Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][C@H:22]5[C@H:28]([F:29])[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl-].[CH3:38][Zn+].[NH4+].[Cl-].O>C1COCC1.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>[F:29][C@H:28]1[C@H:22]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:6]4[CH:7]=[C:2]([CH3:38])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(Br)cn45)nc23)CC1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2nnc(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OC(C)(C)C)CC[C@H]5F)c4n3)n2c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (trans)-tert-butyl 4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (0.125 g, 0.225 mmol) and Pd(PPh3)4 (0.0519 g, 0.0449 mmol) in 1.9 mL THF was added 2M methyl zinc chloride in THF (0.225 mL, 0.449 mmol) by syringe, and the reaction mixture was heated in an 80° C. reaction block. After 6 hours, the reaction mixture was cooled to ambient temperature and saturated NH4Cl and water were added, causing a precipitate to form. The solids were isolated by vacuum filtration through qualitative filter paper, rinsed with water, air dried, and dried in vacuo. The crude was purified on silica gel (1-8% MeOH in DCM gradient) to give the racemic (trans)-product. The resulting mixture was separated by chiral HPLC using a Chiracell OJ-H column, 9.5% EtOH in hexanes, flow rate 16 mL/min to give Peak 1 trans-product (0.018 g, 16%, 99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92% ee) as a white solid.
Reaction SMILES: [CH:1]([OH:6])([OH:5])[CH2:2][CH2:3][CH3:4].[C:7]([OH:14])(=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]>>[C:10]([O-:12])(=[O:11])[CH2:9][CH2:4][CH2:3][CH2:2][C:1]([O-:6])=[O:5].[C:1]([OH:6])(=[O:5])[CH2:2][CH2:10][CH2:9][CH2:8][C:7]([OH:14])=[O:13]
Reactant: CCCC(O)O
Reactant: O=C(O)CCC(=O)O
Agent: *CCCC*
Product: O=C(O)CCCCC(=O)O
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
Examples of the polybutylene succinate (PBS) type aliphatic polyester include polybutylene succinate (PBS) made from butanediol and succinic acid, an adipate copolymer (PBSA) obtained by copolymerizing adipic acid to accelerate biodegradability, and adipate/terephthalate copolymer obtained by copolymerizing terephthalic acid. The commercially available products include “BIONOLLE (trade name)”, “ENPOL (trade name)”, “ECOFLEX (trade name)” and “BIOMAX (trade name)” available from Showa High polymer, Ltd., Ire Chemical, Ltd., BASF AG, and Du Pont, Ltd., respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)C>[C:25]([Si:22]([O:21][CH2:20][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)([CH3:24])[CH3:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
To a solution of 4-chloro-3-fluoro-phenol (10 g, 68 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (19 g, 136 mmol), potassium iodide (11 g, 68 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18 g, 75 mmol, Aldrich). The reaction mixture was heated at 100° C. for 24 h. The crude was cooled, diluted with ethyl ether, washed with water, NaHCO3 solution, and brine. The organic layer was separated, dried over Na2SO4, and concentrated. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:20) to give tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane as colorless oil (Yield 14 g, 69%).
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1)[C:27](O)=O.[NH2:41][NH2:42]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:42][N:41]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)(F)F)cc1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(Cl)c1
Yield: 8.3 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.69 mmol, from preparation B) and 6-chloro-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (523 mg, 1.685 mmol, from preparation AI) were coupled and then reacted with hydrazine (0.211 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (40-100% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (80 mg, 0.14 mmol, 9.0% yield) as a yellow residue. LC-MS (M+H)+ 555.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:14](C(OC)=O)=[CH:13][N:12]=2)=[CH:5][CH:4]=1.[OH-:21].[Na+].[CH3:23][OH:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[N:12]=[CH:13][CH:14]=[CH:19][C:20]=2[C:23]([OH:24])=[O:21])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CO
Reactant: COC(=O)c1ccc(/C=C/c2ccc(OC)cc2)nc1
Agent: [Na+]
Product: COc1ccc(/C=C/c2ncccc2C(=O)O)cc1
Temperature: 0 °C
Yield: 78 %

Procedure:
Methyl 6-[(E)-2-(4-methoxyphenyl)ethenyl]nicotinate (80 mg, 0.297 mmol; see step (i) above) was dissolved in methanol (5 mL) to which sodium hydroxide solution (145 mg in 10 mL water) was added. The reaction mixture was heated under reflux for 3 h. The solvent was removed under partial reduced pressure and the remaining solution was cooled to 0° C. Hydrochloric acid (conc.) was added dropwise with vigorous stirring until pH4 where a precipitate formed. The yellow solid material was collected by filtration, washed with water and dried under reduced pressure at 50° C. to give the title compound (59 mg, 78%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:27])([CH3:26])[CH2:18][NH:19][S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C1COCC1>[OH:27][C:17]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)([CH3:26])[CH2:18][NH:19][S:20]([CH:23]([CH3:24])[CH3:25])(=[O:22])=[O:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(N)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Into a 100 mL single-neck flask, 77 mg of benzoyl chloride was added dropwise to 135 mg of [2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine and 56 mg of triethylamine in THF (20 mL) while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature for 2 h. The mixture was then poured into H2O and the desired product was extracted into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 233 mg as a solid. This material was purified via silica gel chromatography employing the Chromatotron, using a 2000 micron rotor and eluting with a solvent of ethyl acetate to yield the intermediate title compound (151 mg, 80%) as a white solid. Ion spray M.S. 375.2 (M*−1).
Reaction SMILES: II.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH2:11])[CH:5]=1.N.[NH2:21][C:22]([NH2:24])=[O:23]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:11][O:23][C:22]([NH2:24])=[N:21]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1cccc(Br)c1)c1cccc(OC)c1
Reactant: NC(N)=O
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(C2(c3cccc(Br)c3)COC(N)=N2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of iodine (1.65 g, 6.7 mmol) in ethyl acetate (25 mL) was added dropwise over 25 min to a mixture of 1-bromo-3-(1-(3-methoxy-phenyl)-vinyl)-benzene (1.75 g, 6.1 mmol) and silver cyanate in acetonitrile (30 mL) and ethyl acetate (15 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 25 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 70° C. for 30 min, then kept at room temperature overnight. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. The reaction suspension was filtered, the solid was refluxed in toluene (20 mL) for 10 min, filtered hot (to remove residual, undissolved silver iodide), and the filtrate was left to cool to room temperature, followed by 1 h at −10° C. The pale-yellow crystalline solid was filtered off and dried at the rotary evaporator to dive 4-(3-bromo-phenyl)-4-(3-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine (1.2 g, 57%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(N([CH2:16][CH3:17])CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:2]([O:1][S:26]([C:17]3[CH:16]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:3][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)OCCc2ccc(OS(=O)(=O)c3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
2.76 g (20 mmole) p-hydroxyphenethyl alcohol was dissolved in 80 ml dichloromethane. 6 g triethylamine, 8.5 g (41 mmole) 4-methoxybenzenesulfonyl chloride and 0.2 g 4-dimethyl-aminopyridine were added. The mixture was stirred over night at room temperature and filtered through silica gel with dichloromethane as eluent to give 8.5 g (yield 89%) of 4-(4-methoxyphenylsulfonyloxy)phenethyl 4-methoxy-1-benzenesulfonate.
Reaction SMILES: CCOCC.[N:6]([O-])=O.[Na+].[NH:10]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[C:25]#[N:26])[NH2:11].Cl>O>[N:10]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[C:25]#[N:26])=[N+:11]=[N-:6]
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1NN
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1N=[N+]=[N-]
Yield: 43 %

Procedure:
10 ml of ether and then 0.85 g (0.012 mol) of sodium nitrite in 10 ml of water are added to 2.7 g (0.01 mol) of 5-hydrazino-4-cyano-1-(2,4-dichlorophenyl)-pyrazole in a solution of 1.9 ml of concentrated hydrochloric acid in 10 ml of water at 0° C. When the addition has ended, a further 20 ml of water and 30 ml of ether are added, the mixture is filtered, the ether phase is separated off, dried over calcium chloride and concentrated in vacuo and the oil thus obtainable is purified by chromatography (silica gel; mobile phase: methylene chloride/acetone 9:1). 1.2 g (43% of theory) of 5-azido-4-cyano-1-(2,4-dichlorophenyl)-pyrazole are obtained as an oil.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C:9]1([CH:12]=[O:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C=O)CC1
Temperature: 0 °C

Procedure:
N-Boc-1-amino-1-cyclopropanecarboxylic acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-1-amino-1-cyclopropanecarboxaldehyde.
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CN(C=O)C.S(Cl)([Cl:22])(=O)=O>C(Cl)(Cl)Cl>[Cl:22][C:8]1[O:7][C:6]([S:5][CH2:4][CH2:3][C:2]([F:1])=[C:11]([F:12])[F:13])=[N:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)=C(F)CCSc1ncco1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)=C(F)CCSc1ncc(Cl)o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
4.0 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole was added to 40 ml of DMF (dehydrated) to which a mixture of 10 ml of chloroform and 2.6 g of sulfuryl chloride was added dropwise at 50 in 1 hour. After the reaction mixture was stirred at 50° C. for 3 hours, a mixture of 5 ml of chloroform and 0.8 g of sulfuryl chloride was further added dropwise in 15 minutes. After stirring at 50° C. for 15 hours, the reaction mixture was cooled to room temperature, poured into 200 ml of ice water and extracted with 100 ml of hexane. The aqueous layer was neutralized with 1N aqueous solution of sodium hydroxide and further extracted with 100 ml of hexane. The extracted hexane layers were put together, washed with 200 ml of saturated common salt water and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: hexane:dichloromethane=1:1) to obtain 2.4 g of 5-chloro-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 51.5%, n20D=1.4830).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: Cc1ccc(N)c(C(N)=O)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To a solution of 2-amino-5-methylbenzamide (5.80 g, 38.6 mmol) and triethylamine (4.69 g, 46.3 mmol) in THF (200 mL) was added dropwise ethyl chloroglyoxylate (5.80 g, 42.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol to give ethyl ((2-(aminocarbonyl)-4-methylphenyl)amino)(oxo)acetate as a white powder (9.83 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23]C(=O)CC2C=CC=C(C(F)(F)F)C=2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:23][C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1Cl

Procedure:
The title compound was prepared using 2-chlorophenylacetyl chloride in place of 2-phenylacetyl chloride using the procedure described for Intermediate 7: step a.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:32])[CH2:22][CH2:23][S:24][CH2:25][C:26]1[N:27]=[C:28]([NH2:31])[S:29][CH:30]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:32])[CH2:22][CH2:23][S:24][CH2:25][C:26]1[N:27]=[C:28]([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:29][CH:30]=1)[CH3:19]
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Reactant: CCOC(=O)CCSCc1csc(N)n1
Product: CCOC(=O)CCSCc1csc(NC(=O)c2cc(OC(C)C)cc(OC(C)C)c2)n1

Procedure:
3-[2-(3,5-Diisopropoxy-benzoylamino)-thiazol-4-ylmethylsulfanyl]-propionic acid ethyl ester was prepared from 3,5-diisopropoxy-benzoic acid and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester following general procedure A.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Na].C(O)C.[Cl:16][CH:17]=[CH:18][CH2:19]Cl>O>[Cl:16][CH:17]=[CH:18][CH2:19][N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: ClC=CCCl
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(CC=CCl)nc1C

Procedure:
Ethyl 3-methylpyrazole-4-carboxylate (5.0 g) was added to sodium alcoholate prepared from 0.75 g of metallic sodium and 30 ml of ethanol. To the homogeneous mixture was added 3.6 g of 1,3-dichloropropene, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was discharged into water and extracted with ethyl acetate. The extract was chromatographed on a silica gel column, and the column was eluted with hexane/ethyl acetate to give 2.5 g (34%) of a Z isomer of ethyl 1-(gamma-chloroallyl)-3-methylpyrazole-4-carboxylate and 1.5 g (20 %) of its E isomer. The Z isomer (2.5 g) was stirred under heat for 4 hours together with a mixture of 25 ml of ethanol, 2.5 g of sodium hydroxide and 25 ml of water. After the reaction, the reaction mixture was cooled to room temperature, and with cooling, concentrated hydrochloric acid was added to adjust its pH to 4 to 5. The precipitated crystals were collected by filtration and dried. Recrystallization from water gave 0.3 g (yield 14%) of the Z isomer of 1-(gamma-chloroallyl)-3-methylpyrazole-4-carboxylic acid. m.p. 96°-100° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl[CH2:26][CH:27]1[CH2:29][CH2:28]1.[I-].[K+].Cl>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][CH:27]5[CH2:29][CH2:28]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: ClCC1CC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CC4CC4)CC3)c(F)cc2c1=O
Yield: 15.6 %

Procedure:
3.3 g (10 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 90° in 50 ml of dimethylformamide with 1.8 g (20 mmol) of chloromethylcyclopropane, 3.3 g (20 mmol) of potassium iodide and 2.1 g of triethylamine for 5 hours. The solution is poured into 40 ml of water, the pH is brought to 5 with 2N hydrochloric acid and the precipitate is filtered off with suction and recrystallized from methanol. 0.6 g of 1-cyclopropyl-7-(4-cyclopropylmethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 279°-282° (with decomposition) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: Cc1cc(N)ccn1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1cc(Nc2nc(-c3cc(Br)ccc3F)nc3nccnc23)ccn1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-2-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:30][N:31]1[C:35]([NH2:36])=[C:34]([NH2:37])[CH:33]=[N:32]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O>[NH2:36][C:35]1[N:31]([CH3:30])[N:32]=[CH:33][C:34]=1[NH:37][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cn1ncc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a suspension of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]propanoic acid (1.695 g) and 1-methyl-1H-pyrazole-4,5-diamine sulfate (1.05 g) in water (16 ml) were added triethylamine (1.4 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.73 g). The mixture was stirred at room temperature for 2 hours. The resulting suspension was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2-benzyl 1-tert-butyl {(2S)-3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxo-1,2-propanediyl}biscarbamate (1.78 g) as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:22]([O-])([OH:24])=[O:23].O.[OH-].[Na+]>CCOCC>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
Ethyl α -hydroxy-γ-(4-cyclohexylphenyl)butyrate 0.066 mole is added to ice-cold concentrated sulfuric acid (18 ml.) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml.) is added dropwise, maintaining the temperature between 30° and 40° by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for 1/2 hour, then poured into water. The mixture is made alkaline with sodium hydroxide, then ex-racted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue is fractionally distilled to obtain ethyl α-hydroxy-γ-(3-nitro-4-cyclohexylphenyl)butyrate.