Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][C@H:20]([C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH:21]([CH3:23])[CH3:22].C(N[C@H](C(O)=O)C(C)C)(OC(C)(C)C)=O.N1CCOCC1>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][C@H:20]([C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N1CCOCC1
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1COCCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCOCC1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example DlI above) and 4-(L-valinyl)morpholine (prepared from N-BOC-L-valine (Aldrich) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2].[CH2:31]([C:34]1[CH:35]=[N:36]C(Br)=[N:38][CH:39]=1)[CH2:32][CH3:33]>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:38]=[CH:39][C:34]([CH2:31][CH2:32][CH3:33])=[CH:35][N:36]=4)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CCCc1cnc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C#N)c(F)c3)nc2)CC1
Product: CCCc1cnc(N2CCC(c3ccc(COc4ccc(C#N)c(F)c4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-cyano-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 13) (50 mg, 0.12 mmol) and 5-propyl-2-bromopyrimidine (33 μL, 0.24 mmol) following a procedure analogous to that in Example 48 as a white crystal (35 mg, yield 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CSc1ccc(O)cc1C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(OC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
3-Methyl-4-methylsulfanylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform to give 3-methyl-4-methylsulfanyl-phenyl acetate (1.00 g, yield 80%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>ClCCl.CCCCCC.Cl>[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:19](=[O:21])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:43][CH:42]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: COc1ccc(CN)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
To a solution of 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) in 0.50 mL of dry dichloromethane was added triphosgene (6.9 mg, 23 μmol) and N,N-diisopropylethylamine (14 μL, 82 μmol), successively. After the reaction mixture was stirred at room temperature for 10 min, 4-methoxybenzylamine (17 μL, 0.13 mmol) was added. After the reaction mixture was stirred at the same temperature for 30 min, the reaction mixture was diluted with hexane (1 mL) and 1 M HCl (2 mL). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound as a white solid (6.1 mg, 24%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:3]1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([NH:24][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:3]1
Reactant: NCCc1ccccc1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Solvent: CC#N
Product: Cn1cc(C(=O)C(=O)NCCc2ccccc2)c2ccccc21

Procedure:
2-(1-Methyl-1H-indol-3-yl)-2-oxo-N-phenethyl-acetamide was synthesized following scheme II above starting from (1-methyl-1H-indol-3-yl)-oxo-acetic acid and phenethylamine. Yield (61%). HPLC ret. time 3.38 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J=5.9 Hz, 1H), 8.73 (s, 1H), 8.25 (m, 1H), 7.60 (m, 1H), 7.36-7.20 (m, 7H), 3.91 (s, 3H), 3.47 (m, 2H), 2.86 (t, J=7.4 Hz, 2H); ESI-MS 307.3 m/z (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][C:24]1[N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]([Cl:39])([Cl:38])[C:35](Cl)=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[Cl:33][C:34]([Cl:39])([Cl:38])[C:35]([C:30]1[N:29]2[C:24]([CH2:23][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:17])[F:18])=[CH:25][CH:26]=[CH:27][C:28]2=[N:32][CH:31]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)C(F)(F)F)Cc1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 0 °C
Yield: 44 %

Procedure:
To a solution of 11.78 g (25.36 mmol) of 5-[N-tert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine and 13.94 g (114.36 mmol) of 4-(N,N-dimethylamino)pyridine in 250 ml of chloroform was added 8.50 ml (76.09 mmol) of trichloroacetyl chloride. The mixture was heated for 16 hours under reflux. The reaction mixture was poured into ice-water, and extracted with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to afford 6.80 g of the desired compound (44.0%, a pale yellow liquid).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([Cl:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[F:12])=[N:3][CH:4]=[N:5]2
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccn2ncnc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A mixture of 4,5-dichloropyrrolo[2,1-f][1,2,4]triazine (3.73 g, 19.8 mmol), 2-fluoro-4-nitrophenol (3.43 g, 21.8 mmol) and potassium carbonate (5.47 g, 39.6 mmol) in DMF (100 mL) was stirred at 60° C. for 1 h. After cooling to rt, the reaction was filtered through a short plug of silica gel with ethyl acetate and then concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate/hexanes (1:1) to give the title compound (4.37 g, 71%) as a white solid. 1H NMR (CDCl3) δ 8.22-8.17 (m, 2H), 7.92 (s, 1H), 7.77 (d, 1H, J=2.8 Hz), 7.58 (t, 1H, J=7.2 Hz), 6.87 (d, 1H, J=3.2 Hz); MS(ESI+) m/z 309.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CS(C)=O>C1COCC1.COC(C)(C)C>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a suspension of 60% sodium hydride (4.2 g) dispersed in THF (135 ml) was added dropwise at 40-50° C. a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (21.6 g) in THF (40 ml). The mixture was stirred at the same temperature for 30 min and a solution of 3-dimethylaminopropyl chloride (14.4 g) in t-butyl methyl ether (60 ml) was added dropwise. The mixture was stirred for 10 min and dimethyl sulfoxide (135 ml) was added dropwise. The mixture was stirred at 60-70° C. for 5 hr. The reaction mixture was poured into ice water (800 ml) and extracted 3 times with toluene (250 ml). The organic layer was extracted twice with 20% aqueous acetic acid solution (250 ml). The aqueous layer was neutralized, extracted twice with toluene (250 ml) and washed with water. The solvent was evaporated to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (17.9 g, 61.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:20])[CH3:19])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-nitroaniline (6.45 g, 29.7 mmol) was dissolved in dichloromethane (149 mL) and pyridine (2.88 mL, 35.7 mmol). The solution was cooled to 0° C. and then, acetyl chloride (2.325 mL, 32.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with water and dichloromethane and the organic phase was dried over sodium sulfate and was concentrated to dryness. N-(3-bromo-5-nitrophenyl)acetamide was isolated as a beige powder (7.86 g, 30 mmol, 100%) and was of sufficient purity to carry forward without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([Cl:32])[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1c2ccc(Cl)n2nc(C(Cl)C2CC2)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a stirred solution of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.40 g, 4.24 mmol) and pyridine (1.5 mL, 18.5 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (2 M, 4.5 mL, 9.0 mmol) at 0° C. under nitrogen and stirred for 20 min. The reaction mixture was then stirred at rt overnight, poured into ice water, and extracted with CH2Cl2 (3×40 mL). The organic layers were washed with brine and dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1:9) gave the title compound as a white solid (0.96 g, 65%): 1H NMR (CDCl3) δ 7.22 (m, 3H), 7.04 (m, 3H), 6.48 (d, 1H, J=4.4 Hz), 6.05 (d, 1H, J=16.5 Hz), 4.68 (d, 1H, J=16.5 Hz), 3.81 (d, 1H, J=10.45 Hz), 1.96 (m, 1H), 1.19 (m, 1H), 0.72 (m, 1H), 0.57 (m, 1H), 0.22 (m, 1H), −0.35 (m, 1H); 3C NMR (CDCl3) δ 154.2, 148.2, 136.4, 129.2, 128.0, 125.8, 118.0, 117.6, 110.6, 109.0, 62.5, 44.1, 15.3, 7.22, 6.19; MS (ESI+) 348.02 (M++H), 370.01 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:13][N:14]([CH3:24])[S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:10][C@H:9]2[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(CC#N)C=CC=1.[CH2:35]([C:42]1[N:46]=[C:45]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[O:44][N:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([C:42]1[N:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:11][C@@H:9]3[CH2:10][C@@:8]3([CH2:13][N:14]([CH3:24])[S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:49][CH2:48]2)[O:44][N:43]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CN(C[C@@]1(c2cccc(Cl)c2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Reactant: c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Agent: N#CCc1cccc(Cl)c1
Product: CN(C[C@@]1(c2cccc(Cl)c2)C[C@H]1CN1CCC(c2nc(Cc3ccccc3)no2)CC1)S(=O)(=O)c1ccccc1

Procedure:
N-{[(1S,2R)-1-(3-chlorophenyl)-2-formylcyclopropyl]methyl}-N-methylbenzenesulfonamide [made from (3-chlorophenyl)acetonitrile via the sequential methods of Preparations 1, 2, 3A, 4A, 5A, 6A, 7A, 8A] and 4-(3-benzyl-1,2,4-oxadiazol-5-yl)piperidine (incorporating by reference as needed WO 00/39125) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, CD3OD) δ 7.70-7.53 (m, 5H), 7.36-7.23 (m, 9H), 4.07 (s, 2H), 3.83 (d, J=14.0 Hz, 1H), 3.39-3.16 (m, 4H), 3.09 (d, J=14.0 Hz, 1H), 2.78-2.61 (m, 3H), 2.57 (s, 3H), 2.28-2.21 (m, 2H), 2.07-1.94 (m, 2H), 1.53-1.48 (m, 1H), 1.33-1.29 (m, 1H), 1.00-0.96 (m, 1H). ES-LCMS m/z 591.5 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)([O:13]CC1C=CC=CC=1)=[O:12]>C1C=CC=CC=1>[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:29])=[CH:23][CH:22]=1)([OH:13])=[O:12]
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccccc1
Reaction time: 8 h

Procedure:
2-Hydroxy-2-phenylethanamine (0.68 g) and 1-(4-carbobenzyloxyphenyl)propan-2-one (1.34 g) were refluxed in benzene (50 ml) in a Dean and Stark apparatus for 2 hours. The solvent was removed, tetrahydrofuran (50 ml), benzene (10 ml) and water (3 ml) were added followed by sodium borohydride (0.9 g). The reaction mixture was left at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between water and ether. The layers were separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound as the benzyl ester (1.67 g). This was dissolved in ethanol and hydrogenated at 75 psi and 50° for 4 hours. Filtration and evaporation of the solvent gave the title compound mp 180°-190° (ethyl acetate-methanol). τ (TFA-d) 8.5 (3H, d, J=7 Hz), 5.85-7.45 (5H, m), 4.72 (1H, broad), 2.6 (7H, m), 1.8 (2H, d, J=8 Hz). τ (d6DMSO+D2O+NaOD) 9.05 (3H, d, J=7 Hz), 6.9-7.8 (5H, m), 2.85 (2H, d, J=8 Hz), 2.7 (5H, s), 2.17 (2H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(N(C)C)=N>CCOC(C)=O.O>[F:1][C:2]1[C:7]([CH:8]([CH2:17][N+:14]([O-:16])=[O:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)/C=C/c1cccnc1F
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CC(C[N+](=O)[O-])c1cccnc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To (E)-methyl 3-(2-fluoropyridin-3-yl)acrylate (0.945 g, 5.22 mmol) was added nitromethane (10.0 mL, 186 mmol) and 1,1,3,3-tetramethylguanidine (0.120 mL, 0.956 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 50° C. for 1 h, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) gave methyl 3-(2-fluoropyridin-3-yl)-4-nitrobutanoate (0.996 g, 4.11 mmol, 79% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 243.1 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3cccc(F)c3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: BrBr.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH3:23])[NH:10][C:9]2=[O:24].[Br:25]N1C(=O)CCC1=O>C(O)(=O)C.CN(C)C=O>[Br:25][C:18]1[CH:17]=[CH:16][C:15]([O:20][CH2:21][CH2:22][CH3:23])=[C:14]([C:11]2[NH:10][C:9](=[O:24])[C:8]3[C:13](=[C:4]([CH3:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: BrBr
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 105 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Bromine (3.2 g, 0.020 mol) was added dropwise to a stirred solution of 8-methyl-2-(2-n-propoxyphenyl)quinazolin-4(3H)-one (3 g, 0.010 mol) in glacial acetic acid (45 ml) at 95° C. The resulting suspension was heated at 105° C. for 18 hours and then evaporated under vacuum. The resulting solid was dissolved in dimethylformamide (25 ml) and the stirred solution treated dropwise with a solution of N-bromosuccinimide (0.89 g, 0.0051 mol) in dimethylformamide (25 ml). After 1 hour at ambient temperature, the solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (50 ml). This solution was washed with saturated aqueous sodium carbonate solution (50 ml), dried-(Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (30 g) using a methanol in dichloromethane elution gradient (0-100%) to give the title compound as a white solid (1.67 g, 45%), m.p. 179°-180° C.; Rf 0.7 (silica; dichloromethanemethanol; 99:1). This material was used without any further purification.
Reaction SMILES: O[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1.O=P(Cl)(Cl)[Cl:22]>CC#N>[Cl:22][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1
Reactant: N#Cc1ncc2cc(-c3ccccc3)c(O)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ncc2cc(-c3ccccc3)c(Cl)nc2n1

Procedure:
The solution of 7-hydroxy-6-phenylpyrido[2,3-d]pyrimidine-2-carbonitrile (0.300 g, 1.21 mmol) in CH3CN and POCl3 (2 mL) was heated to 100° C. for 4 h. The mixture was concentrated and the residue was basified with saturated NaHCO3 at 0° C. Extracted with CH2Cl2 and the combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (10-20% EtOAc in hexane) to give the title compound. LRMS m/z (M+H) Calcd: 267.7, found: 267.2.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.C(=O)(O)[O-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)CCCC2
Yield: 74.6 %

Procedure:
A refluxing solution of ethyl 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (45.4 g) in ethanol (600 ml) was stirred whilst adding a solution of sodium bicarbonate (11.5 g) in water (300 ml) over 15 minutes. After refluxing a further 4 hours, an additional quantity of sodium bicarbonate solution (1.5 g in 30 ml water) was added and the mixture refluxed for a further 1 hour. The hot solution was acidified with dilute hydrochloric acid and the yellow precipitate filtered off. The damp solid was recrystallised from acetone to give 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid (31.0 g) mp 265°-268°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH3:9][NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12]>>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:11]([NH:10][CH3:9])=[O:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Product: CNC(=O)c1ccc(-c2ccc(F)nc2)cc1

Procedure:
This compound was prepared from 5-bromo-2-fluoropyridine and {4-[(methylamino)carbonyl]phenyl}boronic acid using procedures analogous to those for Example 18, step 1. Analytic LCMS (M+H)+: m/z=231.1.
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:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[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:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cc(Cl)cc(Cl)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCCc1cc(Cl)cc(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 82.7 %

Procedure:
ethyl 6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (76.4 mg, 0.139 mmol) was reacted with 1.0 molar sodium hydroxide (557 μl, 0.557 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (585 μl, 0.585 mmol) and partitioned between saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (72.5 mg, 0.115 mmol, 82.8% yield) as a solid.