Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4OC)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Cl)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (31.0 g, 56.9 mmol) in 3:1 THF/EtOH (200 ml) was added sodium hydroxide (120 ml, 120 mmol), and the reaction was allowed to stir overnight at ambient temperature, at which point it was complete as determined by thin layer chromatography. The reaction was concentrated to about 25% volume, taken up in 100 ml of EtOH and 100 ml of water, and acidified with 10 ml of concentrated HCl with stirring. The product initially oiled out, but became a solid. The solids were collected by filtration and washed with 200 ml of water to yield 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (24.7 g, 47.8 mmol) as a white solid.
Reaction SMILES: [BH4-].[Na+].[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[C:32](=[O:34])[CH3:33])[CH2:23]1)[C@@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6].C(O)(=O)C.C(Cl)(Cl)Cl>C(O)C>[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[CH:32]([OH:34])[CH3:33])[CH2:23]1)[C@@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (60 mg) was added to a solution of 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (250 mg) in absolute ethanol (7 ml). After stirring at room temperature for 4 hours, the solution was cooled and glacial acetic acid (10 ml) was slowly added. The solution was added to chloroform (100 ml) and successively washed with water (3×), 1N sodium bicarbonate (2×), and water (1×) and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the product as a fine white solid. The 200 MHz NMR spectrum of the peracetylated derivative was in accord with the desired structure. TLC data and Rf values are given in the above Table.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=[NH:35])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C([O-])(=O)C.[Na+].Cl.NO>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:35])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Combine 4-(6-chloro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 57, 2.256 g, 7.2 mmol), benzophenone imine (1.568 g, 8.6 mmol), BINAP (269 mg, 0.43 mmol), Pd2(dba)3 (132 mg, 0.144 mmol), sodium t-butoxide (969 mg, 10.08 mmol) and toluene (50 mL) and heat at 95° C. for 12 hr. Quench the reaction with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Dissolve the residue in methanol (70 mL), add sodium acetate (1.42 g, 17.3 mmol) and hydroxylamine hydrochloride (900 mg, 13 mmol), stir at room temperature for 30 min. Partition between 1N NaOH and CH2Cl2, extract the aqueous layer twice with CH2Cl2. Combine the organic layers and wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 12-25% ethyl acetate in hexanes) provides 2.06 g (98%) of the title compound as a yellow solid: mass spectrum (ion spray): 294.1 (M+1); 1H NMR (CDCl3, ppm): 7.35 (t, 1H), 6.08 (d, 1H), 6.06 (d, 1H), 5.09 (m, 1H), 4.32 (s, br, 2H), 3.75 (m, 2H), 3.29 (m, 2H), 1.94 (m, 2H), 1.73 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: C([N:8]1[CH2:16][C:15](=[O:17])[C:14]([CH2:21][CH:22]=[CH2:23])([CH2:18][CH:19]=[CH2:20])[C@H:9]1[C:10]([O:12]C)=[O:11])(OC(C)(C)C)=O.[Li+].[OH-].Cl>O.CO>[CH2:21]([C:14]1([CH2:18][CH:19]=[CH2:20])[C:15](=[O:17])[CH2:16][NH:8][C@@H:9]1[C:10]([OH:12])=[O:11])[CH:22]=[CH2:23]
Reactant: C=CCC1(CC=C)C(=O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCC1(CC=C)C(=O)CN[C@@H]1C(=O)O
Yield: 187.3 %

Procedure:
To a solution of 0.099 g of N-(BOC)-3,3-diallyl-4-oxo-(L)-proline, methyl ester in 0.4 mL of water and 1.6 mL of MeOH was added 25.7 mg of LiOH.monohydrate. The reaction mixture was sonicated for 2 h. The mixture was acidified with 1.2N HCl to pH=2 and concentrated in vacuo. The residue was treated with 1.5 mL of HCl/dioxane solution for 1.5 h. After concentration in vacuo, 0.12 g of 3,3-diallyl-4-oxo-(L)-proline was obtained which was used in the next step without purification.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]4[N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=[CH:36][C:29]=34)[CH:25]=[N:24]2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+]>O.C(O)C>[OH:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]4[N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[CH:35]=[CH:36][C:29]=34)[CH:25]=[N:24]2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ccnc21
Reaction time: 8 h

Procedure:
To {3-{[tert-butyl(diphenyl)silyl]oxy}-1-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (2.0 g, 3.0 mmol, a mixture of diastereomers from Step A) ethanol (82 mL) was added 5.0 M sodium hydroxide in water (9 mL, 50 mmol). The reaction was stirred overnight. The reaction mixture was diluted with water and ethanol was removed in vacuo. The aqueous mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water, then brine, dried over sodium sulfate, decanted and concentrated. The product, as a mixture of diastereomers, was used without further purification in Step C. LCMS (M+H)+: 424.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(F)cc54)CC3)nc2N1
Yield: 16 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 54), (0.7 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 51 mg (16%) product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:16])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O.C(O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[S:16][C:13]3[CH:12]=[C:11]([S:14][CH3:15])[CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(NC(=S)c2ccc(Cl)cc2)cc1
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CSc1ccc2nc(-c3ccc(Cl)cc3)sc2c1
Temperature: 90 °C
Yield: 67.2 %

Procedure:
To a solution of potassium hexacyanoferrate(III) (670 mg, 2.04 mmol) in water (5 mL) at 90° C. was added dropwise over 5 minutes a solution of 4-chloro-N-(4-(methylthio)phenyl)benzothioamide (150 mg, 0.51 mmol) in ethanol (2 mL) and 3M aqueous sodium hydroxide solution (1.4 mL, 4.08 mmol). The resulting mixture was heated at 90° C. for 30 minutes. After cooling, the precipitate formed was filtered off and washed with water to give a yellow solid. The yellow solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 5:95 v/v) to afford 100 mg (67%) of the title compound (LCMS RT=9.37 min, MH+ 292.2)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[CH3:23])[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 83 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].Cl>CO>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc(F)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1NCCc2ccc(F)cc21
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To the solution of 1-methyl-7-fluoro-3,4-dihydroisoquinoline (2.4 g, 14.7 mmol) prepared in Step 2 in methanol (10 ml), sodium borohydride (0.28 g, 1 eq.) was portionwise added. The reaction mixture was stirred for 3 hours and 1N hydrochloric acid solution (20 ml) was added thereto. The reaction mixture was washed with dichloromethane. The water layer was adjusted to pH 12 with potassium hydroxide solution and extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2.0 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:23]([O-])=O)[C:5]([N:8]([CH2:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)[CH:9]=O)=[N:6][CH:7]=1>CCO.CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]2[N:23]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(CN(C=O)c3ncc(F)cc3[N+](=O)[O-])cc2s1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 25 °C
Yield: 28 %

Procedure:
A stirred mixture of N-(5-fluoro-3-nitropyridin-2-yl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide and iron powder (6 g, 108 mmol) in EtOH (70 mL) and HOAc (30 mL) was heated at reflux for 2 h. The mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a gradient of 100% hexanes to 100% EtOAc, to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1 g, 28%) as a white foam. 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.40 (t, J=2.0 Hz, 1H), 8.09 (dd, J=2.6, 9.5 Hz, 1H), 7.99 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.5, 8.4 Hz, 1H), 5.61 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[N:25]1([C:30](N2C=CN=C2)=[S:31])C=CN=C1.N>CN(C=O)C>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:30](=[S:31])[NH2:25])[CH2:21][CH2:20]2)=[O:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=S)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Reaction time: 0.17 h

Procedure:
To a mixture of compound 1B (3.25 g, 8.50 mmol) in DMF (50 mL) was added TEA (4.71 mL, 34.0 mmol). The resulting mixture was stirred for 10 minutes and di(1H-imidazol-1-yl)methanethione (1.818 g, 10.20 mmol) was added. The reaction mixture was stirred at rt for 30 minutes. Ammonia (7 N in MeOH) (48.6 mL, 340 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was concentrated to remove the ammonia and MeOH. The DMF solution was directly used for the next step without further purification. LCMS (APCI): m/z 369 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CC=CC=1.[CH2:16]([O:32][C:33]1[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](Cl)=[O:40])=[CH:35][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:16]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[O:40])=[CH:42][CH:43]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccccc1CO
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CO)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 1.36 g of 0-aminobenzyl alcohol and 2.69 g of pyridine in 60 ml of methylene chloride is added dropwise with stirring over 40 minutes a solution of 3.5 g of 4-hexadecyloxyphenoxyacetyl chloride in 40 ml of methylene chloride. Stirring is continued at room temperature for 4 hours. The mixture is diluted with chloroform and heated to dissolve the solids, washed with water and dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride to give 3.9 g of the desired product as a white solid, m.p. 128°-131° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.C([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1B(O)O)(OC(C)(C)C)=O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1cncc(-c2cc3ccccc3[nH]2)c1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 3-bromopyridine-5-carboxaldehyde (4.12 g, 21.48 mmol), N-Boc-indoleboronic acid (8.59 g, 32.23 mmol), s-Phos (0.68 g, 1.61 mmol), finely crushed potassium phosphate (9.21 g, 42.97 mmol) and toluene (70 mL). After degassing for 1 h, Pd2dba3 (0.40 g, 0.43 mmol) is added, the flask is flushed with nitrogen and the mixture is heated to 85° C. After 30 min, the mixture is allowed to cool to r.t., diluted with ethyl acetate and filtered through a plug of silica gel. Silica gel (50 g) is added to the filtrate and the mixture is concentrated in vacuo. The residue is heated to 60° C. with gentle stirring under oil pump vacuum overnight. The mixture is then loaded on a silica gel flash chromatography column and eluted (heptane-ethyl acetate, 4:1 to 2:3) to give 5-(1H-indol-2-yl)-pyridine-3-carbaldehyde. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02-7.08 (m, 1H), 7.14-7.19 (m, 1H), 7.20 (d, J=1.5 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 8.66 (t, J=2.1 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 9.39 (d, J=2.3 Hz, 1H), 10.18 (s, 1H), 11.86 (br. s., 1H). MS (ESI) m/z 223.02 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Reactant: Cc1ccc(C=O)o1
Product: Cc1ccc(CNCC(C)Oc2ccc3ccccc3c2Cl)o1
Yield: 70 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and 5-methylfuran-2-carbaldehyde in 70% yield as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:14]=[N:15][C:16]([NH:19][CH3:20])=[CH:17][CH:18]=2)[CH:3]=1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:17]1[CH:18]=[C:13]([O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:14]=[N:15][C:16]=1[NH:19][CH3:20]
Reactant: CNc1ccc(Oc2cc(F)ccc2C(=O)OC)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1ncc(Oc2cc(F)ccc2C(=O)OC)cc1Cl
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 377D (0.450 g) and N-chlorosuccinimide (0.239 g) was stirred together in N,N-dimethylformamide (10 mL) at room temperature. The reaction was stirred for 48 hours, diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 5-30% ethyl acetate/hexanes over 30 minutes (flow=40 ml/min) provided the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:12]=2)[O:7][C:6]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:4].[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:17]([CH2:22][CH2:6][CH:5]=[CH2:3])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([CH:14]3[CH2:15][CH2:16]3)[CH:12]=2)[O:7][C:6]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=CCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 110 °C
Yield: 148.9 %

Procedure:
To a solution of 5-cyclopropyl-6-methanesulfonylamino-2-p-tolyl-furo[2,3-b]pyridine-3-carboxylic acid methylamide (900 mg, 2.25 mmol, 1.0 equiv) in DMA (2.0 mL) was added NaI (169 mg, 1.12 mmol, 0.5 equiv) and Cs2CO3 (2.2 g, 6.76 mmol, 3.0 equiv) and the resulting mixture was heated at 110° C. for 1 hour. The mixture was then diluted with EtOAc and washed with water, brine, dried over MgSO4 and concentrated. The residue wad purified by silica gel column chromatography, EtOAc/heptane (70%) to give product 760 mg. MS (ESI) m/z 454.5 (M+1). Retention time=1.58 min, Method LC-C8 broad range-NpH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][N+:17]([O-])=O)[C:7]=2[N:20]=1>[Ni].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][NH2:17])[C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2CCCC1
Agent: [Ni]
Solvent: CO
Product: COc1ccc2c(n1)c(CCN)c1n2CCCC1

Procedure:
Under a hydrogen pressure of 55 psi, 420 mg (1.53 mmol) of the compound obtained in Step E and 170 mg of Raney nickel are stirred in 20 ml of methanol at 60° C. for 15 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to yield the title product in the form of a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]=[CH:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][CH:22]=[CH2:21])[C:6]([O:8][CH3:9])=[O:7])[CH:13]=[CH2:14]
Reactant: C=CCBr
Reactant: CC=Cc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Yield: 87 %

Procedure:
A solution of 3.04 g (15.8 mmol) of methyl 4-hydroxy-3-propenylbenzoate (prepared by the procedure described in patent application WO91/11999) was refluxed with anhydrous potassium carbonate (4.37 g, 2 equiv) and allyl bromide (3.5 mL, 2.5 equiv) in acetone overnight. The mixture was filtered through celite and the filter cake was washed with acetone and dichloromethane. After removing the solvents, the resulting oil was distilled under high vacuum to give 3.2 g (87%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@@H:5]([NH:8][C:9]([C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])[CH2:6][CH3:7].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].N12CCCN=C1CCCCC2>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@@H:5]([N:8]1[C:9](=[O:10])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][C:19]1=[O:20])[CH2:6][CH3:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@@H](CC(=O)OC)NC(=O)c1ncccc1N
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 90.6 %

Procedure:
To a solution of 250 mg of (S)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester in tetrahydrofuran (10 mL) is added 403 mg of 1,1′-carbonyldiimidazole and 0.04 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature and the mixture is stirred at room temperature for 60 h. The reaction mixture is diluted with 50 mL of water and the product is extracted with ethyl acetate (50 mL×3). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 250 mg (91%) of (S)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester.