Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:26])[CH3:23]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). (1R,2S)-2-(3-Methyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.068 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.064 g, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 7 h. The solution was poured into a 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, (1R,2S)-2-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.3 mmol), as a light yellow oil, which was used directly for next step. LC-MS (ESI) calcd for C23H34N4O7S2 542.19, found 543.3 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[ClH:14].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([Cl:14])=[O:11])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1cccnc1
Solvent: c1ccccc1
Product: Cl
Product: O=C(Cl)C=Cc1cccnc1

Procedure:
67 ml of benzene was added to 10 grams of 3-(3-pyridyl)-acrylic acid. 8.1 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:3]([OH:21])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester (50.96 g, 0.16 mol) in methanol (410 mL) was treated with a 1N aqueous sodium hydroxide solution (345 mL, 0.35 mol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (5×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (43.61 g, 90%) as a white solid which was used without further purification: mp 152-154° C.; EI-HRMS m/e calcd for C15H20O4S (M+) 296.1082, found 296.1080.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[N:37][N:36]=[N:35]1)[CH2:12][O:13][CH2:14][C@@H:15]1[CH2:17][C@@H:16]1[CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1>C(Cl)Cl>[Cl-:1].[F:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[N:37][N:36]=[N:35]1)[CH2:12][O:13][CH2:14][C@@H:15]1[CH2:17][C@@H:16]1[CH:18]1[CH2:23][CH2:22][NH2+:21][CH2:20][CH2:19]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(-n3cnnn3)c(F)c2)CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1cc(COC[C@@H]2C[C@@H]2C2CC[NH2+]CC2)ccc1-n1cnnn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 4 M HCl in dioxane (2.4 mL, 9.62 mmol) was added to a solution of tert-butyl 4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step C product, 415 mg, 0.962 mmol) in DCM (3 mL). This mixture was stirred at rt for 1 hr. The reaction mixture was subsequently concentrated under reduced pressure to afford the title compound (351 mg, 99%) as a crude product to be used for the next step. LC/MS (m/z): 332 (M+H)+.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].I[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CC(CC(C)C)=O>C(O)C.O>[CH:1]1([S:7][C:21]2[C:22]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: Ic1cccc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: CCO
Product: c1ccc2c(SC3CCCCC3)cccc2c1
Temperature: 90 °C
Reaction time: 11 h
Yield: 68.9 %

Procedure:
33.5 g of cyclohexanethiol, 37.4 g of sodium ethoxide, and 70 g of 1-iodonaphthalene was dissolved in 1 l of ethanol in a reaction flask, in which the atmosphere was replaced with nitrogen. 3.2 g of tetrakis(triphenylphosphonium)palladium was added. The mixture was stirred for 11 hours at 90° C. Ethanol was condensed under reduced pressure and 1 l of methyl isobutylketone and 1 l of distilled water were added. The mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. 1 l of distilled water was added and the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting solution was dried with anhydrous magnesium sulfate and filtered. After further drying using an evaporator, methyl isobutylketone was evaporated from the dried solution. The residual liquid was dried under reduced pressure and was purified by a silica gel column using n-hexane as a developing solvent. The n-hexane was evaporated under reduced pressure to obtain 46 g of 1-cyclohexylthionaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([O:20]CC(Cl)(Cl)Cl)=[O:19])=[O:7])([CH3:4])(C)C.Cl.[C:27](O)(=O)[CH3:28]>CN(C)C=O.O.[Zn]>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])[CH2:4][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CSC[C@H]12
Reactant: CC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N[C@H]1C(=O)N2C(C(=O)O)=CSC[C@H]12
Reaction time: 3 h

Procedure:
To a solution of 43 mg (0.1 mmole) of trichloroethyl cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 6 ml of dimethylformamide and 6 ml of acetic acid is added over a 1.5 hr period 250 mg (3.8 mmole) zinc dust. The mixture is stirred vigorously for 3 hrs and then diluted with 50 ml of water. The mixture is acidified with dilute HCl, filtered and extracted with ethyl acetate. The organic phase is extracted with 5% NaHCO3 which is acidified and reextracted into ethyl acetate. The final extracts are washed with brine, dried, and evaporated to give cis-7-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A mixture of 2-chloro-4-phenylthiazole-5-carboxylic acid ethyl ester (134 mg, 0.5 mmol), benzimidazole (Aldrich) (73.8 mg, 0.625 mmol) and LiN(TMS)2 (1N tetrahydrofuran solution, 0.63 ml) in tetrahydrofuran (2 ml) was heated in a micro-wave oven at 120° C. for 30 min. Water (3 ml) was added and the mixture was filtered, washed with water and ethyl acetate, dried in air flow to give 2-(benzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (108 mg, 61%). The aqueous solution was concentrated to remove tetrahydrofuran and then extracted with ethyl acetate to recover an additional amount of the product (100 mg, 75% pure). 1H-NMR (CDCl3) 8.84 (s, 1H); 8.16 (d, 1H); 7.81-7.90 (m, 3H); 7.39-7.58 (m, 5H); 4.37 (q, 2H); 1.27 (t, 3H). MS M/z 350 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13]C)=O)=[C:5]([O:15][CH3:16])[C:4]=1OC=C=O.[H-].[Na+].[C:23]([OH:27])(C)(C)C.[C:28](O)(=[O:30])C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH2:9][CH2:10][C:11](=[O:13])[CH:16]([C:28]([O:27][CH3:23])=[O:30])[O:15][C:5]=2[CH:4]=1
Reactant: COC(=O)CCc1ccc(OC)c(OC=C=O)c1OC
Reactant: CC(C)(C)O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1Oc2cc(OC)ccc2CCC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 15 g of methyl 3-(4-methoxy-2-methoxy-carbonylmethyloxyphenyl)propionate in 200 ml of toluene is added dropwise to a suspension of 5.6 g of 60% oily sodium hydride in 200 ml of toluene to which 0.4 ml of tert-butanol is added, for a period of 8 hours with heating under refluxing. The reaction mixture is heated under refluxing for 30 minutes and allowed to stand overnight, and then poured into ice water containing 10 ml of acetic acid. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=4:1) to give 9.5 g of methyl 8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil. A mixture of 7.4 g of methyl 8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, 10.9 g of 1-bromo-3-chloropropane, 1.5 g of potassium iodide, 10 g of anhydrous potassium carbonate and 300 ml of acetonitrile is heated under refluxing with stirring for 5 hours. After cooling, the inorganic substances are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=8:1) to give 9 g of methyl 2-(3-chloropropyl)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as an oil. In 100 ml of methanol is dissolved 9 g of methyl 2-(3-chloropropyl)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, and 0.6 g of sodium borohydride is added in small portions to the solution under ice-cooling with stirring. The reaction mixture is concentrated under reduced pressure, and the residue is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure, and the residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1) to give 3.3 g of methyl trans-2-(3-chloropropyl)-3-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil from the first fraction eluted.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)[N:4]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Temperature: 35 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
4-(Chloromethyl)-2-methyl-thiazole (0.590 g, 3.18 mmol, 1 eq) was suspended in DCM (5 mL). DIPEA (1.39 mL, 7.95 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (1.300 g, 7.0 mmol, 2.2. eq). The mixture was stirred at 35° C. for 5 h, then diluted with EtOAc, and washed with H2O and brine. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (0.940 g, 99%); 1H-NMR (500 MHz, CDCl3): δ 1.47 (s, 9H, C(CH3)3), 2.47 (t, 4H, J=4.5 Hz, piperazine N(CH2)2), 2.73 (s, 3H, Me), 3.48 (t, 4H, J=4.5 Hz, piperazine N(CH2)2), 3.64 (s, 2H, NCH2), 6.96 (s, 1H, thiazole 5-H); LC (Method B)-MS (ESI, m/z): Rt=1.96 min—298 [(M+H)+, 100%].
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[S:20][C:19]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])=[CH:18][CH:17]=3)=[C:11]([CH2:29][CH2:30][CH3:31])[N:10]3[N:32]=[CH:33][N:34]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[S:20][C:19]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])=[CH:18][CH:17]=3)=[C:11]([CH2:29][CH2:30][CH3:31])[N:10]3[N:32]=[CH:33][N:34]=[C:9]23)[CH2:4][CH2:3]1)[CH3:42]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile (0.4 g), rhodium(I) acetate (0.0019 g) and toluene (10 mL) was added dropwise ethyl diazoacetate (0.46 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 53%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[O:15]=[C:10]1[C:9]2[NH:16][CH:17]=[CH:18][C:8]=2[C:7]2[CH:6]=[C:5]([S:2](=[O:3])(=[O:4])[NH:27][C:26]3[CH:28]=[CH:29][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: Cc1ccc(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Yield: 40.8 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 62 μL (0.55 mmol) of 4-methylaniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in diethyl ether, 40 mg (20%) of 4-oxo-8-p-tolylsulfamoyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(Cl)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(Cl)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-chlorophenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 7) 80.0 mg (0.181 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.51-7.48 (4H, m), 7.34 (2H, d, J=8.4 Hz), 6.97 (1H, s), 6.07 (1H, t, J=4.5 Hz), 2.34 (2H, d, J=4.6 Hz), 1.29 (6H, s).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[C:2]1[S:11]([NH2:14])(=[O:13])=[O:12].C1C=C[NH+]=CC=1.[Br:21][Br-]Br.O>O1CCCC1.C(#N)C>[Br:21][CH:8]1[CH2:7][S:6][C:5]2[S:1][C:2]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:3][C:4]=2[C:9]1=[O:10]
Reactant: NS(=O)(=O)c1cc2c(s1)SCCC2=O
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1cc2c(s1)SCC(Br)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution of 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (3.50 g, 0.014 m) in dry tetrahydrofuran (70 ml) was stirred at ambient temperature while a solution of pyridinium bromide perbromide (6.08 g, 0.019 m) in dry tetrahydrofuran (35 ml) and acetonitrile (10 ml) was added over 15 minutes. After stirring at ambient temperature for 1 hour, the reaction mixture was added to water (100 ml) and concentrated in vacuo to remove tetrahydrofuran and acetonitrile. The aqueous mixture was extracted with ethyl acetate (3×100 ml), the combined extracts were washed with water, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was partially purified by chromatography on silica gel, eluting with 50% ethyl acetate-hexane, to yield 3.68 g (80%) of material which was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=C[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.[S:29]1[C:37]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]=2C=C1.C[N:39](C=O)C>>[N:34]1[CH:35]=[CH:36][C:37]([S:29][C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[N:39][CH:3]=2)=[CH:32][CH:33]=1
Reactant: c1cc2c(s1)CCNC2
Reactant: CN(C)C=O
Reactant: Clc1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: c1cnc2ccc(Cn3nnc4ncc(Sc5ccncc5)nc43)cc2c1

Procedure:
The mixture 6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline (60 mg, 0.2 mmol) (prepared according to Compound 60), Cs2CO3 (195 mg, 0.6 mmol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (52 mg, 0.3 mmol) in DMF (1.5 mL) was stirred at 120° C. overnight, then concentrated. The residue was purified by chromatography to afford the title compound MS (m/z): 399 (M+1)+.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=[CH:22][CH:23]=[O:24])=[CH:15][CH:14]=1.[O:36]1CCCC1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=[CH:22][CH:23]([OH:24])[CH2:5][CH2:3][C:2](=[O:36])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C(=O)CCC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)(C)C

Procedure:
The dianion of 1,1-dimethylethyl acetoacetate (9.1 mL of 1M solution, 9.1 mmol) was added to a solution of 5,5-bis-(4-fluorophenyl)-4-(1,1-dimethylethyl)-2,4-pentadienal in 30 mL of tetrahydrofuran at -60° C. The solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0.5% methanol in methylene chloride to give 1.3 g of the title compound; m.p. =95°-97° C.
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([O-:8])=O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][NH-:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[CH3:29][O:30][C:31]1[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=[CH:33][C:32]=1[CH2:41][CH2:42][NH:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[C:48]([O:54][CH3:55])[C:47]=1[O:56][CH3:57]>CN(C)C=O>[CH3:57][O:56][C:47]1[C:48]([O:54][CH3:55])=[C:49]([O:52][CH3:53])[CH:50]=[CH:51][C:46]=1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([O:37][CH3:38])[C:31]=1[O:30][CH3:29])[C:6](=[O:8])[CH:5]([C:4]([NH:28][CH2:27][CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1)=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(CCNCCc2ccc(OC)c(OC)c2OC)c(OC)c1OC
Reactant: COc1ccc(CC[NH-])cc1OC
Reactant: CCOC(=O)C(C(=O)[O-])c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(C(=O)N(CCc2ccc(OC)c(OC)c2OC)CCc2ccc(OC)c(OC)c2OC)c2ccccc2)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 18.0 g (52.4 mmol) of monoethylphenylmalonate-2-(3,4-dimethoxyphenyl)ethylamide in 150 ml of anhydrous dimethylformamide are added, at ambient temperature 9.0 g (55.5 mmol) of N,N'-carbonyldiimidazole in batches. After 30 minutes 18.0 g (44.3 mmol) of di-[2-(2,3,4-trimethoxyphenyl)ethyl]amine are added and the mixture is stirred for 30 minutes. Then the solvent is distilled off in vacuo, the residue is taken up in 1.5 liters of CH2Cl2 and extracted twice with 250 ml of water and 200 ml of 1N HCl, one after the other. The organic phase is evaporated down after drying over Na2SO4 and, after purification over a silica gel column (eluant: CH2Cl2 /MeOH 100:2) the residue is crystallised from ethyl acetate/ether. Yield: 35.5 g
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].O.[CH3:16]S(C)=O>>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Clc1ccc2ccncc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1nccc2ccc(Cl)c(Cl)c12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Alternatively, 7,8-dichloro-1-methylisoquinoline is prepared by the following procedure. 7,8-Dichloroisoquinoline (0.019 mole) in 100 ml. of dimethylsulfoxide is added to a solution of sodium hydride (0.11 mole) in 100 ml of dimethylsulfoxide at 70° C. The reaction mixture is stirred at 70° C. for four hours under a nitrogen atmosphere. The reaction mixture is cooled, 100 ml. of water is added, and the mixture is poured into 1500 ml. of water. The aqueous mixture is extracted with benzene. The extract is washed, dried over sodium sulfate and evaporated to give 7,8-dichloro-1-methylisoquinoline.