Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH:11]=C)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:37]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH2:11][OH:37])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCC(CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CCO)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of tert-butyl-(1-{2-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-ethyl}-but-3-enyloxy)-dimethyl-silane (1.45 g, 2.60 mmol) in 1:1 MeOH/CH2Cl2 (25 mL) at −78° C. was purged with ozone until the blue color persisted. The reaction mixture was then purged with N2 for 5 min, treated with NaBH4 (300 mg, 7.8 mmol) portionwise and slowly warmed to ambient temperature. Over the next 4.5 h, 2 additional portions of NaBH4 (500 mg each) were added, and the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined organic extracts were washed saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. Flash chromatography (5→40% EtOAc/Hex) afforded the title compound (730 mg, 50%): 1H NMR (CDCl3 400 MHz) δ 7.72 (dd, J=8.8, 1.5 Hz, 2H), 7.52 (dd, J=8.8, 1.5 Hz, 2H), 7.02 (m, 1H), 6.38 (m, 1H), 4.90 (dd, J=11.7, 2.2 Hz, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.28 (s, 1H), 3.85 (m, 1H), 3.73-3.64 (m, 2H), 2.76 (m, 1H), 1.91 (br s, 1H), 1.71-1.22 (m, 6H), 0.80 (s, 4.5H), 0.79 (s, 4.5H), 0.03 (s, 3H), −0.04 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15]2[C:14](=[O:22])[NH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].C1C(=O)N([I:30])C(=O)C1.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[I:30][C:11]1[C:10]2[N:9]=[C:8]([NH:7][CH:2]([CH3:1])[C:3]([CH3:5])([CH3:6])[CH3:4])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:16]=3[C:15]=2[C:14](=[O:22])[NH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cnccc12)C(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cnccc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[(1,2,2-trimethylpropyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one (221 mg, 0.746 mmol) in acetic acid (7.5 mL), NIS (336 mg, 1.491 mmol) was added. After stirring for 2 h at room temperature, aqueous sodium hydrogen carbonate was added, and then aqueous sodium thiosulfate pentahydrate (5%) was added. The aqueous mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 4-iodo-6-[(1,2,2-trimethylpropyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one as an orange solid. 1H NMR (500 MHz, C2D6SO) δ 11.58 (d, 1H), 11.00 (s, 1H), 8.74 (s, 1H), 8.47 (d, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 4.93 (m, 1H), 1.23 (d, 3H), 0.99 (s, 9H). LRMS (ESI) calc'd for (C17H19IN4O) [M+H]+, 423.1; found 423.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22]C2C=CC=CC=2)=[O:20])[C:3]=1[Cl:29].CO.C[O-].[Na+]>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:29]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Reaction time: 24 h

Procedure:
Benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (3.00 g, 6.83 mmol) was added to CH3OH (35 mL). Sodium methoxide (25 wt % in CH3OH; 1.9 mL, 8.2 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir for 24 h. Water (50 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove most of the CH3OH. The mixture was extracted with EtOAc (2×40 mL), and the combined organic layers were washed with water (40 mL) and satd sodium chloride (40 mL). Concentration of the volatiles under reduced pressure provided methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate as a pale yellow solid (2.04 g, 88% purity by LC area).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1.Cl>O1CCCC1>[NH2:4][C:3]1[O:13][C:9]([CH3:8])=[CH:10][C:11](=[O:12])[C:2]=1[C:1]#[N:5]
Reactant: C=C1CC(=O)O1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(=O)c(C#N)c(N)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of malononitrile (3.3 g, 50 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (60% w/w, 2.2 g, 55 mmol) at −10° C. The resultant mixture was stirred for 2 hours. Then diketene (4.2 g, 50 mmol) was added dropwise to the solution. The mixture was allowed to warm to room temperature and continued stirring for 30 minutes. The mixture was neutralized with hydrochloric acid and then concentrated in vacuo to give crude 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile (6.0 g, 80%) as a red solid, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:18][CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:36]([CH3:38])[CH3:37])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([OH:30])=[O:29])=[CH:18][CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:36]([CH3:37])[CH3:38])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-n-butyl-3-[(2'-(t-butoxycarbonyl)biphen-4-yl)-methyl]-6-isopropylquinazolin-4(3H)-one (0.198 g, 0.44 mmol) from Example 36B in a mixture of methylene chloride (3 ml) and anhydrous trifluoro acetic acid (3 ml) containing anisole (0.05 ml) was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure and the residue was triturated with dry ether to give the solid product, which was then collected by filteration and dried in vacuo over NaOH and P2O5 to give the desired product as the mono trifluoroacetate salt. 1H-NMR(CDCl3): 0.91 (t, 3H, J=7.35 Hz), 1.32 (d, 6H, J=6.9 Hz), 1.47 (m, 2H), 1.72 (m, 2H), 3.12 (m, 3H), 5.48 (s, 2H), 7.14-7.96 (m, 11H), 8.16 (d, 1H, J=1.9 Hz). FAB-MS: m/e 399 (M+H).
Reaction SMILES: [S:1]=[C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[NH:3]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:27][S:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 100 mg of 4,5-dihydro-5-thioxo-8-(3-(trifluoromethyl)phenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (Example 24) in 10 ml of dry tetrahydrofuran, cooled at 0° C., is added 13 mg of sodium hydride (60 percent dispersion in mineral oil). The reaction mixture is stirred at 0° C. for 15 minutes, then an excess of methyl iodide is added and the mixture is allowed to warm to room temperature and then is stirred for 3 hours. The mixture is quenched with water and extracted with chloroform and evaporation of the extract in vacuo gives 47 mg of the desired product mp 234-237° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1>>[CH3:28][C:29]1[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (225 mg) was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 42 mg of 379. MS (Q1) 505.2 (M)+.
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].IC.[C:14]([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)C>[CH3:14][O:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(O)C(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CC(C)=O
Product: COC(C)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-hydroxypropiophenone (3.00 g, 20.0 mmol), iodomethane (3.40 g, 24.0 mmol), and K2CO3 (granular, anh.; 13.8 g, 99.9 mmol) was refluxed in acetone (75 mL) for 18 h. The reaction mixture was cooled to room temperature and the inorganic salts were removed by filtration. The filtrate was evaporated under vacuum to give an oil which was subsequently dissolved in diethyl ether (200 mL) and then washed with 0.1N NaOH (3×50 mL) followed by H2O (50 ml) The organic layer was dried (anh. Na2SO4), filtered, and evaporated to an orange oil (3.17 g, 96.9%). This material was used in the following step without further purification. TLC, Rf 0.55 (1% MeOH:1% IPA:CHCl3); GC, tr 4.58 min; MS, m/z 164 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=O.C(Br)(=O)C(Br)=O.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:33]=1[NH2:34]>C(Cl)Cl.CN(C=O)C>[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:33]=1[NH:34][C:13](=[O:15])[CH2:12][CH2:11][C:3]1[C:4]([Br:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COc1cc(Br)c(CCC(=O)O)c(Br)c1
Agent: O=C(Br)C(=O)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CCC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a −78° C. solution of 11.56 g of 3-(2,6-dibromo-4-methoxyphenyl)-propionic acid in 300 mL of CH2Cl2 was added dropwise 17.1 mL of a 1.0M solution of oxalyl bromide, then 1.7 mL of DMF. The mixture was allowed to warm to room temperature. When gas evolution ceased, the mixture was recooled to −78° C. Diisopropyl ethylamine (7.14 mL) was added dropwise, then a solution of 5.54 g of 2,6-dichloroaniline in 10 mL of CH2Cl2 was added dropwise. The mixture was allowed to warm to room temperature, then stirred overnight at this temperature. The white precipitate was collected to yield the N-(2,6-Dichlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)-propionamide as a white solid. The filtrate was concentrated and recrystallized from EtOH to yield an additional amount of N-(2,6-Dichlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)-propionamide as a white solid. Mass spectrum (ESI) 481.9 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 9.89 (s, 1H); 7.53 (d, J=8.2 Hz, 2H); 7.34 (t, J=8.0 Hz, 1H); 7.27 (s, 2H); 3.77 (s, 3H); 3.16 (m, 2H); 2.53 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 144 h

Procedure:
3-Hydroxy-4-nitrobenzoic acid (I) (100.3 g, 95% pure, 0.53 mole) was added to methanol (1250 ml) to which had been added acetyl chloride (25 ml). The solid dissolved over a period of two days. After six days, the solution was filtered to remove undissolved impurities. The crude ester was obtained by evaporation of the solution. Several crops of crystals were taken, the last from a 50 ml volume. The combined crops were recrystallized from methanol (150 ml). Two crops of the ester (II) as yellow-brown crystals, m.p. 89°-91°, (98.7 g, 0.50 mole) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[N:3]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[N:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 2-Fluoro-6-(1H-imidazol-2-yl)pyridine (410 mg; 2.51 mmol), tert-butyl bromoacetate (539 mg; 2.76 mmol), potassium carbonate (520 mg; 3.77 mmol), and N,N-dimethylformamide (20 mL) is stirred at room temperature for 16 h. Water (60 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The organic extracts are washed with water (3×40 mL) and brine (1×40 mL), dried (MgSO4), and concentrated to give [2-(6-Fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester as an orange oil (630 mg). 1H NMR (CDCl3) δ 8.12 (dd, 1H), 7.82 (q, 1H), 7.16 (s, 1H), 6.98 (s, 1H), 6.81 (dd, 1H), 5.14 (s, 2H), 1.44 s, (9H), LCMS: 276.1 (M−).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([S:20][CH3:21])[NH:16][C:15]=3[CH:14]=[C:13]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([S:20]([CH3:21])=[O:44])[NH:16][C:15]=3[CH:14]=[C:13]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])=[O:24])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(S(C)=O)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-(methylsulfanyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (26 mg) in THF (3 mL), was added an aqueous solution of m-chloroperbenzoic acid (75%, 12 mg) (1 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to yield the titled compound (10 mg) as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.CC1C=CC(S([CH2:22][N+:23]#[C-])(=O)=O)=CC=1.C(O)C.CC([O-])(C)C.[K+]>COCCOC>[CH3:1][C:2]1[S:3][C:4]2[CH:10]([C:22]#[N:23])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2c(s1)C(=O)CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1nc2c(s1)C(C#N)CCC2
Temperature: 25 °C

Procedure:
To a stirred and cooled solution of 5,6-dihydro-2-methylbenzo[d]thiazol-7(4H)-one (1.67 g, 10 mmol) and TOSMIC (2.5 g, 13 mmol) in a mixture of DME (25 mL) and absolute ethanol (25 mL) was added solid t-BuOK (2.8 g, 24 mmol) portionwise while keeping the reaction temperature between 5 and 10° C. The resulting mixture was stirred at room temperature for 30 minutes and at 30-45° C. for 30 minutes. The resulting suspension was cooled to room temperature. The precipitate (TosK) was removed by filtration and rinsed with DME. The combined DME solutions were concentrated under reduced pressure to give the crude product, which was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([O:14][CH2:15]C)=[O:13])=[C:4]([N:7](C)[C:8]([NH2:10])=O)[S:5][CH:6]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:17][N:10]=[C:8]=[N:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1c(C)csc1N(C)C(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CN=C=Nc1scc(C)c1C(=O)OC

Procedure:
A stirred solution of ethyl 4-methyl-2-(N1 -methylureido)-thiophene-3-carboxylate (2,3 g), triphenylphosphine (2,62 g), triethylamine (1.4 ml) and carbontetrachloride (5 ml) in CH2Cl2 (50 ml) was refluxed for 30 min, whereafter it was evaporated in vacuo. The oily residue was extracted twice with boiling petrol ether. The combined petrol ether solutions were evaporated to give N-methyl N'-(3-carbomethoxy-4-methyl-thien-2-yl)-carbodiimide as an oil. The presence of the carbodiimide moeity was confirmed by an IR absorbtion band at 2140 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C([Li])(CC)C.[O:25]1[C:29]2([CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:32]3([OH:35])[CH2:33][CH2:34][C:29]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:30][CH2:31]3)=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C3(O)CCC4(CC3)OCCO4)c(F)c2F)c(F)c1F
Reaction time: 2 h

Procedure:
4′-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl (s75) (50.0 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M; in n-hexane-cyclohexane; 222 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1,4-Dioxaspiro[4.5]decan-8-one (s7) (28.8 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 8-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decan-8-ol. The compound was mixed with p-toluenesulfonic acid (1.5 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (100 ml) and Solmix A-11 (100 ml), to which Pd/C (2.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from Solmix A-11 to give 8-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decane (s76) (31.9 g). The yield based on the compound (s75) was 42.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].C(O)=O>C1(C)C=CC=CC=1>[CH2:17]([N:19]([C:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH:14]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCNCC
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCN(CC)C1=CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
5.0 g (22.7 mmol) of 1-(4-nitrophenyl)-4-piperidone, 16.0 g (220 mmol) of diethylamine and 5 ml of formic acid in 150 ml of toluene were refluxed with a water trap for 5 h. The solvent was removed under reduced pressure, and 4-(N,N-diethylamino)-1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine was obtained as crude product. 3.45 g (92.5 mmol) of sodium borohydride were added a little at a time to this crude product in 150 ml of ethanol at 10° C. The mixture was left to stir at room temperature for 3 h and then the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride, and the organic phase was dried and concentrated under reduced pressure. This crude product was dissolved in a little isopropanol, and ethereal hydrogen chloride solution was added to give 5.5 g of 4-(N,N-diethylamino)-1-(4-nitrophenyl)piperidine hydrochloride, which was identical to the product from preparation 1. Melting point 183°- 184° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[N:11]1([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1csc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperazinecarboxylate (1.0 g, 3.4 mmol) (i.e. the product of Example 30, Step A) in 10 mL of dichloromethane was treated with 2 M hydrogen chloride in diethyl ether (10 mL) and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was evaporated in vacuo to give 1.0 g of the title compound as a white solid. This compound was of sufficient purity to use in subsequent reactions.