Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH-:19].[Na+:20].[CH2:21]([OH:23])C>C(Cl)(Cl)Cl>[C:1]1([CH:7]2[N:11]([C:21]([O-:23])=[O:19])[N:10]=[CH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:20]
Reactant: CCO
Reactant: C1=NNC(c2ccccc2)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C([O-])N1N=CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl chlorofromate (12 g) was added dropwise under ice cooling to a solution of 14.6 g 5-phenyl-2-pyrazoline and 12 g triethylamine in 100 ml chloroform, and the mixture was stirred at room temperature for three hours. The reaction mixture was washed with 3% hydrochloric acid and 3% aqueous solution of sodium bicarbonate in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off from the dried solution, and the oily residue thus obtained (20 g) was dissolved in 80 ml ethanol. To this ethanolic solution, was added 10 ml of 40% aqueous solution of caustic soda, the mixture was stirred at room temperature for one hour, and the crystals which precipitated out were collected by filtration and dried under reduced pressure, affording 12 g of pure product. M.p.: 210° C. (dec.); NMR (D2O): 2.6-3.4 (2H, m), 4.7 (1H, dd, J=12, 5 Hz), 7.14 (1H, t, J=2 Hz), 7.40 (5H, s).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=O)=O.[C-:35]#[N:36].[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1>[C:35]([CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:21][CH2:22][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:24][CH2:25]4)[C:9]=3[C:8]1=2)#[N:36]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Reactant: [C-]#N
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (900 mg, 1.76 mmol, 1.00 equiv) in 6 mL of DMSO at room temperature. NaCN (600 mg, 12.24 mmol, 6.96 equiv) and 4-dimethylaminopyridine (100 mg, 0.82 mmol, 0.47 equiv) were added and the resulting solution was stirred for 2 h at 80° C. After cooling to room temperature, the reaction was quenched with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to provide tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (709 mg, 91%) as a white solid. MS: m/z 443 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23]OS(C)(=O)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>CS(C)=O>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCOS(C)(=O)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Product: Cl

Procedure:
A solution of 0.84 g. of 5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-3-phenylisoindole-1-carboxylic acid ethyl ester in 5 ml. of dimethylsulfoxide is treated with 5 ml. of diethylamine and boiled at reflux for 17 hours under exclusion of light. The excess diethylamine is then evaporated under reduced pressure and the resulting solution poured into 50 ml. of ice-water. After the addition of 3 g. of sodium chloride, the separated, thick oil is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The oily residue is dissolved in 15 ml. of acetone, treated with 10 ml. of 0.5-N hydrochloric acid and the mixture is thoroughly shaken. After cooling in an ice-bath, the crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 1, and there is obtained 5-chloro-2-[2-(diethylamino)-ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:14]2([O:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16][CH2:15]2)[NH:9][C:10](=[O:13])[C:11]=1[OH:12])=[O:5])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([N:9]1[C:10](=[O:13])[C:11]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[C:8]1[C:14]1([O:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:16][CH2:17]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1nc(C2(OCCO)CCC2)[nH]c(=O)c1O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C2(OCCOS(C)(=O)=O)CCC2)n(S(C)(=O)=O)c(=O)c1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A cold (0° C.) solution of 5-hydroxy-2-[1-(2-hydroxy-ethoxy)-cyclobutyl]-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (7.23 g, 25 mmol) in anhydrous tetrahydrofuran was treated with methanesulfonylchloride (Aldrich) by dropwise addition. The solution was warmed to room temperature and stirred for 4 hrs. The reaction was concentrated in-vacuo, and the crude product was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution. The organic solution was dried (sodium sulfate), filtered to remove solids, and concentrated in vacuo to give the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ: 4.49 (2H, q, J=7.0 Hz), 4.35-4.38 (2H, m), 3.93-4.00 (1H, m), 3.66-3.67 (3H, s), 3.62-3.65 (2H, m), 3.44-3.46 (3H, s), 3.05-3.07 (3H, s), 2.74-2.82 (1H, m), 2.60-2.67 (2H, m), 2.41-2.49 (2H, m), 1.43 (3H, t, J=7.0 Hz). LCMS (M+H): 532.94.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>CCO>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=Cc1cccc(OCC2CO2)c1
Solvent: CCO
Product: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Yield: 63 %

Procedure:
A solution of 3-(oxiran-2-ylmethoxy)benzaldehyde (1.0 g, 5.61 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.49 g, 11.22 mmol) in EtOH (20 mL) was heated at 110° C. for 3 h. The solvent was then removed by concentration and the residue dissolved in ethyl acetate, washed with water and the separated organic layer dried and concentrated. The crude product was purified by column chromatography. (1.1 g, yield 63%.) MS (ESI) e/z: 312.3 [M+1]+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:31]([NH:33][CH3:34])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:31]([N:33]([CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:25]=1)[CH3:34])[CH3:32]
Reactant: CCNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2 drops of acetic acid, ethyl(methyl)amine (59 mg, 1.0 mmol), and stirred at room temperature for 5 h. To this was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and reacted overnight. It was then purified by Gilson Preparatory HPLC to give 30.0 mg of the title compound (61.4%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[OH:26])[CH3:16].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH2:15][CH3:16])[CH:22]=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
Potassium carbonate (19.8 g, 143 mmol) and benzyl chloride (16.5 mL, 143 mmol) were added to a suspension of 4-ethoxy-3-hydroxybenzaldehyde described in Production Example 15-1 (20 g, 120 mmol) in ethanol (200 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 90° C. for 2.5 hours. The mixture was cooled to 0° C., and 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-3:1). The target fraction was concentrated under vacuum to obtain the title compound (28.5 g, 92%).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]4[C:47]([F:48])=[CH:46][C:45]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:44][C:43]=4[F:53])[N:36]=3)=[O:34])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl.O1CCOCC1>CO.C1COCC1>[NH2:24][C@H:16]1[CH2:17][C@@H:18]([C:20]([F:21])([F:22])[F:23])[CH2:19][N:14]([C:13]2[C:12]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]4[C:43]([F:53])=[CH:44][C:45]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:46][C:47]=4[F:48])[N:36]=3)=[O:34])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)C[C@@H](C(F)(F)F)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.015 g, 0.020 mmol) in MeOH (0.8 mL), THF (0.8 mL) and 1.0 M aq. NaOH (0.8 mL, 0.8 mmol) was stirred at room temperature for 0.5 h. The solution was then concentrated under reduced pressure and the remaining aqueous phase was extracted with EtOAc. The organic extract was concentrated to dryness under reduced pressure. The residue was treated with 4.0 M HCl in dioxane (0.20 mL, 0.80 mmol) for 20 min. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in 4.5 mL of MeOH, neutralized with NH4OH solution, and purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford two separated diastereoisomers of the title compound as white powders.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].O>CC(C)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19](=[O:20])[CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:22][CH:23]=1
Reactant: COc1cc(F)ccc1O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(F)ccc1OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluoro-2-methoxy-phenol (3.0 g, 21.1 mmol) in acetone (250 mL) is treated with cesium carbonate (8.3 g, 25.3 mmol) followed by 2-bromo-1-(4-bromo-phenyl)-ethanone (5.9 g, 21.1 mmol). The resulting mixture is stirred at room temperature for 2 h. Water (600 mL) is added slowly to the vigorously stiffing solution. After stirring for 30 minutes, the precipitate is filtered off and washed with copious water to give 1-(4-bromo-phenyl)-2-(4-fluoro-2-methoxy-phenoxy)-ethanone (G-1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a light yellow sold (489 mg).
Reaction SMILES: CS(O[C:6]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:26])(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O.O>[N:27]([C:6]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:26])=[N+:28]=[N-:29]
Reactant: C[C@]12CCC(=O)C(OS(C)(=O)=O)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a stirred solution of 1.0 g of 4-methanesulfonyloxyandrost-4-en-3,17-dione in 5 ml of dimethylformamide are added 220 mg of powdered sodium azide dissolved in 3 ml of water. The resulting mixture is heated at 60° C. for 1 hour, cooled, poured into 250 ml of cold water and extracted with ethyl acetate (4×50 ml). The combined extracts are washed with saturated NaCl aqueous solution, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by flash column chromatography on neutral Al2O3. Elution with n-hexane:diethyl ether 1:1 gives 0.52 g of the title compound, m.p. 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[C:14]([CH2:24][CH:25]4[CH2:27][CH2:26]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH:25]1([CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:29]=[CH:30][C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:28])[CH2:26][CH2:27]1
Reactant: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a stirring solution of Example 165 (0.080 g, 0.189 mmol) and pyridine (0.122 mL, 1.512 mmol) in dichloromethane was added methanesulfonyl chloride (0.017 mL, 0.227 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.079 g, 84% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm -0.39 (m, 1H) −0.13 (m, 1H) 0.03 (m, 2H) 0.21 (m, 1H) 1.24 (m, 1H) 1.43 (s, 3H) 1.78 (m, 1H) 1.99 (m, 1H) 3.01 (s, 3H) 7.38 (m, 3H) 7.50 (m, 3H) 8.07 (d, J=7.35 Hz, 1H) 9.92 (s, 1H) 15.36 (s, 1H).). MS (ESI+) m/z=502 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.Cl[C:14]1[N:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1.[I-].C(N(CC)CC)C>COCCOC>[CH3:20][C:17]1[N:16]=[N:15][C:14]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Reactant: Cc1ccc(Cl)nn1
Agent: [I-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2cccnc2)nn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the solution of 3-[(trimethylsilyl)ethynyl]pyridine (0.175g, 1.0 mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I) iodide (0.019 g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 ml Ethylene glycol dimethyl ether was added tetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). The result solution was heated to 80° C. after degasing by argon for 5 minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was added dropwise. After stirring at 80° C. for 12 hour, the reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc: 9/1 to 1/9) to give 3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. 1H NMR (CDCl3 300 MHz) δ 8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H), 7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10 (M++H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1C=CC=CC=1.S(Cl)(Cl)=O.CO>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([O:18][CH3:20])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccccc1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
In a reaction flask with mechanical stirring and reflux condenser, 263 g of 2-(3-benzoylphenyl)propionic acid (VI with R1 =CH3 and R2 =H) were suspended in 1L of dry benzene. Then 154 g of thionyl chloride were added and the mixture was heated under reflux for 5 hours. After cooling at room temperature, benzene and unreacted thionyl chloride were eliminated under vacuum. To the resulting residue (corresponding to the acid chloride) 400 mL of absolute methanol were added with care. The resulting solution was heated under reflux for 5 hours. After cooling at room temperature, the solvent was eliminated under vacuum and the residue was dissolved in 250 mL methylene chloride. The solution was washed and neutralized by treating it three times with 200 mL of a 5% solution of sodium hydrogencarbonate and then with water. After being dried, the solvent was evaporated under vacuum and 256 g of an oily residue was obtained (92% yield), used without further purification in the reaction of the following example. After 24 hours of drying, a white solid of m.p. 50-2° C. was obtained. After recrystalization from cyclohexane, experimental m.p. was 51-2° C. and the solid was identified as the title compound. By following analogous procedures, compounds Vc of Table 1 were prepared.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]([N:19]1[C:27]2[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[C:22]=2[CH:21]=[N:20]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][CH:24]1[CH2:25][CH2:26][C:27]2[N:19]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=3)(=[O:11])=[O:10])[N:20]=[CH:21][C:22]=2[C:23]1=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ncc3c2CCC(Br)C3=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
According to Scheme 3 Step 3: N-Bromosuccinimide (3.44 mmol, 613 mg) was added to a solution of 1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (3.44 mmol, 1.00 g) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 12 hours. A solution of NaHCO3 was added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to yield 5-bromo-1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (2.44 mmol, 900 mg, 42%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[Cl:7].[I:13][C:14](=[C:27]([I:29])[I:28])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>CN(C)C=O>[I:13][C:14](=[C:27]([I:29])[I:28])[CH2:15][N:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([Cl:7])=[C:2]1[Cl:1]
Reactant: CCOC(=O)c1c[nH]c(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC(I)=C(I)I)c(Cl)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 104 mg (0.5 mmoles) of 2,3-dichloro-4-ethoxycarbonylpyrrole in 5 ml of dry N,N-dimethylformamide were added 303 mg (0.5 mmoles) of 2,3,3-triiodoallyl-p-toluenesulfonate and 0.07 ml (0.5 mmoles) of triethylamine and the resulting mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled, 10 ml of cold water were added with stirring thereto and the so separated crystalline substance, 1-(2',3',3'-triiodoallyl)-2,3-dichloro-4-ethyoxycarbonylpyrrole, was recovered by filtration, washed with water and then dried. Yield 281 mg (90%), mp 117°-119° C.