Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[Cl:24].CN(C=O)C>C(OCC)(=O)C>[Cl:21][C:20]1[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([Cl:24])[C:15]=1[CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 81.5 %

Procedure:
Stir a mixture of potassium phthalimide (1.85 g, 10 mmol), 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (2.68 g, 10 mmol) and DMF (20 mL) at 50° C. for 12 hours. Cool the reaction and dilute with ethyl acetate (60 mL) and wash with water three times and brine one time. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:3 ethyl acetate/hexane to afford 2.74 g (82%) of the title compound. MS (m/z): 336 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)(=[O:26])=[O:25]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following a procedure described in Intermediate-27 by using tert-butyl 4-((6-chloropyridin-3-yl)methoxy)piperidine-1-carboxylate and 5-(methylsulfonyl)-1H-indole (0.410 g, 27.70%); MS: 386.32 (M−100).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Cl[CH:8]([CH:14]=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CC(C)=O>[CH:2]([C:3]1[S:5][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:4]=1)([CH3:6])[CH3:1]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CC(C)C(N)=S
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc(C(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of 2-methylpropanethioamide (3.3 g) and ethyl 2-chloro-3-oxopropanoate (4.82 g) in acetone (50 mL) was heated at reflux under nitrogen for 3 hours. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 12% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.6 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][C:17](C(O)=O)=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CN1C(=O)CCC1.O.[Cu]>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc3cc(C(=O)O)[nH]c3c2CC1
Agent: [Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)N1CCc2sc3cc[nH]c3c2CC1
Temperature: 250 °C
Yield: 93.4 %

Procedure:
To a stirred solution of the product from step (f) (0.50 g, 1.62 mmol) in NMP (10 ml) was added copper dust (0.10 g, 1.62 mmol). The reaction mixture was heated in a microwave reactor to 250° C. for 20 minutes. The cooled solution was diluted with water (100 ml) and extracted with Et2O (3×). The combined Et2O extracts were washed with brine, dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 100% EtOAc in hexanes gave the sub-titled compound as a tan solid (0.40 g). MS: ESI (positive): 265 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:14]([CH3:30])[C:15]([C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1C(OC(C)(C)C)=O)=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]>C(Cl)Cl>[CH2:8]([N:14]([CH3:30])[C:15]([C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][NH:18]1)=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid was added dropwise to a solution of compound 48 (1 g, 1 eq.) in DCM (10 mL). The reaction mixture was stirred for 3 hrs at room temperature, and then trifluoroacetic acid was removed under reduced pressure. The residue was co-evaporated with toluene to yield compound 49 as pale yellow oil in quantitative yield.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])O[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH3:26]>>[CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:26][C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCc1c(C)oc(C)cc1=O
Product: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)cc1=O
Temperature: 25 °C

Procedure:
Compound 2 (0.02 g, 30.6 mmol) was heated at 100° C. with aqueous ammonia in a high pressure tube for 18 h. After the mixture was cooled to room temperature, the crude was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-hexadecyl-2,6-dimethylpyridin-4(1H)-one (4) as a brown solid; yield 0.01 g (51%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.88-0.89 (m, 3H), 1.28-1.32 (m, 28H), 2.28 (s, 3H), 2.34 (s, 3H), 2.44-2.47 (m, 2H) and 6.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(cn1)CCCC2
Yield: 2.3 %

Procedure:
Using the method of Example 63, Step A, 75 mg of 3-aminoisoquinoline (7.73 mmoles) and 8.7 mg platinum oxide in 2 mL of trifluoroacetic acid was shaken under 40 psi of hydrogen for 3 h. The mixture was filtered and catalyst was washed with ethyl acetate. After concentrating the filtrate, the residue was dissolved in 10 mL of ethyl acetate and washed with 5 mL of saturated aquous sodium bicarbonate. The organic solution was dried (sodium sulfate), decanted, and concentrated to give a yellow syrup. Flash coumn chromatography on 19 g of silica gel, eluting with 600 mL of 50% ethyl acetate/hexane gave 26.5 mg (34% yield) of 3-amino-5,6,7,8-tetrahydroisoquinoline as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]([CH2:20][CH2:21][O:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CN(C=O)C.O>[Cl:13][C:6]1[CH:5]=[C:4]([CH:14]([CH2:20][CH2:21][O:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (2.3 g, 5.660 mmol) in a mixture of DMF (50 mL) and water (5 mL) were added Cs2CO3 (6.4 g, 19.815 mmol), Pd(TPP)4 (1.3 g, 1.120 mmol) and 4-(trifluoromethyl)phenyl boronic acid (1.29 g, 6.780 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), filtered off the catalyst and celite bed was washed with EtOAc and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate (1.2 g) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: Fc1ccc(CBr)cc1
Product: O=C(c1ccc(OCc2ccc(F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-fluorobenzyl bromide. MS (ES+) 401.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH2:17])[CH2:9][CH:10](O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:41][C:42]([NH2:44])=[S:43]>C(#N)C>[NH2:44][C:42]1[S:43][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:17])[N:41]=1
Reactant: NC(N)=S
Reactant: C=C(CC(O)C(=O)OCC)c1cccc(Br)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C1CC(C)(c2cccc(Br)c2)N=C(N)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 4-(3-bromophenyl)-2-hydroxypent-4-enoate (5.1 g, 17 mmoles) in acetonitrile (68 mL) is added 2,6-lutidine (2.19 g, 20.4 mmol, 1.2 equiv). The reaction is cooled to 0° C. and trifluoromethanesulfonic anhydride (3.30 mL, 19.6 mmol, 1.15 equiv) is added dropwise over approximately 5 minutes. The mixture is stirred at 0° C. for 20 minutes. Thiourea (2.59 g, 34.0 mmol, 2 equiv) is added and the reaction is warmed to room temperature. After 45 minutes, the mixture is concentrated under reduced pressure. The resulting viscous orange oil is then added via large pipette to stirring sulfuric acid (17.8 M, 8 mL) at room temperature. After 20 minutes, the mixture is added dropwise to a vigorously stirring, 0° C. solution of K2CO3 (ca. 50 g) in 50 mL H2O). Additional water is added to enable stirring upon solid formation during the quench. The tan/orange solid is collected by filtration. The solid is allowed to dry on the filter paper by a stream of air for 1 h to give the title compound as a mixture of diastereomers which is used without further purification: MS (m/z): 357, 359 (M+1).
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[CH:23]=[CH:22][NH:21][N:20]=1
Reactant: Nc1cc[nH]n1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3cc[nH]n3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (2.4 g) was dissolved in water (10 ml). To the solution was added 3-aminopyrazole (0.83 g). The mixture was stirred at ambient temperature overnight. The precipitates were filtered and air-dried to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(3-pyrazolyl)morpholin-2-yl]uracil (1.25 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@H:10]([CH2:39][OH:40])[N:11](O[Si](C(C)(C)C)(C)C)[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[C:12]([NH:11][CH:10]([CH2:9][OH:8])[CH2:39][OH:40])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CO)N(O[Si](C)(C)C(C)(C)C)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To dry ethyl ether (300 ml) is added with stirring lithium aluminum hydride (4.5 g; 0.12 mol) and cooled to 0° C. under nitrogen. The N-trityl-t-butyldimethylsilyloxy serine methyl ester (57 g; 0.12 mol) is added portionwise over 5 minutes as a solid. The reaction mixture is allowed to warm and stir for 30 minutes at 25° C. The mixture is quenched by slow addition of H2O (4.5 ml) at 0° C. followed by 15% NaOH (4.5 ml) and H2O (13.5 ml) at 25° C. After stirring for 3 hours, the mixture is filtered and the solid washed with THF. The combined flitrates are concentrated to which is added ether and petroleum ether to precipitate N-trityl-1,3-dihydroxy-2-propanamine which is used directly in Step D.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[N:33][CH:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:36])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M129) (0.39 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (270 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:7]=1
Reactant: O=C1CCCC1Cl
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCC1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (120.0 g), 2-chloro-1-cyclopentanone (100.0 g), potassium carbonate (163.3 g), and DMF (1.2 l) was stirred at 70° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give Compound IIc-a (141.43 g, 83.9%) as a pale-yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[O:9][C:10]([F:12])([F:11])[F:13]
Reactant: Oc1ccc(Br)c(OC(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-3-(trifluoromethoxy)phenol (1.0 g, 0.0039 mol), phenylboronic acid (1900 mg, 0.016 mol), TEA (3.2 mL, 0.023 mol), cupric acetate (1.3 g, 0.0070 mol) and DCM (40 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.82 (dd, J 8.97, 2.65 Hz, 1H), 7.00 (dd, J=2.78, 1.26 Hz, 1H), 7.02-7.10 (m, 2H), 7.16-7.24 (m, 1H), 7.36-7.45 (m, 2H), 7.55 (d, J=8.84 Hz, 1H).
Reaction SMILES: CN(C=O)C.Cl[N:7]([C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1)[C:8]([CH3:10])=[O:9].O.O.[S:19]1([C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[NH:22]1)(=[O:21])=[O:20].[Na]>O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:7][C:8](=[O:9])[CH2:10][N:22]2[C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[S:19]2(=[O:20])=[O:21])[CH:15]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(=O)N(Cl)c1cc(C)on1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To 2.31 liters of DMF is added 479 grams (2.75 moles) of 3-(chloroacetamino)-5-methylisoxazole followed by 669 grams (2.9 moles) of sodium saccharin dihydrate. The mixture is heated to 100°C. and this temperature is maintained for 2 hours. The cooled reaction mixture is poured into 8 liters of water, filtered and the wet cake is recrystallized from 15 liters of ethanol to give 658 grams (74.8%) of 2,3,dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide, mp 218°-220°C.; I.R. and NMR spectra are consistant with the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])[CH:32]=[CH2:33])=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][N:30]([CH3:35])[C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 33.8 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.05 g, 4.60 mmole), N-(1-benzyl-1H-indol-3-ylmethyl)-N-methyl-acrylamide (1.40 g, 4.60 mmole), Pd(OAc)2 (0.10 g, 0.46 mmole), tri-ortho-tolylphosphine (0.28 g, 0.92 mmole) and diisopropylethylamine (1.20 mL 6.90 mmole) in propionitrile (75 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of Celite®, and the filter pad was rinsed with acetonitrile (300 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (5% MeOH/CHCl3). The title compound (0.70 g. 35%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.ClC1[N:15]=[CH:14][C:13](CCl)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:15][CH2:14][CH3:13])=[CH:5][N:6]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: ClCc1ccc(Cl)nc1
Solvent: ClCCl
Product: CCNCc1cnc(Cl)s1

Procedure:
The reaction procedure of Reference Example 17 was repeated except that crude 2-chloro-5-chloromethylthiazole was used in lieu of 6-chloro-3-pyridylmethyl chloride and that CH2Cl2 was used as the extractant. The procedure gave the title compound as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Yield: 83.8 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.25 g, 4.13 mmol) obtained in Example 5 and t-butyl 4-hydroxy-1-piperidinecarboxylate (1.70 g, 8.44 mmol) were dissolved in toluene (50 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (2.00 g, 8.29 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title compound (1.68 g, 3.46 mmol, 84%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][C@@H:13]3[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=2[CH:19]=1.[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].Cl.C(OCC)C>N1C=CC=CC=1>[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:14][C@@H:13]4[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]4[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=3[CH:19]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)N1CCC[C@@H]2Cc3cc(N)ccc3C[C@H]21
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(=O)N1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(C)C)cc4)ccc3C[C@H]21
Reaction time: 1 h
Yield: 70.5 %

Procedure:
1.21 g of trans-1-(7-amino-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-1-yl)propan-1-one (0.38 mmol) were dissolved in 2 ml of pyridine. At 0-4° C., 0.08 g of 4-isopropyl-benzene sulfonylchloride (0.4 mmol) were added, and the reaction stirred for 1 h under cooling. 40 ml of aqueous 1 N hydrochloride acid and diethyl ether were added, the phases separated, and the aqueous layer extracted twice with diethyl ether. The organic phases were combined, washed three times with water acidified with 1 N aqueous hydrochloric acid, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.118 g of the product.
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S]>>[SH:2][C:1]1[S:3][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Nc1ccccc1
Reactant: S=C=S
Agent: [S]
Product: Sc1nc2ccccc2s1

Procedure:
In a process for purifying crude molten 2-mercaptobenzothiazole, prepared by reacting aniline carbon disulfide and sulfur at elevated temperature and pressure, in which the purification includes the steps of separating dissolved alkali metal salt of 2-mercaptobenzothiazole from undissolved impurities, treating the dissolved alkali metal salt of 2-mercaptobenzothiazole with an excess of a non-oxidizing mineral acid to precipitate a slurry of purified 2-mercaptobenzothiazole, separating the purified 2-mercaptobenzothiazole solids from the slurry to obtain 2-mercaptobenzothiazole solids, washing the solids with water, and drying the purified 2-mercaptobenzothiazole, the improvement comprising; forming said dissolved alkali metal salt at 2-mercaptobenzothiazole and said dissolved impurities by the steps of