Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C@H:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1.Br[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C@H:9]([N:10]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:8][N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CCCO)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a mixture of tert-butyl (3R*,4S*)-3-(3-hydroxypropyl)-4-{[(4-nitrophenyl)sulfonyl]amino}pyrrolidine-1-carboxylate (0.82 g, 1.91 mmol) and 1-bromo-3-methylbutane (0.30 g, 2.0 mmol) in 8 mL DMF, Cs2CO3 (0.93 g, 2.86 mmol) was added and the mixture was stirred at 3.5 hours at 85° C. The mixture was diluted with H2O, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1→5% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Cl)=[CH:10][CH:9]=1.[N:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CS(C)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:9]=1
Reactant: ClCc1ccc(Oc2ccccn2)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Yield: 99.6 %

Procedure:
This compound was prepared in a manner analogous to that of Example 2, Step D, using 2.2 grams (0.010 mole) of 4-(2-pyridyloxy)phenylmethyl chloride, 1.6 grams (0.010 mole) of ethyl 1-piperazinecarboxylate, and 3.9 grams (0.030 mole) of DMSO, yielding 3.4 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OCC)C.[CH2:6]1[O:9][C@H:7]1[CH3:8].[Si:10]([O:27][C@H:28]([CH3:40])[C@H:29]([NH2:39])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl([O-])(=O)(=O)=O.[Li+]>O.C(Cl)Cl>[Si:10]([O:27][C@H:28]([CH3:40])[C@H:29]([NH:39][CH2:6][C@@H:7]([OH:9])[CH3:8])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:24])([CH3:25])[CH3:26])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Reactant: C[C@H]1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A diethyl ether solution (1 mL) of (S)-(−)-propylene oxide (0.1 mL) and (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine (212 mg) was added to a diethyl ether suspension (1 mL) of lithium perchlorate (750 mg). This reaction solution was stirred in nitrogen atmosphere at room temperature overnight. To this reaction solution, methylene chloride and iced-water were added. The organic layer was separated, and the water was re-extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent; ethyl acetate:heptane=9:1 to 4:1) to give 172 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.Br[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]1([S:7]([CH:10]=[CH:11][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH:34]=[CH:33]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(CCO)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(C=Cc1ccc2[nH]ccc2c1)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 23.3 %

Procedure:
To 0.186 g (1.0 mmol) of 2-(phenylsulfonyl)ethanol, 3 ml of acetonitrile was added, followed by 0.19 g(1.1 mmol) of methanesulfonic anhydride and 0.56 ml (4.0 mmol) of triethylamine, and the mixture was stirred for 5 hours at an internal temperature of 50° C. Subsequently, 0.29 g (1.5 mmol) of 5-bromoindole, 0.011 g (0.05 mmol) of palladium acetate, and 0.067 g (0.22 mmol) of tri(o-tolyl)phosphine were added, and the mixture was then refluxed for 17 hours. After cooled to room temperature, the reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate=70/30) to obtain 0.066 g of 5-[2-(phenylsulfonyl)ethenyl]indole. Yield: 23%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[CH:21]=1.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH:21]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: [Cl-]
Agent: [F-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(-c3cccnc3)ccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
3,4-Dihydro-6-trifluoromethylsulfonyloxy-1(2H) -naphthalenone (1.15 g, 3.91 mmol) was dissolved in 12 ml of N,N-dimethylformamide in an argon atmosphere, and 1.75 g (4.75 mmol) of 3-pyridyltributyltin, 0.50 g (11.7 mmol) of lithium chloride and 0.14 g (0.20 mmol) of bistriphenylphosphinepalladium chloride were added to the solution. The mixture was stirred at 120° C. for 4 hours. The reaction product was cooled to room temperature, and ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 30% ethyl acetate and hexane) to obtain 0.80 g of the above-mentioned compound (yield 92%).
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([OH:31])=O)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:36][CH2:37][CH2:38][NH2:39])(=[O:35])[CH3:34]>>[C:1]([NH:6][C@H:7]([C:29]([NH:39][CH2:38][CH2:37][S:36][C:33](=[O:35])[CH3:34])=[O:31])[CH2:8][S:9][C:10]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(=O)SCCN
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Product: CC(=O)SCCNC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C(C)C
Yield: 67 %

Procedure:
The coupling reaction of 13 (3.93 mmol) with S-acetylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 60%). 14 is collected in the form of a colorless foam with a yield of 67%. Rf (AcOEt/petroleum ether, 6/4): 0.5. [α]D20=+9.3° (c 0.97, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]\[C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:14]=[C:13](/[CH:15]=[CH:16]\[C:17]([F:18])([F:19])[F:20])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C\C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C\C(F)(F)F)cc1F

Procedure:
A solution of (Z)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate (35 mg, 0.12 mmol) in CH2Cl2 (5 mL) and TFA (0.5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a white solid. LC-MS: 2.86 min, 233.2 (M−1).
Reaction SMILES: [N:1]([C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)=[O:5])=[C:2]=[O:3].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]([C:2](=[O:3])[NH:1][C:4](=[O:5])[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: COC(=O)c1ccc(C(=O)N=C=O)cc1OC
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)cc1OC
Yield: 81.1 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using methyl 4-(isocyanatocarbonyl)-2-methoxybenzoate (0.84 g, 3.61 mmol), tert-butyl 2-(2,6-dichlorophenyl)hydrazinecarboxylate (Intermediate-44, 1.0 g, 3.61 mmol) and DCM (20 mL) to afford 1.50 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 9H), 3.80 (s, 3H), 3.87 (s, 3H), 7.28-7.42 (m, 6H), 9.57 (s, 1H), 10.85 (s, 1H); MS (m/z): 511.73 (M)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[N+:12]([C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].Cl>O.O1CCOCC1>[N+:12]([C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:18])([O-:14])=[O:13]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To an ice cold suspension of glycine (1.01 g, 13.56 mmol) in water (20 mL) was added Na2CO3 (1.437 g, 13.56 mmol) and stirred for 10 min. A solution of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 2.3 g with SOCl2, 20 mL) in dioxane (20 mL) was added to the above solution and stirred at rt for 4 h. The reaction mixture was diluted with ice cold water and acidified with cold dil. HCl (pH: 6.0). The solution was extracted with EtOAc (5×100 mL) and the combined organic layer was dried over anhyd Na2SO4 and filtered. The solution was evaporated and the residue was chromatographed over silica gel column using chloroform:methanol (95:5) as eluents to give the product as a white color solid (2.5 g, 85%), mp 188-190° C. 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, br s), 9.29 (1H, t, J=5.4 Hz), 8.77 (1H, d, J=2.0 Hz), 8.64 (1H, dd, J=8.4, 2.0 Hz), 7.89 (1H, d, J=8.4 Hz), 3.99 (2H, d, J=6.0 Hz); LC-MS (negative ion mode): m/z 268 (M−H)−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:8]=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=1)#[N:6].[N+]([O-])([O-])=O.[K+]>>[N+:1]([C:12]1[CH:11]=[CH:10][N+:9]([O-:13])=[CH:8][C:7]=1[C:5]#[N:6])([O-:4])=[O:2]
Reactant: N#Cc1ccc[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: N#Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
One hundred fifty mL of stirred 15% fuming nitric acid is cooled to 5°-10° C., and 20.4 grams (0.17 mole) of 3-cyanopyridine N-oxide is added portionwise. Upon completion of addition, the reaction mixture is stirred for about 15 minutes, and then 34.4 grams (0.340 mole) of potassium nitrate is added portionwise. Upon completion of addition, the reaction mixture is warmed to about 100° C. where it is stirred for six hours. The reaction mixture is then poured into about 1000 mL of ice-water. The mixture is stirred until the ice melts, and then the resultant solid is collected by filtration. The solid is dried under reduced pressure at about 100° C., yielding 4-nitro-3-cyanopyridine N-oxide.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:18]=1[CH2:19][NH2:20].C(N(C(C)C)CC)C>>[Br:8][C:6]1[N:7]=[C:2]([NH:20][CH2:19][C:18]2[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:17]=2[Cl:16])[C:3]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:5]=1
Reactant: NCc1c(F)ccc(F)c1Cl
Reactant: COC(=O)CCNc1ncc(Br)nc1Br
Agent: CCN(CC)C(C)C
Product: COC(=O)CCNc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl

Procedure:
Methyl N-{5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}-β-alaninate was prepared from methyl N-(3,5-dibromopyrazin-2-yl)-β-alaninate and 2-chloro-3,6-difluorobenzylamine in the presence of N,N-diethylisopropylamine as described in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([OH:28])[C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:29])[CH:12]=2)[OH:28])=[CH:19][CH:18]=1
Reactant: CN(C)CCCNc1cc(C(O)c2ccc(NC(=O)OC(C)(C)C)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCNc1cc(C(O)c2ccc(N)cc2)ccn1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of tert-butyl 4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylcarbamate (16 mg, 0.04 mmol) in 1 mL of DCM were added Et3SiH (0.1 mL)/TFA in DCM (10%, 0.2 mL). The mixture was stirred for ½ hr and no reaction was detected by LC-MS. Another 0.1 mL of Et3SiH and 0.8 mL of TFA in DCM (10%) were added and the mixture was stirred for 2 h. The solvent was removed and was purified by solid extraction (Waters Oasis MCX extraction cartridge) to give (4-aminophenyl)(2-(3-(dimethylamino)propylamino)pyridin-4-yl)methanol (6.0 mg, 50% yield). MS (ESI+): m/z 301.40 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[S:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-:19].[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>O>[CH:15]([N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:19])([CH3:17])[CH3:16]
Reactant: CC(C)N(Sc1nc2ccccc2s1)C(C)C
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CC(C)N(C(C)C)S(=O)c1nc2ccccc2s1
Reaction time: 10 h
Yield: 84.5 %

Procedure:
133 parts of N,N-diisopropyl-2-benzothiazolesulphenamide are suspended in 400 parts of water in an apparatus provided with a stirrer and a thermometer. 20 parts of sodium carbonate and 20 parts of sodium bicarbonate are added. 400 parts by volume of a sodium hypochlorite solution titrating 180 g. per liter of NaClO are gradually introduced in a period of 1 hour, with good stirring, at a temperature of 25°-28° C. The mixture is stirred for a further 10 hours at 20°-25° C. The solid is filtered off, washed with water until neutral and dried in vacuo. 119 parts of 2-N,N-diisopropylbenzo-thiazole-sulphinamide are obtained, that is a yield of 84.5%. Melting point (uncorrected): 79.5° C. After recrystallising from ethyl alcohol, a product of melting point (uncorrected) 80.5° C. is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]3[O:11][CH:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14][C:15]=3[C:16]([C:18](O)=[O:19])=[CH:17][C:8]=2[N:7]=[C:6]1[CH3:27].[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][N:29]([CH3:28])[C:18]([C:16]1[C:15]2[CH2:14][CH2:13][CH:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:11][C:10]=2[C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([CH3:27])=[N:7][C:8]=2[CH:17]=1)=[O:19]
Reactant: CNCCO
Reactant: COCCn1c(C)nc2cc(C(=O)O)c3c(c21)OC(c1ccccc1)CC3
Product: COCCn1c(C)nc2cc(C(=O)N(C)CCO)c3c(c21)OC(c1ccccc1)CC3

Procedure:
The title compound was prepared as a white solid in quantitative yield from 1-(2-methoxyethyl)-2-methyl-8-phenyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxylic acid (200 mg, 0.55 mmol, Step 12 of Example 1) and 2-(methylamino)ethanol (45 mg, 0.60 mmol) by the same manner in Step 13 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:15])[O:10][C:11]([NH:13][CH3:14])=[N:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][NH2:17]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:12][C:11]([NH:13][CH3:14])=[O:10])[C:8]=1[C:9]([NH:17][CH3:16])=[O:15]
Reactant: CNc1nc2cccc(OC)c2c(=O)o1
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)Nc1cccc(OC)c1C(=O)NC
Yield: 81.2 %

Procedure:
A mixture of 5-Methoxy-2-(methylamino)-4H-3,1-benzoxazin-4-one (1.05 g, 5.09 mmol) and methylamine (2.0 M solution in tetrahydrofuran; 12.7 ml, 25.5 mmol) in dimethylsulfoxide (2 ml) was heated in sealed tube for 15 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum to afford 0.980 g (81%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClC(Cl)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:17](=[O:19])[CH3:18])=[C:4]([OH:12])[CH:3]=1
Reactant: Oc1cc(Br)c2ccccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1c(O)cc(Br)c2ccccc12
Temperature: 0 °C
Yield: 83.4 %

Procedure:
To a solution of 0.625 g (2.80 mmol) 4-bromonapthalen-2-ol in dichloroethane (2.5 mL) was added aluminum chloride (0.561 g, 4.20 mmol), followed by acetyl chloride (0.20 mL, 2.8 mmol). The solution was refluxed for 2 h, then poured into 50 mL ice-cold 1M hydrochloric acid. This solution was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 3:1 hexanes/ethyl acetate) gave 0.619 g (83%) of 1-(4-bromo-2-hydroxynapthalen-1-yl)ethanone as a pale pink solid. 1H NMR (400 MHz, d6-DMSO): 13.22 (s, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.61 (dt, 1H), 7.51 (s, 1H), 7.49 (t, 1H), 2.83 (s, 3H); MS (EI) for C12H9O2Br: 265 (MH+), 267 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(F)cc(CN2CCCC2)c1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
3,5-Difluorobenzaldehyde (2.0 mL, 18.24 mmol), pyrrolidine (1.8 mL, 21.56 mmol), and sodium triacetoxyborohydride (5.8 g, 27.4 mmol) were stirred in THF (50 mL) for 16 h at room temperature. Saturated aqueous NaHCO3 (30 mL) was added and after stirring for 30 min, EtOAc (50 mL) was added. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated to afford 2.65 g (74%) of 1-(3,5-difluorobenzyl)pyrrolidine as a slightly cloudy oil: 1H NMR (CDCl3) δ 6.88-6.83 (m, 1H), 6.68-6.63 (m, 2H), 3.59 (s, 2H), 2.53-2.48 (m, 4H), 1.80-1.77 (m, 4H).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH:36]3[CH2:48][O:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)[S:33][CH:34]=2)=[CH:26][CH:25]=1>CO>[ClH:1].[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH:36]3[CH2:48][O:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)[S:33][CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2csc(N3CCNCC3COc3cccnc3)n2)cc1
Reaction time: 1 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(4-methoxyphenyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (199 mg, 0.280 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 44.2 mg of the free-base of the desired product. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.029 mL) was added. This was concentrated under reduced pressure, yielding 48.2 mg (41%) of the desired product as an off-white solid. LC-MS: RT=4.98 min, [M+H]+=383.0.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=1>ClCCl.O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:32])=[CH:28][CH:27]=1
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc(-c2ccccn2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1ccc(-c2ccccn2)s1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a cooled solution (0° C.) of 0.23 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 523 μl of N,N-diisopropylethylamine in 5 ml of dichloromethane is added 0.436 g of 5-(2-pyridinyl)thiophene-2-carbonyl chloride. The mixture is stirred at room temperature for 16 hours under argon and diluted with 40 ml of CH2Cl2 and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1N NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from ethyl acetate plus a small amount of hexane to give 0.485 g of tan crystals, m.p. 150°-154° C.