Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[NH:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2]>[O-2].[O-2].[Mn+4]>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[C:19]([C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCN3
Agent: [Mn+4]
Agent: [O-2]
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3ncccc3c2c1-c1ccc(OC)c(OC)c1

Procedure:
In the same manner as in Example 7A, the compound obtained in Example 61A and activated manganese dioxide were reacted to yield ethyl 2-diethylaminomethyl-4-(3,4-dimethoxyphenyl)thieno[2,3-b:5,4-b']dipyridine-3-carboxylate, which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 156 to 157° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][CH:37]=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=4)=[O:31])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][CH:37]=[C:36]([C:41]([F:43])([F:44])[F:42])[CH:35]=4)=[O:31])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)c2cc3ccc(C(F)(F)F)cc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)c2cc3ccc(C(F)(F)F)cc3[nH]2)c1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed a solution of methyl 3-(3-((4-(piperidin-1-yl)-2-(6-(trifluoromethyl)-1H-indole-2-carbonyl)phenyl)carbamoyl)benzylthio)-propanoate (60 mg, 0.10 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (100 mg, 2.50 mmol, 26.00 equiv) in water (2 mL). The solution was stirred overnight at 15° C. The solution was then diluted with 30 mL of water. The mixture was washed with 1×20 mL of ethyl acetate. The pH value of the solution was adjusted to 5 with 1N hydrochloric acid. The resulting solution was extracted with 2×30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 2 mL of ether. The product was precipitated by the addition of hexane. The solids were collected by filtration. This resulted in 20 mg (34%) of 3-(3-((4-(piperidin-1-yl)-2-(6-(trifluoromethyl)-1H-indole-2-carbonyl)phenyl)-carbamoyl)-benzylthio)-propanoic acid as a orange solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.30 (1H, s), 10.36 (s, 1H), 7.94-7.91 (d, 1H), 7.76 (s, 1H), 7.68-7.58 (m, 2H), 7.65 (s, 1H), 7.47-7.44 (d, 1H), 7.40-7.32 (m, 2H), 7.25-7.24 (d, 2H), 7.12 (s, 1H), 3.74 (s, 2H), 3.19 (s, 4H), 2.5 (m, 4H), 1.56-1.64 (m, 6H), MS (ES, m/z): 610 [M+H]+.
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C)=C2)C=CC=1C#N.C([O:33]CCCN)(C)C.[CH:38]([O:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]1[CH:53]=[C:52]([N:54]2[C:58]3=[N:59][CH:60]=[CH:61][C:62]([C:63]4[CH:64]=[N:65][C:66]5[C:71]([CH:72]=4)=[CH:70][CH:69]=[CH:68][CH:67]=5)=[C:57]3[C:56]([CH3:73])=[CH:55]2)[CH:51]=[CH:50][C:47]=1[C:48]#[N:49])([CH3:40])[CH3:39]>>[CH:38]([O:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]1[CH:53]=[C:52]([N:54]2[C:58]3=[N:59][CH:60]=[CH:61][C:62]([C:63]4[CH:64]=[N:65][C:66]5[C:71]([CH:72]=4)=[CH:70][CH:69]=[CH:68][CH:67]=5)=[C:57]3[C:56]([CH3:73])=[CH:55]2)[CH:51]=[CH:50][C:47]=1[C:48]([NH2:49])=[O:33])([CH3:39])[CH3:40]
Reactant: Cc1cn(-c2ccc(C#N)c(NCCCOC(C)C)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CC(C)OCCCN
Agent: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: Cc1cn(-c2ccc(C(N)=O)c(NCCCOC(C)C)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 38 %

Procedure:
According to Example 1(6), a crude product of 2-(3-isopropoxypropylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using 3-isopropoxypropylamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (59) (the second stage yield: 38%) was prepared as a white solid using 2-(3-isopropoxypropylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@@H:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.CCN(CC)CC.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:36]([O:26][C@@H:25]1[C:10]2[C:11](=[N:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[O:22][C:23]([CH3:28])([CH3:27])[CH2:24]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)C[C@H](O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@H](OC(=O)c2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reaction time: 2 h

Procedure:
To a solution of the product of Step A (21.6 mg, 0.05 mmol), NEt3 (21 μL, 0.15 mmol), and catalytic amount of DMAP in 10 mL of CH2Cl2 at rt was added benzoyl chloride (11.5 μL, 0.10 mmol). After stirring for 2 h, the reaction was quenched by adding saturated aq NaHCO3 (5 mL) and the resulting mixture was stirred at rt for 30 min. The reaction mixture was partitioned between CH2Cl2 (50 mL) and saturated aq NaHCO3 (50 mL). The aq layer was separated and extracted with CH2Cl2 (3×10 mL). The organic layers were combined, dried over MgSO4, and concentrated. Chromatography on Biotage 40+S cartridges using 3:17 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.57 (s, 3H), 1.65 (s, 3H), 2.24 (dd, J=6.7, 14.2, 1H), 2.46 (dd, J=5.9, 14.3, 1H), 6.40 (t, J=6.2, 1H), 7.00 (d, J=8.4, 2H), 7.16-7.28 (m, 5H), 7.45-7.60 (m, 3H), 7.77 (s, 1H), 8.07 (d, J=7.5, 2H).
Reaction SMILES: [NH:1]([C:8]1[C:16]2[O:15][CH:14]([CH2:17][O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1C=CC(C)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([CH3:30])=[CH:4][CH:3]=4)[C:16]=3[O:15]2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Nc4ccccc4)c3O2)cc1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Yield: 29.3 %

Procedure:
Treatment of (±)-(7-anilino-2,3-dihydro-1-benzofuran-2-yl)methyl-4-methylbenzenesulfonate (0.96 g, 3.0 mmol) in toluene (20 mL) with 1-bromo-4-methylbenzene (0.513 g, 3.0 mmol)dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.061 g, 0.075 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.125 g, 0.225 mmol), sodium tert-butoxide (0.18 g, 1.875 mmol) the reaction was allowed to reflux 3 h. The solvent was removed in vacuo. The residue was washed with water (100 mL) and ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:10) afforded 0.36 g (29%) of (±)-{7-[(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow solid. mp 118-120° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[N:11]1([C:14]2[N:19]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3ncnc(N4CCNCC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting from 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,5-triazin-2-yl]piperazine-1-carboxylic acid tert-butyl ester. Product is the hydrochloride.
Reaction SMILES: [CH2:1]([C@@:3]1([CH:22](OCC)[O:23]CC)[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][CH:12]=2)[C:4]1=[O:21])[CH3:2].C(O)(=O)C.O>C(Cl)(Cl)Cl>[CH2:1]([C@@:3]1([CH:22]=[O:23])[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][CH:12]=2)[C:4]1=[O:21])[CH3:2]
Reactant: CCOC(OCC)[C@]1(CC)CCCN(CCc2c[nH]c3ccc(F)cc23)C1=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC[C@@]1(C=O)CCCN(CCc2c[nH]c3ccc(F)cc23)C1=O

Procedure:
39.05 g of (S)-3-ethyl-3-diethoxymethyl-1-[2-(5-fluoro-indol-3-yl)-ethyl]-2-piperidone are mixed with 80 cc of 99% acetic acid and 20 cc of water. The mixture is heated to the boil for half an hour in an atmosphere of nitrogen. After cooling, the solvent is removed by evaporation; the oily residue is subsequently taken up twice in 50 cc amounts of toluene and again concentrated by evaporation in order to remove most of the water and acetic acid. After crystallization from ethyl acetate/hexane (1:2) at 0°, brownish crystals are obtained. M.P. 116°, [α]D20 = -31.5° (1%, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH3:23])[CH:3]=1.Cl[S:25]([OH:28])(=[O:27])=[O:26]>C(Cl)Cl>[CH2:21]([O:20][C:18]([C:10]1[CH:11]=[N:12][C:13]2[N:14]([N:15]=[CH:16][C:17]=2[S:25]([OH:28])(=[O:27])=[O:26])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:23])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(F)cc1C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Ethyl 7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.500 g, 1.59 mmol) obtained in step 1 was dissolved in methylene chloride (6 mL), chlorosulfonic acid (0.21 mL, 3.19 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, a 1/1 mixed solvent of diisopropyl ether and 2-propanol was added, and the mixture was stirred at room temperature for 1 hr. The resulting crystals were suction filtered and washed with 2-propanol to give the title compound (0.580 g, 92%). ESI-MS m/z: 395 (M+H)+; 1H-NMR (CDCl3, δ): 1.13 (t, J=7.2 Hz, 3H), 2.29 (s, 3H), 3.94 (q, J=7.2 Hz, 2H), 6.96-7.46 (m, 4H), 8.28 (s, 1H), 8.50 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC1CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCC2)CC1

Procedure:
The title compound is synthesized by reductive amination of 1-Boc-piperazine and Cyclopentane-carboaldehyde analogously to the preparation of Example 233 as a colorless oil; ES-MS: M+H=269.2; TLC: Rf=0.45 (DCM/EtOAc=1:1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:7])[CH2:5][CH3:6])[CH3:2].[CH3:8][OH:9]>F[B-](F)(F)F.C[N+](C)(C)C>[CH3:8][O:9][CH:1]([NH:3][C:4](=[O:7])[CH2:5][CH3:6])[CH3:2]
Reactant: CO
Reactant: CCNC(=O)CC
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: CCC(=O)NC(C)OC
Temperature: 40 °C

Procedure:
36.9 g of methanol was charged into an electrolysis cell according to Example 5, wherein 0.37 g of tetramethyl ammonium tetrafluoroborate were dissolved as conducting salt. After switching on the electrolysis current, the anode current density was 2 A/dm2. The temperature was maintained at 40° C. during the electrolysis. Agitation was performed by a magnetic stirrer at from 30 to 35 revolutions per minute. After the passage of a current quantity of 4.06 Faraday per mole of N-ethylpropionic acid amide, the current was switched off. The calculated average cell tension was 54.9 volts. After work up of the electrolysis solution in known manner there were obtained 24.4 g of N-(α-methoxyethyl)-propionic acid amide (melting point 29°-32° C., nD35 = 1.4333), representing a material efficiency of 80.7% and a current efficiency of 40.4%.
Reaction SMILES: C(S[C:4](=[O:23])[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.O.[NH2:25][NH2:26]>CCO>[F:20][C:19]([F:22])([F:21])[CH:5]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:26][NH:25][C:4]1=[O:23]
Reactant: CCSC(=O)C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2ccc(C(F)(F)F)cc2)CC1C(F)(F)F
Temperature: 23 °C
Yield: 99.1 %

Procedure:
A mixture of 4-oxo-2-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-thiobutyric acid S-ethyl ester (example C.26 step 4) (16.0 g, 45 mmol) and hydrazine monohydrate (2.39 mL, 49 mmol) in EtOH (250 mL) was refluxed for 18 h under nitrogen atmosphere. Cooled to 23° C., the solvents were evaporated to leave the title compound as a brown solid (13.83 g, 100%), which was used without further purification [according to Synthesis 2003, (3), 436.]. MS (ISP) 311.1 [(M+H)+]; mp 135-136° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:16][C:17]1/[C:22](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:21]=[CH:20][C:19](=[O:23])[CH:18]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(/N=C2\C=CC(=O)C=C2Cl)c(=O)n(-c2ccccc2)n1C

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 3-chlorophenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: C[O+](C)C
Reactant: Cc1cc[n+]([O-])cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
4-methylpyridine-N-oxide (3.7 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added to the mixture, and the mixture was stirred for 90 minutes at room temperature. The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added under heat reflux. An aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was further added to the mixture after 30 minutes, and the mixture was stirred for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-methyl-2-pyridinyl)methanol (2.9 g). (4-methyl-2-pyridinyl)methanol (2.5 g) was dissolved in methylene chloride (25 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (3.8 ml) was added to the mixture at 0° C. and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and a solution (9.1 ml) of the obtained residue in water was added dropwise to an aqueous solution (64 ml) of 4-aminothiophenol (1.82 g) and sodium hydroxide (1.74 g) in methanol. The mixture was stirred for 1 hour at room temperature, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[(4-methyl-2-pyridinyl)methyl]sulfanyl]aniline (2.0 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[CH3:17][N:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[N:13]=[C:12]1[CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2ccccc2n1C
Product: Cn1c(CCC#Cc2ccccn2)nc2ccccc21
Yield: 30.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (100 mg, 0.49 mmol) and 2-but-3-ynyl-1-methyl-1H-benzoimidazole (90 mg, 0.49 mmol). Reaction time: 18 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 39 mg (0.15 mmol, 31%) of 1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a brown solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][NH:6][CH2:7][CH:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH3:5][N:6]([CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C(CCc1ccccc1)CNC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)CN(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 10.3 g of phosgene in 45 ml of toluene, the solution of 20.3 g of ethyl 2-methylaminomethyl-4-phenylbutyrate (described in example 1) in 19 ml of toluene was added over a period of 20 minutes. The mixture was stirred at room temperature for 4 hours and evaporated to dryness. The residue was stirred for 10 minutes with 100 ml of ether, the solids were filtered, the filtrates were evaporated to dryness and the residue was distilled under high vacuum to give N-methyl-N-(2-ethoxycarbonyl-4-phenylbutyl)carbamoyl chloride, bp 179°-189°/1 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[C:26]([N:39]=[C:40]=[O:41])(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:26]([NH:39][C:40](=[O:41])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCCCCC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1CC
Yield: 71 %

Procedure:
The compound 19 (345 mg, 1.00 mmol) was converted to the carbamate with lauroyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 84 (430 mg, 71%) as crystals. Mp. 100-102° C. Rf 0.32 (1:2 EtOAc - hexane).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][N:8]=1.[CH2:16](O)[CH3:17]>O>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][N:8]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccnc(Cl)c1
Reaction time: 16 h

Procedure:
1 ml of concentrated sulfuric acid is added to a solution of 2.2 g of 2-chloropyridine-4-carboxylic acid in 30 ml of ethanol. The reaction mixture is refluxed with stirring for 16 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 30 ml of water and then extracted with 3×30 ml of dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The oil thus obtained is purified by filtration through 13 g of silica, eluting with dichloromethane. The fractions containing the expected product are concentrated to dryness under reduced pressure. 2.1 g of ethyl 2-chloropyridine-4-carboxylate are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][NH:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1.[Sn](Cl)Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][NH:6][CH:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(NCc2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc(C(NCc2ccc(F)c(F)c2)c2cccc(N)c2)cc1
Yield: 113.9 %

Procedure:
Following a similar procedure to that described in Example (94b), 12.68 g of N-(3,4-difluorobenzyl)-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above]. 25.03 g of tin (II) chloride and 120 ml of ethanol were reacted, to obtain 13.32 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2.S(=O)(=O)(O)O.[I:26](O)(=O)=O.II>C(O)(=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[I:26])[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: [O-][I+2]([O-])O
Reactant: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)ccc21
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(I)cc21
Yield: 49.4 %

Procedure:
288 mg of 6-trifluoromethyl-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is mixed in 5 ml of glacial acetic acid with 0.05 ml of water, 0.012 ml of concentrated sulfuric acid, 34.4 mg of iodic acid and 88.4 mg of iodine and heated for 4 hours to 80° C. After concentration by evaporation, it is taken up in water, adjusted alkaline and extracted with methylene chloride. The organic phase is dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with toluene:glacial acetic acid:water=10:10:1 as eluant. 40 mg of 6-trifluoromethyl-7-iodo-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is obtained. The residue is starting material, which can be used again in the reaction.