Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN1CCCC1=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH:15]=2)[CH2:11][CH2:12]1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4ccc(C#C[Si](C)(C)C)cc43)c2cc1OC
Yield: 93 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 93% yield from 6-trimethylsilanylethynyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (LC-MS: 404 (MH+); anal. RP18-HPLC RT: 6.49 min.).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10](/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC)([OH:18])[C:9]([CH3:34])=[CH:8]2)[O:3]1.[CH:35]1(/[C:38](/I)=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1.[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.O1CCCC1>[CH:35]1(/[C:38](/[CH:20]=[CH:19]/[C:10]2([OH:18])[C:11]([CH3:17])([C:13]([F:16])([F:14])[F:15])[CH2:12][C:4]3([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]3)[CH:8]=[C:9]2[CH3:34])=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1
Reactant: CCOC(=O)/C=C(\I)C1CC1
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Under argon, 2,3,7,9-tetramethyl-8-[(E)-2-(tributylstannyl)vinyl]-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (150 mg, 0.25 mmol) and ethyl (2Z)-3-cyclopropyl-3-iodoacrylate (67 mg, 0.25 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. tetrahydrofuran (4 ml), dichlorobis(acetonitrile)palladium(II) (3 mg, 0.01 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z,4E)-3-cyclopropyl-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]penta-2,4-dienoate (40 mg, 36% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.80/7.78 (d, 1H), 6.40/6.38 (d, 1H), 5.62/5.60 (s, 1H), 5.52/5.44 (s, 1H), 4.28/3.63 (m, 2H), 4.18 (q, 2H), 2.52/2.41 (d, 1H), 2.03/1.94 (d, 1H), 2.00 (br. s, 1H, OH), 1.72/1.69 (s, 3H), 1.62/1.55 (m, 1H), 1.40-1.34 (m, 3H), 1.29-1.17 (m, 6H), 0.92 (t, 3H), 0.83 (m, 2H), 0.58 (m, 2H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]3[CH:18]=[N:19][CH:20]=[CH:21][C:14]=3[N:13]=[C:12]2[C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>CN(C=O)C.O>[C:44]([Si:41]([CH3:43])([CH3:42])[O:40][CH2:39][CH2:38][O:29][C:25]1[C:26]([CH3:28])=[CH:27][C:22]([C:12]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:6][CH:7]=3)[C:16](=[O:17])[C:15]3[CH:18]=[N:19][CH:20]=[CH:21][C:14]=3[N:13]=2)=[CH:23][C:24]=1[CH3:30])([CH3:47])([CH3:46])[CH3:45]
Reactant: CCC(C)c1ccc(-n2c(-c3cc(C)c(O)c(C)c3)nc3ccncc3c2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO[Si](C)(C)C(C)(C)C)c(C)c3)nc3ccncc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-sec-butyl-phenyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-pyrido[4,3-d]pyrimidin-4-one (0.25 g, 0.63 mmol) in anhydrous DMF (10 mL) was added cesium carbonate (0.62 g, 1.9 mmol). The color changed to orange. The reaction mixture was stirred at room temperature for 10 minutes under nitrogen. Then, (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (9) (0.300 g, 1.27 mmol) was added and the reaction mixture was stirred at 80° C. for 5 hours under nitrogen, cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with water (2×50 mL), then brine (50 mL), and dried over anhydrous Na2SO4. The solvent was evaporated. The crude compound was purified by the Simpliflash system (30% ethyl acetate in hexanes as eluent) to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-3-(4-sec-butyl-phenyl)-3H-pyrido[4,3-d]pyrimidin-4-one (10) as a gummy solid. Yield: 0.20 g (58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)(Cl)=O.[OH-].[NH4+:36].O>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH2:36])=[O:30])[CH:26]=3)[CH:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: [NH4+]
Reactant: COc1cc(-c2cc3nccc(-c4cnn(CC(=O)O)c4)c3o2)cc(OC)c1OC
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cc3nccc(-c4cnn(CC(N)=O)c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
2-[4-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]pyrazol-1-yl]acetic acid (0.040 mmol) is dissolved in THF and thionylchloride (0.234 mmol) is added. The mixture is stirred 24 h at RT. Additional thionylchloride (0.234 mmol) is added and the reaction is stirred 24 h at RT. Additional Thionylchlorid (2.343 mmol) is added and the reaction is stirred 48 h. The solvent is removed in vacuo and ammonium hydroxide (32%, 1.205 mmol) is added. Water (3 ml) is added and the precipitate is filtered and resuspended in MeOH and filtered and dried at 50° C. in vacuo. The product is isolated as beige solid in a yield of 92%). HPLC (method A): Rt 2.40 min (purity 95%); LCMS (ESI+) (method E): Rt 1.49 min, M+H+ 409.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.67 (s, 1H), 8.45 (d, J=4.4, 1H), 8.32 (s, 1H), 7.75-7.51 (m, 3H), 7.47-7.26 (m, 3H), 4.93 (s, 2H), 3.95 (s, 6H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[CH:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]([Cl:14])=[CH:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC=C(Cl)Cl)cc1
Product: O=C(Cl)c1ccc(OC=C(Cl)Cl)cc1

Procedure:
A mixture containing 27.8 g. of 4-(2,2-dichlorovinyloxy)benzoic acid and 278 ml. of thionyl chloride was stirred and refluxed on a steam bath for 3 hours. The excess thionyl chloride was distilled off, first at atmospheric pressure and then at reduced pressure. Ethylene dichloride was added to the liquid residue and the solution evaporated in vacuo to remove the ethylene dichloride and remaining traces of thionyl chloride. There was thus obtained a quantitative yield of 4-(2,2-dichlorovinyloxy)benzoyl chloride as a pale yellow, non-volatile liquid.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)=[O:15]
Reactant: NC(=O)C1CCNCC1
Reactant: COCC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(C)(C)C(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of isonipecotamide (1.0 g, 8.0 mmol), 3-methoxy-2,2-dimethylpropanoic acid (Bulletin of the Chemical Society of Japan 2001, 74, 1695–1702, 1.1 g, 8.0 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 3.3 g, 8.8 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol) in N,N-dimethylformamide (8 mL) was stirred at room temperature for 18 h. Water (8 mL) was added and the mixture was extracted with ethyl acetate (20 mL×6). Removal of solvent gave a crude of 1-(3-methoxy-2,2-dimethylpropanoyl)piperidine-4-carboxamide as a brown oil, which was dissolved in tetrahydrofuran (15 mL) and added to a suspension of lithium aluminum hydride (2.26 g, 47.7 mmol) in tetrahydrofuran (15 mL) at 0° C. The mixture was stirred at 40° C. for 3 h and quenched with sodium sulfate decahydrate and potassium fluoride. Filtration through a pad of Celite and concentration of the filtrate gave 925 mg (54%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:20]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[N:29][OH:30])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=C[CH:32]=1.C[C:38]#[C:39][C:40]([O-:42])=[O:41].O>CS(C)=O>[CH3:32][O:42][C:40](=[O:41])[CH:39]=[CH:38][O:30]/[N:29]=[C:26]1/[C:27]2[C:22]([CH2:23][CH2:24][CH2:25]/1)=[N:21][N:20]([C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:28]=2
Reactant: ON=C1CCCc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Reactant: CC#CC(=O)[O-]
Reactant: c1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C=CO/N=C1\CCCc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a solution of 2-trityl-2,5,6,7-tetrahydro-indazol-4-one oxime 3B (0.51 mmol) in dry DMSO (1 mL) and a catalytic amount of pyridine, methylpropiolate (1.1 eq) was added and the reaction mixture was stirred at rt for 1.5 h. The mixture was poured into water and the slurry was extracted with AcOEt. The organic layer was washed with brine, dried (Na2SO4) and concentrated to yield the title compound (94%). ESI (+) MS: m/z 478 (MH+). 1H NMR: 1.73-1.93 (m, 2H), 2.10-2.28 (m, 2H), 2.52-2.60 (m, 1H), 2.71-2.79 (m, 1H), 3.83 (s, 3H), 5.40 (d, J=12, 1H), 7.03 (s, 1H), 7.20-7.31 (m, 15H), 8.50 (d, J=12, 1H).
Reaction SMILES: CC[N:3]([CH:7](C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=2.ClC1C=NC2C(=CC=C([C:35](Cl)=[O:36])C=2)N=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([N:3]([O:36][CH3:35])[CH3:7])=[O:22])=[CH:16][CH:15]=2
Reactant: O=C(Cl)c1ccc2ncc(Cl)nc2c1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc2nc(Cl)cnc2c1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of O, N-dimethyl-hydroxylamine hydrochloride salt (29 g, 0.30 mol, 1.1 eq) and DIEA (182 mL, 1.08 mol, 4.0 eq) in DCM (300 mL) was added the mixture of 3-chloro-quinoxaline-6-carbonyl chloride and 2-chloro-quinoxaline-6-carbonyl chloride (52 g, 0.27 mol, 1.0 eq) at 0° C. The mixture was stirred at rt overnight, then concentrated. The resulting residue was washed with water (300 mL×2) and extracted with EA (300 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting solid was triturated with EA/PE =1/1 (300 mL) to afford 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (16.5 g, 24.3%).
Reaction SMILES: C(O[C:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O:25]CC=C)=[O:24])[CH2:8]1)=O)C=C.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.C(OCC)(=O)CCCCC.[Na]>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([OH:25])=[O:24])[CH2:8]1)[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCCCCC(=O)OCC
Solvent: CCO
Product: C=CCN1CCC(C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 267.5 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.24 g) in a mixture of tetrahydrofuran (20 ml) and ethanol (5 ml) were added triphenylphosphine (0.16 g), sodium 2-ethyl hexanoate (1.1 g), and tetrakis(triphenylphosphine)palladium(0) (0.37 g). After stirring at ambient temperature for 1 hour, the reaction mixture was washed with dichloromethane, and evaporated in vacuo. The residue was chromatographed on nonionic adsorption resin "Dialon HP-20" eluting with a mixture of water and acetonitrile (95:5, V/V). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[1-allylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (500 mg).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH:3]=1.FC(F)(F)C(O)=[O:25]>>[OH:20][CH:19]([CH2:21][OH:25])[CH2:18][O:17][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[CH:5]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: O=C(O)C(F)(F)F
Reactant: O=c1c2ccccc2oc2cc(OCC3CO3)cc(O)c12
Product: O=c1c2ccccc2oc2cc(OCC(O)CO)cc(O)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
1-hydroxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.11 mmol) synthesized in Step 2 of Example 2 and 50% trifluoroacetic acid (TFA) (5 mL) were charged to a round-bottom flask, followed by stirring at 50° C. for 4 hours. After the reaction was completed, the solvent was removed, followed by drying under reduced pressure to give the title compound (20 mg, 62.7%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](SCC2C=CC=CC=2)=[C:4]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.ClCl.[S:21](Cl)(Cl)(=[O:23])=[O:22].[NH3:26]>C(O)(=O)CC.O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[CH3:9])[C:3]=1[S:21]([NH2:26])(=[O:23])=[O:22]
Reactant: N
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(F)c1cccc(Cl)c1SCc1ccccc1
Agent: ClCl
Solvent: C1CCOC1
Solvent: O
Solvent: CCC(=O)O
Product: CC(F)c1cccc(Cl)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.0 g of 3-chloro-2-phenylmethylthio-(1-fluoroethyl)benzene in a mixture of 45 mL of propionic acid and 1.5 mL of water at -10° was added 5.2 mL of liquified chlorine. The reaction was stirred an additional 30 min and then poured into a mixture of ice/water. The aqueous phase was extracted with n-butyl chloride and the combined organic phase was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated to provide an oil. The crude sulfonyl chloride was dissolved in 100 mL of THF, cooled to -78° and treated with 1.6 mL of liquified anhydrous ammonia. The reaction was allowed to slowly warm to room temperature and stirred overnight. The solids were removed by filtration and then concentration provided the crude sulfonamide. Recrystallization from ethanol/water yielded 2.7 g of the title compound as a white solid, mp 151°-153°.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([SH:7])=[N:5][N:6]=1.[NH2:8][C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=1.Cl[C:16]1[C:17]2[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[NH2:1][C:2]1[NH:3][C:4]([S:7][C:24]2[CH:23]=[CH:22][C:18]3[N:19]=[CH:20][N:21]=[C:16]([NH:8][C:9]4[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=4)[C:17]=3[N:25]=2)=[N:5][N:6]=1
Reactant: Cn1ccc(N)n1
Reactant: Nc1nnc(S)[nH]1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cn1ccc(Nc2ncnc3ccc(Sc4nnc(N)[nH]4)nc23)n1

Procedure:
The compound of Example 63 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 5-amino-3-mercapto-4H-[1,2,4]triazole, 3-amino-1-methyl-1H-pyrazole and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 14.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][C:10](=[O:15])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].CCN(CC)CC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH:8]([CH2:9][C:10](=[O:15])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
7-Oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (5.91 g, 27.9 mmol) was dissolved in methylene chloride (60 mL). Et3N (7.76 mL, 55.9 mmol) and 4-chlorobenzenesulfonyl chloride (7.08 g, 33.6 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous phase was separated and extracted once with methylene chloride (50 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1) to give 9.52 g (88%) of 9-(4-chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester. Retention time (min)=2.100, method [1], MS (ESI) 408.1 (M+Na); 1H NMR (300 M Hz, CDCl3) δ 7.81 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 4.61-4.57 (m, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.80 (dd, J=17.0, 7.1 Hz, 2H), 2.67-2.51 (m, 1H), 2.41 (d, J=16.4 Hz, 2H), 1.99-1.90 (m, 2H), 1.80 (dt, J=13.2, 4.4 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18].[C:9]([NH2:8])(=[O:18])[C:10]1[CH:5]=[CH:6][CH:7]=[CH:12][CH:11]=1
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(Cl)c1
Product: NC(=O)c1ccccc1
Yield: 60 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 3-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 112-mg of 3-chloro-N-methyl-N-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 60%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:32][CH3:33])=[C:21]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)[CH:17]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:32][CH3:33])=[C:21]([O:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:22]=2)[CH:17]1[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1C=Cc2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1C=C(C=O)c2cc(OC3CCCC3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
To anhydrous N,N-dimethylformamide (0.151 mL, 1.95 mmol) at 0° C. was added phosphorus oxychloride (0.079 mL, 0.85 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (350 mg, 0.78 mmol) in dichloromethane (2 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (228 mg, 2.32 mmol) in water (2 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 mL). The organic layer was washed water (2×20 mL), saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-cyclopentyloxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (386 mg, 99% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18].[C:19](=O)([O-])[O-].[K+].[K+].Cl>CO>[O:18]=[C:13]1[NH:12][CH2:17][CH2:16][N:15]([CH2:19][C:11]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=2)[CH2:14]1
Reactant: O=C1CNCCN1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc(CBr)c1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=C1CN(Cc2ccc(C(=O)O)cc2)CCN1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 3-bromomethylbenzoic acid (4.30 g, 20 mmol), piperazin-2-one (2.0 g, 20 mmol) and powdered potassium carbonate (2.76 g, 20 mmol) in methanol (50 mL) is stirred for 17 hours at room temperature. The resulting mixture is filtered and the solvent is evaporated off under reduced pressure to give a residue which is treated with hydrochloric acid (80 mL of 0.25 M) and stirred for 5 min. The precipitated product is filtered, washed with water, dried and recrystallised from methanol to give the title compound as a cream crystalline solid.