Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[Cl-].[CH3:29][Zn+]>C1COCC1.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>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([CH3:29])[C:7]=3[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)nc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc12

Procedure:
A mixture of Example 9 (30 mg; 0.08 mmol), Pd(PPh3)4 (4.5 mg) and 2M methylzinc chloride (0.16 mL, 0.31 mmol) in THF (5 mL) was stirred at 80° C. for 16 hours then concentrated in vacuo. The residue was partitioned between EA and aq. citric acid and the two phases separated. The aqueous layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA/EtOH/AcOH, 90/10/1) afforded the title compound as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH:18]=[CH2:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B.C1C[O:27]CC1.[O-][O-].[Na+].[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[C:10]([CH2:20][CH2:21][CH3:22])=[CH:11][C:12]([CH2:18][CH2:19][OH:27])=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=Cc1cc(CCC)c(O[Si](C)(C)C(C)(C)C)c(CCC)c1
Reactant: C1CCOC1
Agent: B
Agent: [Na+]
Agent: [O-][O-]
Solvent: CCOC(C)=O
Product: CCCc1cc(CCO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 475 mg (1.48 mmol) of the product of Step B in 3 mL of THF at 0° C. was added 1.6 mL (1.62 mmol) of a 1N borane/THF solution. After 1 hour TLC indicated that the starting material had been consumed. The reaction mixture was quenched with 3 drops of methanol and then 0.70 mL (6.22 mmol) of 30% sodium peroxide and 6.2 mL (6.2 mmol) of 1N sodium hydroxide were added. After two hours the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was then dried over sodium sulfate, filtered and concentrated. Flash chromatography (silica gel, hexane/ethyl acetate 4:1) gave 265 mg of the title compound as a clear oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C@@:16]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:51])([F:50])[F:49])=[N:26][N:27](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1.C([SiH](CC)CC)C>ClCCl>[CH3:8][N:9]1[C:17]2[C@@:16]3([CH3:21])[C:18]([CH3:19])([CH3:20])[C@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:49])([F:50])[F:51])=[N:26][NH:27][CH:28]=1
Reactant: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c(=O)n1Cc1c[nH]nc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.3 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of (4S,7R)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (210 mg, 0.35 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 3.5 h. Triethylsilane (56 μL, 0.35 mmol) was added and the solution was stirred for 5 min, and then evaporated and held under high vacuum overnight. The residue was taken up in dichloromethane and water and the pH was adjusted to ˜7 by adding saturated sodium bicarbonate solution. The layers were separated and the organic layer was dried (magnesium sulfate), filtered, evaporated, and chromatographed, eluting with 1-3% methanol/ethyl acetate to give (4S,7R)-1,7,8,8-Tetramethyl-2-(3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (86 mg, 69%). ES(+)-MS (M+H) 355.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH3:30][NH:31][CH3:32].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:30][N:31]([CH3:32])[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Reactant: CNC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)NC2C(C)(C)[C@@H]3CC[C@@]2(C)C3)cc1S(=O)(=O)N1CCOCC1
Temperature: 100 °C
Yield: 49 %

Procedure:
4-Bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2.4.AaBa, 0.400 g, 0.824 mmol), dimethylamine (Cd, 2 mL 2M in THF), and 3 mL N,N-dimethylformamide were mixed. Tris(dibenzylideneacetone)dipalladium(0) (0.08 g, 0.08 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.08 mmol), and potassium tert-butoxide (0.9 g, 8 mmol) were then added. The reaction was heated to at 100° C. for 24 hours. After aqueous workup and acidic extraction, the organic layer was evaporated to yield a yellow solid. The product was then purified by SiO2 chromatography (5-20% ethyl acetate/hexane) to yield 4-(dimethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2E) as an off-white solid (180 mg, 49% yield). MS analysis (m+1)=450.6.
Reaction SMILES: [F:1][C@@H:2]([CH3:27])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23]COC)[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].Cl.O1CCOCC1>CO>[F:1][C@@H:2]([CH3:27])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6]
Reactant: COCOc1cc2c(cc1N(C[C@H](C)F)S(=O)(=O)c1nc(C)cs1)CCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.1 %

Procedure:
630 mg of N-[(2S)-2-fluoropropyl]-N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide was dissolved in 3.50 mL of methanol, and 1.50 mL of a 4 M hydrogen chloride/dioxane solution was added thereto, followed by stirring at room temperature for 6 hours. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain 586 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: S1(=O)C=CC=N1.C(N1C(=O)C=CS1)CCCCCCC.[Cl:21][C:22]1[S:26][N:25]([CH3:27])[C:24](=[O:28])[CH:23]=1.CN1SC=CC1=O.CN1SC([Cl:43])=CC1=O.CN1C(=O)C=CS1>>[Cl:43][C:23]1[C:24](=[O:28])[N:25]([CH3:27])[S:26][C:22]=1[Cl:21]
Reactant: Cn1sc(Cl)cc1=O
Agent: CCCCCCCCn1sccc1=O
Agent: Cn1sccc1=O
Agent: O=S1C=CC=N1
Product: Cn1sc(Cl)c(Cl)c1=O

Procedure:
A number of isothiazolone compounds useful as component (B) in the present invention are available commercially from, for example, the Rohm & Haas Company, Philadelphia, Pa. under various trade names. For example, 2-n-octyl-3-isothiazolone is available under the general trade name Skane M-8. The corresponding 4,5-dichloro-n-octyl-derivative is available under the trade designation Kathon 287. The product 5-chloro-2-methyl-3-isothiazolone is available under the general trade designation Kathon 886. Also available commercially from Rohm & Haas is a mixture of 5-chloro-2-methyl-3-isothiazolone and 2-methyl-3-isothiazolone.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]=[C:8]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)[C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)[C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC=C(c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NCCC[C@@H](c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 9.8 %

Procedure:
To a solution of (S)-tert-butyl 3-(4-acetamido-1-(6-fluoro-3′-methylbiphenyl-3-yl)but-1-enyl)piperidine-1-carboxylate (110 mg, 0.85 mmol) in anhydrous MeOH (3 mL) was added anhydrous Pd(OH)2 (20 mg). The reaction mixture was stirred overnight under a hydrogen atmosphere (monitored by LC-MS) and filtered through a plug of silica. The filtrate was concentrated in vacuo to afford a mixture with two isomers. Purification by preparative HPLC gave (S)-tert-butyl 3-((R)-4-acetamido-1-(6-fluoro-3′-methylbiphenyl-3-yl)butyl)piperidine-1-carboxylate (40 mg, 36% yield). 1H NMR (400 MHz, MeOH):7.31-7.37 (m, 2 H), 7.20 (d, 2 H), 7.13 (d, 2 H), 6.97-7.01 (m, 3 H), 3.95-4.18 (m, 1 H), 3.80-3.92 (m, 1 H), 3.03 (m, 2 H), 2.61-2.72 (m, 1 H), 2.42-2.52 (m, 1 H), 2.38 (d, 3 H), 1.90 (s, 3 H), 1.78 (m, 1 H), 1.42-1.65 (m, 4 H), 1.43 (s, 9 H), 1.15-1.31 (m, 3 H), 1.03 (m, 1 H). MS (E/Z): 483 (M+H+)
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:10][C:11](=O)[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C>CCOCC>[CH2:14]([O:13][CH:12]([CH:11]=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)OCc1ccccc1

Procedure:
To a suspension of sodium hydride (3.3 g, 60% in paraffin oil, 82.5 mmol) in dry ether (100 mL) and dry ethyl formate (5.55 g, 75 mmol) was added ethyl(benzyloxy)acetate (14.57 g, 75 mmol) dropwise with stirring. The resulting mixture solution was then refluxed for 2 h and concentrated to give crude ethyl 2-(benzyloxy)-3-oxopropanoate which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:10][CH:12]1[CH2:13][O:14]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: ClCC1CO1
Product: Clc1ccc(OCC2CO2)cc1Cl

Procedure:
The title compound was prepared from 3,4-dichloro-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1.ClCCl>[Pd].C(O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1nnc2cnccn12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: FC(F)(F)c1nnc2n1CCNC2

Procedure:
3-(Trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine (540 mg, 2.87 mmol, from Step A) was hydrogenated under atmospheric hydrogen with 10% Pd/C (200 mg) as a catalyst in ethanol (10 mL) at ambient temperature for 18 h. Filtration through Celite followed by concentration gave a dark colored oil. Dichloromethane was added to the above oil and the insoluble black precipitate was filtered off. Concentration of the filtrate gave the title compound as an oil.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.[Si:21]([O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[O:14]=[C:1]([N:32]1[CH2:33][CH2:34][CH:29]([O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:30][CH2:31]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve lauric acid (0.77 g) in methylene chloride (50 mL) and cool to 0° C. Add oxalyl chloride (0.37 mL) and dimethylformamide (3 drops). Allow to warm to room temperature and stir for 1 hour. Add this solution to a mixture off 4-(O-tert-butyldimethylsilyloxy)piperidine and triethylamine (1 mL) in methylene chloride (25 mL). Heat at reflux overnight. Dilute with methylene chloride (50 mL) and separate the organic phase. Wash twice with 10% sodium hydroxide, once with water, and once with brine. Dry (Na2SO4) and evaporate the solvent in vacuo. Dissolve the residue in hexane (100 mL) and wash twice with 10% hydrochloric acid (50 mL), once with saturated sodium hydrogen carbonate and once with brine. Dry (Na2SO4) and evaporate the solvent in vacuo to give 1-oxododecyl-4-(O-tert-butyldimethylsilyloxy)piperidine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)\[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(C(F)(F)F)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-4-trifluoromethyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3) δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.37 (d, 1H), 6.67 (dd, 2H), 7.08 (t, 1H), 7.35-7.40 (m, 7H), 7.49 (d, 2H), 7.71 (d, 2H), 7.95 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OC)=[C:18](I)[CH:17]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:2]([NH:9][S:10](/[CH:13]=[CH:14]/[C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)(=[O:12])=[O:11])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Reactant: COc1ccc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Temperature: 140 °C
Yield: 45.9 %

Procedure:
Ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (8.5 g, 38.8 mmol) and 4-chloroiodoanisole (7.87 g, 33.0 mmol) was dissolved in N,N-dimethylformamide (65 ml). Palladium acetate (139 mg, 0.62 mmol) and triphenylphosphine (357 mg, 1.36 mmol) was added to the reaction followed by triethylamine (12.5 ml, 89.3 mmol). The reaction was flushed with nitrogen and heated at 140° C. for 16 hours. The reaction was cooled to room temperature and quenched with 1N HCl (250 ml). The aqueous solution was extracted with ethyl acetate (3×200 ml). The organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was dissolved in dichloromethane and purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-(4-chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.0 g, 46% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[CH:21])[CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>O1CCCC1.[C].[Pd]>[CH2:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc2ccnc(Cc3ccc(CCCC)cc3)c2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCc1ccc(Cc2nccc3ccc(CC)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
Palladium-carbon (10%, 5.0 mg) was added to a solution of the compound of Example B158 (2.0 mg) in tetrahydrofuran (2.0 ml), and the mixture was stirred at room temperature under nitrogen atmosphere (1 atm) for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.21 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[C:8]2[N:7]=1)=[O:5])C.CO.[OH-].[Na+].Cl>O1CCCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[N:12][N:9]3[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a mixture of 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester (18.00 g), 120 ml of methanol, and 120 ml of tetrahydrofuran, 60 ml of a 2N aqueous sodium hydroxide solution was added, and stirred at room temperature over 2 hours. To the reactant, 60 ml of 2N hydrochloride was added dropwise, and the precipitated crystal was filtered to yield 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid (14.02 g, 86%) as a yellow crystal.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[S:32]1(=[O:38])(=[O:37])[CH2:36][CH2:35][CH2:34][NH:33]1>>[O:37]=[S:32]1(=[O:38])[CH2:36][CH2:35][CH2:34][N:33]1[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCN(C)C3=O)CC2)nc1C
Yield: 41.2 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (57 mg) described in Preparation Example 259 and isothiazolidine 1,1-dioxide (24 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (28 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32]>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]3[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=3)=[CH:18][C:17]=2[O:23][CH2:27][C:28]2[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(O)cc2O)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(OCc3cccc(C#N)c3)cc2OCc2cccc(C#N)c2)CC1
Yield: 53.4 %

Procedure:
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.85 g, 2.42 mmol) and 3-bromomethyl-benzonitrile (1.89 g, 9.68 mmol) and other reagents as described in Example 75(a) were used to afford 0.75 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 1.75 (4H, m), 3.15 (1H, m), 3.65 (2H, m), 4.55 (1H, m), 5.25 (4H, s), 6.72 (2H, m), 6.9 (1H, s), 7.7 (6H, m), 7.85 (4H, m), 7.94 (1H, s), 8.04 (1H, s).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]=[C:16]=[O:17].P([O-])(OCCCC)(OCCCC)=O>C1(C)C=CC=CC=1>[CH3:14][NH:15][C:16]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:17]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CN=C=O
Agent: CCCCOP(=O)([O-])OCCCC
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
0.5 mole of diphenylamine was taken together with 0.53 mole of methyl isocyanate and 0,6 g of di-n-butyl phosphate in 150 ml of toluene. The mixture was heated at 100° C. for 10 hours, with stirring. After cooling to room temperature, the N-methyl-N',N'-diphenylurea formed was filtered off wtih suction. The filtrate was made up to 150 ml with toluene, and 0.5 mole of diphenylamine and 0.53 mole of methyl isocyanate were added. The mixture was heated again at 100° C. for 10 hours, with stirring, and then cooled to room temperature. Recycling of the filtrate and subsequent addition of in each case 0.5 mole of diphenylamine and 0.53 mole of methyl isocyanate was repeated a further three times. After these five reactions with only a single addition of catalyst, 2.4 moles of N-methyl-N',N'-diphenylurea were obtained. The urea was washed with in each case 100 ml of cold toluene after each reaction. Melting point: 170°/yield: 96% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]=1[NH2:10])([O-:3])=[O:2].[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[Br:17][C:6]1[C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]([NH2:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(-c2cccnc2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
To a 0° C. cooled stirred solution of 5-nitro-2,3′-bipyridin-6-amine (4.8 g, 22.2 mmol) in DMF (50 mL), N-bromosuccinimide (4.75 g, 26.7 mmol) was added in portions. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure. The crude residue was solved with ethyl acetate and washed with saturated potassium carbonate aqueous solution. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (6.6 g, 100%) as a solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[S:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].F[B-](F)(F)F.[CH3:22][O+](C)C.O>C(Cl)Cl>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([S:16][CH3:22])=[N:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1CCCC(=S)N2
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CSC1=Nc2cccc(OC(C)=O)c2CCC1
Yield: 91.8 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-thione (235 mg, 1.0 mmol) in 25 mL of CH2Cl2 was added at 0° 295 mg (2.0 mmol) of trimethyloxonium tetrafluoroborate. After stirring at room temperature for about 30 min. water was added and the CH2Cl2 layer was separated. Drying over Na2SO4 and removal of the solvent gave 229 mg of 4,5-dihydro-6-acetoxy-2-methylthio-3H-benzazepine.