Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:3]=1.FC1C=C(CC(OC(C)(C)C)=O)C=C2C=1C=CC=N2.Cl>C(O)(=O)C.O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Cc1cc(F)cc2ncccc12
Agent: CC(C)(C)OC(=O)Cc1cc(F)c2cccnc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(F)cc2ncccc12
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of tert-butyl 2-(7-fluoroquinolin-5-yl)acetate and tert-butyl 2-(5-fluoroquinolin-7-yl)acetate (0.50 g, 1.91 mmol) in acetic acid (5 mL) was added 4M hydrochloric acid in 1,4-dioxane (10 mL). The reaction mixture was heated in an oil bath set at 60° C. under condenser with N2 (g) inlet overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica, 60:40 ethyl acetate/hexane followed by 20:80 methanol/dichloromethane). Further purification and separation by prep HPLC yielded the single regio-isomer 2-(7-fluoroquinolin-5-yl)acetic acid (0.025 g, 6%). Retention time (min)=0.337, method [4], MS (ESI) 206.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: Nc1ccc(I)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2-fluoro-4-iodophenylamine (1.50 g) was dissolved in dichloromethane (40 ml) and to the solution were added pyridine (1.02 ml) and methanesulfonylchloride (700 μl). The mixture was stirred at room temperature for 1 hour and 1.5 N aqueous hydrochloric acid was added thereto to quench the reaction. The resulting mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was column-chromatographed (ethyl acetate/hexane=1/1) to yield the compound 3-2 (1.89 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:36][CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C19H16FN3O2S, 369.09; m/z found, 370.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.55-8.49 (m, 1H), 8.33 (s, 1H), 8.13 (dd, J=8.0, 1.2, 1H), 8.11-8.05 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.48 (dd, J=7.6, 1.1, 1H), 7.43-7.36 (m, 2H), 2.35-2.26 (m, 1H), 1.04-0.91 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH2:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH:43][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Indazole-3-carboxylic acid (30 mg; 0.182 mmol), DCC (56 mg, 0.273 mmol) and DMAP (2 mg) were dissolved in DCM:DMF (1:1, 4 ml). 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine (46 mg, 0.182 mmol) was added and the reaction mixture was stirred for overnight at RT. DCM (30 ml) was added and organic layer washed with water (3×15 ml). Combined organic phases were dried over Na2SO4, evaporated and purified by chromatography (silica column, eluent: 1% MeOH/DCM) to give 25 mg (34%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.00 (t, 2H), 3.63 (q, 2H), 6.37 (d, 1H), 7.02 (d, 1H), 7.23 (t, 1H), 7.41 (t, 1H), 7.60 (d, 1H), 7.61 (d, 2H), 7.85 (d, 1H), 8.16 (d, 1H), 8.54 (d, 1H), 13.56 (s, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:15][CH2:16]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
Diethyl malonate (9.8 g, 1.1 eq) was added to a stirred suspension of sodium hydride (60% in mineral oil, 2.09 g) in DMF (88 mL) over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL) and brine (100 mL), dried (MgSO4) and filtered. Evaporation of the volatiles under reduced pressure gave 10.0 g of crude product which was purified by chromatography over silica gel (hexane/EtOAc) gave of diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (7.0 g). 1H-NMR (CDCl3, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d, 2H).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:23]COC)[C:13]=1[CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH3:32]O>>[CH3:32][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([OH:4])[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:23])[CH:11]=1
Reactant: COCOc1cc(C(=O)O)cc(OCOC)c1C/C=C/c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(C/C=C/c2ccccc2)c(O)c1
Yield: 73 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzoic acid (220 g) (18 g, 0.05 mol) in MeOH (300 mL) was added catalytic amount of conc. H2SO4 (3 mL) in one portion. The mixture was refluxed overnight. The solution was concentrated. The residue was dissolved in CH2Cl2 (75 mL) and washed with sat. NaHCO3 (25 mL). The organic layers were dried and concentrated to give a brown solid (12 g, 73% yield). 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 2H), 7.11-7.34 (m, 5H), 6.93 (s, 2H), 6.32 (s, 2H), 3.77 (s, H), 3.42 (s, 2H).
Reaction SMILES: F[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+].O>CO>[F:10][C:3]1[CH:2]=[CH:9][CH:8]=[C:7]([O:12][CH3:11])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cccc(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(F)c1C#N
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
640.5 g (4.6 mol) of difluorobenzonitrile were dissolved in 3.5 l of methanol and then cooled to 0-5° C. 828.8 g of 30% strength sodium methoxide solution were added dropwise in this temperature range, and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was added to 20 l of water and the precipitate was filtered off with suction and washed twice with water and twice with heptane. The solid was dried in vacuo at 50° C. Yield: 740 g (99% of theory) of a white solid with a purity of >95% according to GC. 1H NMR (in CDCl3): δ=3.95 ppm (s, 3H, O—CH3), 6.85 ppm (m, 2H, arom. H), 7.5 ppm (q, 1H, arom. H).
Reaction SMILES: C[N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1.C(OCC)C>[C:21]([N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the solution of 1.9 g of 2-methyl-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 50 ml of benzene, 2.14 g of ethyl chloroformate are added and the mixture is refluxed for 3 days. It is diluted with diethyl ether, washed with N hydrochloric acid and with both saturated aqueous sodium chloride and sodium bicarbonate, dried and evaporated, to yield the 2-carbethoxy-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine showing in the NMR-spectrum peaks at 8.55(t), 6.60(m), 5.65(q) and 3.90(d) ppm, and in the mass-spectrum a molecular ion of 311.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:21][CH:20]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(Br)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Br)cc1
Yield: 76.8 %

Procedure:
Example 20 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-bromo-4-isocyanatobenzene (0.027 g) to give the title compound (0.033 g). LC-MS (System A): Rt 2.49 mins, Mass Spectrum m/z 472 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=2)[N:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (300 mg, 2.0 mmol), 4-aminobenzoic acid methyl ester (302 mg, 2.05 mmol) in acetonitrile (3 mL), DIPEA (0.35 mL, 2.0 mmol) was added. After 30 minutes at room temperature, resulting solid was filtered and washed with acetonitrile and dried to give methyl 4-(4-chloro-1,3,5-triazin-2-ylamino)benzoate (Int-1). MS found for C11H9ClN4O2 as (M+H)+ 265.07. A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)H-imidazo[1,2-a]pyridine (139 mg, 0.57 mmol), Int-1 (150 mg, 0.57 mmol), 2.0M Sodium carbonate solution (0.6 mL, 1.25 mmol), PdCl2(dppf) (14 mg, 0.02 mmol), dioxane (2 mL) was heated in a microwave (Emry's Optimizer) at 125° C. for 15 minutes. The reaction mixture was then poured into water and the resulting solid was filtered and washed with ether and dried to give 5 methyl 4-(4-(H-imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-ylamino)benzoate (Int-2) which was used without further purification. MS found for C18H14N6O2 as (M+H)+ 347.25. To solid Int-2 in MeOH (5 mL) was added 1N NaOH (5 mL) and stirred at 60° C. for 2 hours. The reaction mixture was concentrated, diluted with water and neutralized with 6N HCl (1.5 mL). The aqueous phase was then extracted with ethyl acetate and the combined organic layers were concentrated to give 4-(4-(H-imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-ylamino)benzoic acid (Int-3). MS found for C17H12N6O2 as (M+H)+ 333.34. To Int-3 in DMF (6 mL), was added HATU (260 mg, 0.7 mmol), 1,2-phenylenediamine (123 mg, 1.1 mmol) and DIPEA (0.4 mL, 2.3 mmol) and stirred at room temperature for 3 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound, after lyophilization. MS found for C23H18N8O as (M+H)+ 423.09. 1H NMR (400 MHz, dmso-d6): δ 10.49 (s, 1H); 9.89 (brs, 1H); 9.56 (s, 1H); 8.78 (s, 1H); 8.57 (s, 1H); 7.99-7.77 (m, 6H); 7.54 (t, J=7.6 Hz, 1H); 7.23 (t, J=6.4 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 6.94 (m, 1H); 6.75 (d, J=8.0 Hz, 1H); 6.57 (t, J=7.6 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.S(Cl)([Cl:21])=O.[Cl-].[Li+].O>CN(C)C=O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][Cl:21])=[CH:4][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCl)cc1-c1ccccc1

Procedure:
To a solution of 10.5 g (43.3 mmol) of methyl 4-hydroxymethyl-2-phenylbenzoate in 50 mL of N,N-dimethylformamide was added 4.5 mL (62 mmol) of thionyl chloride, and 2.0 g (47 mmol) of lithium chloride. The reaction was complete upon dissolution of the lithium chloride. The solution was poured into 350 mL of water, then extracted with diethyl ether (3×100 mL). The combined diethyl ether layers were back extracted with water (2×100 mL), saturated aqueous sodium bicarbonate solution (1×100 mL), and brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to 11.1 g (98%) of 4-chloromethyl-2-phenylbenzoic acid methyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)c1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccccc3C(F)(F)F)cc2)c1C
Yield: 13.4 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.25 g, 0.67 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.038 g, 0.033 mmol), crude 1-bromo-4-(2-(trifluoromethyl)phenylsulfanyl)-benzene (0.27 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-phenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.045 g, 16%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[CH:41]1>>[CH3:39][N:40]1[CH:44]=[C:43]([S:45]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][N:6]3[C:2](=[O:1])[C:3]([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)([CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[NH:4][C:5]3=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[O:16])[CH2:9][CH2:10]2)(=[O:47])=[O:46])[N:42]=[CH:41]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Product: Cn1cnc(S(=O)(=O)N2CCC(CN3C(=O)C(Cc4ccncc4)(Cc4ccncc4)NC3=CC(=O)c3ccc(C#N)cc3)CC2)c1

Procedure:
According to the procedure of Example 13, the title compound of 40B (100 mg, 0.20 mmol) and 1-methylimidazol-4-ylsulfonyl chloride (50 mg, 0.30 mmol) were reacted to generate the title compound as a white solid (9 mg, 0.014 mmol, 7% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]([C:19](OC(C)(C)C)=O)[NH:11][C:12](OC(C)(C)C)=O)=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:26]OC(OC)CC(OC)OC.CCO.OS(O)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:10]2[CH:19]=[CH:26][CH:12]=[N:11]2)=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cnc(F)c1F
Reactant: COC(CC(OC)OC)OC
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ncc(Cl)c(-n2cccn2)c1F
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 74.2 %

Procedure:
To a stirred mixture of di-tert-butyl 1-(5-chloro-2,3-difluoropyridin-4-yl)hydrazine-1,2-dicarboxylate (4.0 g, 0.010 mol, 1.0 equiv) and 1,1,3,3-tetramethoxypropane (17 mL, 0.10 mol, 10 equiv) was added a mixture of EtOH (100 mL) and concentrated H2SO4 (28 mL). The vessel was then sealed and heated to 45° C. After stirring for 45 minutes, the mixture was diluted with EtOAc (300 mL) and washed with water (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified over silica gel using 100% dichloromethane as eluent to give the desired product (1.6 g, 70%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=[O:9])[CH:2]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:8](=[O:9])[CH2:7][C:3]1[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-m-tolylacetic acid (1 g, 6.7 mmol), N,O-dimethylhydroxylamine hydrochloride (654 mg, 6.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.7 mmol), hydroxybenzotriazole (910 mg, 6.7 mmol) and triethylamine (3.38 g, 33.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-m-tolylacetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=10:1) to afford N-methoxy-N-methyl-2-m-tolylacetamide (900 mg, yield 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([OH:26])[CH:28]=1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3C(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl-4-amino-2-methyl-5-(piperidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 111b) and 3-hydroxybenzoic acid as a white solid (28%). MS 464 (MH+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[NH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:16][C:2]([F:1])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:19][CH:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=2)[C:21]([OH:23])=[O:22])=[O:13])=[CH:14][CH:15]=1
Reactant: NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Agent: Cl
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCCC(F)(F)F)cc1
Yield: 95 %

Procedure:
A reaction similar to that described in Example 70 (70a) was conducted using 4-(4,4,4-trifluorobutoxy)benzoic acid (6.21 g) prepared in Example 81 (81a) and 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (7.20 g) prepared in Reference Example 2 to give 11.4 g of the title compound (white powder).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[CH:14]=1>O.C(O)(=O)C>[CH3:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[C:14]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: COCCOCCOc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOCCOc1nc(N)nc(N)c1N=O
Reaction time: 2 h
Yield: 349.9 %

Procedure:
A solution of 9.11 g (0.013 mol) of sodium nitrite in 40 ml of water was added in drops to a solution of 22.8 g (0.100 mol) of 6-[2-(2-methoxyethoxyl)ethoxy]pyrimidine-2,4-diamine in 200 ml of acetic acid (10% in water) over 1 h at 3-5° C. while stirring was performed. Then stirring was performed further for 2 h at room temperature. The resulting precipitate was sucked off, post-washed with water, and dried, whereby 6-[2-(2-methoxyethoxyl)ethoxy]-5-nitrosopyrimidine-2,4-diamine (11.7 g, 45%) was obtained as a purple solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccncc2)nc(N2CCOCC2)n1
Temperature: 120 °C
Yield: 19.9 %

Procedure:
A mixture of 0.048 g (0.51 mmol) of 4-aminopyridine and 0.095 g (0.26 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (1.5 mL) was heated at 120° C. for 1 hr. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration and washed with water to give 0.022 g (20% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyridinyl)-1,3,5-triazin-2-amine: mp (MeOH) 222-224° C.; 1H NMR (DMSO-d6) δ 10.30 (br s, 1H), 8.59-8.46 (m, 3H), 7.91-7.86 (m, 4H), 7.55-7.44 (m, 2H), 3.88 (br s, 4H), 3.77-3.76 (m, 4H); HRMS (FAB+) MNa+ Calcd. for C20H18F2N8NaO: m/z 447.1466. Found: m/z 447.1464; HRMS (FAB+) MH+ Calcd. for C20H19F2N8NO: m/z 425.1644. Found: m/z 425.1629.