Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25]([O:27]CC)=O>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 65.1 %

Procedure:
A solution of 12.63 g of aniline and 10.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent). The resultant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 7.55 g (65%) of 1,2-dihydro-4-hydroxy-1-phenyl-N-phenyl-3-quinolinecarboxamide, m.p. 120° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22](OC4C=CC=CC=4)=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1.[CH:32]([NH2:36])([CH2:34][CH3:35])[CH3:33]>C(OC(C)C)(C)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([NH:36][CH:32]([CH2:34][CH3:35])[CH3:33])=[O:23])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC(C)N
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC(C)OC(C)C
Product: CCC(C)NC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 65 °C

Procedure:
A mixture of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (8.6 g.) and sec-butylamine (40 cc.) is heated at 65° C. until dissolution. The reaction mixture is then diluted with diisopropyl ether (240 cc.). The precipitate formed is filtered off and recrystallised from acetonitrile (60 cc.). 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-sec-butylaminocarbonyloxy-isoindolin-1-one (3 g.), melting at 220°-222° C., is thus obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:12]Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:12][NH:4][CH2:3][CH2:2][OH:1])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrCC1CCCCCC1
Reactant: NCCO
Product: OCCNCC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmelthyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 4-cyanophenyl isothiocyanate to give 2-(4-cyanophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
To a stirred mixture of 4-amino-1-benzylpiperidine (1.53 mL, 7.5 mmol), K2CO3 (2.28 g, 16.5 mmol) and DMF (15 mL) heated at 50° C. was added dropwise over 60 min bis(2-bromoethyl) ether (0.96 mL, 7.65 mmol). After stirring for 6 hours at 80° C., the solvent was removed by blowing with a stream of nitrogen over 2 hours. The residue was purified on a silica gel column to give 1.7 g (87%) of 4-(1-benzyl-piperidin-4-yl)morpholine as a waxy solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:23]=2)[N:18]([C:33](=[O:54])[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:43])=[C:37]([O:52][CH3:53])[CH:36]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:33](=[O:54])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:43])=[C:37]([O:52][CH3:53])[CH:36]=1)[CH2:17][CH2:16][NH:15]2)[CH3:32])[CH3:31]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(C)c1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
Trifluoroacetic acid (574 μl) was added to a stirred solution of 7-(2-ethoxycarbonyl-1-methyl-ethyl)-4-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (376 mg, Reference Example 18) in dichloromethane (4 ml) at 0° C. After stirring at 0° C. for 2 hours a further aliquot of trifluoroacetic acid (3.5 ml) was added and stirring was continued at 0° C. for a further 4 hours. The reaction mixture was poured onto a mixture of ice (75 ml) and sodium hydroxide solution (55 ml, 1M). The resulting mixture was extracted three times with dichloromethane (50 ml). The combined extracts were washed twice with water (20 ml), then dried over magnesium sulfate and then evaporated (40 mbar, 40° C.). The residue was subjected to flash chromatography (20 g silica, 0.040-0.063 mm particle size) eluting with a mixture of dichloromethane and methanol (99:1, v/v) to give the title compound as a white powder (279 mg). TLC: RF=43/64 (dichloromethane:methanol, 9:1). 1H NMR (250 MHz, (CD3)2SO, at a temperature of 373° K.]: δ1.16 (t, J=7 Hz, 3H); 1.23 (d, J=7.5 Hz, 3H); 2.28 (s, 3H); from 2.45 to 2.55 (m, 2H); 3.06 (m, 1H); 3.25 (m, 2H); 3.69 (m, 2H); 3.82 (s, 2H); 3.85 (s, 3H); 4.05 (q, J=7 Hz, 2H); 5.73 (broad band :1H); 6.43 (dd, J=8 and 2 Hz, 1H); 6.50 (d, J=2 Hz, 1H); 6.70 (dd, J=9 and 1.5 Hz, 1H); 6.81 (d, J=1.5 Hz, 1H); 6.97 (broad t, J=7.5 Hz, 1H); from 7.10 to 7.30 (m, 3H); 7.71 (broad d, J=9 Hz, 1H); 7.98 (d, J=8.5 Hz, 1H); 8.25 (broad s, 1H); 8.29 (broad s, 1H). MS (EI): 544(M+).
Reaction SMILES: COC1C=C(C=CC=1OC)C[C:7]1[C:16]2[C:11](=[CH:12][C:13](OC)=[C:14](OC)[CH:15]=2)[CH:10]=[CH:9][N+:8]=1[O-:21].CN(C)C=O.COC1C=CC=CC=1N1CCNCC1>C(N(CC)CC)C>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N+:8]=1[O-:21]
Reactant: COc1ccc(Cc2c3cc(OC)c(OC)cc3cc[n+]2[O-])cc1OC
Agent: COc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [O-][n+]1ccc2ccccc2c1

Procedure:
A mixture of 2.5g 4-chloromethyl-1-(3,4-dimethoxybenzyl-6,7-dimethoxyisoquinoline 2-oxide, 35 ml dimethylformamide, 1.8 triethylamine and 1.29 g 1-(2-methoxyphenyl)piperazine was stirred and heated under nitrogen at 50° for 7 hours. After evaporation of the solvent, the residue was partitioned between methylene chloride and water. The methylene chloride solution was washed with water and dried. After removal of the solvent in vacuo, the residue (3.5 g) was crystallized from methylene chloride/ethyl acetate to yield 3.05 g of yellow, hygroscopic crystals of 1-(3,4)-dimethoxybenzyl)-6,7-dimethoxy-4-{]4'-(2-methoxyphenyl)-1'-piperazinyl]methyl} isoquinoline 2-oxide, mp 128°-129° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8]>CCCCCC.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCC[C@H]3c3ccnn3C)cc2F)c(OC)c1

Procedure:
The N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide prepared in Example 14c was optically resolved with CHIRALPAK AD (Daicel Corp.; hexane/isopropanol=4:1), to yield the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH2:45][CH:46]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][CH2:46][N:15]([CH2:14][CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)[CH2:16][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: O=C1CSc2ccc(N3C[C@H](CCNCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Product: CC(C)(C)[Si](C)(C)OCCCN(CC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)CC1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 87 %

Procedure:
Starting from the compound of Example 4 and 3-(tert-butyldimethylsilyloxy)-propionaldehyde and using procedure E, the title compound was obtained as a yellow foam (82 mg; 87% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:24]([CH2:23][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ICOc1ccccc1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1nonc1-c1nc2ccccc2n1COc1ccccc1

Procedure:
To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g, 0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) and iodomethoxy benzene (0.128 g, 0.546 mmol). The mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue between water and ethyl acetate followed by drying of the organic solution over sodium sulphate and chromatography of the residue gives the title compound as a colorless solid, m.p. 171-173° C.
Reaction SMILES: [O:1]1CCC[O:3][CH:2]1[CH2:7][CH2:8][C:9]([C:11]1[C:12](=[O:36])[N:13]([CH3:35])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=1)[CH:15]=2)=[O:10].C(OC(C1C=CC(C2C=C3C(C(O)=C(C(OC)=O)C(=O)N3C)=CC=2)=CC=1)=O)(C)(C)C.[H-].[Na+]>C1COCC1.CCOC(C)=O>[C:2]([CH2:7][CH2:8][C:9]([C:11]1[C:12](=[O:36])[N:13]([CH3:35])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=1)[CH:15]=2)=[O:10])([OH:3])=[O:1]
Reactant: Cn1c(=O)c(C(=O)CCC2OCCCO2)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: COC(=O)c1c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2ccc(-c3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(3-(3-(1,3-dioxan-2-yl)propanoyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)benzoate. Methyl 7-(4-(tert-butoxycarbonyl)phenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (452 mg, 1104 μmol) was dissolved in THF (11 mL). Sodium hydride (60% in oil, 442 mg, 11040 μmol) was then added, and the resulting mixture was stirred at room temperature for 1 hour. 2-[2-(1,3-Dioxanyl)]ethylmagnesium bromide in THF (2208 μL, 1104 μmol) was then added dropwise, and the reaction mixture was then stirred for 1 hour. The reaction mixture was diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with 3 N HCl (aqueous), washed 2 times with 75 mL of brine (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotary evaporation to give initial product. The initial product was purified via flash chromatography (silica gel) to provide the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of ethyl 5-(3,4-dichlorophenyl)isoxazole-4-carboxylate (8.60 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 65 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3,4-dichlorophenyl)-4-isoxazolylmethanol (6.97 g, yield 95%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 101–102° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:19](=[O:20])[NH:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 50 °C

Procedure:
Mixture of quinolin-6-ol (0.58 g., 4 mmol), hexyl isocyanate (0.70 ml, 4.8 mmol) and dry pyridine (0.2 ml) in dry dimethylformamide (1 ml) was heated at 50° C. for 5 hours. Reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum and crystallized with ether to give 1a; yield: 0.7 g. (59.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13]O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.P(Br)(Br)[Br:16].O.C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][Br:16])[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12
Reactant: COc1cc(CCO)cc2c1OCO2
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(CCBr)cc2c1OCO2
Yield: 122.1 %

Procedure:
2.74 g (14 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl alcohol (3) was dissolved in 10 ml of ethyl ether, to which was added portionwise 1.64 g (6.1 mmol) of phosphorus tribromide in 2 ml of ethyl ether under ice-cooling. The mixture was refluxed under heating for one hour, then cooled and further stirred while adding 10 ml of water and 15 ml of a saturated sodium hydrogencarbonate aqueous solution. The reaction mixture was separated and the ether layer was washed with 10 ml of a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluate: ethyl acetate / n-hexane=1/2) to obtain 1.93 g of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl bromide (6) as a crystal with a yield of 53%. Melting point: 78°-79° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@H](CO)C(=O)O
Product: COc1ccc(CN[C@H](CO)C(=O)O)cc1

Procedure:
The title compound was prepared from D-serine (29.6 g, 0.3 mmol) and p-methoxybenzaldehyde (68.0 mL, 0.6 mmol) according to Method W and was obtained as a white solid (36.2 g, 57%) that required no further purification. δH (DMSO-d6) 7.37 (2H, dd, J 8.7 and 1.9 Hz), 6.93 (2H, dd, J 8.7 and 1.9 Hz), 3.99 (2H, s), 3.55 (3H, s), 3.73 (3H, m), 3.15 (1H, t, J 4.7 Hz). Some exchangeable protons were not observed. LCMS (ES+) 225.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[NH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH3:30]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][CH:24]([NH2:23])[CH:25]([CH3:30])[CH2:26]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CC1CNCCC1N
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: COc1c(N2CCC(N)C(C)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 50 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-amino-3-methylpiperidine was carried out in a similar manner as described in example 1, gave the titled product. Yield 50%, m.p 260–62° C., C20H25FN4O4, m/z 405 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:5][C:6]([CH3:27])=[C:7]([C:9](=[O:26])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)[N:8]=1.C(O)(=O)C>CO.CN(C)C=O>[CH3:3][C:4]1[O:5][C:6]([CH3:27])=[C:7]([CH:9]([OH:26])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:24][CH:25]=2)[N:8]=1
Reactant: Cc1nc(C(=O)COc2ccc(C=C3SC(=O)NC3=O)cc2)c(C)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(C)o1
Temperature: 0 °C
Yield: 96.9 %

Procedure:
Sodium borohydride (0.16 g) was added to a suspension of 5-{4-[2-(2,5-dimethyl-oxazolyl)-2-oxoethoxy]benzylidene}-2,4-thiazolidinedione (1.5 g) in methanol-N,N-dimethylformamide (1:1, V.V, 40 ml) under ice-cooling. After stirring under ice-cooling for 20 minutes, the reaction solution was poured into ice-water, and the aqueous mixture was made acid with acetic acid, and the crystals which separated out were collected by filtration to give 5-{4-[2-(2,5-dimethyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione (1.47 g, 97.5%). Recrystallization from chloroform-ethanol afforded colorless prisms, m.p. 223°-224° C. Elemental analysis for C17H16N2O5S, Calcd.: C, 56.66; H, 4.47; N, 7.77. Found: C, 56.36; H, 4.55; N, 7.56.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1ccc(Sc2ccc(Br)cc2)c(F)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(F)cc3F)cc2)c1C
Yield: 16.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,4-difluorobenzene (0.176 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,4-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.04 g, 16%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12]O>>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1O
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-methyl-4-hydroxybenzoic acid (342 g, 2.24 mol) in MeOH (3.5 I) is bubbled HCl (g) for 5 m. The mixture is stirred for 12 h at RT. The reaction is concentrated to give the title compound (372 g, quant).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([F:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:38][CH:37]=2)[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Nc2nc(Cl)ncc2F)c1
Reactant: COCCOc1ccc(N)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cc([N+](=O)[O-])ccc3OCc3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 36.2 %

Procedure:
In a 100 mL 3-neck RBF, N-(2-(benzyloxy)-5-nitrophenyl)-2-chloro-5-fluoropyrimidin-4-amine (0.205 g), 4-(2-methoxyethoxy)aniline (0.137 g), Cs2CO3 (0.266 g) and Xantphos (0.032 g) were taken in degassed 1,4-dioxane (8.0 mL) and reaction mixture was degassed under argon for 30 minutes. Palladium acetate (0.013 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80° C. and stirred for 3.5 h. The reaction was monitored on TLC using hexane:ethyl acetate: (5:5) as mobile phase. After completion, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 mL). The ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by triturating with diethyl ether to give 0.1 g of N4-(2-(benzyloxy)-5-nitrophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine. 1H NMR: CDCl3 (400 MHz): 3.47 (d, 3H, J=11.6), 3.77 (dd, 2H, J=4.8, 8.8), 4.15 (t, 2H, J=4.8), 5.28 (s, 2H), 6.96 (d, 1H, J=8.8), 7.03 (d, 1H, J=8.8), 7.08 (d, 1H, J=9.2), 7.45 (m, 7H), 7.83 (s, 1H), 7.9 (d, 2H, J=2.8), 8.02 (dd, 1H, J=2.1, 6.8), 9.18 (s, 1H).