Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:16]([O:28][CH3:29])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:27][C:24]2[CH:23]=[CH:22][C:21]([C:17]3[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=3[O:28][CH3:29])=[CH:26][CH:25]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)n1
Temperature: 130 °C
Yield: 89.5 %

Procedure:
A mixture of 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (prepared according to US 2004/0266856 A1) (3.0 g, 11.99 mmol), 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (3.09 g, 13.08 mmol), potassium carbonate (6.5 g, 47.03 mmol) and potassium iodide (1.1 g, 6.626 mmol) in DMF (25 mL) was heated under microwave conditions at 130° C. for 15 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with 1/1 water/brine (2×100 mL) and brine (100 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, 120 g, 20% to 100% ethyl acetate in hexanes) to give 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid ethyl ester (4.35 g, 89.5%) as an orange oil. LC-MS (ES) calculated for C20H17F2NO4S, 405.42; found m/z 406 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:9])[F:11])[C:3]=1[CH2:12][OH:13]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)F)c(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 36.8 g (187.6 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol was added, with ice-cooling, into a solution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in 500 ml of methanol. The mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 35.4 g (yield: 95.4%) of (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [Li].[H-].[C:3]([N:11]1[CH2:24][CH2:23][C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]=3[NH:15][C:14]=2[CH2:13][CH2:12]1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH2:3]([N:11]1[CH2:24][CH2:23][C:22]2[C:21]3[CH:20]=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]=3[NH:15][C:14]=2[CH2:13][CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(-c4ccccc4)ccc3c2CC1
Agent: [H-]
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Yield: 90.6 %

Procedure:
A solution of lithium alunmnum hydride (1.40 g, 36.9 mmol) in tetrahydrofuran (15.0 mL) and a solution of 3-benzoyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.40 g, 3.82 mmol) in tetrahydrofuran (30.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give an oil. Column chromatography (silica gel, 20-30% EtOAc/heptane) afforded 1.22 g (90%) of the title compound as a white solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 7.74, 7.63-7.61, 7.48, 7.45-7.40, 7.36, 3.84, 3.00-2.92; 13C NMR (100 MHz, CDCl3) δ 142.5, 139.3, 136.9, 135.2, 134.5, 128.9, 128.6, 128.5, 128.3, 127.3, 127.0, 126.4, 119.1, 117.8, 112.8, 108.8, 60.7, 55.7, 53.8, 28.6, 23.9; IR (drift) 3385, 3371, 1467, 1344, 1328, 1120, 1027, 870, 820, 765, 756, 750, 735, 728, 698 cm−1; MS (EI) m/z 352 (M+); Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.24; H, 6.89; N, 8.05.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]=1[O:41][CH3:42]>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:28][C:27]=1[O:41][CH3:42]
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)ccc1O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 39 mg, 0.100 mmol) and 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, Buchs, Switzerland, 30 mg, 0.120 mmol) to give the title compound as a lightly yellow foam. (HPLC: tR 2.50 min (Method A); M+H=430 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.23 (s, 1H), 8.93 (s, 1H), 8.06-7.99 (m, 1H), 7.92-7.85 (m, 1H), 7.51-7.46 (m, 1H), 7.03-6.96 (m, 1H), 6.94-6.89 (m, 1H), 6.87-6.81 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:31])[C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:34]>O1CCOCC1>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:31])[C:23]4[CH:28]=[CH:27][C:26]([CH2:29][Cl:34])=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CO)cc2)cc1Nc1nccc(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.3 %

Procedure:
To the solution of Example K (410 mg, 0.99 mmol) in 1,4-dioxane (40 mL) was slowly added SOCl2 (650 mg, 5.50 mmol) at RT. After being stirred at RT for 3 h, the solvent and excessive SOCl2 was removed in vacuo to yield N-(3-(4-phenylpyrimidin-2-ylamino)-4-methylphenyl)-4-(chloromethyl)benzamide as a yellow solid (460 mg), which was used without further purification. 1H NMR (CDCl3-d6) δ: 8.42 (s, 1H), 8.22 (d, J=6.0 Hz, 3H), 8.05 (m, 1H), 7.94 (d, J=1.0 Hz, 2H) 7.53-7.62 (m, 5H), 7.26 (s, 2H), 4.63 (d, J=5.4 Hz, 2H), 2.44 (s, 3H); MS (ESI) m/e: 429.20 (M++1)
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:61](Br)[CH3:62].CN(C)C=O>C(OCC)(=O)C>[CH2:61]([N:9]1[CH2:10][CH2:11][C:6]2[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([C:36]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:7]=2[CH:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:62]
Reactant: CCBr
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(CC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl-1 H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.00 g), potassium carbonate (1.16 g), ethyl bromide (0.61 g) and dimethylformamide (10 ml) is stirred overnight at room temperature. The mixture is diluted with ethyl acetate, and the solution is washed with water, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.12 g) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:25])[NH:14][C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13](=[O:25])[N:14]([CH2:31][CH3:32])[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)Nc2ccc(C(F)(F)F)nc2)COC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(C(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(C(F)(F)F)nc1
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a stirred solution of (R)-2,2-dimethyl-4-(6-trifluoromethyl-pyridin-3-ylcarbamoyl)-oxazolidine-3-carboxylic acid tert-butyl ester (0.20 g, 0.51 mmol) in dimethylsulfoxide (4 ml) under an argon atmosphere was added sodium hydride (0.028 g, 0.59 mmol) and the mixture was stirred for 20 min. Iodoethane (0.05 ml, 0.61 mmol) was added and the mixture was stirred overnight at room temperature. Water (20 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. After removal of the solvent the residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1) to yield a light yellow oil (0.15 g, 70%), MS (ISP): 418.2 ([M+H]+).
Reaction SMILES: [CH2:1]([Li])CCC.[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]3=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.IC>CCCCCC.C1COCC1>[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]3[CH2:24][CH2:25][CH2:26][CH:27]([CH3:1])[C:22]3=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Nc2nccc(-c3cnc4n3CCCC4)n2)cc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCn2c(-c3ccnc(Nc4ccccc4)n3)cnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
n-Butyllithium (1.2 ml of a 1.6M solution in hexane, 1.92 mmol) was added slowly to a stirred solution of 2-anilino-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyrimidine (Example 2; 200 mg, 0.69 mmol) in dry THF (10 ml) cooled to −78° C. under nitrogen making sure that the reaction temperature remained below −65° C. The mixture was stirred at −70° C. for 15 minutes, then iodomethane (45 μl, 0.72 mmol) was added and the reaction stirred at −70° C. for 10 minutes and then allowed to warm and stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between EtOAc and water and the layers separated. The organic layer was washed with saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was purified by chromatography eluting with DCM/MeOH (98:2). The purified product was twice triturated with diethyl ether, collected by filtration and dried to give the title compound (33 mg, 16%) as a pale yellow solid. NMR: 1.37 (d, 3H), 1.57 (m, 1H), 1.92 (m, 1H), 2.07 (m, 2H), 2.97 (m, 1H), 4.25 (m, 1H), 4.65 (m, 1H), 7.02 (t, 2H), 7.15 (d, 1H), 7.33 (t, 2H), 7.72 (m, 3H), 8.38 (d, 1H), 9.42 (s. 1H); m/z 306.
Reaction SMILES: [CH3:1][O:2][C:3]1N=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15](C[CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1.[C:35]([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN(C=O)C>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([F:33])[CH:30]=1)[O:26][CH2:25][CH2:24][NH:22][CH:18]([CH3:17])[CH2:19][C:20]1[CH:15]=[N:14][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:35]=3)[N:9]=[CH:8][CH:7]=2)[CH:21]=1
Reactant: Fc1cc(F)cc(OCCBr)c1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nccc(-n3cc(CC(C)NCCOc4cc(F)cc(F)c4)cn3)c2c1
Reaction time: 48 h
Yield: 22.7 %

Procedure:
To a solution of 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (160 mg, 0.54 mmol) in DMF (3 mL) was added 1-(2-bromo-ethoxy)-3,5-difluoro-benzene (154 mg, 0.65 mmol), Cs2CO3 (267 mg, 0.82 mmol) and catalytic NaI (25 mg, 0.002 mmol). After 48 h at 50° C., the mixture was concentrated, and the residue was dissolved in EtOAc, washed with H2O, dried (MgSO4), and concentrated. The resulting residue was purified by basic reverse phase HPLC to provide 53.8 mg (29%) of the title compound as a brown gum. MS (ESI): exact mass calculated for C25H24F2N4O2, 450.48; m/z found, 451.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.74 (d, J=4.9, 1H), 8.01 (d, J=9.2, 1H), 7.95 (s, 1H), 7.71 (d, J=2.7 1 H), 7.50-7.48 (m, 2H), 6.61 (dd, J=9.2, 2.1, 2H), 6.52 (tt, J=9.2, 2.2, 1H), 4.14 (t, J=5.3, 2H), 3.90 (s, 3H), 3.13-3.09 (m, 4H), 3.00-2.96 (m, 1H), 2.83 (ddd, J=16.6, 10.7, 5.8, 1H), 2.54-2.51 (m, 1H), 2.26-2.23 (m, 1H), 1.85-1.77 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:9][NH2:10]>C(O)C>[CH:2]([C:3]1[NH:10][N:9]=[C:5]([NH2:6])[CH:4]=1)([CH3:8])[CH3:1]
Reactant: NN
Reactant: CC(C)C(=O)CC#N
Solvent: CCO
Product: CC(C)c1cc(N)n[nH]1
Yield: 103.3 %

Procedure:
A solution of 4-methyl-3-oxopentanenitrile (25 g, 225 mmol) and hydrazine (6.75 mL, 215 mmol) in ethanol (250 mL) was stirred at room temperature for 3 h, at which point LC/MS indicated exclusively product remained. The mixture was concentrated on a rotary evaporator followed by under high vacuum to give the desired product (27.8 g, 99%) as a yellow semisolid that was used without further purification.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14].[OH-].[K+].Cl>O>[CH3:1][S:2]([NH:10][C:11]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])(=[O:5])=[O:3]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 130 °C
Reaction time: 2 h

Procedure:
First, 2-methylsulfonamidoterephthalic acid was prepared as follows. 19.4 g methanesulfonic anhydride was placed in a flask and heated to produce a liquid. 10.3 g dimethyl 2-aminoterephthalate was added to the liquid over a period of 2-3 minutes. The mixture was initially heated at 130° C. for 15 minutes and then at 100° C. for 2 hours and 30 minutes. The mixture was then cooled, 50 ml of cold water added, the mixture stirred for 1 hour and then filtered. The precipitate was recrystallized from 100 ml of methanol which yielded 10 g precipitate having a melting point of 120° C. To a flask were added 1 g of the precipitate, 40 ml of water and 0.6 g potassium hydroxide and the mixture stirred at room temperature. After 15 minutes the slurry became a solution and stirring continued for a total of 12 hours. The solution was then acidified to a pH of about 2 with 6 molar hydrochloric acid to produce a thick precipitate. The precipitate was filtered and dried to yield 0.4 g of a material having a melting point of 296°-298° C. The material was identified by NMR through its potassium salt to be 2-(methylsulfonamido)terephthalic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:18][CH3:19])[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu](I)I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:12][C@H:13]([CH2:18][CH3:19])[CH2:14][C:15]([OH:17])=[O:16])=[CH:3][CH:4]=1
Reactant: CC[C@@H](N)CC(=O)O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 60 h

Procedure:
To a solution of 1-bromo-4-trifluoromethylbenzene (2530 g, 11.24 mole) and (R)-3-aminovaleric acid (659 g, 5.63 mole) in N,N-dimethylformamide (12 liter), were added copper iodide (210 g, 1.10 mole) and potassium carbonate (2330 g, 16.86 mole), and the mixture was sealed under nitrogen atmosphere and stirred at 100° C.-120° C. for about 60 hours. When the reaction was completed, the reaction mixture was concentrated in vacuo at 60° C.-70° C. of the bath temperature, the residue was dissolved in water (6.0 liter) and the solution was adjusted to pH about 5.0 with addition of hydrochloric acid. Ethyl acetate (6.0 liter) was added and the mixture was stirred, filtered and washed with ethyl acetate (2.4 liter). The filtrate was separated and the aqueous layer was extracted with ethyl acetate (3.6 liter). The organic layer was combined and extracted with 25% ammonia water (3.0 liter) and water (3 liter). The aqueous layer was acidified to pH about 5.0 with addition of hydrochloric acid, and extracted with ethyl acetate (6.0 liter). The organic layer was dried over magnesium sulfate (600 g), filtered and washed with ethyl acetate (2.4 liter). The filtrate was concentrated in vacuo at 45° C.-55° C. of the bath temperature, and the titled compound was obtained as an oily residue, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Reactant: C1COCCN1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(N5CCOCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.1 g, 0.2 mmol) and morpholine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A pink solid is produced (15 mg). Mp: 88-89° C.; 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=6.6 Hz, 3 H), 1.25-1.38 (m, 3H), 1.75 (d, J=12.6 Hz, 2H), 2.78-2.86 (m, 2H), 3.64 (s, 9H), 3.77 (d, J=12 Hz, 1H), 6.07 (d, J=5.7 Hz, 1H), 6.77 (d, J=12 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 2.30-7.33 (m, 2H), 7.49-7.60 (m, 2H), 7.89-7.99 (m, 3 H), 8.13 (s, 1H), 8.18 (d, J=5.7 Hz, 1H); MS 542 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([CH2:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(CC)c1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The diethyl acetal of 2-(2,6-diethylanilino)acetaldehyde (10.0 grams), sodium carbonate (4.0 grams) dissolved in water (50 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0° C. and chloroacetyl chloride (3.0 ml) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the diethyl acetal of 2-(N-α-chloroacetyl-2,6-diethylanilino)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[N:26][N:27]([CH2:29][CH:30]3[CH2:34][O:33]C(C)(C)[O:31]3)[CH:28]=2)[CH:21]=[CH:20][C:19]=1[CH3:37])=[O:17].Cl.CCOC(C)=O.O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[N:26][N:27]([CH2:29][CH:30]([OH:31])[CH2:34][OH:33])[CH:28]=2)[CH:21]=[CH:20][C:19]=1[CH3:37])=[O:17]
Reactant: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cn(CC(O)CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of compound 123 (1.05 g, 2.02 mmol) in THF (10 mL) was added HCl (10 mL, aq., 10, 1N) and the mixture was stirred for 16 h at RT. The reaction mixture was poured into a mixture of EtOAc/water/NaHCO3. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 10:90 as the eluent to afford the title compound as white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[CH:12]=1.[C:28](=O)([O-])[OH:29].[Na+]>CN(C)C=O>[OH:6][C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[C:12]=1[CH:28]=[O:29]
Reactant: O=C([O-])O
Reactant: CC(C)c1csc(COc2ccn3c(=O)cc(O)nc3c2)n1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1csc(COc2ccn3c(=O)c(C=O)c(O)nc3c2)n1
Reaction time: 1 h
Yield: 14 %

Procedure:
Dimethylformamide (3 ml) was added with phosphorus oxychloride (130 μl, 1.42 mmol) under ice cooling, and further added dropwise with 2-hydroxy-8-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-4H-pyrido[1,2-a]pyrimidin-4-one (300 mg, 0.945 mmol) dissolved in dimethylformamide (6 ml) under ice cooling. Then, the reaction solution was returned to room temperature and stirred for 1 hour. The reaction was stopped with saturated aqueous sodium hydrogencarbonate, and the reaction solution was extracted with chloroform. The resulting organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→30:1→10:1) to obtain 45 mg (14%) of the title compound.