Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([CH:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)O)[CH:16]=1.[OH-].[Na+]>C(Cl)Cl.O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([CH:16]=1)[CH2:17][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)cc1C(O)c1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.7 %

Procedure:
3.06 g (80.89 mmol, 10.48 eq.) NaBH4 (granules) were added slowly to 50 ml Trifluoroacetic acid at 0° C. To this mixture a solution of 2.65 g (7.72 mmol) (5-Bromo-2-methoxy-phenyl)-napthalen-1-yl-methanol (62) in 30 ml dry CH2Cl2 was added which led to an brownish mixture. After stirring this mixture for 19 h at r.t. it was diluted with water and cooled again to 0° C. At this temperature NaOH-pellets were added carefully to adjust the pH to 10 before the solution was extracted with ether. The comb. org. fractions. were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2) yielded 2.42 g (7.39 mmol, 95.72%) 1-(5-Bromo-2-methoxy-benzyl)-naphthalene (63) as a pale yellow oil. Rf (CH2Cl2)=0.73. 1H-NMR (400 MHz, CDCl3): δ=3.84 (s, 3H, OMe), 4.35 (s, 2H), 6.76 (d, 1H, J=8.72 Hz), 6.91 (d, 1H, J=2.53 Hz), 7.20 (dm, 1H, J1=6.82 Hz), 7.26 (dd, 1H, J1=8.84 Hz, J2=2.53 Hz), 7.38 (m, 1H), 7.41-7.49 (m, 2H), 7.74 (d, 1H, J=8.34 Hz), 7.84 (m, 1H), 7.91 (m, 1H). MS (EI): m/z=329 (18), 328 (97), 327 (20), 326 (100), 248 (16), 247 (35), 232 (22), 231 (25), 216 (20), 215 (41), 203 (17), 202 (25), 142 (21), 141 (61), 115 (10), 101 (14). HR-MS (EI): Calcd. for C18H15BrO: 326.030626. Found: 326.030567.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14]([O:16]CCCC)=[CH2:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CC#N.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:16])[CH3:15]
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc(OC)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)cc1C(C)=O
Temperature: 97 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A mixture of methyl 2-bromo-4-methoxybenzoate (4) (5.9 g, 23.9 mmol), butyl vinyl ether (15.4 mL, 119.4 mmol), Ph3P (939.0 mg, 3.6 mmol), Et3N (4.3 mL, 31.0 mmol), and Pd(OAc)2 (343.0 mg, 1.8 mmol) in MeCN (45 mL) is stirred under argon at 97° C. for 18 h, cooled to room temperature, diluted with H2O (50 mL), and filtered through Celite® (H2O rinse). The filtrate is concentrated to dryness at reduced pressure. The residue plus tetrahydrofuran (140 mL) and 10% HCl (140 mL) were stirred for 2 h. After tetrahydrofuran removal at reduced pressure, the residue is extracted with dichloromethane (3×70 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (16.7% to 33.3% ethyl acetate/hexane) to give 4.8 g (96%) of 5 as a yellow solid, mp 48-50° C. IR 2962, 1733, 1688, 1258 cm−1; 1H NMR (CDCl3) δ 2.50 (s, 3H, CH3CO), 3.86 (s, 6H, CH3O, CO2CH3), 6.76 (d, J=2.0 Hz, 1H, 3-PhH), 6.93 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.90 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][OH:4].CCN(CC)CC.[Br:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Br)=[O:21])=[CH:18][CH:17]=1.O>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][O:4][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:15][Br:14])=[CH:17][CH:18]=1
Reactant: O=C(Br)c1ccc(CBr)cc1
Reactant: OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2,2-trichloroethanol (2.46 g, 16.5 mmol) and NEt3 (1.67 g, 16.5 mmol) in CH2Cl2 (40 ml) at 0° C. was dropwise added 4-bromomethyl benzoylbromide (4.17 g, 15.0 mmol) in CH2Cl2 (20 ml) and stirred to room temperature overnight. The reaction mixture was added H2O (20 ml) and the organic layer separated. The organic layer washed with aqueous 1 M HCl (20 ml) and H2O (20 ml). The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo to leave the expected product as a white solid. The product was used directly in the next step without any further purification (to be filled in).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+].O.C(O[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)C>C(OCC)(=O)C.Cl(O)(=O)(=O)=O>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(=O)CCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 65 h
Yield: 85 %

Procedure:
To a solution of 5-oxohexanoic acid (25 g, 192 mmol) in t-butyl acetate (600 mL) was added perchloric acid (500 μL, 8.31 mmol) and the resulting pale yellow solution was allowed to stir at room temp, with a drying tube in place, for 65 h. The reaction was diluted with ethyl acetate (400 mL) and then quenched with a mixture of sodium bicarbonate (50 g, 595 mmol) and water (100 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (5×150 mL), water (1×100 mL), brine (1×75 mL), dried over sodium sulfate, and filtered. The solvent was removed in vacuo to give the title compound (30.55 g, 85%) as a light oil. 1H NMR (500 MHz, chloroform-d) δ 2.50 (t, J=7.2 Hz, 2H), 2.25 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.89-1.83 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([NH2:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([N:30]=[C:41]=[O:43])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-amine (125 mg, 0.29 mmol) (see Example 102 for preparation) and DIPEA (109 uL, 81 mg, 0.63 mmol) in THF (6 mL) was added to a solution of triphosgene (34 mg, 0.14 mmol) in THF (6 mL) at 0° C. The reaction mixture was stirred for 30 at 0° C. and 30 min at room temperature, then directly used for next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][CH2:25][C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.ClCC(OCC)=O.Cl>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:25][C:26](=[O:27])[N:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[C:15]2=[O:16])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C=NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(O)CNc1cccc(Cl)c1
Agent: Cl
Solvent: CCOC(=O)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(c2cccc(Cl)c2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
In accordance with the synthesis process (B), 1.0 g (81%, 3.49 mmol) of 2-naphthalenesulfonyl isocyanate was added to a solution of 647 mg (3.49 mmol) of N-3-chlorophenylaminoacetic acid in 50 ml of tetrahydrofuran at room temperature, and the resultant mixture was stirred for 16 hours. After completion of the reaction, the liquid reaction mixture was cooled to 0° C. and added with 881 mg (8.72 mmol) of triethylamine and 417 mg (3.84 mmol) of ethyl chloroacetate, followed by stirring at 0° C. for 1 hour. After completion of the reaction, the liquid reaction mixture was added with 20 ml of 1N hydrochloric acid and 30 ml of saturated saline and subjected to extraction with ethyl acetate. After washing the resultant extract with water, it was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus-obtained crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=3:1) and subjected to crystallization from hexane/ethyl acetate, thereby obtaining 324 mg (0.81 mmol) of the title compound as white crystals (yield: 23.2%).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([O:15][C:16]2[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+].[CH2:36](I)[CH3:37]>O.O1CCOCC1>[CH2:36]([S:22]([C:20]1[C:19]([O:26][CH3:27])=[CH:18][C:17]([CH:28]([CH3:30])[CH3:29])=[C:16]([CH:21]=1)[O:15][C:11]1[C:12]([NH2:14])=[N:13][C:8]([NH2:7])=[N:9][CH:10]=1)(=[O:24])=[O:23])[CH3:37]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1S(=O)(=O)Cl
Reactant: CCI
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Temperature: 80 °C
Yield: 19.6 %

Procedure:
To a solution of sodium sulfite (541 mg, 4.29 mmol) in water (20 mL) was added 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonyl chloride (400 mg, 1.07 mmol) and the reaction was heated at 80° C. for 1 hour. Sodium bicarbonate (361 mg, 4.29 mmol-dissolved in 5 mL water), dioxane (20 mL), and ethyl iodide (0.10 mL, 1.29 mmol) were added and the reaction was heated at 80° C. for 2 hours. The reaction was concentrated, extracted with dichloromethane (150 mL) and water (20 mL). The dichloromethane layer was dried using anhydrous sodium sulfate, concentrated, and purified via silica gel column chromatography (95/5/0.1 dichloromethane/methanol/ammonium hydroxide) to yield 5-(5-ethanesulfonyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (77 mg, 20%) as white solid, MS (M+H)=367.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C=O.C(Cl)(Cl)Cl.N>C(O)=O>[C:36]([C:33]1[CH:34]=[CH:35][C:29]2[O:28][C:27]([CH2:26][CH:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C@H:10]4[CH2:11][CH2:12][N:8]([CH3:6])[CH2:9]4)=[CH:15][CH:16]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:31][C:30]=2[CH:32]=1)#[N:37]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: C=O
Agent: N
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C)C2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
1.8 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate was dissolved in 28 ml of formic acid, and the solution was stirred at 70° C. for 1 hour. The resulting reaction solution was concentrated to dryness, and the residue thus obtained was dissolved in 8 ml of formic acid. 0.29 ml of 37% formaldehyde was added thereto, and then refluxed under heating for 4 hours. After cooling, the reaction solution was mixed with chloroform, and then adjusted to pH 10-11 with aqueous ammonia, and the resulting organic layer was collected and dried. Thereafter, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography using a chloroform/methanol mixture as an eluant. In this way, 1.07 g of the title compound was obtained in an oily form.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.C(Cl)[Cl:32].CN(C=O)C.CS(Cl)(=O)=O>O.CCN(CC)CC>[Cl:32][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-{4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (539.5 mg), CH2Cl2 (5 ml) and DMF (5 ml) were combined under N2 atmosphere. Then, Et3N (0.211 ml) and MsCl (0.108 ml) were added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 3.5 hours. The reaction mixture was poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-{4-{2-[4-(chloromethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (537.5 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[H-].[Na+].CI.[C:17]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:17][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C([O-])O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(OC)cc1[N+](=O)[O-]

Procedure:
To 4-methoxy-2-nitroaniline (10 mmol, 1.68 g) in 20 mL of DMF was added NaH (12 mmol, 480 mg of a 60% dispersion in mineral oil) (exothermic, H2 evolution), affording a deep red slurry. After 15 min MeI (20 mmol, 1.2 mL) was added (exothermic). After 30 min the reaction was poured into a solution of brine and NaHCO3, resulting in formation of a bright orange precipitate. The slurry was filtered and the filter cake was washed with H2O. The solid was dried under reduced pressure, affording a bright orange solid. HPLC A: 1.77 min.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[CH2:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1)[CH3:9]>C(#N)C>[CH2:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH:3][CH3:1])[CH:13]=1)[CH3:9]
Reactant: CCN(CC)CC
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CC#N
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(NC)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Methylamine•monohydrochloride (1.23 g) and triethylamine (2.5 ml) were added to a solution of N-ethyl-3-fluoro-4-nitrobenzamide (1.92 g) in acetonitrile (40 ml), followed by stirring at 50° C. for 15 hours. The reaction solution was concentrated under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain N-ethyl-3-(methylamino)-4-nitrobenzamide (1.99 g) as a yellow orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[N:8][C:7]([CH3:24])=[C:6]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:31]>>[Cl-:31].[Cl-:31].[NH3+:16][CH2:15][CH2:14][NH:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:7]([CH3:24])[NH+:8]=1
Reactant: Cl
Reactant: COc1ccc2c(NCCNC(=O)OC(C)(C)C)nc(C)c(-c3ccccc3)c2c1
Product: COc1ccc2c(NCC[NH3+])[nH+]c(C)c(-c3ccccc3)c2c1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
Tert-butyl 2-[(6-methoxy-3-methyl-4-phenylisoquinolin-1-yl)amino]ethylcarbamate (0.61 g) was treated with 100 mL of HCl-saturated EtOAc. The reaction was stirred at 0 C for 30 min, then at room temp for 3.5 h, then concentrated to dryness. Recrystallization from methanol/EtOAc provided the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[N:11]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Reaction time: 8 h

Procedure:
To a solution of 4-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (prepared from Intermediate C and piperazine-1-carboxylic acid tert-butyl ester according to General Method N) (7.32 g, 17.8 mmol) in 1,4-dioxane (200 mL) is added 4M HCl in 1,4-dioxane (22.2 mL, 88.9 mmol). The resulting slurry is stirred overnight. The reaction is poured into water (600 mL) and basified with 2M aqueous Na2CO3. The product is extracted with DCM, and the combined extracts washed with brine and dried over Na2SO4 to afford the title compound (S) as an oil that partially crystallizes.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:20])=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7].[CH3:21][C:22](C)([O-])[CH3:23].[K+].BrC(C)C>>[Br:1][C:2]1[C:3]([O:20][CH:22]([CH3:23])[CH3:21])=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1c(O)c(Br)c(Br)n1Cc1ccccc1
Agent: [K+]
Solvent: CC(C)Br
Product: CCOC(=O)c1c(OC(C)C)c(Br)c(Br)n1Cc1ccccc1
Yield: 84.2 %

Procedure:
Prepared using the method described in Example 107 from ethyl 4,5-dibromo-3-hydroxy-1-(phenylmethyl)-1H-pyrrole-2-carboxylate (3.2 g, 0.008 moles), potassium tert-butoxide (1.0 g, 0.009 moles) and 2-bromopropane (2.0 g, 0.016 moles). The product crystallized upon aqueous workup and was filtered off, rinsed with water and dried to afford the pure product (3.0 g); mp 46°-48° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=O.[C:24](=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]([F:23])([F:22])[CH2:3][S:4][C:5]1[CH:12]=[C:11]([C:13]2[C:14]([C:18]([F:21])([F:20])[F:19])=[N:15][NH:16][CH:17]=2)[CH:10]=[CH:9][C:6]=1[CH:7]=[CH2:24]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 43.6 %

Procedure:
2.83 g (8.0 mmol) of 2-(2,2,2-trifluoroethylthio)-4-(3-trifluoromethylpyrazolyl)benzaldehyde (Compound No. V-275 of the present invention) prepared in the same manner as in Example 8 (9), 2.85 g (8.0 mmol) of methyltriphenylphosphonium bromide and 1.38 g (10.0 mmol) of potassium carbonate were refluxed in a solvent mixture of 20 ml of dioxane and 0.3 ml of water with heating for 5 hours. After cooling down to room temperature, the insolubles were filtered off, and the dioxane was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.23 g of [2-ethenyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (yield 43.8%) as a pale yellow liquid (nD20 1.5328).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:8]2[C:9]([O:20][CH3:21])=[CH:10][CH:11]=[C:12]([C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[C:7]=2[O:6][C:5]=1[C:22]([O:24]CC)=[O:23].CO>O>[CH3:3][C:4]1[C:8]2[C:9]([O:20][CH3:21])=[CH:10][CH:11]=[C:12]([C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[C:7]=2[O:6][C:5]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1oc2c(C(=O)c3cccs3)ccc(OC)c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)c2cccs2)c2oc(C(=O)O)c(C)c12

Procedure:
To a solution of potassium hydroxide (1.96 g, 34.86 mmol) in water (75 mL) was added compound 1 (4.00 g, 11.62 mmol) and the resulting suspension was heated to reflux for two hours. During the reflux a small portion of methanol was rinsed into the reaction mixture. After cooling, the reaction mixture was diluted with water (225 mL) and acidified with 2N HCl (25 mL). The resulting suspension was cooled in an ice bath, and the product collected by filtration. After vacuum drying, 3-methyl-4-methoxy-7-(2-thienoyl)-benzofuran-2-carboxylic acid, compound 2, was obtained. mp 252°-255° C.; 1H NMR d 2.80 (3H, s), 2.80 (1H, br s), 4.06 (3H, s), 6.76 (1H, d, J=8 Hz), 7.19 (1H, m), 7.70 (1H, dd, J=4 Hz, 1 Hz), 7.76 (1H, dd, J=4 Hz, 1 Hz), 7.90 (1H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([NH:21][NH2:22])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].COC(OC)OC.[C:34](#N)C.[CH3:37][N:38]1[C:42]([NH2:43])=[CH:41][CH:40]=[N:39]1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:43]([C:42]4[N:38]([CH3:37])[N:39]=[CH:40][CH:41]=4)[CH:34]=[N:22][N:21]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC#N
Reactant: Cn1nccc1N
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cn1nccc1-n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to general Method B. using 4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.234 mmol), trimethylorthoformate (80 mg, 0.75 mmol), acetonitrile (2 mL), 2-Methyl-2H-pyrazol-3-ylamine (48 mg, 0.50 mmol) and acetic acid (1.0 mL). MS (ES) [M+H]+ expected 518.0. found 518.0.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[CH3:22][S-:23].[Na+].O1CCOCC1>CO>[CH3:22][S:23][CH2:6][C@@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CSC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 45 °C
Yield: 76.1 %

Procedure:
(S)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate (600 mg, 1.902 mmol) and sodium thiomethoxide (593 mg, 7.61 mmol) were added to a 20 mL microwave tube equipped with mechanical stir bar and charged with Dioxane (10 ml). The reaction was allowed to heat overnight at 45° C. The reaction was poured into 5 mL MeOH and 5 g silica, and the solvents were evaporated in vacuo. The dry-loaded crude product was purified on 50 g SNAP column 10-50% EtOAc/hexanes to provide (S)-tert-butyl (2-(methylthio)-1-phenylethyl)carbamate (387 mg, 1.447 mmol, 76% yield).