Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)[C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C(F)(F)F)OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (17.0 g, 92.3 mmol) in toluene (80 mL) was added benzylalcohol (11.4 mL, 109.6 mmol). The mixture was stirred at 120° C. by using Dean-Stark for 5 h, and then the reaction mixture was cooled to 0° C. Drying the solution under high vacuum yielded compound D1-3 (21.2 g, quant.) as a colorless oil, which was used to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:1].[ClH:49].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (72 g, 0.20 mmol) was reacted with (4-methoxyphenyl)boronic acid (45 g, 0.30 mmol) followed by formation of the dihydrochloride salt to afford the desired product (80 mg, 79%) as an orange solid: 1H NMR (300 MHz, CD3OD) δ 9.13 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.15-8.03 (m, 2H), 7.24-7.12 (m, 2H), 5.73-5.59 (m, 1H), 3.91 (s, 3H), 3.13 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.75 (s, 3H), 2.50-2.42 (m, 2H), 2.09-1.96 (m, 3H), 1.77-1.60 (m, 2H), 1.45-1.25 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC>99% (AUC), tR=9.83 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.CNOC>ClCCl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:13][CH3:14])[C:10]([N:30]([O:29][CH3:25])[CH3:31])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (S)-2-(dibenzylamino)butanoic acid (27 g, 80.0 mmol, Eq: 1.00) was combined with dichloromethane (250 ml) to give a white suspension. At 0° C., TBTU (36.0 g, 112 mmol, Eq: 1.4) was added. The reaction was stirred for 2 h at 0° C. Then N-methylmorpholine (24.3 g, 26.4 ml, 240 mmol, Eq: 3) and N,O-dimethylhydroxylamine hydrochloride (19.5 g, 200 mmol, Eq: 2.5) were added. The reaction was stirred overnight at RT. The reaction mixture was extracted with water (2×75 ml) and brine (50 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The residual solvent was removed under vacuum. The title compound was obtained as a light yellow oil (35.5 g, 95.1%, MS (m/e)=327.3 [M+H+]).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH3:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:30]([CH:37]([CH3:41])[C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([CH3:29])[C:38](=[O:39])[CH:37]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:41])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(Oc1ccccc1)C(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(C)C(=O)C(C)Oc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(3-methyl-4-methylaminomethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenoxy-propionyl chloride.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([NH:32][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:15])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCCc1ccccc1

Procedure:
8-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-ylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and phenethylamine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1) 428.2.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:25]=1[S:34]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (1 g, 5.37 mmol) in DCM (40 ml) was added DIPEA (1.969 ml, 11.28 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.737 g, 5.37 mmol). The mixture was stirred for 1 h 20 min at room temperature before it was washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:20][C:21]([C:23]2[C:24]3[C:46]([CH3:47])=[N:45][N:44](C4CCCCO4)[C:25]=3[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35]CC4C=CC=CC=4)=[CH:31][C:30]=3[F:43])[CH:28]=2)=[O:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[C:14]1([C:11]2([NH:20][C:21]([C:23]3[C:24]4[C:46]([CH3:47])=[N:45][NH:44][C:25]=4[N:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=4[F:43])[CH:28]=3)=[O:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)NC3(c4ccccc4)CCN(Cc4ccccc4)CC3)c12
Solvent: CO
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(C(=O)NC3(c4ccccc4)CCNCC3)c12
Temperature: 40 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-benzyl-4-phenyl-piperidin-4-yl)-amide (275 mg) was dissolved in methanol (10 mL) and purged with argon, then hydrogen. Palladium (10% on charcoal, 82 mg) was added and the mixture was stirred at 40° C. for 2 h, then at r.t. over night. The catalyst was filtered off, the solvent was evaporated and the residue was dissolved in methanol (4 mL) and water (1 ml). Concentrated aqueous hydrochloric acid (1 mL) was added and the solution was stirred for 3 d. The solution was kept at −20° C. in a freezer until a precipitate appeared, which was filtered off and washed with methanol giving 6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4-phenyl-piperidin-4-yl)-amide (144 mg). A second fraction of title compound was obtained by storing the filtrate at −20° C. for a day and filtering off the precipitated product (31 mg, 95% overall yield).
Reaction SMILES: C([O:9][C@H:10]1[CH2:33][C@H:32]([O:34]C(=O)NC)[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=O)C1C=CC=CC=1.COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:25][O:24][CH:21]([O:22][CH3:23])[CH:20]([CH3:26])[C@@H:19]1[C@:27]2([CH3:40])[C@H:16]([C:15]3[C@H:30]([CH2:29][CH2:28]2)[C@:31]2([CH3:39])[C:12]([CH2:11][C@@H:10]([OH:9])[CH2:33][C@@H:32]2[OH:34])=[CH:13][CH:14]=3)[CH2:17][CH2:18]1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 91.8 %

Procedure:
The reaction and workup procedures of Example 164 were repeated except that 100 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregna-5,7-diene was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 65 mg of 21,21-dimethoxy-20-methylpregna-5,7-diene-1α,3β-diol showing the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:4][CH2:3][CH2:2][Br:1])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: BrCCCOc1ccc(Br)cc1

Procedure:
The title compound was prepared and worked up by the method of Example 6 using 4-bromophenol in place of 3,4-dichlorophenol. After chromatography the title compound (3.45 g) was found to be homogeneous by thin layer chromatography (10% by volume of methylene chloride/hexane on silica gel plates).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:33]1[C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[C:37]=2[CH:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:43]([C:38]3[C:37]4[CH:36]=[CH:35][N:34]=[CH:33][C:42]=4[CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:45])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc4cnccc34)C2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.6 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (48.0 mg, 0.106mmol) in anhydrous dichloromethane (4 ml) was added isoquinoline -5-sulfonyl chloride (42.1 mg, 0.16 mmol) and DIEA (37.0 μl, 0.21 mmol). The reaction stirred at room temperature over 72 hours, was diluted with dichloromethane and washed with sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (60.0 mg, 88% ). Calcd for C35H37F3N2O4S (M+H) 638.74, Found 639.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]4([OH:43])[CH2:42][CH2:41][S:40][CH2:39][CH2:38]4)=[CH:30][C:29]=3[CH3:44])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].ClC1C=CC=C(C(OO)=[O:60])C=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]4([OH:43])[CH2:42][CH2:41][S:40](=[O:60])[CH2:39][CH2:38]4)=[CH:30][C:29]=3[CH3:44])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)CC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl) [(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.24 g, 3.04 mmol) in ethyl acetate (15 mL) was added m-chloroperbenzoic acid (70%, 0.46 g, 1.88 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate-ethyl acetate/methanol=17/3) to give ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, yield 60%) as a colorless amorphous powder. To a solution of the obtained ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, 1.81 mmol) and mercaptoacetic acid (0.38 mL, 5.43 mmol) in N,N-dimethylformamide (10 mL) was added lithium hydroxide monohydrate (0.46 g, 10.86 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) to give the title compound (0.52 g, yield 50%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[ClH:12].[N:13]([O-])=O.[Na+]>O.C(OCC)C.C(O)C.[Fe]>[ClH:12].[ClH:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:13])=[C:5]([CH2:9][CH3:10])[CH:4]=1
Reactant: O=N[O-]
Reactant: CCc1cccc(N(C)C)c1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCc1cc(N(C)C)ccc1N
Temperature: 5 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a 250 cm3 round bottom flask was added N,N-dimethyl-m-ethylaniline ((CH3)2NC6H4CH2CH3, MW 149.23, 4.68 g, 31.3 mmol), water (100 cm3), and hydrochloric acid (HCl, 8.5 cm3, 37%). The solution was cooled to 5° C. A solution of sodium nitrite (NaNO2, MW 69.0, 2.46 g, 35.7 mmol) in water (80 cm3) was then added dropwise. The mixture was stirred for 3 hours at room temperature. Iron fillings (Fe, MW 55.85, 5.24 g, 94 mmol) and hydrochloric acid (HCl, 8.5 cm3, 37%) were added. The mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate collected. The pH of the filtrate was adjusted to pH 7 using sodium bicarbonate (NaHCO3) solution, and extracted into ethyl acetate (3×50 cm3). The combined extracts were dried over magnesium sulfate (MgSO4). The mixture was filtered and the filtrate concentrated to yield a brown oil. The oil was dissolved in diethyl ether/ethanol (1:1) (175 cm3). Hydrochloric acid (HCl, 5 cm3, 37%) was added. The solution was filtered to give the product, N,N-dimethyl-m-ethyl-p-phenylenediamine dihydrochloride ((CH3)2NC6H4(CH2CH3)NH2.2HCl, MW 237.17, 4.44 g, 1.87 mmol, 60%) as a light brown solid. δH (250 MHz; D2O): 7.66 (1H, s, ArH), 7.56 (2H, s, ArH), 3.29 (6H, s, NCH3), 2.74 (2H, q, 7.5, CH2), 1.25 (3H, t, 7.5, CH3); δc (62.9 MHz; CDCl3): 15.5 (CH3) 25.6 (NCH2), 48.9 (NCH3), 122.1 (ArC), 124.6 (ArC), 128.1 (ArC), 132.6 (ArC), 143.3 (ArC), 144.9 (ArC).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][NH:28][CH3:29].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][N:28]([CH3:29])[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CNCC(=O)N(C)C
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 135 °C

Procedure:
Into a 10 mL pressure vessel equipped with a magnetic stir bar was placed 0.1 g (0.266 mmol) 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (see Example 126), 0.031 g (0.27 mmol) N,N-dimethyl-2-(methylamino)acetamide, 0.726 mL (0.8 mmol) N,N-diisopropylethylamine and 5 mL DMF. The vessel was sealed and heated on an oil bath to 135° C. for 18 hrs., after which the mixture was cooled and the solvent removed in vacuo. The residue was purified by reverse phase HPLC on a C18 column using acetonitrile/water as eluent to give 5-[[2-(dimethylamino)-2-oxoethyl](methyl)amino]-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C=O)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
The NaH 60% dispersion in oil (0.94 g, 23.4 mmol) was added to a solution of 4-bromoindole (3.07 g, 15.6 mmol) and triisopropylsilyl chloride (3.62 g, 18.8 mmol) in CH2Cl2 (50 mL) and DMF (2 mL). The reaction was stirred at room temperature for 1 h and quenched with water. The insoluble material was filtered off and the solvent was removed. Purification by column chromatography (SiO2, CH2Cl2/heptane 1:4) yielded 3.44 g (63%) of the title compound: 1H NMR (CDCl3) δ 7.42–6.63 (m, 5 H), 1.66 (sept, J=8 Hz, 3 H), 1.10 (d, J=8 Hz, 18H; MS (ESI) 354.4 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)O)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)C(O)=O>CCOC(C)=O>[CH2:37]([N:3]([CH2:1][CH3:2])[C:4](=[O:36])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)=[CH:9][CH:10]=1)[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc(C(O)(c2cccc3cccnc23)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Yield: 83.5 %

Procedure:
A mixture of the compound of Example 19 (45 mg), trifluoroacetic acid (1.0 mL) and trifluoromethanesulforic acid (1 mL) was refluxed for 8 hrs., and then condensed. The residue was dissolved in AcOEt (50 ml). The resulting solution was washed with 1 N NaOH solution, aqueous NH4Cl solution and brine, dried over Na2SO4. Removal of solvents gave a crude product, which was purified by silica gel column eluting with NH4OH (1N)-MeOH—CH2Cl2 (2.5:17.5:80) to provide N,N-diethyl-4-(8-quinolinyl-piperidin-4-ylidene-methyl)-benzamide (29 mg, 84%):
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5](=[O:19])[NH:4][NH:3]1>C(Cl)Cl>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:5](=[O:19])[N:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCCCCn1c(=O)[nH][nH]c1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)N=NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
To tert-butyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)butylcarbamate (15 mg, 0.055 mmol) in CH2Cl2 (0.551 mL) was added SiO2—HNO3 (35 mg). The mixture was stirred at room temperature for 15 minutes, then filtered, concentrated in vacuo and dried, giving tert-butyl 4-(3,5-dioxo-3H-1,2,4-triazol-4(5H)-yl)butylcarbamate (I-8c: 15 mg, quantitative yield) as a red oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:15]=[N:14]3)[CH:10]=2)[CH2:5][CH2:4][CH2:3]1>CO.[OH-].[Na+]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14]3)[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(C)CCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCCc2ccc(Cn3cc(C(=O)O)cn3)cc21
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Ethyl 1-((1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)methyl)-1H-pyrazole-4-carboxylate (233 mg, 0.607 mmol) was dissolved in a mixture of MeOH (6 ml) and 1N NaOH (3.00 ml). The reaction mixture was stirred for 8 hr at 20° C. and the solvents were removed by evaporation under reduced pressure to afford the title compound. HPLC (Method A) Rt=1.348 min; MS (Method A) [M+H]+=271.9