Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](O)=[O:34]>>[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:34]
Reactant: O=C(O)c1cncc(Cl)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cncc(Cl)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-chloro-nicotinic acid.
Reaction SMILES: O.NN.[CH2:4]([N:11]=[C:12]=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:14]12CCN(CC1)CC2.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:4]([NH:11][C:12]([NH2:14])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C=NCc1ccccc1
Reactant: C1CN2CCN1CC2
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Example 190, (1) (87 mg) was dissolved in toluene (2 ml), and benzyl isocyanate (14 μl) was added to the solution. 1,4-Diazabicyclo-[2,2,2]octane (4.7 μl) was added to the mixture under ice cooling, and the resulting mixture was warmed to room temperature and stirred for 2 hours. Ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=20:1:0.1) to obtain a benzylurea compound (62 mg). (2) By using the compound obtained in (1) mentioned above (62 mg) as a starting material, a deprotected compound (55 mg) was obtained in the same manner as that of Example 2, (2). (3) By using the compound obtained in (2) mentioned above (55 mg) as a starting material, the compound shown in Table 5 (20 mg) was obtained in the same manner as that of Example 11.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1
Reactant: OCc1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of {2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-methanol (370 mg, 1 mmol) in DCM (20 mL) was added Dess-Martin periodinane (467 mg, 1.1 mmol) and the reaction mixture stirred at RT for 30 minutes. The reaction mixture was diluted with DCM (20 mL) and the solution washed with sodium hydroxide solution (1 M, aqueous). The organic layer was separated, dried (MgSO4) and then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 90% ethyl acetate in cyclohexane) to yield the title compound as a white solid (253 mg, 70%). LCMS: RT=4.10, M+H+=364
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)[CH3:22]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:28][CH2:27]2)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 556.9 [M+H]+; single peak at tR=3.36 min (System 1); Rf=0.13 (CH2Cl2/MeOH+1% NH33aq, 9:1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:25]([F:28])([F:27])[F:26])([C:5]1[N:6](C)[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)[NH2:4].ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:28][C:25]([F:26])([F:27])[C:3]1([C:2]([F:29])([F:30])[F:1])[C:5](=[N:9][C:8](=[O:39])[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:4]1
Reactant: Cc1ccc(-c2nc(C(N)(C(F)(F)F)C(F)(F)F)n(C)c2-c2ccc(C)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)N=C2NC(c3ccc(C)cc3)=NC2(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 4.1 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-methylphenyl)-1-methyl-1H-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, m-chloroperbenzoic acid (0.40 g, 2.3 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution. 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue (75% benzamide and 25% ester analyzed by HPLC with a (DL)-phenylglycine column eluted with 10% isopropanol-hexane) was purified by HPLC on a silica sorbax column which was eluted with dichloromethane to give the title compound (40 mg, 4%) as a semisolid: MS m/e 442 (M+ +H); 1H NMR (CDCl3 /TMS) δ 3.00(s,6H,CH3), 3.13(s,3H,NCH3), 7.27-7.37(m,4H,Harom), 7.57(d,J= 7 Hz,2H,Harom), 7.90(d,J=7 Hz,2H,Harom).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:30])[N:16]([CH2:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)O1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:30])[N:16]([CH2:18][C:19]4[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccc(O)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 90 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (64 mg, 0.13 mmol) in THF (2 mL) at room temperature under argon was added 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (84.9 mg, 0.39 mmol), Pd(dppf)Cl2.CH2Cl2 (10.5 mg, 0.013 mmol), and K3PO4 (82 mg, 0.39 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 48 h, and then cooled to room temperature. Analysis by HPLC/MS indicated that starting material was still persent and one major new product had formed. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, 10 mg, 15%. HPLC/MS: retention time=3.34 min, [M+H]+=511. 1H NMR (CDCl3): δ 7.82 (d, J=7.0 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.25 (m, 3H), 7.06 (dd, J=2.2, 6.6 Hz, 4H), 6.66 (m, 3H), 5.26 (s, 2H), 4.1 (br s, 1H), 2.73 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1I.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1cc(I)c(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Temperature: 80 °C
Yield: 23.5 %

Procedure:
To a solution of methyl 5-chloro-4-iodo-2-thiophenecarboxylate (1.75 g, 5.8 mmol) in dioxane/H2O (50:5 mL) was added K2CO3 (3.4 g, 24.9 mmol), tetrakistriphenylphosphine Pd(0) (0.96 g, 0.83 mmol), and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (3.4 g, 16.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 15 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 4:1) to give the title compound (0.35 g, 24%) as a yellow oil: LC-MS (ES) m/z=257 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:19]3[C:11](=[CH:12][C:13]4[CH:14]([C:21]5[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=5)[C:15](=[O:20])[NH:16][C:17]=4[CH:18]=3)[NH:10][C:9]2=[O:28])=[CH:4][CH:3]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(=O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:14]2[C:15](=[O:20])[NH:16][C:17]3[C:13]=2[CH:12]=[C:11]2[C:19](=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[C:9](=[O:28])[NH:10]2)[CH:18]=3)=[CH:22][CH:23]=1
Reactant: O=C1Nc2cc3c(cc2C1c1ccc(Br)cc1)NC(=O)C3c1ccc(Br)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Product: O=C1Nc2cc3c(cc2=C1c1ccc(Br)cc1)NC(=O)C=3c1ccc(Br)cc1
Temperature: 50 °C
Yield: 62.5 %

Procedure:
3,7-Bis-(4-bromo-phenyl)-5,7-dihydro-1H,3H-pyrrolo[2,3-f]indole-2,6-dione (7.250 g, 14.55 mmol) (1.2) was dissolved into acetic acid (215 cm3), chloranil (7.157 g, 29.11 mmol) is added and the reaction mixture heated to 50° C. for 16 hours. After cooling down, the resulting precipitate is filtered and washed with acetic acid. The recovered solid is purified by trituration with nitrobenzene (120 cm3) at 200° C. followed by trituration with diethyl ether (100 cm3) to obtain the pure product (4.512 g, Yield: 63%). NMR (1H, 300 MHz, DMSO): δ 10.37 (br, 2H), 7.71 (d, J=8.7 Hz, 4H), 7.61 (d, J=8.7 Hz, 4H), 6.34 (s, 2H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.Cl.[OH-].[Na+]>[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[NH:8]1[CH2:11][CH:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [C+4]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
tert-Butyl 4-[1-(diphenylmethyl)azetidin-3-yl]piperidine-1-carboxylate (1.9 g) was mixed with MeOH (50 ml), and 1 M hydrochloric acid (5.1 ml) and 20% palladium carbon hydroxide (600 mg) were added thereto, followed by stirring at room temperature for 4 hours under hydrogen atmosphere of 3 atm. After returning to normal pressure under argon atmosphere, a 1 M aqueous NaOH solution (1 ml) was added thereto. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. CHCl3 and a 1 M aqueous NaOH solution were added to the obtained residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 4-(azetidin-3-yl)piperidine-1-carboxylate (1.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16][N:17]([CH3:27])C3C=CC(N(C)C)=CC=3)[S:14][CH:15]=2)[CH:8]=[C:7]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:6]=1[OH:32])([CH3:4])([CH3:3])[CH3:2].[N+:33]([C:36]1[CH:43]=[CH:42][C:39](C=O)=[CH:38][CH:37]=1)([O-:35])=[O:34].CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16][NH:17][CH2:27][C:39]3[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=3)[S:14][CH:15]=2)[CH:8]=[C:7]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:6]=1[OH:32])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1ccc(N(C)Cc2nc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cs2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(-c2csc(CNCc3ccc([N+](=O)[O-])cc3)n2)cc(C(C)(C)C)c1O
Yield: 55 %

Procedure:
0.5 g (1.57 mmol) of the compound of Example 9, 0.237 g (1.57 mmol) of 4-nitrobenzaldehyde and 1 g of previously activated pulverulent 4 Å molecular sieve are added successively to a flask containing 30 ml of anhydrous MeOH, under an inert atmosphere. The reaction mixture is vigorously stirred for 18 hours before the addition, by portions, of 0.06 g (1.57 mmol) of NaBH4. Stirring is maintained for another 4 hours before the addition of 5 ml of water. After a quarter of hour, the sieve is filtered out and the reaction mixture is extracted with two times 100 ml of CH2Cl2. The organic phase is washed successively with 50 ml of water then with 50 ml of salt water, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: 50% ethyl acetate in heptane). A yellow oil is obtained with a yield of 55%.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([S:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][N:28]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=2)=[CH:24][CH:23]=1
Reactant: CCCn1cc(-n2ccc3ccc(Cl)cc32)cn1
Reactant: CCOC(=O)c1cccc(S)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (372 mg, 2.03 mmol) in CH2Cl2 (20 mL) under inert atmosphere was added NCS (271 mg, 2.03 mmol) at 0° C.; warmed to RT and stirred for 45 min. To this, compound 2 (500 mg, 1.93 mmol) was added at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 3 (700 mg, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.76-7.74 (m, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.49-7.47 (m, 2H), 7.40 (s, 1H), 7.24-7.23 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.01-1.96 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H); LC-MS (ESI): 72.2%; m/z 440.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1>[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(C(=O)OC)cc1N
Yield: 96.1 %

Procedure:
3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared by following General Procedure B starting from 4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10% by weight, 82 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]#[N:9].O.[OH-].[Na+]>CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: N#CCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: NCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 555.6 %

Procedure:
The product of Example 41 (8.3 g, 10.5 mmol) dissolved in 25 ml of Et2O was added dropwise (15 min.) to a stirred slurry of lithium aluminium hydride(LAH) in 125 ml of dry Et2O under an Ar atmosphere at room temperature. After the addition was complete the reaction was stirred at room temperature an additional 18 h. With great care, 8.0 ml of water were added dropwise to the vigorously stirred reaction mixture. Following this, 8.0 ml of 4N NaOH were then carefully added. Finally 22 ml of H2O were added and the aluminum salts were filtered from the Et2O solution. The filtrate was concentrated to give 8.24 g of the title products which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cnc(OC)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(OC)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(6-methoxy-4-methylpyridin-3-yl)amino]-1H-benzimidazol-1-yl}butanoate (170 mg, 0.359 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (24 mg, 1.08 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 12 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (109 mg, 0.252 mmol, 70%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:29])=[O:4].[OH-].[Na+].Cl>CO>[NH2:27][CH:24]1[CH2:25][CH2:26][CH:21]([O:20][C:15]2[C:14]([NH:13][C:12]3[C:7]4[C:6]([CH3:29])=[C:5]([C:3]([OH:4])=[O:2])[S:28][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCC(N)CC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCC(N)CC3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 0.05 g 4-[2-(4-amino-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 1M sodium hydroxide solution in 5 ml MeOH was stirred at 70° C. for 1 hour. The reaction mixture was neutralized with 1M hydrochloric acid and concentrated. The residue was dissolved in DCM and MeOH, dried and filtered. The filtrate was concentrated. The residue was triturated with diethylether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxyphenylboronic acid (20.10 g) and ethyl 2-chloroisonicotinate (18.56 g) were suspended in a mixted solvent of toluene (200 mL) and THF (100 mL), and to the suspension 2 M sodium carbonate (200 mL) and tetrakis(triphenyl phosphine) palladium(0) (5.78 g) were added. The mixture was stirred at 90° C. overnight under an argon atmosphere. Ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with brine, dried over anhydrous sodium magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (5:1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(F)ccc2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Fluoro-2-methyl-benzoxazole (5.20 g, 0.0344 mol) was added to ice cooled Sulfuric acid (15.0 mL) such as to maintain the temperature below 25° C. After complete addition, a mixture of Sulfuric acid (2.75 mL) and Nitric acid (2.50 mL, 0.0536 mol) was added dropwise, maintaining the temperature below 18° C. After the addition was complete, the cooling bath was removed and the mixture was stirred at ambient temperature for 3 h, then was poured onto 100 mL ice with stirring. The solids were collected and washed with water (3×100 mL) and dried to give 5-Fluoro-2-methyl-6-nitro-benzoxazole as yellow solids. 1H-NMR (DMSO): 8.64 (d, 1H, J=5.4 Hz), 7.97 (d, 1H, J=10.8 Hz), 2.71 (s, 3H).