Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].CCOC(C)=O.CCCCCC>CO.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1occc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: Cc1ccoc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of commercially available methyl 3-methylfuroate (20.0 g, 140 mmol) in 100 mL of MeOH, NaOH (11.43 g, 280 mmol) in 20 mL of water was added. The yellowish solution was stirred at room temperature for 3 hours. TLC (1:9 EtOAc/hexane) showed no starting material. MeOH was removed and the pH of the aqueous solution was adjusted to 4 with 1N HCl. The slurry was extracted with ethyl acetate (5×100 mL). The combined ethyl acetate layers were washed brine, and dried over sodium sulfate. 3-methyl furoic acid was obtained as a white solid (13.2 g, 73%) after evaporation of the solvent. To a mixture of 3-methyl furoic acid (8.60 g, 68 mmol), N,O-dimethylhydroxylamine hydrochloride (8.0 g, 82 mmol), EDC (15.7 g, 82 mmol), and HOBT (11.07 g, 82 mmol) in dichloromethane (200 mL), triethylamine (14.4 mL, 100 mmol) was added. The solution was stirred at room temperature for 4 hours, and washed with 1N NaOH (50 mL), 1N HCl (50 mL), brine, and dried over sodium sulfate. The title compound was obtained as a colorless liquid upon removal of the solvent. 1H NMR (CDCl3, 400 MHz): 7.40 (s, 1H), 6.38 (s, 1H), 3.81 (s, 3H), 3.36 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:10][C@@H:11]1[C@@H:15]([CH2:16][O:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:14][C@@H:13]([N:37]2[CH:44]=[C:43]([F:45])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[CH2:12]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[C].[Pd]>[F:45][C:43]1[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]([CH:44]=1)[C@@H:13]1[O:14][C@H:15]([CH2:16][OH:17])[C@@H:11]([O:10][CH2:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCC=Cc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCCCc3ccccc3)[C@@H](CO)O2)cc1F
Reaction time: 1 h

Procedure:
To a solution of 500 mg of the 2'-deoxy-3'-O-cinnamyl-5-fluoro-5'-O-trityluridine prepared in Reference Example 143 in 30 ml of methanol was added 50 mg of 5% palladium-carbon, and the catalytic reduction was conducted at room temperature for 1 hour.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]1([C:8]2[NH:7][C:6](=[O:5])[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[CH:9]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)Oc1cc(-c2c[nH]c3ncccc23)cc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2c[nH]c3ncccc23)cc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of EXAMPLE 34D in 1 mL dichloromethane was added 1 mL trifluoroacetic acid. The solution was stirred at room temperature for 25 minutes and the solvent was removed. The crude material was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound. MS (ESI) m/e 287.9 (M+H)+; 1H NMR (DMSO-d6) δ 6.70 (s, 1H), 7.03 (s, 1H), 7.11-7.30 (m, 1H), 7.37-7.64 (m, 3H), 7.76-8.01 (m, 2H), 8.18-8.48 (m, 3H), 11.52 (s, 1H), 12.23 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COCCNC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-methanesulphonyl-piperidine-4-one (182 mg; prepared from N—BOC-piperidone by reaction of piperidone-4-one TFA salt with methane sulphonyl chloride), stirring in anhydrous 1,2-dichloroethane (6 ml) was added 2-methoxyethylamine (90 μl) followed by glacial acetic acid (62 μl). Sodium triacetoxy borohydride (284 mg), was added in aliquots over 30 minutes and the reaction mixture stirred for 12 hours at room temperature, then diluted with dichloromethane (40 ml), washed with 50% NaHCO3 solution and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by silica flash chromatography to give 1-methanesulphonyl-piperidin-4-yl-2-methoxy-ethylamine (148 mg), as a white solid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[S:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]=[N:9]1>C1(C)C=CC=CC=1>[N:5]([S:2]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:10]=[N:9][S:8][CH:12]=1)(=[O:4])=[O:3])=[C:6]=[O:7]
Reactant: Oc1ccccc1-c1csnn1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1csnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
By the procedure of Example 1, 7.9 g of chlorosulfonyl isocyanate was reacted with 10 g of 2-(1,2,3-thiadiazol-4-yl)phenol [prepared by the procedure of U.S. Pat. No. 3,940,407] in 125 ml of dry toluene. The reaction mixture was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for 1 hour. The resulting solution was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 14 g of the title compound as a crude oil. The IR showed an isocyanate absorption at 2220 cm-1.
Reaction SMILES: O.[OH-].[Cs+].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([NH2:12])[CH3:11].[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]1[CH2:29][NH:12][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][N:4]=1)[CH3:11])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CC(N)c1ccccn1
Agent: CN(C)c1ccncc1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
To a suspension of crushed and dried 3 A molecular sieves (1.0393 g) in DMF (15 mL) was added cesium hydroxide monohydrate (0.6272 g, 3.7 mmol) and DMAP (0.0366 g, 0.3 mmol), and the mixture was stirred at room temperature for 15 minutes. To this was added 1-pyridin-2-yl-ethylamine (0.4168 g, 3.4 mmol) in DMF (10 mL), and was stirred for 30 minutes. Then 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (1.1050 g, 4.1 mmol) was added and the reaction was stirred at room temperature for 19 hours. The reaction mixture was filtered with CH2Cl2, concentrated, and diluted with 1N NaOH (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (4×150 mL). The combined organic layers were washed with brine (1×100 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (33:1:1 CH2Cl2-MeOH—NH4OH) provided 0.7260 g (61%) of 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as an orange oil. 1H NMR (CDCl3) δ 1.47 (d, 3H, J=6.0 Hz), 1.66 (s, 9H), 2.92 (d, 2H, J=31.0 Hz), 4.00-4.07 (m, 1H), 4.13-4.29 (m, 1H), 7.03-7.04 (m, 1H), 7.27-7.33 (m, 3H), 7.48-7.55 (m, 1H), 7.65-7.70 (m, 1H), 7.82-7.86 (m, 1H), 8.48 (d, 1H, J=4.8 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCCCl)cc1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of methyl 4-sulfanylbenzoate (2.00 g, 11.9 mmol) in N,N-dimethylformamide (13 mL) was added potassium carbonate (6.57 g, 47.6 mmol) and 1-bromo-3-chloro-propane (2.35 mL, 23.8 mmol). The mixture was heated at 60° C. for 16 h. The reaction mixture was filtered and the solvent removed in vacuo. The material was dissolved in dichloromethane (10 mL) and washed with water (3×10 mL) and a saturated aqueous NH4Cl (10 mL). The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo. Silica gel chromatography (0-100% dichloromethane/hexane) provided methyl 4-(3-chloropropylsulfanyl)benzoate (1.87 g, 64%) as a colorless viscous liquid. ESI-MS m/z calc. 244.0. found 245.1 (M+1)+; Retention time: 1.83 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 3.84 (s, 3H), 3.79-3.61 (m, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.20-1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35](Br)=[CH:34][N:33]=2)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CO.C(Cl)Cl>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:18][C:15]3[N:16]=[N:17][C:12]4[CH:11]=[C:10]([C:3]5[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=5[Cl:1])[CH:20]=[C:19]([CH3:21])[C:13]=4[N:14]=3)=[CH:34][N:33]=2)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Reactant: O=C(NCCN1CCCC1)c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(C(=O)NCCN5CCCC5)nc4)nnc3c2)c1
Yield: 54.9 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.090 g, 0.299 mmol, 1 equiv), 5-bromo-pyridine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (0.134 g, 0.449 mmol, 1.5 equiv), cesium carbonate (0.293 g, 0.899 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.035 g, 0:059 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.027 g, 0.0299 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 24 hours, then sonicated and slowly diluted with water. The resulting orange precipitate was filtered and dried. Column chromatography (1:5 MeOH/DCM) provided desired product as a yellow solid (0.085 g, 55% yield).
Reaction SMILES: [C:1]([O:5][C:6](N=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC.[CH3:16][NH:17][CH:18]([NH:24][CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([C:18]([NH:24][CH3:25])([NH:17][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(NC)NC
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CCCCCC(NC)(NC)C(=O)OC(C)(C)C

Procedure:
Tert-butoxycarbonyl azide in ether ("Organic Synthesis V", p. 157-158) (2.9 g, 20 mmol, 5.2 ml) was added dropwise to a stirred solution of N,N'-dimethyl-hexane diamine (Aldrich Cat. No. D16110-1) (Beilstein 4(1), p. 422) (2.92 g, 20 mmol) in dimethyl sulphoxide (DMSO) (30 ml). The temperature was kept at 20° C. with external cooling. After the addition was complete (30 minutes), stirring was continued at room temperature for 1 hour, whereupon water (30 ml) was added. The solution was acidified (pH 5) with 2N HCl and extracted with ether (2 ×200 ml). The DMSO/water-mixture was made alkaline (pH 11) with 6N NaOH and extracted with ether (4×200 ml). Evaporation of the ether gave the title compound (1) (1.2 g) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.C(OC([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOCC>C(Cl)Cl.CO>[NH2:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38]([NH:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1)=[O:39]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.10 g, 0.26 mmol), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.06 g, 0.26 mmol), and HBTU (0.10 g, 0.26 mmol) in DCM (3 ml) was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was then passed through a silica plug. The resulting foam was placed in dioxane (4 ml) and 4 M HCl in dioxane (1 ml) was then added, and the reaction was stirred for 3 hours. The reaction was then concentrated to give a solid which was dissolved in a minimal amount of MeOH (0.5 ml) with stirring, followed by fast addition of ether (50 ml). The resulting solid was filtered, washed with ether, and dried to give the title compound (0.033 g, 26%). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J=10.7 Hz, 1H), 7.49-7.46 (m, 2H), 7.07-7.02 (m, 2H), 5.80 (s, 1H), 5.09-5.04 (m, 1H), 4.58 (dd, J=15.4, 6.8 Hz, 1H), 4.26 (dd, J=15.4, 5.2 Hz, 1H), 3.71 (d, J=6.0 Hz, 1H), 2.23-2.18 (m, 1H), 2.01-1.97 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.19-1.13 (m, 2H), 1.05-1.03 (m, 6H), 0.85-0.81 (m, 2H). MS: Calcd.: 483. Found: [M+H]+ 484.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:27]([O-:34])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCC(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: O
Product: CCCCCC(=O)[O-]

Procedure:
7.08 g (2.10-2 moles) of vincamine and 2.32 g (2.10-2 moles) of caproic acid are reacted according to the same method of the preceding example. There are obtained 8.2 g of an oily substance, insoluble in water and in the common solvents. The vincamine content is 67%.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])CC1C=CC=CC=1)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH:14]=[O:15])=[CH:8][NH:9]2.[C:28]([OH:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.OC1C(OCCCNC(C)C)(C=O)C2C(=CC=CC=2)N=1>[Pd].CO>[C:28]([OH:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH:1][CH:2]([CH2:16][NH:17][CH:25]([CH3:27])[CH3:26])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH:14]=[O:15])=[CH:8][NH:9]2
Reactant: CC(C)N(Cc1ccccc1)CC(O)COc1cccc2[nH]cc(C=O)c12
Agent: [Pd]
Agent: CC(C)NCCCOC1(C=O)C(O)=Nc2ccccc21
Agent: O=C(O)c1ccccc1
Solvent: CO
Product: CC(C)NCC(O)COc1cccc2[nH]cc(C=O)c12

Procedure:
6.6 g. 4-[2-hydroxy-3-(N-benzylisopropylamino)-propoxy]-3-formylindole (see Example 1) are dissolved in 150 ml. methanol, mixed with 0.5 g. 10% palladiumcharcoal and hydrogenated at ambient temperature and under a hydrogen pressure of 1 bar. The reaction mixture is subsequently filtered and concentrated to a volume of about 20 ml. and the equivalent amount of benzoic acid is added thereto. After suction filtration, there are obtained 3.1 g. (44% of theory) 4-[2-hydroxy-3-(isopropylamino-propoxy]-3-formylindole benzoate; m.p. 204°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH2:27][CH3:28]>O1CCCC1>[CH2:27]([N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1=[O:19])[CH3:28]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CCI
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Yield: 98.1 %

Procedure:
In a manner similar to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (160 mg, 0.468 mmol), lithium (bis-trimethylsilyl)amide (0.94 mL of a 1 M solution in tetrahydrofuran, 0.940 mmol), and iodoethane (0.22 mL, 2.81 mmol) was prepared ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (170 mg, 95% yield) as a yellow oil. The product was carried on without further purification. 1H NMR (CDCl3) δ 8.37 (s, 1 H), 7.34 (s, 1 H), 7.10-7.05 (m, 2 H), 6.95-6.91 (m, 2 H), 4.39 (m, 2 H), 4.11 (m, 2 H), 4.06 (s, 2 H), 1.35 (m, 3 H), 1.15 (m, 3 H); MS m/z 393 (M+23).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][N:20](COCC[Si](C)(C)C)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8].C1COCC1.C(O)C.[OH-].[NH4+]>Cl.O>[CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8]
Reactant: CSCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CSCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 50.7 %

Procedure:
A solution of 5-(methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 3.0 M HCl (HCl) in water (4 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a pale orange oil. The oil was stirred in ethanol (3 mL, 0.05 mol) and 8.0 M ammonium hydroxide in water (1 mL) overnight. The reaction was concentrated and purified by prep LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give 125 mg of a white foam. The white foam was triturated with MTBE (˜1.5 mL). The resulting solid was filtered, washed and dried to give 80 mg of the product (32% yield).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:15])=[CH:10][N:9]=1.C1OCCOCCOCCOCCOCCOC1.[CH2:34]([O:36][C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=2)[N:41]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:51][CH:50]=2)[C:40]=1[CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[O:38])[CH3:35]>CCOC(C)=O.CN(C=O)C>[CH2:34]([O:36][C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:8]3[CH:13]=[CH:12][C:11]([CH2:14][Cl:15])=[CH:10][N:9]=3)[CH:46]=2)[N:41]([C:49]2[CH:50]=[CH:51][C:52]([O:55][C:56]([F:59])([F:57])[F:58])=[CH:53][CH:54]=2)[C:40]=1[CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[O:38])[CH3:35]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
K2CO3 (138 mg, 1.0 mmol), 2-chloro-5-chloromethylpyridine (32 mg, 0.2 mmol) and 18-crown-6 (5 mg) were added to a mixture of 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (90 mg, 0.2 mmol, see step (b) Example 9) and DMF (5 mL). The mixture was stirred for 48 h at 70° C., cooled, diluted with EtOAc, filtered through Celite®, concentrated and purified by chromatography. Yield 60 mg (520%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[C:22]([O:29][CH3:30])=[C:21]([CH3:31])[C:18]=1[CH:19]=O>>[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[C:22]([O:29][CH3:30])=[C:21]([CH3:31])[C:18]=1[CH2:19][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:18]2[C:21]([CH3:31])=[C:22]([O:29][CH3:30])[C:23]([O:27][CH3:28])=[C:24]([O:25][CH3:26])[C:17]=2[O:16][CH3:15])[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Product: COc1c(C)c(CNCCCN2CCN(CCCNCc3c(C)c(OC)c(OC)c(OC)c3OC)CC2)c(OC)c(OC)c1OC

Procedure:
The title compound was prepared by a similar way as in Preparation Example 1, except that 1,4-bis(3-aminopropyl)piperazine was used instead of trans-1,2-cyclohexane diamine and 2,3,4,5-tetramethoxy-6-methylbenzaldehyde was used instead of veratraldehyde.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:29]1[CH:30]=[C:25]([CH2:24][OH:23])[CH:26]=[CH:27][CH:28]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)cnc12
Product: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (3-benzyl-4-bromo-8-(trifluoromethyl)quinoline in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-(hydroxymethyl)phenylboronic acid in place of phenyl boronic acid; MS (ES) m/z 392.5.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[OH:28][CH2:27][CH2:26][O:25][C:24]1[C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:29])[C:3]([OH:30])=[O:2])=[CH:10][CH:9]=2)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCO)cc1
Yield: 69 %

Procedure:
A mixture of 4-[[2-[3-(2-hydroxyethoxy)-2-naphthalenyloxy]ethyl]oxy]-alphaoxobenzeneacetic acid methyl ester (0.6 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve the solids, was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2 N hydrochloric acid, and extracted with dichloromethane-tetrahydrofuran. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.4 g of 4-[[2-[3-(2-hydroxyethoxy)-2-naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 176°-177° C.