Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]([O:17][C:18]([N:20]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])([CH3:16])[CH3:15].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH3:26][C:23]([O:22][C:21]([N:20]([C:28]1[S:29][C:30]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:31][N:32]=1)[C:18](=[O:19])[O:17][C:14]([CH3:13])([CH3:15])[CH3:16])=[O:27])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M in hexanes, 30 mL, 0.48 mol), was added to diisopropylamine (6.7 mL, 0.48 mol) in THF (480 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins then cooled to −78° C. tert-Butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(1,3-thiazol-2-yl)carbamate (12 g, 0.05 mol) was added and solution stirred for 30 minutes. Tributyltin chloride (16.3 mL) was added and solution stirred for 30 minutes before allowing to warm to RT. The reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL) and the product extracted with ethyl acetate. The organics were dried over sodium sulphate, concentrated in vacuo and chromatographed on silica, eluting with 5-15% ethyl acetate in hexane, to give the desired material as a clear oil (9 g).
Reaction SMILES: [C:1]([C:13]1[CH:38]=[CH:37][C:16]([CH2:17][N:18]([C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCOC(C)=O>[CH2:34]([O:33][C:31](=[O:32])[C:30]([N:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:38][CH:37]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1)=[O:36])[CH3:35]
Reactant: CCCCCCCCCCC#Cc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 95 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) but using ethyl {(4-dodec-1-ynylbenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate in EtOAc gave the title compound as a colorless oil (95%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (d, 0.7H, J=8.2 Hz), 7.60 (d, 1.3H, J=8.1 Hz), 7.39 (d, 0.7H, J=8.2 Hz), 7.33 (d, 1.3H, J=8.1 Hz), 7.15 (m, 4H), 4.54 (s, 1.3H), 4.48 (s, 0.7H), 4.41-4.30 (m, 4H), 2.61 (m, 2H), 1.61 (m, 2H), 1.38-1.27 (m, 2H), 0.89 (t, 3H, J=6.7 Hz). HPLC (Condition A), Rt: 7.24 min (HPLC purity: 99.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)(=[O:24])=[O:23])([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:29][CH:28]=1)(=[O:23])=[O:24])([O-:15])=[O:14]
Reactant: O=C1CCc2cccc(O)c2C1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccc(O)c3C2)cc1)Cc1ccccn1
Yield: 105.3 %

Procedure:
Using General Procedure B: Reaction of 8-hydroxy-2-tetralone (110 mg, 0.68 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (280 mg, 0.68 mmol) and NaBH(OAc)3 (287 mg, 1.4 mmol) in a mixture of CH2Cl2 (10 mL) and acetic acid (0.2 mL) for 18 hours gave, after work-up, ˜400 mg (quant. yield) of the title compound as a yellow foam.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[ClH:17].[C:18]([C:21]1[C:30]2[O:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:27]([CH3:37])[C:26](=[O:38])[C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>CO.C(OCC)C.O1CCOCC1>[ClH:17].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:1][CH2:19][C:18]([C:21]2[C:30]3[O:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:27]([CH3:37])[C:26](=[O:38])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:13][CH2:12]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=O
Reactant: CC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CCC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Reaction time: 12 h

Procedure:
A solution of 10 ml of 37% formaldehyde in 15 ml of methanol was dropped, over a period of 3 minutes at 0° C., into a solution of 5.75 g of 1-(2-methoxyphenyl)piperazine in 10 ml of methanol. After 12 hours at 0° C., the mixture was stripped in vacuo and redissolved in 15 ml of methanol. 20 ml of 3.6N hydrogen chloride in diethyl ether was added at 0° C. After stripping in vacuo, the residue was suspended in 15 ml of 1,4-dioxane. A solution of 8.3 g of Intermediate V in 100 ml of 1,4-dioxane was added under stirring at 20°-25° C. After stirring for 8 hours at reflux the reaction mixture was cooled to 30°-40° C. 50 ml of methanol was added and the mixture was refluxed for a further 2 hours. After cooling to 20°-25° C., the resultant solution was diluted with 300 ml of diethyl ether. Stirring was continued for a further 3 hours at the same temperature. The title compound was collected by suction filtration and recrystallization from ethanol. Yield 4 g, m.p. 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=O)=[C:4]([CH3:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=2)=[N:35]\[OH:36])=[C:4]([CH3:33])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 2-(5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-2-oxopyridin-1(2H)-yl)acetamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid, MS (ESI−): m/z=500.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])#[N:35].O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[C:34]#[N:35])(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccccc3C#N)c3cnc4ccc(Cl)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 50 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (6 ml) was added 2-cyanobenzene-1-sulfonyl chloride (42 mg, 0.21 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 24 mg (33%); 1H NMR (CDCl3, 300 MHz): δ 9.698 (s, 1H), 8.496-8.525 (d, 1H, 8.7 Hz), 8.093-8.123 (d, 1H, J=9 Hz), 7.823-7.920 (m, 3H), 7.71-7.739(d, 2H, J=8.7 Hz), 7.525-7.563 (dd, 1H, J=9.3, 2.1 Hz), 7.46-7.488(d, 2H, J=8.4 Hz), 6.863-6.870 (d, 1H, 2.1 Hz), 1.798 (s, 6H); MS: m/z 528 (M+).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5]2.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>Cl>[CH:9]1([NH:15][C@@H:2]2[CH2:3][N:4]([CH2:7][CH3:8])[CH2:5][C@H:6]2[OH:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCCC1
Reactant: CCN1CC2OC2C1
Agent: Cl
Product: CCN1C[C@@H](O)[C@H](NC2CCCCC2)C1
Temperature: 130 °C
Yield: 70.6 %

Procedure:
A mixture of 11.3 g (0.10 mole) of 3,4-epoxy-1-ethyl-pyrrolidine, 11.9 g (0.12 mol) of cyclohexylamine and one drop of conc. hydrochloric acid was heated at 130° C. under a nitrogen atmosphere for 18 hr. The mixture was cooled and diluted with 200 ml of petroleum ether. The precipitate was collected and recrystallized from petroleum-ether-cyclohexane to give 15 g (71%) of a white powder; m.p. 68°-71° C.
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:37][C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40](Cl)[N:39]=2)=[C:29]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:37][C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40]([NH:1][C:2]3[C:21]([O:22][CH3:23])=[CH:20][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[O:13])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:39]=2)=[C:29]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])[CH:30]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(Cl)cc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCOCC1)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.034 g, 24%). MP: 100-115° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.21 (s, 1H), 8.45 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.93 (s, 1H), 7.87-7.85 (m, 1H), 7.53-7.47 (m, 2H), 6.65 (s, 1H), 3.88 (s, 3H), 3.75-3.62 (m, 9H), 3.30 (s, 2H), 2.90-2.85 (m, 2H), 2.77 (s, 6H), 2.75-2.63 (m, 6H). MS: 664.19 (MH)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[F:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:43]([Si:48]1([CH3:62])[CH2:53][CH2:52][CH:51]([CH:54]2[CH2:59][CH2:58][CH:57]([CH:60]=O)[CH2:56][CH2:55]2)[CH2:50][CH2:49]1)[CH2:44][CH2:45][CH2:46][CH3:47].O>C1COCC1.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:60][CH:57]2[CH2:56][CH2:55][CH:54]([CH:51]3[CH2:52][CH2:53][Si:48]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH3:62])[CH2:49][CH2:50]3)[CH2:59][CH2:58]2)[CH:32]=[CH:33][C:34]=1[O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reactant: CCCCC[Si]1(C)CCC(C2CCC(C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC[Si]1(C)CCC(C2CCC(C=Cc3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g of potassium t-butoxide was added to a mixture of 60 g of 3-fluoro-4-(t-butyldimethylsiloxy)benzyltriphenylphosphonium bromide and 200 ml of THF to prepare an orange-colored ylide solution. A solution, in 50 ml of THF, of 33 g of 4-(4-n-pentyl-4-methyl-4-silacyclohexyl)cyclohexane carbaldehyde was added to the ylide solution. The reaction mixture was agitated at room temperature for 2 hours, followed by pouring into iced water and extraction with ethyl acetate. After ordinary washing, drying and concentration, n-hexane was added to the resultant residue. The resulting crystals of triphenylphosphine oxide was removed by filtration and the filtrate was concentrated. The resultant reside was purified through silica gel chromatography to obtain 4-(4-(2-(3-fluoro-4-(t-butyldimethylsiloxy)phenyl)ethenyl)cyclohexyl)-1-pentyl-1-methyl-1-silacyclohexane. This product was dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of a catalyst composed of 200 mg of platinum oxide at a pressure of 0.1 MPa. After theoretical consumption of hydrogen, the catalyst was removed by filtration and the resultant filtrate was concentrated. 100 ml of a THF solution of 1 mol/liter of tetrabutylammonium fluoride was added to the concentrate, followed by agitation at room temperature for 3 hours. The reaction mixture was poured into 10% hydrochloric acid. After ordinary washing, drying and concentration, the resultant residue was purified through silica gel chromatography. The purified product was reacted with 24 g of sodium hydride in 1,3-dimethyl-2-imidazolidinone to obtain a sodium salt. After ordinary washing, drying and concentration, the sodium salt was purified through silica gel chromatography, followed by recrystallization to obtain 15.0 g of the intended trans isomer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[N:11]([O-])=O.[Na+]>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][N:11]=[C:9]2[CH3:10]
Reactant: O=N[O-]
Reactant: CCc1cc(Br)ccc1N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
To a solution of 4-bromo-2-ethylbenzenamine (1.5 g, 7.50 mmol) in AcOH (20 mL) was added NaNO2 (570 mg, 8.14 mmol). After stirring for 2.5 h at room temperature, the resulting mixture was concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% methanol in dichloromethane to afford 5-bromo-3-methyl-1H-indazole as a light red solid (700 mg, 44%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].[CH3:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([N:17]2[CH:18]=[CH:19][C:15]([CH3:14])=[N:16]2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: Cc1cc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(-n2ccc(C)n2)c(C=O)c1
Reaction time: 120 h
Yield: 4.3 %

Procedure:
To a solution of 2-formyl-4-methoxyphenylboronic acid (2.5 g, 13.89 mmol) in CH2Cl2 (30 mL) and DMF (15 mL) are added 3-methyl-1H-pyrazole (0.80 g, 9.72 mmol), Cu(OAc)2 (3.78 g, 20.84 mmol), pyridine (2.27 mL, 27.78 mmol) and molecular sieves (2.5 g) at room temperature. The mixture is stirred at the same temperature for 5 days with loose cap. The mixture is filtered through a short pad of diatomaceous earth and the solids are washed with CH2Cl2. The combined filtrates are concentrated and the remaining residue is diluted with water and ethyl acetate. The layers are separated and the aqueous phase extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered, and concentrated. The remaining residue is purified via flash chromatography (silica gel, 0-15% EtOAc/heptane) to afford 5-methoxy-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (90 mg, 3%).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[NH:3][C:2]1=S.C(Cl)[Cl:12].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:12][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][N:8]=2
Reactant: S=c1[nH]c2nccnc2s1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: Clc1nc2nccnc2s1
Temperature: 40 °C
Yield: 53 %

Procedure:
A mixture of 3H-thiazolo[4,5-b]pyrazine-2-thione (4.36 g, 25.8 mmol) and DCM (60 mL) was sonicated (5 min). The suspension was treated with sulfuryl chloride (99.9 g, 740 mmol, 60 mL) and heated (40° C., 16 h). The reaction mixture was cooled (0° C.) and slowly treated with H2O (250 mL), followed by 4 N NaOH (550 mL). The aqueous mixture was extracted with EtOAc (2×1800 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a solid (2.63 g, 53%). MS (ESI): mass calculated for C5H2ClN3S, 170.9; m/z found, 172.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.84 (d, J=2.5, 1H), 8.75 (d, J=2.5, 1H).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:16](=O)[CH2:17]Br)=[C:13]([CH3:15])[N:14]=2)=[N:5]1)(=O)C.Br.C(N1C=CC(NC2SC(C(=O)CBr)=C(C)N=2)=N1)(=O)C.[C:40]([CH2:42][C:43]([NH2:45])=[S:44])#[N:41].CCOCC>CCO>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][NH:4][N:5]=2)[S:11][C:12]=1[C:16]1[N:45]=[C:43]([CH2:42][C:40]#[N:41])[S:44][CH:17]=1
Reactant: N#CCC(N)=S
Reactant: CC(=O)n1ccc(Nc2nc(C)c(C(=O)CBr)s2)n1
Agent: Br
Solvent: CCO
Solvent: CCOCC
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1csc(CC#N)n1
Temperature: 80 °C
Yield: 62 %

Procedure:
To a solution of 1-{2-[(1-acetyl-1H-pyrazol-3-yl)amino]-4-methyl-1,3-thiazol-5-yl}-2-bromoethanone, (Intermediate 4) (150 mg; 0.35 mmol; 1 eq.) in EtOH (5 ml) is added 2-cyanothioacetamide (35.4 mg; 0.35 mmol; 1 eq.). The resulting mixture is heated 10 min at 60° C., 10 min at 70° C. and 10 min at 80° C. under microwave action. As the reaction is complete, Et2O is added. The resulting precipitate is filtered and washed with Et2O, affording Compound (55) as beige solid (84.1 mg; 62%). 1H NMR (DMSO-d6) δ 2.46 (s, 3H), 4.61 (s, 2H), 6.01 (d, J=2 Hz, 1H), 7.65 (s, 1H), 7.72 (d, J=2 Hz, 1H), 11.26 (br s, 1H). M− (ESI): 301.13; M+ (ESI): 303.14. HPLC (method A), Rt: 1.84 min (purity: 92.7%).
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]S)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][S:10][CH:13]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: COc1ccc(CS)cc1
Product: CCOC(=O)C1=CCCCC1SCc1ccc(OC)cc1
Yield: 95.6 %

Procedure:
In the same manner as in Reference Example 1, ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (1 g) and (4-methoxyphenyl)methanethiol (893 mg) were reacted to give ethyl 6-[(4-methoxybenzyl)-sulfanyl]-1-cyclohexene-1-carboxylate (848 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([CH2:11][C:12]([F:15])([F:14])[F:13])=[O:10])=[CH:4][C:3]=1[OH:16].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][O:16][C:3]2[CH:4]=[C:5]([S:9]([CH2:11][C:12]([F:13])([F:15])[F:14])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:23][CH:24]=1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: O=S(CC(F)(F)F)c1cc(O)c(Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(CC(F)(F)F)c1cc(OCCc2ccc(C(F)(F)F)cc2)c(Cl)cc1Cl
Reaction time: 16 h
Yield: 51.5 %

Procedure:
In 30 ml of tetrahydrofuran were dissolved 0.5 g (1.71 mmol) of 2,4-dichloro-5-(2,2,2-trifluoroethylsulfinyl)phenol, 0.33 g (1.74 mmol) of 2-(4-trifluoromethylphenyl)ethanol and 0.49 g (1.87 mmol) of triphenylphosphine. Thereto was added 0.38 g (1.87 mmol) of diisopropyl azodicarboxylate at room temperature, and the reaction mixture was stirred for 16 hours. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=5:1), to obtain 0.41 g (yield: 52%) of an intended product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][C@@H:26]([CH3:28])[N:25]([CH3:29])[CH2:24][C@@H:23]2[CH3:30])=[CH:18][CH:17]=1.BrC1C=C2C(=CC=1)[C:38](=[O:42])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:42][CH3:38].[CH3:30][CH:23]1[CH2:24][N:25]([CH3:29])[CH:26]([CH3:28])[CH2:27][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([NH2:15])=[CH:21][CH:20]=1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)[C@@H](C)CN1C
Product: CC1CN(c2ccc(N)cc2)C(C)CN1C
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.078 g (49.7% yield) of light brown solid is obtained from 0.10 g (0.30 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 4-(2,4,5-trimethyl-piperazin-1-yl)-phenylamine (0.073 g, 0.33 mmol) after purified by column chromatography over silica gel using 5% MeOH/CHCl3 as eluent: mp 199-200° C.; MS (ESI) m/z 517.1 (M+H)+1
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.O.O.O.O.O.O.O.O.[S-2:21].[Na+].[Na+]>O>[NH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[SH:21]
Reactant: [S-2]
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(F)ccc1S
Temperature: 25 °C
Reaction time: 32 h
Yield: 24.4 %

Procedure:
To a solution of 2-chloro-5-fluoronitrobenzene (1.81 g, 10.31 mmol) dissolved in 30 mL of deionized water at room temperature was added sodium sulfide nonahydrate (9.90 g, 41.24 mmol) in a single portion. The resulting solution was heated to reflux and stirred under nitrogen for 32 hours. The resulting light yellow solution was then cooled to room temperature and was washed with 5×50 mL of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to yield a yellow oil. The crude material was purified by flash chromatography eluting with CH2Cl2:MeOH=10:1 to yield 0.36 g (25%) of the title compound. MS (m/z, ES+): 144.0 (M+1, 100%); IR (KBr): 3430, 3340, 1615, 1573, 1482, 1281, 1248, 1172, 1124, 1044, 975, 840, 792 cm−1; 1H NMR (300 MHz, ppm, DMSO-d6) δ: 6.89 (dt, 1H), 6.50 (dd, 1H), 6.21 (dt, 1H), 5.80 (br s, 2H).