Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][C@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>O.CC(C)=O>[CH3:6][C@H:7]1[CH2:12][N:11]([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH2:10][CH2:9][NH:8]1
Reactant: C[C@H]1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Sodium hydrogen carbonate (21.7 g) and acetone (50 ml) was added to a solution of (S)-(+)-2-methylpiperazine (6.0 g) in water (75 ml). The resulting suspension was cooled (0-5° C.) and a solution of 2-nitrobenzenesulphonyl chloride (15.9 g) in acetone (25 ml) was added, the reaction mixture was allowed to stir at ambient temperature overnight. Water (60 ml) was added and volatile material was removed by evaporation. The residue was acidified to pH 2 by the addition of HCl (2 M, 75 ml) and the mixture was extracted into DCM (2×100 ml). The aqueous phase was adjusted to pH 10-11 by the addition of NaOH (2 M, 50 ml) and extracted into EtOAc (2×150 ml). The organic washings were combined, dried and concentrated to leave the title compound (14.1 g) as a yellow oil. NMR: 1.06 (d, 3H), 2.35-2.43 (m,1H), 2.73-3.06 (m, 4H), 3.65-3.71 (m, 2H), 7.59-7.62 (m, 1H), 7.68-7.72 (m, 2H), 7.95-7.98 (m, 1H); m/z (+ve ESP): 286 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.ClC[CH2:26][O:27][CH2:28]CCl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH2:26][O:27][CH3:28])[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: ClCCOCCCl
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
Incremental portions of 3.6 g of sodium hydride (50% strength in white oil) is added to a solution of 21 g of 4,5-bis(4-methoxyphenyl)imidazole in 75 ml of absolute dimethylformamide. The mixture is stirred for another 30 minutes, and then 6.3 ml of 1-chloromethylmethyl ether in 35 ml of dimethylformamide is added dropwise. After 30 minutes the mixture is poured on ice water, the product is taken up in chloroform, the organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from benzene/hexane, thus obtaining 18.31 g of 4,5-bis(4-methoxyphenyl)-1-methoxymethylimidazole, mp 99°-101°.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.C(O)C.[BH4-].[Na+]>O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of 0.43 g of 11β-fluoro-3-hydroxy-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one in 4 ml of tetrahydrofiran, 2.3 ml of ethanol and 1 ml of water is mixed in portions at 0° C. with 111 mg of sodium borohydride, and it is stirred for 2 hours. Then, it is added to ice water, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/acetone. 0.32 g of 11β-fluoro-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol with [α]D22=+16.2° (c=0.51% in methanol) is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][CH:31]1[C:39](Cl)=[O:40]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:39]([CH:31]3[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:30]3)=[O:40])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C(Cl)C1Cc2ccccc2O1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnnc1C(=NOCc1cccc(NC(=O)C2Cc3ccccc3O2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (100 mg, 0.32 mmol) in dry dichloromethane (4 mL) under argon was added pyridine (39 μL, 0.48 mmol) at room temperature, followed after fifteen minutes by 2,3-dihydro-1-benzofuran-2-carbonyl chloride (88 mg, 0.48 mmol). The reaction mixture was stirred overnight at room temperature and quenched by filtration on bi-layer cartridge filled with 1.4 g of basic alumina and 1 g of silica. The cartridge was rinsed twice by 10 mL of dichloromethane. The combined filtrated solutions were evaporated in vacuo to yield a colorless oil. Purification on silica gel afforded of N-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-2,3-dihydro-1-benzofuran-2-carboxamide as a colorless oil [150 mg, yield 96%; HPLC/MS: nm/z=456 (M+H); log P(HCOOH)=3.67].
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([O:28]CC)=O)[C:8]1=[O:31])(=[O:3])[CH3:2].[CH3:33][NH2:34]>C(O)C>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:34][CH3:33])=[O:28])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine in ethanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6 (90° C.) δ ppm 1.80-1.87 (m, 3 H), 2.95 (d, J=4.94 Hz, 6 H), 3.53 (t, J=6.79 Hz, 2 H), 4.18 (s, 2 H), 4.36 (s, 2 H), 7.12 (t, J=8.44 Hz, 2 H), 7.35-7.40 (m, 2 H), 8.05 (s, 1 H), 8.54 (s, 1 H), 10.07 (s, 1 H), 17.05 (br. s., 1 H); ES+ MS: 427 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.[F:16][C:17]1[CH:18]=[C:19]([C@@H:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[N:25]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:20]=[C:21]([F:23])[CH:22]=1.IC>COCCOC>[F:16][C:17]1[CH:18]=[C:19]([C@H:24]2[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:26](=[O:30])[C@H:27]([CH3:11])[CH2:28][CH2:29]2)[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@H]1c1cc(F)cc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COCCOC
Solvent: CI
Product: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.642 mL, 0.642 mmol) at −78° C. was added dropwise a solution of tert-butyl (2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate (200 mg, 0.642 mmol, described in Intermediate 26) in DME (10 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodomethane (0.040 mL, 0.642 mmol) was added. After stirring at −78° C. for 30 min and at −30° C. for 30 min, the reaction mixture was cooled to −78° C. and quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10. MS: m/z=270 (M−C4H7).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:33])[F:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:35](N1C=CN=C1)([N:37]1C=CN=[CH:38]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:32])[F:33])[CH:21]=1)[CH2:16][C:17]([N:37]([CH3:38])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 3-(4-acetylamino-1 ,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid (350 mg, 0.72 mmol) in tetrahydrofurane was added carbonyldiimidazole (175 mg, 1.08 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added dimethylamine in THF (0.73 ml, 1.45 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (200 mg, 55%): mp, 83–85° C.; 1HNMR (CDCl3): 2.25 (s, 3H, CH3CO), 2.91 (s, 3H, NCH3), 3.06–3.13 (m, 4H, CHHCO+NCH3), 3.85 (dd, J=10, 15 Hz, 1H, CHHCO), 5.85–5.91 (m, 1H, CHN), 6.80 (t, JH-F=75 Hz, 1H, OCF2H), 6.84 (t, JH-F=75 Hz, 1H, OCF2H), 7.23 (d, J=7.5 Hz, 1H, Ar), 7.41–7.47 (m, 3H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=7.5 Hz, 1H, Ar), 9.51 (s, 1H, NHCO). 13C NMR (CDCl3): 24.8, 34.5, 35.4, 36.9, 50.5, 111.4, 111.5, 115.2, 115.6, 115.7, 117.9, 119.8, 119.9, 122.0, 122.4, 124.7, 126.1, 131.1, 135.8, 137.4, 138.2, 141.9, 142.2, 167.7, 168.8, 169.1, 169.7; Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.88; N, 8.13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:23](Cl)[Cl:24]>O>[Cl:24][CH2:23][O:16][C:15](=[O:17])[CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)OCCl)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1 g, 4.1 mmol) in DCM (25 mL) and H2O (25 mL) were added NaHCO3 (1.38 g, 16.4 mmol) and TBAHSO4 (0.14 g, 0.41 mmol). The reaction was stirred at 0° C. for 10 min, followed by the addition of a solution of chloromethyl sulfochloridate (499 μL, 5.5 mmol) in DCM (5 mL). The mixture was stirred at rt for 20 h, then washed with brine (25 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as colorless oil (826 mg, 69.1%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C([O-])(O)=O.[Na+].[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH:18]([CH3:20])[CH3:19]>O.CC#N>[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:22])[CH:18]([CH3:20])[CH3:19]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 5 °C

Procedure:
H-Gln-OH (2 eq.) and NaHCO3 (2 eq.) were dissolved under stirring in water at maximum 45° C. and then cooled to about 5° C. Z-Val-OSu (1 eq.) was dissolved in MeCN and added in the aqueous solution in such way that the temperature did not rise above 10° C. The mixture was stirred for at least 1 h at ±5° C. before being warmed to room temperature for at least two hours. The peptide solution was concentrated under vacuum, diluted with water and washed twice with AcOEt. The aqueous phase was then diluted with i-BuOH and the pH was adjusted to 2.5 with a solution of KHSO4. DCM was then added to extract the peptide into the organic phase which was washed with a 5% weight NaCl solution and finally with water. The organic phase was collected and concentrated under reduced pressure until water content in the evaporates was <1% weight. The concentrate was diluted with hot isopropyl acetate and left to cool to 25° C. under gentle stirring to crystallize the peptide. The solid was recovered by filtration, once washed with AcOiPr at 25° C. and dried under vacuum until AcOiPr content in the peptide was ≦5% weight. After drying under vacuum not less than 70% of Z-Val-Gln-OH was recovered.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:14]1[C:15]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:16][C:17]([NH:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][C:37]4=[O:43])=[C:30]([CH:33]=[O:34])[N:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])=[N:18][CH:19]=1)#[N:13]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:12]([C:14]1[C:15]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:16][C:17]([NH:20][C:21]([N:23]2[C:32]3[N:31]=[C:30]([CH:33]=[O:34])[C:29]([CH2:35][N:36]4[CH2:41][CH2:40][N+:39]([O-:6])([CH3:42])[CH2:38][C:37]4=[O:43])=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[O:22])=[N:18][CH:19]=1)#[N:13]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CC[N+](C)([O-])CC4=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chlorobenzoperoxoic acid (9.3 mg, 0.041 mmol) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Example 83, 20 mg, 0.039 mmol) in CHCl3 (0.1 ml) at 0° C. After stirring for 20 min, the mixture was warmed to room temperature and stirred for another 2 h. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3. The aqueous layer was back-extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a light purple solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH:17]=O)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([CH2:17][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: C1COCCN1
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Solvent: ClCCl
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)cc(CN2CCOCC2)n1-c1c(F)cccc1F
Yield: 28.4 %

Procedure:
The title compound was prepared by reacting 5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.456 g, 1 mmol) with morpholine (0.13 ml, 1.5 mmol) and triacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (7 mL) by using a similar procedure to the one described for Example 468. The crude product was purified by flash column chromatography. Elution with (50:50→0:100) hexanes-ethyl acetate to give 0.15 g (29% yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.57 (m, 2H), 7.43-7.31 (m, 3H), 7.20 (dt, J=8.64, 2.48 Hz, 2H), 6.85 (s, 1H), 5.44 (s, 2H), 3.37 (app t, J=4.37 Hz, 4H), 3.13 (s, 2H), 2.08 (t, J=4.19 Hz, 4H); ES-HRMS m/z 527.0600 (M+H calcd for C23H20BrF4N2O3 requires 527.0594).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:26])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 16.6 %

Procedure:
A solution of 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (prepared as in Example 31 (B)(c), 83.3 mg, 0.21 mmol) in tetrahydrofuran (2.1 mL) was added to a cooled (0° C.) slurry of lithium aluminum hydride (12.0 mg, 0.32 mmol) in tetrahydrofuran (1.54 mL). The reaction mixture was stirred at 0° C. for 2.5 h. The reaction was then quenched by the dropwise addition of water (25 mL). The reaction was further diluted with water and was then extracted with ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide (12.5 mg, 16.1%) as a white solid: mp 60-62° C.; EI-HRMS m/e calcd for C20H23ClN2O2(M+) 358.1448, found 358.1443.
Reaction SMILES: Cl[CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].Cl.[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1>ClCCl>[O:4]([CH:2]([N:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]1=[O:19])[CH3:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(Oc1ccccc1)n1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by adding a solution of α-chloroethoxybenzene [see Preparation 8] (4.5 mmol) in dichloromethane (5 ml) to a solution from 5-chloropyrimidin-2-one hydrochloride (4.5 mmol) in dichloromethane (15 ml) at 5° C., and the mixture was stirred at room temperature for 2 h before being worked up. The product was a mixture of the desired N-isomer and the O-isomer in the ratio 3:2; yield 0.85 g (76%). The isomers were separated by chromatography on silica gel using chloroform as above; m.p. 92° C. (CH2Cl2 /Pet.ether). (Found: C58.02; H 4.51 Calc. for C12H11ClN2O2 : C57.49; H4.43) 1H NMR (CDCl3): δ 1.72 (Me, d, J 5Hz), 6.4-7.3 (Ph,H-α), 7.79 and 8.40 (H-4 and H-6, respectively, J 3 Hz). IR (KBr): 1665 cm-1 (CO). MS [70 eV, m/z (% rel. int.)]: 250 (l,M), 159 (30)), 157 (100), 121 (23), 77 (30), 65 (17).
Reaction SMILES: [CH3:1][Li].[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[CH:5]1>C1COCC1>[CH3:3][N:4]1[C:12]2[C:7](=[C:8]([C:13](=[O:15])[CH3:1])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: Cn1ccc2c(C(=O)O)cccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1ccn2C

Procedure:
Methyl lithium (1.59M solution in ether; 13.8 ml) was added dropwise to a stirred cold (-65° to -55°) solution of 1-methyl-1H-indole-4-carboxylic acid (1.75 g) in dry THF (50 ml) under nitrogen and stirring was continued while the mixture warmed to 0° over 2 h. The reaction was then quenched with saturated ammonium chloride solution (50 ml) and the layers were separated. The aqueous layer was further extracted with dichloromethane (2×50 ml) and the combined organic layers were washed with brine (2×50 ml), dried and evaporated in vacuo. The residual solid (1.8 g) was purified by FCC eluting with dichloromethane to give the title compound (1.6 g), m.p. 63°-64°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:24][CH2:23][CH2:22][O:21][CH3:20])[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: COCCN
Product: COCCNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 257 mg (3.43 mmol) of 2-methoxyethylamine to give 61 mg (56% of theory) of the title compound.
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:34]=[CH:35][C:36]2[CH:37]=[CH:12][C:2]3[C:3]([C:39]=2[CH:40]=1)=[CH:4][CH:5]=[C:6]1[C:11]=3[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Product: Brc1ccc2ccc3c4ccccc4ccc3c2c1

Procedure:
3-Bromochrysene was prepared from (1-napthylmethyl)triphenylphosphonium chloride and 4-bromobenzaldehyde using the procedure described in Example 1, part a.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[CH:10]2)([CH3:3])[CH3:2].[O:16]1CCOCC1>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10]2)([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: Cc1ccc2nccc(OC(C)C)c2n1
Product: CC(C)Oc1ccnc2ccc(C=O)nc12
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 8-isopropoxy-2-methyl-[1,5]naphthyridine (1.13 g, 5.60 mmol) in 1,4-dioxane (40 mL) was added SeO2 (0.80 g, 7.20 mmol) and the reaction mixture was refluxed for 2 hrs, when the TLC showed no starting material left, then cooled to room temperature and filtered through celite. The solid was washed with hot AcOEt and the filtrate was then concentrated to give 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde as a light yellow solid (1.20 g, 100%). HR-MS-EI (+) m/e calcd for C12H12N2O2 (M+) 216.0899. found 216.0900