Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.ClS([N:32]=[C:33]=O)(=O)=O.CCN(CC)CC>C1COCC1.[Cl-].[Na+].O>[C:33]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([NH:11][C:12]([C:14]2[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=2)=[O:13])[CH:6]=1)#[N:32]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C#N)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (300 mg, 0.82 mmol) in THF (8 mL) is cooled to 0° C., treated with chlorosulfonyl isocyanate (86 μL, 0.99 mmol) and the mixture is stirred at rt for 1 h. The mixture is treated with Et3N (138 μL, 0.99 mmol) and stirred for 1 h. The mixture is diluted with brine, extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 25% -35% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-cyano-5-fluoro-indol-1-yl)-amide (120 mg, 38%). MS: 390 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.78 (s, 3H), 7.32 (m, 1H), 7.46 (m, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.77 (m, 1H), 8.20 (m, 1H), 8.35 (m, 1H), 8.65 (s, 1H), 9.28 (s, 1H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg (0.225 mmol) of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C) in DCE (2420 μL) was added morpholine (200 μL, 2.297 mmol), acetic acid (1.288 μL, 0.023 mmol) and sodium triacetoxyborohydride (95 mg, 0.450 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with sat. sodium bicarbonate solution and extracted with DCM (2×10 mL). The combined organic layers were washed with sat NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the crude title compound as an oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8]C2CCCCO2)=[CH:5][CH:4]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]#N.[Cl-].[NH4+].[O:26]1CCCC1>>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:15][CH:16]=1)=[O:26]
Reactant: Brc1ccc(COC2CCCCO2)cc1
Reactant: C1CCOC1
Reactant: N#Cc1cccs1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: O=C(c1ccc(CO)cc1)c1cccs1
Reaction time: 4 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 7.2 parts of magnesium and 81.4 parts of 2-(p-bromobenzyloxy)tetrahydropyran in 200 parts of dry tetrahydrofuran, is added dropwise a solution of 32.7 parts of 2-thiophenecarbonitrile in 70 parts of dry tetrahydrofuran (exothermic reaction: reflux temperature is maintained). Upon completion, stirring at reflux is continued for 4 hours. The reaction mixture is cooled and decomposed with 150 parts of a saturated ammonium chloride solution at about 15° C. The whole is poured onto water and the product is extracted with ether. The organic layer is washed four times with water, dried, filtered and acidified with gaseous hydrogen chloride: an oil is separated. The ether is decanted and the oily product is dissolved in 300 parts of water and 150 parts of concentrated hydrochloric acid solution. The solution is stirred with activated charcoal, filtered and the filtrate is stirred and refluxed for 10 minutes. The product is extracted with chloroform. The latter is washed with water, dried, filtered and evaporated. The residue is distilled, yielding α-hydroxy-p-tolyl 2-thienyl ketone; b.p. 180°-190° C at 0.2 mm. pressure.
Reaction SMILES: [C:1]1([C:7]2[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23](C)([O-])[CH3:24].[K+].BrCC=C.O>CC(O)C>[CH2:24]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([O:12][CH2:13][CH2:14][CH3:15])[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:9]1)[CH:23]=[CH2:22]
Reactant: CCCOc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)O
Solvent: O
Product: C=CCn1nc(-c2ccccc2)c(OCCC)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
3,5-Diphenyl-4-n-propoxypyrazole (9.0 g, 0.038 mole) is dissolved in 2-propanol (90 ml). Potassium t-butoxide (4.65 g, 0.042 mole) is added at room temperature and the reaction mixture stirred and heated at 50°C for 3 hours. It is then cooled to room temperature and 3-bromoprop-1-ene (5.53 g, 0.046 mole) is added dropwise. A white solid forms. Stirring is continued at room temperature overnight, the mixture is then poured into water and extracted with chloroform. The chloroform layer is washed with water (3 × 150 ml) and stripped under vacuum. The residual oil is purified by dry column chromatography (silica gel/toluene). The toluene solution is stripped under vacuum to afford 6.64 g (55%) product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:42]([NH:52][C@H:53]([C:55](O)=[O:56])[CH3:54])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>>[C:42]([NH:52][C@H:53]([C:55]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:56])[CH3:54])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-L-alanine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:12][C:10]1[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:25]([O:24][CH3:23])=[O:26])[CH:28]=2)[CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1N
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)Nc2cc(Cl)c(-c3ccc4c(ccn4C)c3)cc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of methyl 2-amino-4-chloro-5-(1-methyl-1H-indol-5-yl)benzoate (Intermediate 45) (150 mg, 0.477 mmol) in dichloromethane (10 mL) was added {3-[(methyloxy) carbonyl]phenyl}acetic acid (Akos, 97 mg, 0.500 mmol), HATU (236 mg, 0.620 mmol) and triethylamine (0.073 mL, 0.524 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was washed with water and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography using cyclohexane to cyclohexane/ethyl acetate 80:20 as eluant gave the title compound methyl 4-chloro-2-(2-(3-(methoxycarbonyl)phenyl)acetamido)-5-(1-methyl-1H-indol-5-yl)benzoate (205 mg, 0.418 mmol, 88% yield) as a white amorphous solid. LCMS: (M+H)+=491; Rt=4.19 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45]([CH2:48][CH2:49][NH2:50])(=[O:47])=[O:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Reaction time: 18 h
Yield: 61 %

Procedure:
Prepared according to Procedure D from a mixture of 5-(4-(4-benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.13 grams) in 1,2-dichloroethane (3 ml), diisopropylethylamine (65 mg), acetic acid (45 mg), 2-methanesulphonylethylamine (0.125 grams), and sodium triacetoxyborohydride (0.27 grams). The mixture was stirred for 18 hours. The reaction mixture was quenched with methanol (3 ml) and poured into a separatory funnel containing aqueous saturated sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml). The mixture was extracted. The organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was treated with ethyl acetate/hexanes and collected by filtration (0.083 g, 61% yield). δ1H NMR (400 MHz, DMSO-d6) 9.98 (s, 1H), 8.83 (d, 1H), 8.44 (s, 1H), 7.58 (m, 3H), 7.44 (m, 2H), 7.37 (m, 2H), 7.31 (m, 1H), 7.03 (d, 1H), 6.91 (m, 1H), 6.5 (d, 1H), 5.1 (s, 2H), 3.84 (s, 1H), 3.25 (m, 2H), 2.99 (s, 3H), 2.96 (m, 2H). ESI-MS m/z 545 (M−1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([O:25]CC)=[O:24])=[N:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([OH:25])=[O:24])=[N:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OCC)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)O)nc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.0 g sample of the crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol -1-yl)methyl]-2-pyridinyl]benzoate from step 8 in 10 mL of water was treated with 3 mL of 10% aqueous sodium hydroxide and stirred at ambient temperature overnight. The reaction mixture was washed with 30 mL of ether and the pH adjusted to six with dilute hydrochloric acid. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic acetonitrile/water (28:72) (0.05% TFA) gave 5 mg of 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoic acid: NMR (D2O+NaO3S(CH2)3Si(CH3)3 ]δ0.80 (t, J=7 Hz, 3H), 0.86 (t, J=7 Hz, 3H), 1.19-1.33 (m, 4H), 1.54-1.68 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.82 (t, J=7 Hz, 2H), 5.43 (s, 2H), 7.45-7.59 (m, 5H), 7.64 (dd, J=8 and 2 Hz, 1H), 8.37-8.45 (m, 1H); MS (FAB) m/e (rel intensity) 393 (80), 375 (30), 212 (40), 182 (100); HRMS. Calc'd for M+Li: 399.2373. Found: 399.2374.
Reaction SMILES: [Br:1][C:2]1[CH:13]=C[C:5]2NC(=O)OC(=O)[C:4]=2[CH:3]=1.[C:14](#N)[CH:15]([CH2:17][C:18]#[N:19])[OH:16].C([N:23](CC)CC)C>CN(C=O)C>[NH2:23][C:18]1[CH:17]=[C:15]([OH:16])[C:14]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:13]=2)[N:19]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: N#CCC(O)C#N
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cc(O)c2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 106.5 %

Procedure:
A solution of 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (90 g, 0.373 mol) in (N,N-dimethylformamide) (DMF) (400 ml) was added to a solution of malonitrile (37 g, 0.41 mol) and triethylamine (41.4 g, 0.41 mol) in DMF (150 ml) at 50–60° C. The reaction mixture was maintained at 50–60° C. for 30 min. A reverse quench into ice-cold 0.2N HCl (400 ml) produced a precipitate. This material was isolated by filtration and vacuum dried. It was then dissolved in 8 N KOH (2 l) and the solution was refluxed for 40 h. After cooling to rt, the mixture was neutralized with HCl, and the resulting precipitate was filtered and air dried to afford 2-amino-6-bromo-quinolin-4-ol as a pale yellow solid (95 g, 97%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1ccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1
Yield: 35 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-methoxybenzene. Yield 35%, colorless gel (195 mg, 35%). 1H NMR (DMSO-d6, 400 MHz): s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.71 (s, 3H), 4.48 (s, 2H), 5.18 (s, 2H) 6.87 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 8.18 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NCCOc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl

Procedure:
Prepared according to the method of Example 4 using 2-chloro-5-(2-chloroethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.17 g) and (R)-2-amino-1-propanol (0.11 ml). The reaction mixture was partitioned between ethyl acetate and sodium hydrogencarbonate solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by RPHPLC (eluting with 25-95% MeCN in 0.1% AcONH4 aqueous) to give the title compound as the acetate salt. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentrated under reduced pressure. Trituration with diethyl ether gave the title compound as a solid (0.05 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20].CO.N>C(O)CCC>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[CH3:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: Cc1ccc(C)c(Nc2ccnc(Cl)n2)c1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CCCCO
Solvent: CO
Product: Cc1ccc(C)c(Nc2ccnc(Nc3ccc(OCC(O)CN(C)C)cc3)n2)c1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
2-Chloro-4-(2,5-dimethylanilino)pyrimidine (Reference Example A-1; 250 mg, 1.07 mmol) was dissolved in n-butanol (5 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 295 mg, 1.07 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 100° C. for 8 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was recrystallized from acetonitrile to give the title product as a solid (104 mg, 24%). NMR (300 MHz): 2.13 (s, 3H), 2.25 (s, 3H), 2.79 (s, 6H), 3.19 (m, 2H), 3.88 (m, 2H), 4.21 (m, 1H), 5.88 (brs, 1H), 6.05 (d, 1H), 6.73 (d, 2H), 6.93 (d, 1H), 7.12 (d, 1H), 7.26 (s, 1H), 7.55 (d, 2H), 7.9 (d, 1H), 8.6 (s, 1H), 8.88 (s, 1H); m/z: (ES+) 408.4 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=O)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2].Cl.[NH2:36][OH:37]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:36][OH:37])[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)cc21
Reactant: NO
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NO)c4ccc(OC)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-hydroxyimino-2-(4-methoxy-phenyl)ethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.47 g, 1 mmole) and hydroxylamine hydrochloride (0.14 g, 2 mol) by a method similar to that described for Example 3 (74% yield). Mp: 221° C. (dec). 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=7.2), 2.61 and 3.24 (two m, 8H), 3.41 and 3.77 (two s, 2H), 3.78 (s, 3H), 4.56 (q, 2H, J=7.2), 6.93 (m, 2H),7.15 (d, 1H, J=7.6),7.72 (m, 2H), 7.89 (d, 1H, J=13.6), 8.93 (s, 1H), 10.95 and 11.26 (two s, 1H), 15.29 (br s, 1H). Anal. Calcd. for C25H27FN4O5•0.25 H2O: C, 61.66; H, 5.69; N, 11.50. Found: C, 61.61; H, 5.70; N, 11.27.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C1COCC1.ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([O:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][N:27]4[CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4)c23)cc1
Reactant: N#CCCCBr
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4CCCC#N)c23)cc1
Temperature: 25 °C

Procedure:
Add 221.2 mg (0.996 mmol) of 4-bromobutyronitrile at RT to a solution of 300 mg (0.747 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)furo[2,3-d]pyrimidine, 0.37 ml (2.24 mmol) of diisopropylethylamine and 12.4 mg of potassium iodide in 3 ml of THF. Stir the mixture under reflux for 6 h. After cooling to RT, dilute with dichloromethane, wash with satd. sodium hydrogencarbonate solution, remove the organic phase, dry over sodium sulphate and concentrate under reduced pressure. After drying the residue by means of preparative RP-HPLC (eluent: acetonitrile/water gradient), 178.1 mg of the target product are obtained (50.9% of theory).
Reaction SMILES: Cl[C:2]1[C:3]2[Se:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[Se:18][C:17]=1[C:25]([NH2:27])=[O:26].CN(C=O)C.[OH-].[Na+]>>[C:11]([C:9]1[Se:10][C:3]2[C:2]([NH:15][C:16]3[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[Se:18][C:17]=3[C:25]([NH2:27])=[O:26])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncnc(Cl)c2[se]1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3cc(C(C)(C)C)[se]c23)c(C(N)=O)[se]1

Procedure:
The reaction of 4-chloro-6-(tert-butyl)selenopheno[3,2-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a white color solid, mp 260-262° C. IR (KBr) vmax 3439, 3173, 2960, 1666, 1605, 1564, 1503, 1458, 1381, 1330, 1244, 1086, 1038, 848, 773 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.32 (1H, s, exchangeable with D2O), 8.75 (1H, s), 8.73 (1H, s), 7.37 (1H, s), 5.34 (2H, br s, exchangeable with D2O), 1.47 (9H, s), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3): δ 171.9, 168.8, 168.5, 164.4, 154.8, 147.8, 122.7, 121.6, 118.4, 108.9, 37.3, 37.1, 32.5, 32.4; LC-MS (positive ion mode): m/z 481, 483, 485 (M+H)+.