Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])[CH2:36][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2ccccc2SC)CC1
Yield: 64.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH2:5][S:4]1(=[O:12])=[O:11])[CH3:2].[NH3:13]>CO>[CH2:1]([NH:3][S:4]([CH2:5][C:6](=[O:10])[CH:7]=[C:8]([NH2:13])[CH3:9])(=[O:12])=[O:11])[CH3:2]
Reactant: CCN1C(C)=CC(=O)CS1(=O)=O
Reactant: N
Solvent: CO
Product: CCNS(=O)(=O)CC(=O)C=C(C)N

Procedure:
A suspension of 13 g of 2-ethyl-3-methyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 130 ml of methanol was reacted with ammonia in accordance with the procedure described in Example 1. The dark yellow solution obtained was concentrated to dryness under reduced pressure and the crystalline residue was recrystallized from ethanol. There were obtained 12.2 g of N-ethyl-4-amino-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 112°-114°.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[Br:11][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:8]([O-:10])=[O:9])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ncccc1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 115.1 %

Procedure:
3-Hydroxy-2-nitropyridine (100 g, 0.714 mole) was dissolved in DMF (1 L), the solution was cooled to 0° C., and N-bromosuccinimide (165 g, 0.927 mole) was added portionwise over 5 hr. The mixture was then stirred at RT for 15 hr and concentrated in vacuo. The residue was taken up in Et2O (500 mL) and the mixture was stirred for 30 min. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford the title compound (180 g): MS (ES) m/e 219.0 (M+H)+. This material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH2:13]1)([CH3:10])[CH3:9].C=O.[C:49]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([CH3:49])[C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:39])=[O:40])[CH2:13]1)([CH3:10])[CH3:9]
Reactant: [BH3-]C#N
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a solution of Example 48 (25 mg, 44 μmol) in methanol (1.5 mL) was added a solution of 37% aqueous formaldehyde (14 mL, 178 μmol). The resulting mixture was stirred for 2 h, then sodium cyanoborohydride (5 mg, 67 μmol) was added. After stirring for 3 h, the mixture was treated with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue was purified by preparative TLC (90:10:1 CHCl3/MeOH/NH4OH). After concentrating the material in vacuo, the resulting oil was dissolved in CH3CN/H2O/TFA and lyophilized to give the title compound (10 mg, 33%) as a white solid and mixture of diastereomers: ESI MS m/z 577 [C29H35F3N4O3S+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Absolute ethanol was degassed by applying a vacuum while simultaneously bubbling nitrogen through it. A solution of 188 mg (0.5201 mmol) ethyl 6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]nicotinoate in 2 ml absolute ethanol was treated with 800 ml of a 1.65M (1.32 mmol) solution of potassium hydroxide in ethanol and water. The mixture was stirred at room temperature for 18 hours and then the solvent removed in vacuo. The residue was dissolved in water and extracted with 50 ml ether, which was discarded. The aqueous layer was then acidified with glacial acetic acid and extracted with 4×50 ml ether. The ether extracts were combined, washed with water, saturated NaCl solution and then dried (MgSO4). Solvent was removed in vacuo to give the title compound as a pale yellow solid. PMR (CDCl3): δ1.31 (12H, s), 1.71(4H, s), 7.34 (1H, d, J~7.8 Hz), 7.40 (1H, d, J~7.8 Hz), 7.62 (1H, s), 8.39 (1H, dd, J~7.3 Hz, 2.1 Hz), 9.33 (1H, d, J~2.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[NH2:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.[H-].[Na+].CS(C)=O>O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:12])[CH:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Cc1c[nH]c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Temperature: 160 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
A mixture of 5-hydroxy-3-methylindole (4.7 g), 2-amino-4-chloropyridine (4.1 g), sodium hydride (1.3 g), and dimethyl sulfoxide (40 ml) was stirred at 160° C. for 15 hours. Water was added thereto; extraction was performed with ethyl acetate; and purification was performed by silica gel column chromatography (ethyl acetate, sequentially, ethyl acetate:methanol=20:1). The solvent was distilled off to yield the title compound as a brown solid (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:19]O>S(Cl)(Cl)=O>[CH3:19][O:10][C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:12][C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
The solution of 2-(4-Chloro-phenyl)-3-pyridin-4-yl-acrylic acid 3.5 g in thionyl chloride 25 mL was heated to 70° C. for five hours. The reaction was cooled to 0° C., then was added methanol 50 mL. After warm to room temperature over one hour, all the solvent removed under reduced pressure. Work up using ethyl acetate and sodium bicarbonate give the light yellow solid. MS (ES+): 274 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:12]3[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](OC)=[O:30])[CH:21]=[CH:22][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:12]3[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:38][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:30])[CH:21]=[CH:22][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCCn1c(-c2ccc(C#N)cc2)nc2ccc(OCCCCCC(=O)OC)cc21
Reactant: COCCCN
Product: COCCCNC(=O)CCCCCOc1ccc2nc(-c3ccc(C#N)cc3)n(CCCOC)c2c1

Procedure:
2-(4-Cyano-phenyl)-6-[(5-(methoxycarbonyl)pentyl)oxy]-1-(3-methoxypropyl)-benzimidazole is reacted with 3-methoxypropylamine according to general operating instructions 7. 2-(4-Cyano-phenyl)-1-(3-methoxy-propyl)-6-[(5-((3-methoxy-propyl)aminocarbonyl)-pentyl)oxy]-benzimidazole is obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH2:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=2)[CH2:14][CH2:15]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 140 °C

Procedure:
To a solution of 4-chloropicolinic acid (0.8 gm, 0.0051 mol) in DMSO (4 mL) was added benzyl 4-(aminomethyl)piperidine-1-carboxylate (2.5 gm, 0.010 mol) and the mixture warmed to 140° C. for 18 h. The reaction was cooled and diluted with 10% sodium bicarbonate (100 mL) and washed with ether (2×25 mL). The aqueous extract was washed with dichloromethane (3×50 mL), and the dichloromethane extract dried over sodium sulfate and concentrated to an oil (2.4 gm). The oil was chromatographed on silica using dichloromethane/methanol/acetic acid/water—90/10/1/1 to give 4-[(1-benzyloxycarbonyl-piperidin-4-ylmethyl)-amino]-pyridine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[NH:8][CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[N:8]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1nc(Cl)nc2c1NCC1COCCN21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc(Cl)nc2c1N(Cc1ccc(S(C)(=O)=O)cc1)CC1COCCN21
Temperature: 25 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
To a round-bottom flask was added 2-chloro-4-methyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x20, 264 mg, 1.097 mmol) in DMSO (8.6 mL). Sodium tert-butoxide (126 mg, 1.316 mmol) was then added, followed by 1-(bromomethyl)-4-(methylsulfonyl)benzene (287 mg, 1.152 mmol). The reaction mixture was stirred for 2 days at room temperature. The mixture was subsequently filtered and the filtrate was purified by preparatory HPLC using a gradient of 5-60% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (94 mg, 21%). ESI-MS m/z [M+H]+ calc'd for C18H21ClN4O3S, 409.1. found 409.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O[N:51]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[N:52]1>ClCCl>[N:51]1([O:27][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:18]=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:12][CH:13]=4)[O:21][N:20]=3)=[CH:30][CH:29]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[N:52]1
Reactant: On1nnc2ccccc21
Reactant: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a mixture of 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid (2.0 g) and triethylamine (1.1 g) in dichloromethane (60 ml) was added 3-(3-dimethylaminopropyl)-1-ethylcarbodimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (0.8 g). The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was triturated with isopropyl ether. The precipitates were collected by filtration, washed with isopropyl ether and dried to give 4-[5-(4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid benzotriazol-1-yl ester (2.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[BH4-].[Na+]>[Ni](Cl)Cl.CO>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1
Reactant: Cc1ccc2c(Oc3ccccc3)cccc2n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CCc2c(cccc2Oc2ccccc2)N1
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A glass, screw-cap vial equipped with a magnetic stir bar was charged with 2-methyl-5-phenoxyquinoline (0.05 g, 0.213 mmol), methanol (1 mL), and nickel(II) chloride (4.96 mg, 0.038 mmol). Sodium borohydride (0.032 g, 0.850 mmol) was added portion-wise over 30 sec at rt. The reaction mixture turned dark purple (almost black), and an exotherm was observed. After 10 min, the reaction mixture was concentrated under a stream of nitrogen. The residue was then treated with 1 N aqueous sodium hydroxide solution (1 mL) and dichloromethane (2-3 mL). The resulting emulsion was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated to afford rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.051 g) as a pale yellow syrup. The crude product was carried forward without further purification. MS (ESI, pos. ion) m/z 240 [M+1].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:17][CH2:18][C:19]1[N:2]=[C:1]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[S:3][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A solution of tert-butyl 4-thiocarbamoylpiperazine-1-carboxylate (650 mg, 2.65 mmol) and 1,3-dichloroacetone (672 mg, 5.3 mmol) in 1,2-dichloroethane was treated with sodium bicarbonate (22 mg, 2.65 mmol). The reaction mixture was stirred at 70° C. for 18 hours and then diluted with chloroform. The dilution was washed with water and brine, dried over sodium sulfate and concentrated. Product was purified from the residue on a silica gel column, using ethyl acetate/hexanes (3/7) as eluent, to provide tert-butyl 4-(4-chloromethylthiazol-2-yl)piperazine-1-carboxylate (830 mg, 100% yield). HNMR (dmso-d6): 6.92 (1H, s), 4.57 (2H, s), 3.40 (8H, m), 1.42 (9H, s).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.CN(C)C=O>[CH2:27]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)[CH:26]=[CH2:25]
Reactant: CC(C)Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(OC(C)C)cc2)cc1
Reaction time: 0.4 h
Yield: 69 %

Procedure:
To a mixture of 1.23 g of 4-(4-isopropoxyphenoxy)phenol, 1.4 g of potassium carbonate and 10 ml of N,N-dimethylformamide, 0.65 ml of allyl bromide was added dropwise at room temperature with stirring. After 24 minutes, the reaction solution was poured into water, and acidified by adding 10% hydrochloric acid. The solution was extracted with 50 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.98 g of 4-(4-isopropoxyphenoxy)phenyl allyl ether (yield, 69%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])[CH3:4].C[O-].[Na+].CO[CH:21](OC)[CH2:22][NH2:23]>ClCCl.CO>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][CH:7]([C:8]1[NH:9][CH:21]=[CH:22][N:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(CN)OC
Reactant: CN(C)CCC(C#N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCC(c1ccccc1)c1ncc[nH]1
Reaction time: 8 h

Procedure:
Hydrogen chloride was passed into a solution of α-(N,N-dimethylaminoethyl)benzeneacetonitrile (18.8 g) and dry methanol (6.3 ml) in dry dichloromethane (200 ml) for 8 h at 5°-15°. Solvent was removed to give a colourless oil which was taken up in dry methanol (150 ml) and treated with 2 M sodium methoxide solution (65 ml). Aminoacetaldehyde dimethyl acetal (10.6 g) was added and the mixture left to stand overnight. Methanol was then removed and the residue dissolved in 2 N hydrochloric acid (200 ml) and heated at 80° for 30 min. The mixture was cooled, adjusted to pH 9.5 with potassium carbonate and extracted with ethyl acetate (3×200 ml). The extracts were washed with brine (200 ml), concentrated and dried in vacuo to give the title compound, m.p. 135°-136° (16.3 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([N:18]1[CH2:23][CH2:22][CH:21](Br)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C)C=O>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(SCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To benzyl mercaptan (17 ml, 152 mmol)in dimethylformamide at 0° C. under nitrogen was added sodium hydride (80% dispersion in mineral oil, 4.38 g, 152 mmol) the solution was stirred at room temperature for 15 minutes then cooled to 0° C. prior to adding N-Boc-(4-bromo)piperidine (10.8 g, 38 mmol). The mixture was stirred for 14 h at room temperature then poured into water (50 ml), extracted with diethyl ether (2×100 ml), the organic layers combined, dried (MgSO4), filtered, evaporated, and the crude product purified by flash column chromatography using 10% ethyl acetate in hexane to yield the product as a pale yellow oil (2.86 g); δH (CDCl3) 1.46 (9H, s, t-Bu), 1.51 and 1.87 (4H, m, 3,5-piperidinyl CH2), 2.85 and 3.91 (4H, m, 2,6-piperidinyl CH2), 2.69 (1H, m, 4-piperidinyl H), 3.77 (2H, s, SCH2), and 7.24-7.32 (5H, m, ArH).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[Se](=O)=[O:23].OO.O>C(O)C>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[O:23])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(CSc2nc3cnccc3[nH]2)c1
Reactant: O=[Se]=O
Agent: OO
Solvent: CCO
Solvent: O
Product: O=S(Cc1cccc(C(F)(F)F)c1)c1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[[3-(Trifluoromethyl)phenyl]methyl]thio]-1H-imidazo[4,5-c]pyridine (0.91 g, 0.0029 mol) was dissolved in 10 mL of ethanol. An oxidizing solution was prepared by dissolving 0.32 g (0.0029 mol) of selenium dioxide in 17 mL of ethanol by heating and adding 0.33 g (0.0029 mol) of 30% hydrogen peroxide and 0.25 mL of water. The oxidizing solution was added dropwise to the sulfide solution and the reaction mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture which was then extracted with chloroform (3×25 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue amounted to 0.65 g. Purification by HPLC gave a product which on recrystallization from ethanol had a m.p. 194°-197° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17].CN(C=O)C.S([O-])(O)(=O)=O.[Na+].O>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](/[N:19]=[CH:3]/[N:4]([CH3:6])[CH3:5])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: COC(OC)N(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (14.6 mL, 104 mmol) was added to a solution of 2-bromobenzene-1-sulfonamide (20.4 g, 86.4 mmol) in DMF (56 mL, 720 mmol) and the resulting solution was stirred at room temperature for 90 minutes. A solution of sodium hydrogen sulfate (1.7 g, 14 mmol) in water (170 mL, 9.4 mol) was cooled at 0° C. and then added to the reaction mixture. The precipitate was filtered, washed with water, and dried to yield the title compound (24.3 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>CN(C=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:15][NH2:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CN
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CN)c([N+](=O)[O-])c1

Procedure:
(4-Methanesulfonyl-2-nitro-phenyl)methyl-amine (182 mg) was prepared by following General Procedure A starting from 1-fluoro-4-methanesulfonyl-2-nitro-benzene (219 mg) and methylamine (2 M in THF, 1.0 ml) in DMF (5 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[O:3]1.C[Al](C)C.[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30](=O)[O:31]C)[N:23]=1.C(O)(=O)C>C(Cl)Cl.Cl>[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30]([NH:14][S:11]([C:10]2[C:4]3[O:3][C:2]([CH3:15])([CH3:1])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[O:31])[N:23]=1
Reactant: CC1(C)Oc2cccc(S(N)(=O)=O)c2O1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)O3)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.2 %

Procedure:
To a solution of 1.0 g 2,2-dimethyl-1,3-benzodioxole-4-sulfonamide, prepared in Example 1, in 50 ml methylene chloride a room temperature under nitrogen was added 2.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at room temperature, 0.7 g of methyl [4-methoxy-6-methyl-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 5, was added and the reaction mixture was heated at reflux 72 hours. The reaction mixture was cooled to room temperature and 75 ml ice, 3 ml glacial acetic acid, and 10 drops of hydrochloric acid were sequentially added. The organic phase was separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from a mixture of ether, methylene chloride, and hexane gave 0.1 g of white solid, m.p. 160°-168° C. The infrared spectrum showed a carbonyl absorption at 1705 cm-1 indicative of the title compound.