Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1([C@]2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B.B.CSC>C1COCC1>[S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C@@H:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCS(=O)(=O)c2sccc21
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: OC[C@@]1(c2ccccc2)CCCN1c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: O=S1(=O)CC[C@@H](O)c2ccsc21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (9) (1.00 g, 4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol--borane complex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to -15° C. and a solution of borane-methyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) was added at a rate to maintain the internal temperature at -15° C. The solution was stirred at -15° C. for 1 hour then at 22° C. for 6 hours. The product was isolated by the method decribed in Example 34 Step E. The enantiomeric ratio of the purified product was 95.5.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[CH3:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[NH2:26]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:26][C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH3:8])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:4]
Reactant: O=C(Cl)C(F)(F)F
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CSCCCCCNc1c(NC(=O)C(F)(F)F)cnc2ccccc12
Yield: 153.8 %

Procedure:
A cool solution of trifluoroacetyl chloride (3.5 g, 26.5 mmol) in toluene was slowly added to a solution of N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (6 g, 23.1 mmol) in a mixture of toluene and pyridine. A heavy yellow precipitate formed. The reaction mixture was stirred over the weekend and then concentrated under reduced pressure to provide 13.2 g of crude 2,2,2-trifluoro-N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)acetamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[CH2:20][CH2:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([F:31])[C:27](F)=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>>[Cl:23][C:24]1[CH:25]=[C:26]([F:31])[C:27]([O:1][C:2]2[CH:3]=[C:4]([CH3:22])[C:5]([CH:9]3[C:10](=[O:21])[CH:11]4[CH:16]([CH:15]5[CH2:19][CH2:20][CH:12]4[CH2:13][CH2:14]5)[C:17]3=[O:18])=[C:6]([CH3:8])[CH:7]=2)=[N:28][CH:29]=1
Reactant: Cc1cc(O)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Reactant: Fc1cc(Cl)cnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ncc(Cl)cc2F)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1,3-dione (0.40 g, 0.0013 mol), 5-chloro-2,3-difluoropyridine (0.20 g, 0.0013 mol) and potassium carbonate (0.40 g, 0.0029 mol) is added N,N-dimethylaminopyridine (10 ml), and the reaction mixture is then heated at 140° C. for 40 minutes under microwave irradiation. After cooling to room temperature 2M aqueous hydrochloric acid is added, and the crude product is extracted with ethyl acetate. The organic phase is separated, washed with distilled water, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is then purified by preparative reverse phase HPLC to afford 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-2,6-dimethylphenyl]hexahydro-4,7-ethanoindene-1,3-dione as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(O[Cl:22])(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=2)[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Yield: 91.9 %

Procedure:
To a solution of 5.0 g of 4-(3,5-difluorophenoxy)phenol in 50 ml of carbon tetrachloride, there was added dropwise 2.45 g of t-butylhypochlorite with vigorously stirring and ice-cooling. After completion of the addition, the reaction mixture was stirred at room temperature for 5 hours and concentrated, followed by addition of 200 ml of ethyl acetate. The obtained solution was washed with an aqueous solution of 5% wt. sodium dicarbonate, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.31 g of 2-chloro-4-(3,5-difluorophenoxy)phenol. Yield. 92%. nD25 : 1.5639
Reaction SMILES: [C:1]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][N:12]=[N:11]1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:25](N(CC)CC)C.CI>O1CCCC1>[C:1]([CH2:6][N:7]([CH3:25])[CH2:8][CH2:9][N:10]1[C:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:13][N:12]=[N:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)CN(C)CCn1nnnc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 10 mmol of 1-[2-[[(carbethoxy)-methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole and 10 mmol of triethylamine in 20 ml. of dry tetrahydrofuran is added 10 mmol of methyliodide. After stirring at room temperature for 24 hours, the mixture is filtered. The filtrate is stripped in vacuo to dryness, and the residue is dissolved in chloroform and chromatographed on silica gel eluting with a gradient of ethylacetate in chloroform. Evaporation of the product-containing fractions gives 1-[2-[[(carbethoxy)methyl]methylamino]ethyl]-5-[(4-methoxy-benzyl)thio]-1H-tetrazole. Deblocking with mercuric acetate as above gives 1-[2-[(carboxymethyl)methylamino]ethyl]-1,4-dihydro-5H-tetrazole-5-thione which when substituted in the reaction with 7-D-mandelamidocephalosporanic acid gives 7-D-mandelamido-3-[1-[2-[(carboxymethyl)methylamino]ethyl]tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:44]([C:45]2[NH:46][CH:47]=[CH:48][N:49]=2)=[CH:43][N:42]=[C:41]([NH:50][CH2:51][CH2:52][NH:53]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:40]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:44]([C:45]2[NH:49][CH:48]=[CH:47][N:46]=2)=[CH:43][N:42]=[C:41]([NH:50][CH2:51][CH2:52][NH:53][C:24]2[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=2)[N:40]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: Clc1cc(Cl)ncn1
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2nc(NCCNc3cc(Cl)ncn3)ncc2-c2ncc[nH]2)c(Cl)c1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(6-chloropyrimidin-4-yl)amino]ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 4,6-dichloropyrimidine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2]([C:31]3[C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: COC(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 160 °C
Yield: 67.5 %

Procedure:
A sealed tube containing 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.30 g, 0.75 mmol), (2-methoxycarbonylphenyl)boronic acid (0.29 g, 1.50 mmol), Pd(PPh3)4 (87 mg, 0.08 mmol), 2 M Na2CO3 (4 mL) and DME (4 mL) was heated at 160° C. for 25 minutes. Cooled to room temperature, the mixture was extracted with EtOAc. The EtOAc extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc in hexanes to give 0.23 g (68%) of the title compound (248) as off-white solid. mp 177-178° C. 1H NMR (400 MHz, CDCl3): δ 0.96 (s, 6H), 0.97 (s, 6H), 1.32 (s, 2H), 2.03 (s, 4H), 3.57 (s, 3H), 4.60 (s, 1H), 6.78 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.36-7.44 (m, 2H), 7.48-7.56 (m, 1H), 7.76-7.82 (m, 1H). LCMS (ESI): m/z 455 (M+H)+, 453 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:16](=[O:17])[N:15]3[C:10]([C:11](=[O:18])[O:12][CH2:13][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=1.[NH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22]>C(#N)C>[OH:12][CH2:13][CH2:14][N:15]1[C:16](=[O:17])[C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:8][CH:9]=[C:10]1[C:11]([NH:19][C@@H:20]([CH3:23])[CH2:21][OH:22])=[O:18]
Reactant: C[C@H](N)CO
Reactant: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Solvent: CC#N
Product: Cc1cn(-c2ccc(C(=O)N[C@@H](C)CO)n(CCO)c2=O)cn1
Temperature: 85 °C

Procedure:
A mixture of 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (1.440 g, 5.872 mmol) and (2S)-2-aminopropan-1-ol (1.714 g, 22.82 mmol) in acetonitrile (3 mL) was heated to 85° C. for 20 minutes. The reaction mixture was then allowed to cool to room temperature and diluted with additional acetonitrile (10 mL). Filtration and rinsing with acetonitrile (10 mL) afforded the product as a white solid. Yield: 1.62 g, 5.06 mmol, 86%. 1H NMR (400 MHz, DMSO-d6) δ 1.11 (d, J=6.8 Hz, 3H), 2.14 (d, J=0.9 Hz, 3H), 3.33-3.46 (m, 2H), 3.59-3.66 (m, 2H), 3.89-4.01 (m, 1H), 4.18-4.29 (m, 2H), 4.80 (t, J=5.8 Hz, 1H), 4.94 (t, J=5.4 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 7.32-7.34 (m, 1H), 7.69 (d, J=7.5 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 8.67 (br d, J=8.3 Hz, 1H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[C:28]([C:32]1[CH:33]=[C:34]([CH:40]=[C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:42]=1[OH:43])[CH:35]=[CH:36][C:37](Cl)=[O:38])([CH3:31])([CH3:30])[CH3:29]>C1C=CC=CC=1>[C:44]([C:41]1[CH:40]=[C:34]([CH:33]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:42]=1[OH:43])[CH:35]=[CH:36][C:37]([N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH2:5]1)=[O:38])([CH3:46])([CH3:47])[CH3:45]
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(C=CC(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 16.8 g. (50 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate dihydrochloride and 200 ml. anhydrous pyridine is added dropwise at 5°-10° C., in the course of 40 minutes, a solution of 14.8 g. 3,5-di-tert.-butyl-4-hydroxycinnamoyl chloride and 50 ml. anhydrous benzene. The reaction mixture is stirred for 4 hours at 20° C., the benzene and pyridine are substantially distilled off in a vacuum and the residue is stirred into about 1 liter ice water. The separated, greasy precipitate is taken up in methylene chloride and the methylene chloride phase is washed with aqueous sodium carbonate solution, dried with anhydrous sodium sulphate and evaporated to dryness in a vacuum. The crude base is dissolved in ethanol, gassed with hydrogen chloride and finally precipitated as the hydrochloride by the addition of diethyl ether. The yield is 17.3 g. (62% of theory) of the desired product which, after stirring up with diethyl ether, melts at 193°-195° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C@H:25]([CH2:28][CH3:29])[CH2:26][OH:27]>>[OH:27][CH2:26][C@H:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH2:28][CH3:29]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 85 %

Procedure:
As described for example 208, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (R)-(+)-2-amino-1-butanol instead of (S)-(+)-2-amino-1-butanol, to the title compound (210 mg, 85%) which was obtained as a white solid. MS: m/e=380.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Yield: 79.1 %

Procedure:
5-Bromo-2,3-dihydro-isoindol-1-one (1.0 g, 4.72 mmol), 1-bromomethyl-4-methyl-benzene (1.14 g, 6.14 mmol) and cesium carbonate (3.08 g, 9.44 mmol) were suspended in anhydrous NMP (10 mL). The mixture was immersed in a 60° C. oil bath for 16.5 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Column chromatography (20% to 40% ethyl acetate/hexanes) provided the title compound as a yellow solid (1.18 g, 79%). 1H NMR CDCl3: 7.76 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 4.76 (s, 2H), 4.24 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7][C:8](F)=[N:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O>[Cl:4][C:5]1[C:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7][C:8]([C:1]#[N:2])=[N:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: [C-]#N
Reactant: Fc1nc(Nc2ccc(Cl)cc2)c(Cl)c(N2CCOCC2)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(Nc2ccc(Cl)cc2)c(Cl)c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (0.057 g) was added to a solution of the product from step (ii) (0.2 g) in dimethylsulphoxide (5 ml) and the mixture stirred at room temperature. After 18 h, the mixture was partitioned between ethyl acetate and water, the organics separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in toluene. Yield 0.09 g
Reaction SMILES: [C:1](C(CC)C(OCC)=O)#N.CNC(N)=O.[NH2:16][C:17]1[N:22]([CH2:23]C)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]=1[CH3:27]>>[NH2:16][C:17]1[N:22]([CH3:23])[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:27][CH3:1]
Reactant: CCn1c(N)c(C)c(=O)[nH]c1=O
Reactant: CCOC(=O)C(C#N)CC
Agent: CNC(N)=O
Product: CCc1c(N)n(C)c(=O)[nH]c1=O

Procedure:
Ethyl 2-cyanobutanoate was reacted with 1-methylurea according to the method described for synthesis of C9 in Example 5. The product was obtained as a white solid. Yield: 5.95 g, 35.2 mmol, 66%. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 6.41 (s, 2H), 3.22 (s, 3H), 2.22 (q, J=7.3 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([P:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](O)[CH3:24].C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([P:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH2:23][CH3:24])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1ccccc1P(c1ccccc1)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2-(Diphenylphosphanyl)benzoic acid (0.50 g, 1.63 mmol) and 4-dimethylaminopyridine (DMAP, 20 mg, 0.163 mmol) were dissolved in CH2Cl2 (10 mL). Ethanol (0.29 mL, 4.89 mmol) was added, and the solution was placed under Ar(g) and cooled to 0° C. N,N′-Diisopropylcarbodiimide (DIC, 0.25 mL, 1.63 mmol) was added dropwise, and the resulting solution was allowed to warm to room temperature and stirred overnight. The solution was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with 10% EtOAc(ethylacetate)/hexanes, to give phosphine 1a as a pale yellow solid (0.44 g, 1.32 mmol, 81% yield). 2-(Diphenylphosphanyl)benzoic acid was purchased from Sigma-Aldrich (St. Louis, Mo.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17](O)(=O)[CH:18]([CH3:20])[OH:19].C>Cl>[CH3:17][CH:18]([C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:19]
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: CC(O)C(=O)O
Agent: Cl
Product: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21
Temperature: 140 °C

Procedure:
3-Amino-4-(2-methylpropylamino) quinoline (29.0 g; 0.135 mol) and lactic acid (36 mL; 0.48 mol) were mixed and heated at 140° C. for 6 hr. The mixture was then dissolved in dilute hydrochloric acid and treated with charcoal. The solids were filtered from the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as an oil. The oil was extracted into ethyl acetate. The ethyl acetate solution was treated with decolorizing carbon and the solids were filtered from the mixture. The filtrate was evaporated to dryness to yield a greenish oil which was pure enough for further reactions. A small sample was triturated with hexane to obtain a solid which was recrystallized from ethyl acetate for analysis. m.p. 152-166° C. Analysis: Calculated: C, 71.4; H, 7.11; N, 15.6. Found: C, 71.1; H, 7.33; N, 15.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+](=[CH2:19])=[N-]>C1COCC1>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH:11]1[CH2:12][CH:10]1[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(C2CC2CC(=O)O)cc1F
Solvent: C1CCOC1
Product: COC(=O)CC1CC1c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid (0.075 g, 0.33 mmol) obtained in Step D was dissolved in THF (1 mL), diazomethane (2.7 ml, 0.66 mmol, 0.25M ether) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.063 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][CH:16]=[C:17]([CH:20]=1)[C:18]#[N:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C#N)cc2C)CC1
Yield: 106.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methylbenzoic acid (215 mg) and 5-methyl-6-piperazin-1-ylnicotinonitrile (202 mg), the title compound (426 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH:19]C(OCC1C=CC=CC=1)=O)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:4]([OH:30])(=[O:3])[CH3:5].[CH2:1]([O:3][C:4](=[O:30])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH2:19])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)OP(=O)(CCNC(=O)OCc1ccccc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)OP(=O)(CCN)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 174.8 %

Procedure:
A solution of 2-[(2-benzyloxycarbonylamino-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester 218 (240 mg, 0.551 mmol) with approximately 50% purity and a ratio of 2:1 of diastereomers was dissolved in 5.5 mL of ethanol with acetic acid (63 μL, 1.10 mmol). To this solution was added 36 mg of 10% Pd/C and the solution was degassed under a hydrogen atmosphere three times. The solution was vigorously stirred at room temperature for 3 hours when TLC showed complete consumption of the starting materials. The mixture was filtered through a pad of Celite and dried to provide 174 mg (87%) of 2-[(2-amino-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester; compound with acetic acid 219 as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3C)CC1

Procedure:
2.18 g of 6,7-dichloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 3.5 cm3 of 1-methylpiperazine and 25 cm3 of dimethylsulphoxide were heated at 110° C. for 3 hours. The solvent was evaporated off in vacuo and the residue was taken up in 100 cm3 of water. The suspension was stirred and mixed with 20 cm3 of N sodium hydroxide solution. The solution obtained, which was slightly turbid, was stirred with animal charcoal and filtered, and then brought to pH 7.5 by the addition of acetic acid. The precipitate was filtered off, washed with water and then recrystallised from methyl cellosolve. 1 g of 6-chloro-1-methyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 286° C., were obtained.