.3 g of 2-trimethylsilyl-ethoxymethyl chloride are added. The reaction is stirred at RT for 18 h. The solvents are removed under reduced pressure, the residue is dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate, filtration and evaporation, the product is purified by silica gel chromatography eluting with a gradient of ethyl acetate in heptane. Yield 1.8 g.