Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:39][C:35]1[CH:36]=[N:37][CH:38]=[C:33]([N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:34]=1)=[C:3]([CH3:26])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5]2
Reactant: Cc1c(N2CCC[C@@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCC[C@@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (R)-tert-butyl 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidine-2-carboxylate (350 mg, 0.91 mmol) and 5-morpholinopyridin-3-amine in toluene to give (R)-tert-butyl 1-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)pyrrolidine-2-carboxylate. 1H NMR (CDCl3) δ ppm 7.90 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=2.2 Hz), 7.10 (1H, ddd, J=10.3, 2.4, 1.2 Hz), 6.85 (1H, d, J=12.5 Hz), 6.66 (1H, ddd, J=14.0, 8.9, 2.5 Hz), 6.61 (1H, t, J=2.3 Hz), 4.68 (1H, t, J=7.0 Hz), 3.77-3.90 (5H, m), 3.56-3.68 (1H, m), 3.12-3.21 (4H, m), 2.23-2.39 (1H, m), 2.13-2.21 (1H, m), 2.12 (3H, s), 1.90-2.07 (2H, m), 1.44 (9H, s). Mass Spectrum (ESI) m/e=526.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:6][C:11](=[O:12])[N:13]5[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)[C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33](=[O:34])[N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1cc(C(=O)N2CCC(n3c(=O)n(CC(=O)N4CCCCC4)c4ccccc43)CC2)c2ccc(Cl)cc21)N1CCCCC1

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of 2-chloro-1-piperidin-1-yl-ethanone. The crude reaction mixture was directly purified by preparative HPLC to afforded 4 mg of the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:10]([O:22][CH3:23])[CH:9]=2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[C:12]([O:14][CH3:15])[CH:13]=2)=[N:6][CH:7]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(-c2ccc(N)cn2)cc(OC)c1OCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(-c2cc(OC)c(OCC(F)(F)F)c(OC)c2)nc1
Temperature: 0 °C

Procedure:
To a solution of 5-amino-2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]pyridine (melting point: 176.0-177.5° C.)(28.2 g, 85.4 mmol) synthesized by a similar procedure to that described in Reference Example 11 in methylene chloride (550 mL) was added N,N-diisopropylethylamine (18.0 mL, 103 mmol). To the ice-cold stirred solution was added acryloyl chloride (7.00 mL, 86.0 mmol) dropwise over about 10 minutes. A saturated aqueous sodium hydrogencarbonate was added, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chloroform-hexane (1:2, 300 mL) was added to the residue and the resulting precipitate was collected by filtration to yield crude 5-acryloylamino-2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]pyridine was obtained as colorless needles (melting point: 207.0-209.0° C.)(38.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][CH2:14][C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:22][C:23]([CH3:31])=[CH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>>[Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:24]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:31])[NH:22][C:15]([CH2:14][F:13])=[C:16]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CC(=O)CF
Reactant: CC(N)=CC(=O)OC(C)C
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1Cl
Yield: 42.2 %

Procedure:
2-Chloro-3-nitrobenzaldehyde (1.38 g, 7.5 mmoles), methyl 4-fluoro-3-oxobutanoate (1.0 g, 7.5 mmoles) and 1-methylethyl 3-amino-2-butenoate (1.06 g, 7.5 mmoles) were heated at 90° for 2.5 hours. The reaction mixture was chromatographed on silica eluting with petroleum ether (60°-80°)/ethyl acetate mixtures. The title compound (1.35 g) was obtained after crystallisation from petroleum ether (60°-80°)/2-propanol. mp 156°-7°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[Li+].[BH4-].N#N>C1COCC1.CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([CH2:12][N:13]([CH:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[C:4]([CH2:3][OH:2])[CH:9]=1)#[N:11]
Reactant: COC(=O)c1cc(C#N)ccc1CN(C1CCCc2cccnc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: N#N
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(CO)c1
Yield: 84.8 %

Procedure:
To a solution of 5-cyano-2-{[(2-nitro-benzenesulfonyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}-methyl}-benzoic acid methyl ester (2.32 g, 5.72 mmol) dissolved in THF (50 mL) and MeOH (50 mL), LiBH4 (1.26 g, 57.2 mmol) was slowly added. The mixture was stirred at room temperature under a positive pressure of N2 for 2 hours. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (50 mL). Brine (30 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow solid. Purification via column chromatography on silica gel (hexanes:EtOAc, 1:1, v/v) afforded N-(4-cyano-2-hydroxymethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide as a yellow solid (2.32 g, 85%). 1H NMR (CDCl3) δ 1.56 (s, 9H), 1.91 (m, 2H), 2.36 (m, 1H), 2.61 (m, 2H), 2.98 (m, 1H), 4.23 (d, 1H, J=16.7 Hz), 4.61 (m, 2H), 4.90 (d, 1H, J=16.2 Hz), 5.21 (m, 1H), 7.03 (dd, 1H, J=5.3, 9.7 Hz), 7.37 (m, 3H), 7.67 (m, 4H), 7.95 (d, 1H, J=7.9 Hz), 8.16 (d, 1H, J=4.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(N2CCCC2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-fluorobenzaldehyde (2.50 g, 15.8 mmol, 1.00 equiv), pyrrolidine (2.20 g, 30.9 mmol, 2.00 equiv), potassium carbonate (4.40 g, 31.8 mmol, 2.00 equiv), DMSO (50 mL). The resulting solution was stirred overnight at 100° C., diluted with H2O (50 mL), extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.40 g (73% yield) of 2-chloro-4-(pyrrolidin-1-yl)benzaldehyde as a yellow solid. LCMS: (ESI, m/z): 210 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:7][P:8]([CH2:17][C:18]([CH3:35])=[CH:19][CH2:20][C:21]1[C:22]([OH:34])=[C:23]2[C:27](=[C:28]([CH3:32])[C:29]=1[O:30][CH3:31])[CH2:26][O:25][C:24]2=[O:33])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])C.[OH-].[Na+]>C1COCC1>[OH:34][C:22]1[C:21]([CH2:20][CH:19]=[C:18]([CH3:35])[CH2:17][P:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:7][CH:5]([CH3:6])[C:4]([OH:36])=[O:3])=[O:9])=[C:29]([O:30][CH3:31])[C:28]([CH3:32])=[C:27]2[C:23]=1[C:24](=[O:33])[O:25][CH2:26]2
Reactant: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(Oc1ccccc1)OC(C)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2-{[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionic acid ethyl ester (10 mg, 0.019 mmol) in THF (3 mL) was added 1N NaOH (232 μL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to provide 6 mg (77%) of the desired product as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.41 (d, J=7 Hz, 3H), 1.97 (s, 3H), 2.16 (s, 3H), 2.59 (d, J=22 Hz, 2H), 3.45 (m, 2H), 3.79 (s, 3H), 4.83 (m, 1H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 27.02 ppm; MS (m/z) 413 [M−H]−, 415 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].CN(C=O)C.[O:43]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[S:53])=[CH:47][CH:46]=1)[CH3:44]>CC#N>[CH3:44][O:43][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([N:22]2[CH2:21][CH2:20][N:19]([C:17]3[S:18][C:14](=[CH:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]5[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:3]=5[C:2]([F:36])([F:1])[F:37])=[C:8]([O:26][CH3:27])[CH:9]=4)[C:15](=[O:25])[N:16]=3)[CH2:24][CH2:23]2)=[S:53])=[CH:47][CH:46]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(NC(=S)N2CCN(C3=NC(=O)C(=Cc4ccc(OCc5ccc(C(F)(F)F)cc5C(F)(F)F)c(OC)c4)S3)CC2)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
To a N2 purged flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (120 mg, 220 μmol) from Example 23, DMF (8 mL) and MeCN (8 mL). To the reaction solution was added 4-methoxylphenyl isothiocyanate (55 mg, 330 μmol). The reaction was stirred at 55° C. for 20 h and LC analysis should product was formed. The reaction solution was concentrated under reduced pressure and then taken into EtOAc (100 mL), washed with aq. NH4Cl (70 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed using reverse phase preparative HPLC, H2O/MeCN gradient 90:10 to 10:90) to provide the title compound as a white solid (24 mg, 13% yield). 1H NMR (DMSO-d6) δ 8.17 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.02 (1H, d, J=8.1 Hz), 7.64 (1H, s), 7.15-7.23 (5H, m), 6.88 (2H, d, J=8.9 Hz), 5.42 (2H, s), 4.16 (2H, br s), 4.09 (2H, m), 4.03 (2H, m), 3.86 (3H, s), 3.80 (2H, m), 3.74 (3H, s); MS (ESI) 711 (MH+).
Reaction SMILES: N1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21][C:22]([N:24]4C=CN=C4)=[O:23])=[N:18][C:17]=3[CH3:29])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])C=CN=C1.[F:30]C1C=C(C2SC(N)=NC=2C)C=CC=1S(C)(=O)=O>>[F:30][C:6]1[CH:7]=[C:8]([C:16]2[S:20][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[N:18][C:17]=2[CH3:29])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Product: Cc1nc(NC(N)=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
The title compound is prepared by the same procedure as imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Example 150a) by replacing 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) with 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72)
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[CH3:17][O:18][C:19]([CH3:30])([CH3:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:28][CH2:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([O:18][CH3:17])([CH3:29])[CH3:30])[CH2:26][CH2:25]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Reactant: COC(C)(C)CN1CCC(CN)CC1
Product: COC(C)(C)CN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(C)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 6 in EXAMPLE 1 from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, Step 5) and [1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methylamine (EXAMPLE 4, Step 6).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:15])[CH3:2].C(NC(C)C)(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[N:3]([CH2:1][CH3:2])[CH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNCc1cc(S(C)(=O)=O)ccc1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCN(Cc1cc(S(C)(=O)=O)ccc1O)C(=O)OCc1ccccc1

Procedure:
To 2-ethylaminomethyl-4-methanesulfonyl-phenol (0.229 g, 1.0 mmol) and diisopropylamine (0.94 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added benzyl chloroformate (0.16 mL, 1.1 mmol). Some over-acylation product was observed, so additional benzyl chloroformate (0.21 mL) was added to convert all of the product to the diacylated product. After aqueous work-up, the organic layer was concentrated, and the residue was dissolved in MeOH (10 mL) and treated with 1N aqueous LiOH (4 mL). Once the hydrolysis was complete, the mixture was worked-up, and the residue was purified to give the title compound.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(O)=O)=C(C)C=3)C=N2)=CC=1.[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([OH:49])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: NCc1cccnc1
Reactant: Cc1cc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 87 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 3-methyl-5-(5-oxo-1-(4-(trifluoromethyl)-benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 87% yield: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.52 (d, J=3.2 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.27 (dd, J=7.9, 3.2 Hz, 1H), 6.88 (s, 1H), 6.45 (t, J=5.5 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=5.5 Hz, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 150.5, 149.2, 149.0, 140.7, 139.2, 135.6, 134.4, 133.7, 132.6, 130.3, 128.6, 125.8 (q, JC-F=3.8 Hz), 125.5, 123.6, 120.4, 49.1, 41.4, 16.0; MS (ES+) m/z 474.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([C:10]2[CH:15]=[C:14](C)[N:13]=[C:12]([NH:17]C(=O)C)[N:11]=2)=[CH:5][C:4]=1F)#[N:2].[H-].[Na+].O.[NH2:25][NH2:26].O.CN([CH:31]=[O:32])C>CCO>[NH2:17][C:12]1[N:11]=[C:10]([C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH2:2])=[N:25][NH:26]3)=[C:8]([O:32][CH3:31])[CH:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CC(=O)Nc1nc(C)cc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: NN
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2ccnc(N)n2)cc2[nH]nc(N)c12
Temperature: 90 °C
Reaction time: 0.21 h

Procedure:
To a solution of N-[4-(4-cyano-3,5-difluorophenyl)-6-methyl-2-pyrimidinyl]acetamide in DMF (3 mL) was added sodium hydride (1.5 eq.). To the basic solution was added dropwise a solution of the appropriate alcohol (1 eq.) and sodium hydride (1 eq.) in DMF (3 mL). The vial that contained the alkoxide solution was rinsed with more DMF (1 mL). When the reaction was judged complete (HPLC, ˜1 hour), the reaction mixture was poured onto saturated aqueous ammonium chloride. After standing for ˜10-15 minutes, the precipitate formed was collected by vacuum filtration. To the resulting solid in EtOH was added hydrazine monohydrate (50 eq.), and the reaction mixture was stirred overnight at 90° C. The reaction was poured onto EtOAc and water. The organic phase was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were concentrated. Work-up from here varies according to the compound.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].P(=O)(O)(O)O>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[P:6](=[O:7])([OH:10])([OH:9])[OH:8]
Reactant: O=S(=O)(O)O
Reactant: O=P([O-])([O-])[O-]
Agent: O=P(O)(O)O
Product: O=S(=O)([O-])[O-]

Procedure:
The sulfuric acid fed into the extraction battery reacts with the phosphate in the wet process phosphoric acid to form sulfate and phosphoric acid. The sulfuric acid is converted into sulfate which is easily extracted into the aqueous phase. On the other hand, the phosphate is converted into phosphoric acid which is easily extracted into the solvent phase. The fact for increasing the yield of phosphoric acid by the addition of sulfuric acid is given by such effect of sulfuric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=O)[C:12]3=[O:21])[C:6]=2[CH:22]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[N:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=4)[C:12]3=[O:21])[C:6]=2[CH:22]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(Cc2csc3ccc(Cl)cc23)c2ccccc21
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1Cc1csc2ccc(Cl)cc12
Temperature: 140 °C
Yield: 20 %

Procedure:
A mixture of 1-[(5-chloro-1-benzothien-3-yl)methyl]-2H-indole-2,3-dione (50 mg, 0.15 mmol) (prepared as described below) and 3-trifluoromethylaniline (0.020 mL, 0.15 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 1:3 ethyl acetate and hexane as the eluent giving the desired product as a yellow solid (13 mg, 0.030 mmol, 18%). 1H NMR (400 MHz): δ 7.98 (d, J=2.0, 1H), 7.80 (d, J=8.6, 1H), 7.58 (t, J=7.7, 1H), 7.52 (d, J=8.1, 1H), 7.43 (s, 1H), 7.38 (dd, J=8.6, 1.9, 1H), 7.31 (overlapping singlet and dt, J=1.2, 7.8, 2H), 7.24 (d, J=7.8, 1H), 6.87 (d, J=7.9, 1H), 6.77 (t, J=7.7, 1H), 6.59 (d, J=7.7, 1H), 5.20 (s, 2H). ESI-MS m/z found 471 (MH+ with 35Cl), 473 (MH+ with 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:53][Si:54]([C:57]#[CH:58])([CH3:56])[CH3:55]>CN(C)C=O.N1CCCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:58]#[C:57][Si:54]([CH3:56])([CH3:55])[CH3:53])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#C[Si](C)(C)C)c(OCc1ccccc1)c2=O
Temperature: 50 °C
Yield: 62.7 %

Procedure:
A solution of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.277 g, 0.49 mmol) in a mixture of N,N-dimethylformamide (3 ml) and piperidine (1.2 ml) was treated under argon with dichlorobis(triphenylphosphine)palladium(II) (0.020 g), triphenylphosphine (0.010 g), copper(1) iodide (0.010 g) followed by (trimethylsilyl)acetylene (0.21 ml, 1.47 mmol). The resulting mixture was sealed and heated at 50° C. for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.164 g (63% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 0.27 (9H, s, SiCH3), 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.71 (2H, d, J=6.1 Hz, NCH2), 5.32 (2H, s, OCH2), 6.99 (1H, m, aromatic), 7.19 (1H,dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.3-7.37 (4H, m, aromatics), 7.48-7.51 (2H, m, aromatics), 7.75 (1H, broad t, NH). HRMS (ESI+) calculated for C29H33FN3O4Si [M+H+]: 534.2224; found: 534.2229.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:4]([O:17][CH3:18])[CH:3]=1.[F:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([CH2:26][CH2:27][CH2:28][Cl:29])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Br-].[K+]>>[ClH:29].[ClH:29].[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH2:26][CH2:27][CH2:28][N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][C:4]=3[O:17][CH3:18])[CH2:10][CH2:11]2)=[O:25])=[CH:30][CH:31]=1
Reactant: COc1cc(C)ccc1OCCN1CCNCC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Product: COc1cc(C)ccc1OCCN1CCN(CCCC(=O)c2ccc(F)cc2)CC1
Product: Cl

Procedure:
A mixture of 25.0 grams of 1-[2-(4-methyl-2-methoxyphenoxy)ethyl]piperazine, 20.1 grams of 3-(4-fluorobenzoyl)propyl chloride, 13.8 grams of potassium carbonate and 10 grams of potassium bromide was heated under gentle reflux for a period of 24 hours. The resulting reaction mixture was filtered while hot and the filtrate after cooling was acidified by adding thereto with stirring a 10% solution of hydrochloric acid, whereupon the compound that is specified in the heading separated. The resulting precipitate was then separated by filtration and recrystallized from a mixture of 80 parts by volume of ethanol and 20 parts by volume of water. In this manner, 15 grams of the salt specified in the heading, having a melting point of 211°-213°C, was obtained.