Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:17][CH:16]([OH:18])[CH2:15][CH:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]3)[CH:5]=[CH:6][C:7]=1[F:8].CO>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(NC1=NC2(c3ccc(F)c(Br)c3)CC(O)CC2CS1)c1ccccc1
Solvent: CC#N
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3ccc(F)c(Br)c3)C[C@H](O)C[C@H]2CS1)c1ccccc1
Yield: 34.9 %

Procedure:
Racemic N-((4aRS,6RS,7aSR)-7a-(3-bromo-4-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.492 g, 1.09 mmol) is purified by chiral HPLC: Column: Chiralcel OJ-H 3×25 cm; eluent: 75:25 (methanol:acetonitrile); flow: 40 mL/min at UV 225 nm. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (0.171 g, 35%). ES/MS m/e (79Br/81Br) 449, 451 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:34]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)Cl>[F:33][C:2]([F:1])([F:32])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16]([Br:34])=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC[C@@H](NC(=O)c1c(Br)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide (Comp. No. 16e) (200 mg, 0.43 mmol) in chloroform (5 ml) was added N-bromo-succinimide (76 mg, 0.43 mmol) and the mixture was stirred for 18 h at 25° C. Then excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The crude product was purified by reverse phase HPLC to give 200 mg (86%) of 7-bromo-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 3): Rt=1.81 min; m/z=543.1 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)(=[O:23])[CH3:22]>C(N(CC)CC)C>[C:21]([NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:27]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NCC1CCCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 6 h
Yield: 83.5 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(2.83 g), 3-acetamidomethylpiperidine (1.87 g) and triethylamine (1.5 g) inacetonitrile (60 ml) was refluxed with stirring for 6 hours. The precipitate was filtered to give 7-(3-acetamidomethylpiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.5 g). The product (3.0 g) was suspended in 6N hydrochloric acid (50 ml) and heated at 100° C. with stirring for 5 hours. The reaction mixture was concentrated in vacuum, and the crude material was dissolved in 20 ml of aqueous ammonium hydroxide under ice-cooling. Removal of the solvent followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave 7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.6 g), which was recrystallized from methanol-water to afford colorless prisms. m.p. 242°-243° C.
Reaction SMILES: C1COCC1.C(=S)(OC1C=CC=CC=1)[O:7][C@H:8]1[CH2:15][C@@:14]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:16](=[O:17])[C@H:10]([C:11](=[O:25])[CH:12]=[C:13]2[O:23][CH3:24])[C@:9]1([CH3:40])[CH2:26][CH2:27][CH2:28][C:29]([CH3:39])([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:30].[Li]N1C(C)(C)CCCC1(C)C.CCCCCC>CCOC(C)=O>[OH:7][C@@H:8]1[C@@:9]([CH3:40])([CH2:26][CH2:27][CH2:28][C:29]([CH3:30])([O:31][Si:32]([CH2:35][CH3:36])([CH2:37][CH3:38])[CH2:33][CH3:34])[CH3:39])[C@@H:10]2[C:16](=[O:17])[C@@:14]([CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])([C:13]([O:23][CH3:24])=[CH:12][C:11]2=[O:25])[CH2:15]1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1OC(=S)Oc1ccccc1)C2=O
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1O)C2=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
A THF (2 mL) solution of 40 (144 mg, 0.269 mmol, 1 equiv.) was cooled to −78° C. in a 25-mL recovery flask, and a freshly prepared THF solution of lithium tetramethylpiperidide (0.50 M, 2.2 mL, 1.1 mmol, 4 equiv.) was added. The resulting orange solution was stirred at −78° C. for 15 min and then stirred at 0° C. for 40 min. The reaction was then quenched with saturated aqueous NaHCO3 at 0° C. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to an orange oil. Flash column chromatography (75 mL SiO2, 7:3 hexane:EtOAc) afforded 104.3 mg (0.2117 mmol, 79% yield) of 41 as a faint yellow oil. TLC Rf 0.56 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.63 (s, 1H), 4.95 (t, J=7.0 Hz, 1H), 3.78 (d, J=7.8 Hz, 1H), 3.73 (s, 3H), 3.15 (s, 1H), 2.47 (dd, J=14.5, 6.4 Hz, 1H), 2.37 (dd, J=14.5, 7.6 Hz, 1H), 2.09 (dd, J=13.4, 5.4 Hz, 1H), 1.88 (s, 1H), 1.73 (dd, J=13.3, 11.6 Hz, 1H), 1.65 (m, 7H), 1.52 (td, J=12.6, 3.5 Hz, 1H), 1.39 (td, J=12.5, 4.1 Hz, 1H), 1.34-1.27 (m, 2H), 1.23 (m, 4H), 1.18 (s, 3H), 0.92 (t, J=7.9 Hz, 9H), 0.86 (s, 3H), 0.54 (q, J=7.8 Hz, 6H). 13C NMR (126 MHz; CDCl3): δ 205.4, 193.1, 177.4, 134.4, 119.0, 105.9, 73.6, 72.0, 69.2, 57.0, 56.0, 46.2, 45.6, 39.4, 38.4, 30.6, 29.50, 29.48, 26.1, 18.1, 17.9, 15.7, 7.3, 6.9. HRMS-ESI (m/z): [M+Na]+ calculated for C28H48O5Si, 515.3163. found, 515.3170.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:4]1[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])cc(C)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)cc(C)n1C

Procedure:
A catalytic amount of palladium-on-charcoal is added to a solution of 3.0 g (0.01 mole) of ethyl 1,5-dimethyl-3-(2-nitrophenyl)amino-1H-pyrrole-2-carboxylate in 50 ml of ethyl acetate, and the mixture is hydrogenated (in a circulatory hydrogenation apparatus under a slightly elevated pressure at room temperature) until the theoretical amount of hydrogen has been absorbed. After the catalyst has been filtered off, the filtrate is concentrated in vacuo, and the crystalline residue is recrystallized from a little isopropanol. Yield: 2.1 g.
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[Cl:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=2[Cl:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: Fc1cccc(N=C=S)c1Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2Cl)c1O
Yield: 71.1 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (500 mg, 2.0 mmol) and 2chloro-3-fluorophenylisothiocyanate (374 mg, 2.0 mmol) were coupled to form the desired thiourea (623 mg, 71%). LC-MS m/z 438.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:28]C)[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1.Cl.O.C([O-])(O)=O.[Na+]>CCO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[N:10]=[C:11]([OH:28])[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: COc1nc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1-c1nc(O)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Temperature: 90 °C

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.3 g, 8.51 mmol) in EtOH (30 mL) in a 150 mL sealed tube was added concentrated hydrochloride (21 mL). The tube was sealed, stirred, and heated at 90° C. for 16 h. The reaction mixture was cooled to r.t. and poured onto iced-water. Solid NaHCO3 was added to neutralize the mixture. The mixture was extracted by DCM three times. The combined organic layers were dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to give 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol. 1H NMR (400 MHz, CD2Cl2) δ ppm 9.95 (br. s., 1 H), 7.21-7.36 (m, 1 H), 7.13 (d, J=7.3 Hz, 2 H), 5.76 (s, 1 H), 3.87 (s, 2 H), 3.68 (s, 3 H), 3.22 (t, J=5.7 Hz, 2 H), 2.77-2.97 (m, 3 H), 2.22 (s, 6 H), 1.22 (d, J=7.1 Hz, 6 H). MS (ESI+) m/z 378.3 (M+H)+.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:45]([O:44][C@@H:9]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:8][OH:7])([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C

Procedure:
To the solution of ((S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzo[d]thiazol-6-yl)ethyl pivalate (20 mg) in THF/MeOH (1 mL/1 mL) was added sodium hydroxide solution (1 mL, 1 N, 1 mmol). The mixture was heated at 50° C. for 12 hours. The mixture was diluted with water, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and filtered. Concentration gave (S)-1-(6-(1-tert-butoxy-2-hydroxyethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-3-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one. LCMS-ESI+: calc'd for C32H34ClN5O3S: 604.2 (M+H+); Found: 604.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2([CH3:26])[CH2:25][O:24]2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].[Na].[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([OH:24])([CH3:26])[CH2:25][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C1=C(COCC2(C)CO2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: c1nc[nH]n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCC(C)(O)Cn2cncn2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.4 %

Procedure:
A mixture of 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxymethyl}-2-methyloxirane (0.80 g), 1,2,4-triazole sodium salt (0.60 g) and "18-Crown-6" (20 mg) in tetrahydrofuran (25 ml) was stirred at room temperature for two days and then partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (12 g) using toluene plus 0-100% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue was triturated with ether. The resulting solid was collected, washed with ether and dried to give the title compound (0.49 g), m.p. 149°-160° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>ClCCl.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1-c1cnn(C)c1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnn(C)c1
Yield: 22.2 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (119 mg, 0.54 mmol) and 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-phenylamine (100 mg, 0.49 mmol) using in analogous manner the procedure described in example 206c). Column chromatography (25 g silica, dichloromethane/ethyl acetate 0-25% v/v) afforded the title compound (42 mg, 22%) as a light yellow viscous oil. MS ISP (m/e): 386.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.82 (s, 1H), 7.76 (m, 2H), 7.39 (d, 1H), 7.29 (m, 5H), 7.08 (s, 1H), 6.98 (dd, 1H), 6.44 (s, 1H), 3.96 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:24])C.O.Cl>C(O)C.[OH-].[Na+]>[Cl:24][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:10]=2[CH:22]=[CH:23][C:7]=1[O:6][CH2:5][C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(Cl)c(Cl)c3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)c(Cl)c3)noc2c1Cl

Procedure:
To a suspension of 19 g of the ester in 400 ml of ethanol, 20 ml of 50% NaOH is added. A precipitate forms and the heterogeneous mixture is refluxed for 1 hour. To the hot mixture 400 ml of water is added followed by concentrated HCl until the mixture is acidic. The suspension is stirred one half hour, filtered and recrystallized from DMF-ethylacetate to give {[7-chloro-3-(3,4-dichlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 222°-224° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].C1(C)C=CC=CC=1.C(N(CCCC)CCCC)CCC>O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:21]=[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 20 °C

Procedure:
To a 250 mL round bottom flask, was added 5.52 g of benzophenone (1 eq), 8.46 g of glycine ethyl ester hydrochloride (1, 2 eq), 67 mL of toluene, and a trace amount of BF3 Et2O. The slurry was heated to reflux (112˜113° C.). Tributylamine (11.2 g) was then added dropwise over 120 min. The reaction mixture was stirred at reflux (114-116° C.) until the area percent (AP) of benzophenone <9.0% by HPLC (22-29 h). The reaction mixture was cooled to 15-25° C. and water (35 mL) was added. After phase separation, the organic phase was concentrated to 50% (w/w) under reduced pressure at <40°. The concentrated solution was then cooled to 20° C., followed by addition of methanol (3 mL). The slurry was cooled to 10° C. and stirred for 30 min. The resultant slurry was filtered. The wet cake was washed with cold water/methanol (5:1 v/v, 2×20 mL), and dried under vacuum at 20° C. for 24 h to give N-(diphenylmethylene)glycine ethyl ester (2) as an off-white to yellow solid (5.5 g, 95% pure by HPLC, 65.6% isolated yield). 1H NMR (CDCl3): δ1.27 (t, J=7.25 Hz, 3H), 4.20 (s, 2H), 4.20 (q, J=7.07, 2H), 7.17-7.67 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].N>C(O)(=O)C.S(=O)(=O)(O)O.Cl>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1Cl
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NNc1ccc(Cl)c(Cl)c1Cl
Temperature: 60 °C
Yield: 79.9 %

Procedure:
2,3,4-Trichloroaniline (100 g) was dissolved with stirring in glacial acetic acid (875 ml) at 55°-60° C. A solution of sodium nitrite (39.5 g) in concentrated sulphuric acid (300 ml) was then added over 15 minutes at 55°-60° C. to the solution thus obtained. The viscous mixture obtained was cooled to 5°-10° C. and a solution of stannous chloride dihydrate (437 g) in concentrated hydrochloric acid (375 ml) was added at 5°-10° C. over 20 minutes. A fine, off-white solid precipitated. To aid filtration, the mixture was warmed to 60° C., allowed to cool to laboratory temperature and then filtered. The precipitate was washed on the filter with saturated aqueous sodium chloride solution (100 ml). The damp powder thus obtained was added to a stirred mixture of aqueous ammonia (1.3 liters; S.G. 0.880) and ice. The fine slurry which formed was filtered and the precipitate obtained was dried at 80° C., and boiled twice with chloroform (2×1.5 liters). The chloroform extracts were combined and evaporated to dryness to give 2,3,4-trichlorophenylhydrazine (86 g), m.p. 142°-143° C., in the form of a colourless powder.
Reaction SMILES: [C:1]([C:4]12[CH2:13][C:8]3([OH:14])[CH2:9][CH:10]([CH2:12][C:6]([C:15]([OH:17])=[O:16])([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[I-].[Sm+3].[I-].[I-].[C:22](OC(C)=C)(=[O:25])[CH:23]=[CH2:24]>O1CCOCC1>[C:15]([C:6]12[CH2:7][C:8]3([O:14][C:22](=[O:25])[CH:23]=[CH2:24])[CH2:9][CH:10]([CH2:11][C:4]([C:1]([OH:3])=[O:2])([CH2:13]3)[CH2:5]1)[CH2:12]2)([OH:17])=[O:16]
Reactant: O=C(O)C12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Reactant: C=CC(=O)OC(=C)C
Agent: [I-]
Agent: [Sm+3]
Solvent: C1COCCO1
Product: C=CC(=O)OC12CC3CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Yield: 82 %

Procedure:
To 2 mL of dioxane were added 1.00 mmol of 1,3-dicarboxy-5-adamantanol, 0.10 mmol of samarium iodide (SmI2), 2.20 mmol of isopropenyl acrylate, and the resultant mixture was stirred at a temperature of 50° C. for 4 hours. The analysis by gas chromatography showed the formation of a 1,3-dicarboxy-5-acryloyloxyadamantane (yield: 82%, white solid) in the reaction mixture.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH:19]=[O:20].O>CS(C)=O>[F:1][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH:19]=[O:20]
Reactant: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
10.5 g (180.2 mmoles) of potassium fluoride was added to a solution of 33.0 g (120.1 mmoles) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 500 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 26.5 g (yield: 85.0%) of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]([C:26]([OH:28])=[O:27])[C:19](=[O:25])[N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[NH:30][N:31]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]1[CH3:37].[C:38]([O:44][CH2:45]Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(#N)C>[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]([C:26]([O:28][CH2:45][O:44][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:27])[C:19](=[O:25])[N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[NH:30][N:31]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]1[CH3:37]
Reactant: CCN1C(=O)C(C(=O)O)C(=O)c2cc(Nn3c(C)ccc3C)c(Cl)cc21
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCN1C(=O)C(C(=O)OCOC(=O)C(C)(C)C)C(=O)c2cc(Nn3c(C)ccc3C)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a solution of 21 mg of 7-chloro-6-(2,5-dimethylpyrrol-1-ylamino)-1-ethyl-4-oxo-1,4-dihydroquinolonecarboxylic acid (Example 36) in 3 ml of acetonitrile and stirred at room temperature for 30 minutes. Then 36 μl of chloromethyl pivalate were added, and reaction was allowed to take place at room temperature for 5 days. The resulting precipitate was filtered off with suction to afford 3.3 mg of pure product.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][C:35]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:36]
Reactant: O=C(O)CCCBr
Reactant: Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 4-bromobutyric acid (2.5 g, 15 mols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through preparative thin-layer chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.6 g (yield: 58%) of 4-bromo-N-(2,4-difluorophenyl)butanamide as colorless needle-like crystals.