Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([Cl:16])=[CH:9][C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[C:24]1([C:30]2[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:30]2[CH:31]=[CH:32][C:33]([CH2:34][O:14][CH2:13][C:11]3[CH:12]=[C:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:8]([Cl:16])=[CH:9][C:10]=3[Cl:15])=[CH:36][CH:37]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCc1cc(-c2ncccn2)c(Cl)cc1Cl
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(Cl)c(-c2ncccn2)cc1COCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux cndensor and an argon inlet was added 3.32 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.34 gm sodium hydride was added. The system was stirred for an additional 20 minutes and 3.16 gm of 4-phenylbenzylchloride was then added. The system was allowed to come to room temperature and stirred there for 1 hour. Afterwards, the system was heated at reflux for 48 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride extract was washed with water and dried over sodium sulfate. The methylene chloride was removed by stripping to give 3.66 m of the 5-pyrimidyl--2,4-dichlorophenylcarbinol 4-phenylbenzylether --Compound 12 in Table I.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.C1(C)C=CC=CC=1.[OH-:20].[K+]>O>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:20])[N:3]=1)[CH3:10]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Reactant: [OH-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 100 ml, three-necked, flask equipped with an agitator and condensor were added 3.0 g (0.014 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl) thiazoline (prepared as in Example 1), 47 ml of toluene, 1 ml of water and 0.79 g (0.014 mol) of solid potassium hydroxide. The resulting solution was stirred at room temperature for 45 minutes. A 1 μl sample of the reaction mixture was then removed from the flask and diluted according to the procedure described in Example 4. The HPLC assay set forth in Example 3 indicated that 72.6% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: C1COCC1.[Al+3].[Cl-].[Cl-].[Cl-].[N-:10]=[N+:11]=[N-:12].[Na+].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:35]#[N:36])([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([N:21]1[CH2:22][CH2:23][C:24]([C:35]2[NH:36][N:12]=[N:11][N:10]=2)([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:25][CH2:26]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1(Nc2ccccc2F)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccccc1NC1(c2nnn[nH]2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To 250 ml of stirring dry THF in a 500 ml r.b. flask at 0° C. under N2, AlCl3 (23.0 g, 172 mmol) was added in small portions. Subsequently, NaN3 (47.4 g, 729 mmol) and 1-benzyl-4-cyano-4-(2-fluoroanilino)piperidine (21.8 g, 70 mmol) were added. The resulting mixture was refluxed for 20 hours. It was cooled to room temperature and poured onto stirring water (300 ml). The THF layer was separated and the aqueous layer was extracted with additional THF (3×500 ml). The combined THF layers were dried over MgSO4 and filtered. The filtrate was kept at 0° C. for 15 hours. After a filtration, the desired compound (17.1 g, 49 mmol) as white powder was obtained: m.p. 195°-198° C.; IR (nujol) 3360 cm-1 ; NMR (270 MHz, DMSO-d6) δ2.29, 2.46 and 2.67 (3 m, 8H, piperidine CH2 's), 3.53 (s, 2H, benzyl CH2), 6.12, 6.61, 6.72 and 6.98 (4m, 4H, anilinophenyl H's), 7.2-7.4 (m, 5H, benzylphenyl H's). Anal. Calcd. for C19H21FN6 : C, 64.75; H, 6.01; N, 23.85. Found: C, 64.52; H, 5.94; N, 23.56. ##STR21##
Reaction SMILES: N1C=CC=CC=1.C(N1CCCOC(C[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C1)C1C=CC=CC=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:23]1([NH:22][C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1CC1
Temperature: 0 °C

Procedure:
Pyridine (3.64 mL, 45.0 mmol) was added to a solution of crude amine 80 (30.0 mmol) in CH2Cl2. The solution was cooled to 0° C. in an ice bath, then cyclopropyl carbonyl chloride (2.99 mL, 33.0 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature and stirred until the reaction was judged complete by TLC (3.25 h). CH2Cl2 and saturated NaHCO3 were added. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2×). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by alumina gel chromatography (96:2:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain 4-benzyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (85) as a pale yellow oil. 1H NMR (CD3OD) 7.46–7.24 (8H, m), 7.13 (2H, broad d, J=7.2 Hz), 3.90–3.42 (5H, m), 2.92–2.76 (2H, m), 2.62–2.51 (1H, m), 2.30 (1H, dd, 13.7, 8.5Hz), 1.40–1.20 (2H, m), 0.96–0.82 (3H, m), 0.61 (2H, dd, J=7.9, 2.8 Hz) ppm. 13C NMR (CD3OD) 175.84, 144.04, 140.20, 130.82, 130.54, 129.55, 129.08, 128.43, 77.04, 68.00, 63.63, 59.72, 55.83, 52.94, 31.28, 13.76, 9.34,9.07 ppm. LRMS: 364.57.
Reaction SMILES: [CH3:1][C:2]12[CH2:10][CH2:9][CH:5]([CH:6]([OH:8])[CH2:7]1)[C:4]([CH3:12])([CH3:11])[NH:3]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C>[C:13]([O:8][CH:6]1[CH2:7][C:2]2([CH3:1])[CH2:10][CH2:9][CH:5]1[C:4]([CH3:12])([CH3:11])[NH:3]2)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC12CCC(C(O)C1)C(C)(C)N2
Solvent: CC(=O)O
Product: CC(=O)OC1CC2(C)CCC1C(C)(C)N2
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of 1.8 g (0.016 moles) of 1,3,3-trimethyl-2-azabicyclo[2.2.2]octane-5ol in 30 ml of glacial acetic acid in a 100 ml flask equipped with a magnetic stirrer, thermometer, condenser, and drying tube was added 1.0 ml (0.106 moles) of acetic anhydride. The solution was boiled under reflux for 20 hours. The reaction mixture was then cooled and evaporated under reduced pressure. The residue was taken up in hexane, and allowed to stand at room temperature overnight. The solution was then filtered and the filtrate evaporated under reduced pressure and dried under vacuum at 35° C, yielding 1.23 g of the desired material as a colorless oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1C[C@@H](c2ncc(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 46.2 %

Procedure:
A solution of (2S,45)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (2.25 g, 4.4 mmol) in 18 mL ethanol and 18 mL water was treated with sodium sulfite (5.59 g, 44.4 mmol) and heated at 90° C. overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with more ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulphate, filtered, concentrated, and purified by silica gel chromatography to give 766 mg (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(NCCN2CCCCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCN3CCCCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.8 %

Procedure:
To a solution of 2-fluoro-N1-(2-(piperidin-1-yl)ethyl)benzene-1,4-diamine (1.00 g, 4.21 mmol) in CH2Cl2 (30 mL) was added trimethylaluminium (6.3 mL, 12.6 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.6 g, 10.18 mmol) in CH2Cl2 (8 mL). The reaction mixture was stirred at rt for 24 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=20:1) to give the title compound as a pale yellow solid (0.07 g, 5%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[N:14]=[C:13]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[N:1]1([C:9]2[N:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Brc1cccc(COC2CCCCO2)n1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(COC2CCCCO2)nc(-n2ccnc2)c1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 7.4 %

Procedure:
Imidazole (500 mg, 74 mmol) was added to a stirred mixture of sodium hydride (300 mg of a 60% dispersion in oil, 75 mmol) and dimethylformamide (20 ml), at room temperature under nitrogen. After 0.75 h, 6-bromo-2-[(tetrahydropyran-2-yl)oxymethyl]pyridine (400 mg 14.6 mmol) prepared following the procedure given for Example 11 part a in dimethylformamide (5 ml) was added. The mixture was heated at 80° C. for 24 h then in a sealed tube at 120° C. for 4 h. The solvent was evaporated in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4), and evaporated in vacuo and the residue flash chromatographed on silica gel, eluting with 5% methanol/dichloromethane to give the title-compound (280 mg, 73%), 1H NMR (250 MHz, CDCl3), δ 1.5-1.8 (6H, m, 3 of CH2), 3.58 (1H, m, CH2O), 3.93 (1H, m, CH2O), 4.66 (1H, d, J=14.1 Hz, CH2O), 4.82 (1H, d, CH), 4.90 (1H, d, J=14.1 Hz, CH2O), 7.19 (1H, br s, Ar—H), 7.24 (1H, d, J=8.2 Hz, Ar—H), 7.43 (1H, dd, J=7.6 Hz and 7.1 Hz, Ar—H), 7.64 (H, t, J=1.2 Hz, Ar—H), 7.83 (1H, t, J=7.9 Hz, Ar—H), 8.35 (1H, s, Ar—H); MS (ES+) m/e 260 [MH]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:14]O>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1CCOCC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCOCC1
Temperature: 25 °C

Procedure:
Into a solution of oxane-4-carboxylic acid (50 mg, 0.38 mmol, 1.00 equiv) in methanol (10 mL) was added thionyl chloride (46 mg, 0.39 mmol, 1.01 equiv) dropwise with stirring at room temperature. The resulting solution was stirred for 3 h at room temperature. Concentration under reducing pressure gave the title compound, which was used directly for next step without further purification (brown oil).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:28])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@@H:11]2[O:27][C@@H:10]2[CH2:9]1)=[O:4].C(=O)(O)[O-].[Na+].[C:34]([OH:37])(=[O:36])[CH3:35]>>[C:34]([O:37][C@H:10]1[CH2:9][C@@:8]2([CH3:28])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:7]2[C@@H:6]([O:5][C:3](=[O:4])[CH2:2][Cl:1])[CH2:25][C@@:24]2([CH3:26])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]1[OH:27])(=[O:36])[CH3:35]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(=O)CCl)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O

Procedure:
11β-Chloroacetoxy-2α,3α-epoxy-5α-pregnan-20-one (5 g) was dissolved in glacial acetic acid (25 ml) and heated on a steam bath for 3.1/2 hrs. The solution was poured into saturated sodium bicarbonate solution, the white precipitate filtered off, washed well with water and dried. Preparation thick layer chromatography in ethyl acetate-petrol gave the title compound as a white foam (3.26 g). [α]D +93.2°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=O)[CH3:8].Cl.[NH2:17][OH:18]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=[N:17][OH:18])[CH3:8]
Reactant: CC(=O)c1sc(-c2cccnc2)nc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NO)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone (0.5 g, 2.1 mmol) in a mixture of pyridine (2 ml) and methanol (15 ml) was added hydroxylamine hydrochloride (0.29 g, 4.2 mmol). The resluting solution was stirred at ambient temperature for 18 hours. The precipitated white solid was filtered and dried at vacuum to afford the desired 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone oxime. 1H NMR (300 Mz, DMSO-d6): δ:12.2 (s, 0.29H), 11.89 (s, 0.69H), 9.10 (s, 1H), 8.70 (d, 1H, J=4.8 Hz), 8.30 (m, 1H), 7.55 (m, 1H), 2.41 (s, 1H), 2.29 (s, 2H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C:12](=[O:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)(C(C)(C)C)(C)C>CCO.Cl>[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C:12](=[O:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: CCO
Product: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 86 %

Procedure:
To a stirred suspension of 3β-tert-butyldimethylsilyloxyandrostane-6,17-dione (2.00 g) in EtOH (20 mL), 37% HCl (40 μL) was added. After 3 h the solution was quenched with 5% aqueous NaHCO3 to pH 7. The organic solvent was evaporated and the aqueous phase was extracted with CH2Cl2 (4×350 mL). The combined organic extracts were washed with saturated aqueous NH4Cl, brine, H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/EtOAc 90/10) to give 3β-hydroxyandrostane-6,17-dione (1.25 g, 86%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.56 (1H, d), 3.31 (1H, m), 2.45-1.15 (20H, m), 0.77 (3H, s), 0.65 (3H, s).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1)[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH2:24][CH3:25])[CH:27]=3)[C:33]2=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CCc1cccc(N=C=O)c1
Product: CCc1cccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c1
Yield: 66.9 %

Procedure:
1-Cyclopentyl-3-(3-ethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (89 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-ethyl-3-isocyanato-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:23])[CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[H-].[Na+]>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([O:23][CH3:1])[CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(c1ccc(Cl)c(Cl)c1)C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
Methyl iodide (0.1 mL, 1.20 mmol) was slowly added to 15 mL of tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (200 mg, 0.602 mmol) and NaH (44 mg, 1.20 mmol) dissolved in a distilled methylene chloride solution at 0° C., and the mixture was stirred for 4 hours. Thereafter, purified water (3 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with methylene chloride (3*30 mL), and the organic layer was washed with a saturated sodium chloride solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain a colorless liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (4:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (4:1, v/v)).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:3].C(N(CC)C(C)C)(C)C.[C:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][C:30]([CH2:31][NH:32][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:33][CH:34]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: NCc1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2ccccc2)cc1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.069 ml (0.522 mmol) of 4-fluorophenyl chloroformate and 0.149 ml (0.82 mmol) of N,N-diisopropylethylamine are added, dropwise and at ambient temperature, to a solution of 0.107 g (0.58 mmol) of 4-phenylbenzylamine in 4 ml of methylene chloride. The mixture is stirred at ambient temperature for 1 h. The reaction medium is diluted with a further 2 ml of methylene chloride and washed with a saturated aqueous ammonium chloride solution and with a saturated aqueous sodium chloride solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the solid residue is washed with 5 ml of diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)[CH3:2].[CH3:16][C:17]1([CH3:26])[CH2:22][CH2:21][C:20](B(O)O)=[CH:19][CH2:18]1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:20]2[CH2:21][CH2:22][C:17]([CH3:26])([CH3:16])[CH2:18][CH:19]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Reactant: CC1(C)CC=C(B(O)O)CC1
Product: CCOC(=O)Cc1ccc(N)c(C2=CCC(C)(C)CC2)n1

Procedure:
This compound was prepared from (5-nitro-pyridin-2-yl)-acetic acid ethyl ester (as prepared in the previous step) according to the procedure for nitro reduction and bromination in Example 33, step (b), followed by Suzuki coupling to 4,4-dimethyl-1-cyclohexen-1-ylboronic acid according to the procedure in Example 1, step (e). Mass spectrum (APCI, m/z): Calcd. for C17H24N2O2, 289.2 (M+H). found 289.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([NH:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[N:7][C:8]=1[CH:9]=O)#[N:2].O.[NH2:22][NH2:23]>CO>[C:1]([C:3]1[C:8](=[CH2:9])[NH:7][C:6]([NH:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]=1[NH:22][NH2:23])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(C=O)nc1NC(C)CC
Reactant: NN
Solvent: CO
Solvent: O
Product: C=C1NC(NC(C)CC)=C(C(=O)OCC)C(NN)=C1C#N

Procedure:
2.8 g of 5-cyano-6-formyl-2-[(1-methylpropyl)amino]-3-pyridine-carboxylic acid, ethyl ester (0.01 mol) are dissolved in 10 ml of methanol and 1 g of hydrazine hydrate is added with stirring. After standing over night the title compound precipitates. Yield 2.1 g (73%); m.p. 120°-121° C. (methanol).
Reaction SMILES: Br[Mg][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:8][C:9]1[C:10]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1>O1CCCC1>[Cl:8][C:9]1[C:10]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])=[CH:11][C:12]([OH:16])=[C:13]([NH:14][C:15]([CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:17])[CH:18]=1
Reactant: Br[Mg]C1CCCC1
Reactant: CC(C)[Si](Oc1cc2oc(=O)[nH]c2cc1Cl)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cc(O)c(NC(=O)C2CCCC2)cc1Cl)(C(C)C)C(C)C
Temperature: 70 °C
Yield: 86.9 %

Procedure:
Bromo(cyclopentyl)magnesium (0.58 mL, 1.16 mmol, 2 M in diethylether) was added under inert atmosphere to a solution of 5-chloro-6-[(triisopropylsilyl)oxy]-1,3-benzoxazol-2(3H)-one (66 mg, 0.19 mmol) in tetrahydrofuran (3 mL). After stirring over night at 70° C., the solution was evaporated and dissolved in ethylacetate. The organic layer was washed with water and 1M hydrochloric acid, dried and finally concentrated to give 68 mg (89%) of the subtitled compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1)c1ccccc1
Temperature: 80 °C
Yield: 18.9 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-amino(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.32 mmol) in pyridine (3 mL) was added benzoyl chloride (45 μL, 0.38 mmol). The solution was stirred for 12 hours when water (80 mL) was added and the solid filtered. The solid was then taken up in methanol (3 mL) and 6N HCl (3 mL) and heated to 80° C. for 3 hours. Water (80 mL) was then added and the solid filtered and dried to give the title compound (20 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.3 (br s, 1H), 10.37 (s, 1H), 8.57 (s, 1H), 8.0–7.9 (m, 5H), 7.78 (d, 1H), 7.6–7.5 (m, 4H), 7.40 (t, 2H); ES-MS (m/z) 332 [M+1]+.