Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[S:6](F)(=[O:15])([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C>C(O)CCC>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:15])=[O:7]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: COCCN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COCCNS(=O)(=O)c1ccc(N)cc1
Yield: 65.4 %

Procedure:
A mixture of 2-methoxyethylamine (859 mg, 11.4 mmol), sulphanilyl fluoride (1.0 g, 5.71 mmol) and triethylamine (1.72 g, 22.9 mmol) in 1-butanol (15 ml) was heated at reflux for 18 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was purified by chromatography eluting with ethyl acetate/hexane (50:50) increasing in polarity to (70:30) to give the title compound (860 mg, 65%). NMR: 2.78 (q, 2H), 3.15 (s, 3H), 3.25 (t, 2H), 5.87 (s, 2H), 6.58 (d, 2H), 7.10 (t, 1H), 7.40 (d, 2H); m/z 231.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=1.[Na].[CH3:24]S(O)(=O)=O.C=O>CO.O>[CH3:10][N:8]([CH3:9])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][CH2:24][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[N:7]=1
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: CS(=O)(=O)O
Reactant: COc1nc(N)nc(N(C)C)n1
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1nc(NCS(=O)(=O)c2ccc(C)cc2)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.5 g (0.05 mole) of 2-amino-4-dimethylamino-6-methoxy-1,3,5-triazine and 9.1 g (0.05 mole) of toluene-4-sulfinic acid, sodium salt, are suspended in 100 ml of methanol and to the stirred suspension are added, in succession, 4.8 g (0.05 mole) of methanesulfonic acid and 4.7 g (0.055 mole) of aqueous 35% formaldehyde. The batch is then stirred for 30 minutes at room temperature and then for another 90 minutes under reflux. After cooling, the mixture is diluted with 1 liter of water and the crystalline precipitate is filtered with suction and dried. Melting point: 188°-190° C. Yield: 10 g (59% of theory).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])[CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:19]([CH:15]3[CH2:16][CH2:17][CH2:18][N:13]([C:11]([NH:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:38])=[O:2])=[O:12])[CH2:14]3)([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[C:20](=[O:29])[NH:21]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester (50 mg, 0.090 mmol) (from Example 68 supra) in tetrahydro furan (2 mL) was added the suspension of lithium hydroxide monohydrate (38 mg, 0.9 mmol) (Aldrich). The mixture was stirred at room temperature for 2 days. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH<5 with dilute HCl, then extracted with ethyl acetate several times. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The rsidue was triturated with Dichloromethane-Hexane to give rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid as a white solid. (Yield 40 mg, 81.6%).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:11]=[C:10]([CH:12]=O)[NH:9][C:8]=1[C:14]([O:16][CH3:17])=[O:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:11]=[C:10]([CH:12]=[CH2:1])[NH:9][C:8]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1[nH]c(C=O)cc1Cl
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(Cl)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A suspension of methyl(triphenyl)phosphonium bromide (3.97 g, 11.1 mmol) in 20 mL of THF was cooled to −78° C. n-Butyllithium (1.6 M in Hexanes, 6.93 mL, 11.1 mmol) was added and the resulting yellow solution stirred for 20 minutes. A THF solution of methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (0.522 g, 2.78 mmol) was added and the reaction was warmed to RT. The reaction mixture was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over MgSO4, filtered and the solvent evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.210 g, 40%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.05 (br. s., 1H), 6.62 (dd, 1H), 6.42 (d, 1H), 5.83 (d, 1H), 5.25 (d, 1H), 3.79 (s, 3H). LCMS: m/z=184.6 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:5]2.Cl[CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=23)[S:22]1(=[O:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=45)[S:22]3(=[O:34])=[O:33])[CH2:16][CH2:17]1)=[CH:5]2
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: Fc1ccc2[nH]c(CC3CCNCC3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2cc3cc(F)ccc3[nH]2)CC1
Yield: 39.7 %

Procedure:
A mixture of 4-[(5-fluoro-2-indolyl)methyl]piperidine (2.9 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.5 g) and sodium hydrogen carbonate (1.1 g) in tetrahydrofuran (30 cc) and dimethylformamide (30 cc) is brought to reflux for 12 hours. After evaporation to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is taken up with water (150 cc) and extracted with ethyl acetate (2×75 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a cyclohexane/ethyl acetate mixture (50:50 by volume) as eluent. 2-{2-[4-((5-Fluoro-2-indolyl)methyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g), m.p. 154° C., is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[Cl:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCc1ccccc1Cl
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Product: Clc1ccccc1CN1CCN([C@H]2CC[C@H](c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]piperazine and 2-chlorobenzyl chloride by the method described in example to give the product (89%, mp: 89°-90° C.). Calc'd for C24H29ClN2O2 : C, 69.81%; H, 7.08%; N, 6.79%. Found: C, 69.50%; H, 7.03%; N, 6.71%.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30](O)(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C>[C:30]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period active anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in dimethylformamide.
Reaction SMILES: [CH2:1]([NH2:5])[C:2]([OH:4])=[O:3].C([O-])(O)=O.[Na+].[CH2:11]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([NH:29][CH3:30])=[C:20]2[S:25](Cl)(=[O:27])=[O:26])[CH2:12][CH2:13][CH3:14]>O.CC(C)=O>[CH2:11]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([NH:29][CH3:30])=[C:20]2[S:25]([NH:5][CH2:1][C:2]([OH:4])=[O:3])(=[O:27])=[O:26])[CH2:12][CH2:13][CH3:14]
Reactant: NCC(=O)O
Reactant: CCCCc1cccc2c(S(=O)(=O)Cl)c(NC)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCc1cccc2c(S(=O)(=O)NCC(=O)O)c(NC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mmoles of L-glycine and 3 mmoles of NaHCO3 were dissolved in 5 ml of water. A solution containing 1 mmol of 3 in acetone was slowly added. More acetone was added until the solution was clear. The mixture was stirred overnight at room temperature, and protected from light. Acetone was removed by flash evaporation and the remaining water solution was acidified to pH=4.5 to 5 by adding 2M citric acid. Then, NaCl was added until saturation and the solution was extracted with three portions of ethyl acetate (20 ml each). The extracts were combined, dried over MgSO4 and solution filtered Solvent was removed and residue purified by liquid chromatography on silica gel. A gradient of 0 to 5% methanol in dichloromethane was used as eluent. Fractions containing desired products were combined and solvents removed. The residue was triturated in 1:1 ether: petroleum ether. Precipitate was filtered out and dried in vacuum overnight thus affording 5-Butylmethylamino-naphtalene-1-sulfonyl-glycine (NST703).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([N+:23]([O-:25])=[O:24])[C:10]([S:12][C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][N:17]=[CH:18]4)=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:26])[CH3:2].[OH2:27].[OH-:28].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([N+:23]([O-:25])=[O:24])[C:10]([S:12]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][N:17]=[CH:18]4)(=[O:28])=[O:27])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:26])[CH3:2]
Reactant: O
Reactant: [OH-]
Reactant: CCn1c(C)nc2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCn1c(C)nc2cc(S(=O)(=O)c3cccc4cnccc34)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
1-Ethyl-5-(5-isoquinolylsulfanyl)-2-methyl-6-nitro-1H-benzo[d]imidazole 300 mg (0.8 mmol) was dissolved in concentrated sulfuric acid 3 ml, Beckmann's reagent (K2Cr2O7 1 g, H2SO4 1 ml, H2O 9 ml) 6 ml was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 4N sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and 1-ethyl-5-(5-isoquinolylsulfonyl)-2-methyl-6-nitro-1H-benzo[d]imidazole 70 mg (20.8%) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 900 mg (S)-4-benzyloxy-2-tert-butoxycarbonylamino-butyric acid in 10 ml DMF were added 1.5 ml N-ethylmorpholine, 0.43 ml 1-ethoxycarbonylpiperazine and 955 mg TOTU. The solution was stirred for 12 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.23 g.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH2:45][CH3:46]>C1COCC1.CN(C=O)C>[F:41][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[CH:25]([O:26][CH2:45][CH3:46])[CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CCI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (20.4 mg, 0.034 mmo) in THF (0.15 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 4.1 mg, 0.10 mmol). The mixture was stirred at room temperature for 30 minutes, recooled to 0° C. and DMF (5 drops) was added followed by iodoethane (8 μL, 0.10 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford the title compound (11.5 mg, 54%). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 1H) 1.1 (t, J=7.1 Hz, 3H) 1.4(m, 2H) 1.7(m, 1H) 1.8(d, J=13.3 Hz, 1H) 3.2 (m, 4H) 3.9 (dd, J=11.6, 3.3 Hz, 1H) 4.0 (dd, J=11.4, 3.9 Hz, 1H) 4.2 (s, 3H) 4.2 (d, J=7.1 Hz, 1H) 4.7 (d, J=13.3 Hz, 1H) 4.7 (s, 2H) 4.9 (d, J=15.8 Hz, 1H) 7.3 (s, 1H) 7.6 (m, 2H) 7.6 (s, 2H) 7.8 (s, 1H). MS (ES+) Calc: 625.2, Found: 626.4 (M+1) According to the procedure described in example 33 and using the appropriate secondary alcohol and alkylating reagent, examples 34-40 were prepared.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1.[C:29](N1C=CN=C1)(=[O:31])[CH3:30]>CN(C=O)C.C(=O)([O-])O.[Na+]>[C:29]([O:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)n1ccnc1
Reactant: O=c1c2c(Cc3ccc(O)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (192 mg, 0.52 mmol, prepared in Example 41) in DMF (2 ml) was added a solution of 1-acetylimidazole (114 mg, 1.04 mmol, 2 eq.) in DMF (2 ml) while ice-cooling, and the mixture was stirred overnight at room temperature, and then diluted with aqueous sodium hydrogen carbonate. Precipitates were filtered off, and the mixture was dried and purified by flash column chromatography to afford 3-(4-acetoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (128 mg, 60%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([NH:22][CH2:19][CH2:20][CH3:21])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Reaction time: 0.5 h

Procedure:
Powdered 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carbonyl chloride (5.0 g.) was stirred while a solution of n-propylamine (5 ml) in methanol (100 ml.) was added, the resulting solution was stirred for 30 minutes, and the solvent was evaporated under reduced pressure to give a sticky solid residue. The residue was triturated with water and the resulting suspension was stirred for 30 minutes and filtered. The solid product was washed with water, dried and crystallised from ethanol to give 3,4-dihydro-4-oxo-N-propyl-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carboxamide, m.p. 228°-230° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(NC(C)C)(C)C>N1C=CC=CC=1>[C:19]([O:8][CH2:7][C@H:5]1[O:6][C@@H:1]([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18])[CH2:2][C@@H:3]1[OH:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Solvent: c1ccncc1
Solvent: CC(C)NC(C)C
Product: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c1
Temperature: 25 °C
Reaction time: 29 h
Yield: 80.4 %

Procedure:
To a solution of 1-(2-deoxy-β-D-ribofuranosyl)-4-(1-propynyl)pyrrole-2-carbaldehyde (249 mg, 1.00 mmol) (I. Hirao, et al., Nature Methods, 3: 729-735 (2006)) dissolved in anhydrous pyridine (10 ml) were added trityl chloride (1.18 g, 4.21 mmol) and N,N-diisopropylamine (1.11 ml, 6.40 mmol), and the reaction mixture was stirred at room temperature for 29 hours, and then at 50° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, and the organic layers were washed twice with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The resulting crude product was purified by column chromatography on silica gel (eluent:dichloromethane:ethyl acetate=100:0→400:3, then dichloromethane:methanol=100:2) to give the title product (395 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[CH3:2].Cl.Cl.[CH3:34]OC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.C(OC1C=C(C=CC=1OC)C=O)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[O:31][CH3:34])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: CCOc1cc(C=O)ccc1OC
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1OC

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid (example 201) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3-ethoxy-4-methoxy-benzaldehyde (commercially available) in a yield of 15.3 mg (22%). MS (ISP): 454.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[OH:24])[C:16]([CH2:18][C:19]#[N:20])=[O:17].NCCC(O)=O.O>C(O)C>[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[OH:24])[C:16]([C:18](=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[C:19]#[N:20])=[O:17]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N#CCC(=O)c1ccc(O)c(O)c1
Agent: NCCC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC(=Cc1ccc2[nH]ccc2c1)C(=O)c1ccc(O)c(O)c1
Yield: 28.3 %

Procedure:
5-Formyl indole (145 mg, 1 mmole), 3,4-dihydroxybenzoylacetonitrile (177 mg, 1 mmole) and β-alanine (30 mg) in 30 ml ethanol were refluxed for 3 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was concentrated and the resulting oily residue was purified by chromatography on silica gel to give 86 mg (31%) of the title compound as an orange solid, m.p. 185° C.