Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
847 mg (2.43 mmol) of ethyl 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoate was dissolved in 50 ml of ethanol. 5 ml of 1 N sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 3 days. The reaction solution was concentrated and then treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.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.C1(C)C=CC=CC=1>[CH3:11][N:6]1[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[C:3]2[CH:12]2[CH2:14][CH:13]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[N:7]1
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)NCC1CC1c1c(-c2cccnc2)ccc2nn(C)cc12
Temperature: 80 °C
Yield: 94 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29, pyridin-3-ylboronic acid (191 mg, 1.552 mmol), 2 M aqueous sodium carbonate solution (6 mL) and tetrakis(triphenylphosphine)palladium(0) (71.8 mg, 0.062 mmol) were added to a mixed solution of ethanol (3 mL) and toluene (3 mL), and the mixture was stirred under nitrogen atmosphere with heating at 80° C. for 16 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was is purified by silica gel column chromatography (methanol/ethyl acetate=0/100→20/80) to give the title compound (187 mg, yield 94%)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:60][C:61]1[CH:66]=[C:65]([CH2:67]O)[CH:64]=[C:63]([CH3:69])[N:62]=1>C(Cl)Cl>[Cl:60][C:61]1[CH:66]=[C:65]([CH2:67][O:30][C:24]2[CH:23]=[C:22]3[C:27]([C:18]([NH:17][C:16]4[CH:31]=[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])[C:33]([CH3:35])=[CH:34][C:15]=4[F:14])=[N:19][CH:20]=[N:21]3)=[CH:26][C:25]=2[O:28][CH3:29])[CH:64]=[C:63]([CH3:69])[N:62]=1
Reactant: Cc1cc(CO)cc(Cl)n1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4cc(C)nc(Cl)c4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Diethyl azodicarboxylate (296 μl, 1.88 mmol) was added dropwise to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (350 mg, 0.94 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (492 mg, 1.88 mmol) and 2-chloro-4-hydroxymethyl-6-methylpyridine (178 mg, 1.12 mmol) in methylene chloride (30 ml) and the mixture stirred for 30 minutes at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (75/25). The purified product was triturated with ether, the solid collected by filtration, washed with ether and dried under vacuum to give 7-((2-chloro-6-methyl-4-pyridyl)methoxy)-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline (373 mg, 78%). 1H NMR Spectrum: (DMSOd6) 2.15(s, 3H); 2.5(s, 3H); 3.85(s, 3H); 3.98(s, 3H); 5.35(s, 2H) 7.25(s, 1H); 7.3(d, 1H); 7.35(s, 1H); 7.4(m, 2H); 7.85(s, 1H); 8.35(s, 1H); 9.58(1H) MS-ESI: 513 [MH]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:32])=[C:27](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:17][C:15]([NH:14][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:24]=[C:23]([Cl:22])[CH:28]=[CH:27][C:26]=2[F:32])=[CH:3][CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of (R)-4-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)butanoic acid (HBC2251, 14 g, 39 mmol) and 5-chloro-2-fluorophenylboronic acid (8.5 g, 49 mmol) in 300 mL H2O was added Na2CO3 (12.5 g, 118 mmol). This solution was warmed to 40° C. and 9 mL of THF was added followed by Pd(PPh3)2Cl2 (0.6 g, 0.86 mmol). The reaction mixture was then stirred at 60° C. for approximately 1 day. The reaction mixture was cooled to 23° C., and the THF was removed in vacuo. The resulting aqueous suspension was filtered through celite and the solids washed with H2O. The combined filtrate and H2O wash was then extracted with approximately 3:1 isopropyl acetate/acetone (400 mL). After separation, the organic layer was discarded. TBME (300 mL) was added to the aqueous layer followed by slow addition of 6N HCl (32 mL). The organic layer was then separated and filtered through celite. The solids were washed with TBME. The combined filtrate and washes were concentrated to an off-white solid (14.96 g, 36.7 mmol, 94% yield, approx. 96% UV purity by LCMS). LCMS (ES) C21H23ClFNO4: Calc.: 407.1; Found: 406.4[M−H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[NH2:9][C:10]([NH2:12])=[S:11]>C(O)C>[ClH:1].[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:2][S:11][C:10](=[NH:9])[NH2:12]
Reactant: NC(N)=S
Reactant: ClCc1cnccn1
Solvent: CCO
Product: Cl
Product: N=C(N)SCc1cnccn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A solution of chloromethylpyrazine (88 g) in ethanol (200 cc) is added dropwise and in the course of 15 minutes to a suspension of thiourea (68 g) in boiling ethanol (370 cc). After stirring for 1 hour 30 minutes at the boil, the reaction mixture is cooled for 15 hours at a temperature of about 5° C. The resulting crystals are filtered off, washed twice with ethanol (120 cc) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Pyrazinylmethyl)-isothiourea hydrochloride (74 g), melting at 183° C., is thus obtained.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([NH2:8])=O)[NH:3][CH2:2]1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([N:3]1[C@@H:4]([C:6]#[N:8])[CH2:5][S:1][CH2:2]1)=[O:12]
Reactant: NC(=O)C1CSCN1
Reactant: O=C(Cl)CCl
Product: N#C[C@H]1CSCN1C(=O)CCl
Yield: 59.1 %

Procedure:
In a similar procedure as employed in the Intermediate Example 1, the thiazolidine-4-carboxylic acid amide (102 mg) obtained above was reacted with chloroacetyl chloride (105 mg) and then subjected to dehydration reaction to give the title compound (87 mg, Y.:59%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].N1C=CC=CC=1>ClCCl>[CH3:15][O:16][CH2:17][CH2:18][NH:19][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: COCCN
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 33 %

Procedure:
A solution of 5-chlorosulfonyl-2-oxindole (5 g), 2-methoxyethylamine (2.25 mL) and pyridine (7 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The reaction was concentrated and dichloromethane (15 mL) was added. The precipitate was filtered, washed with dichloromethane and dried to give 1.9 g (33%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (2-methoxy-ethyl)-amide.
Reaction SMILES: [Cl-].[CH3:2][O:3][P:4](=O)([OH:7])[O:5][CH3:6].[CH2:9]([OH:12])[C:10]#[CH:11]>>[CH3:2][O:3][P:4](=[O:7])([O:5][CH3:6])[O:12][CH2:9][C:10]#[CH:11]
Reactant: C#CCO
Reactant: COP(=O)(O)OC
Agent: [Cl-]
Product: C#CCOP(=O)(OC)OC

Procedure:
1 mole of phosphoric acid dimethyl ester-chloride was reacted with 1 mole of propargyl alcohol analogously to Example 9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Yield: 56.9 %

Procedure:
A solution of 1-(2-methoxyphenyl)piperazine (41.2 mmol) in 100 mL of acetonitrile and 12 mL of dimethylformamide was combined with N-(2-bromoethyl)phthalimide (43.3 mmol) and potassium carbonate (61.8 mmol). The mixture was heated to reflux for 8 hours. After cooling, the reaction mixture was quenched with water, extracted with dichloromethane. The organic phase was washed with brine, water, and dried over magnesium sulfate. Filtration and evaporation of the solvents gave a yellow oily residue that was purified by flash chromatography using hexanes and ethyl acetate (1:1) to give 1-(2-methoxyphenyl)-4-[(2-phthalimido)ethyl]piperazine (8.56 g, 57%).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([N:15]1[C:19](=[O:20])[C:18]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:16]1(=[O:35])=[O:34])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([N:15]1[C:19](=[O:20])[C:18]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][CH2:23]2)=[C:17]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:16]1(=[O:35])=[O:34])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)Cc3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 78 %

Procedure:
The title compound was prepared as described for Example 105 from phenylacetic chloride and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.103 g, 78%). 1H NMR (500 MHz CDCl3): δ 7.54-7.47 (m, 2H), 7.47-7.41 (m, 3H), 7.34-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7.18 (d, 2H), 5.12 (d, 1H), 4.43-4.26 (m, 1H), 3.70-3.61 (m, 3H), 3.11-3.02 (m, 1H), 2.55-2.47 (m, 1H), 2.28-2.20 (m, 1H), 1.90-1.65 (m, 11H), 1.54-1.47 (m, 1H), 1.19 (dq, 1H), 0.91 (dq, 1H); 13C δ NMR (125 MHz CDCl3): 169.5, 159.7, 135.0, 133.9, 131.8, 130.2, 129.0, 128.9, 128.6, 127.2, 125.2, 107.5, 61.9, 50.2, 44.6, 41.3, 41.2, 40.4, 32.6, 32.1, 27.8; Mass Spectrum: M+H+ 482.
Reaction SMILES: CS(C)=O.[CH3:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.[CH:12]1([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:28])=[C:22](F)[C:23]=3[O:25][CH3:26])[C:18](=[O:29])[C:17]([C:30]([OH:32])=[O:31])=[CH:16]2)[CH2:14][CH2:13]1>O>[CH3:5][CH:6]1[NH:7][CH2:8][CH2:9][N:10]([C:22]2[C:23]([O:25][CH3:26])=[C:24]3[N:15]([CH:12]4[CH2:13][CH2:14]4)[CH:16]=[C:17]([C:30]([OH:32])=[O:31])[C:18](=[O:29])[C:19]3=[CH:20][C:21]=2[F:28])[CH2:11]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O
Solvent: CS(C)=O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 48.5 °C
Yield: 104.2 %

Procedure:
A 100 L reactor was charged with DMSO (120 L) and 2-methylpiperazine (8.6 Kg) at 55° C. under nitrogen atmosphere. 1-cyclopropyl-6,7-difluoro-1,4 dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid (12 kg, divided in 4 portions of 3 kg each) of were added every 2 hours. After completion of the reaction (about 24 hours, monitoring by HPLC), the reaction mixture was cooled to about 47-50° C. and 24 L of water were added at this temperature. The resulting reaction mixture was cooled to 5° C. over 2 hours and maintained at this holding temperature for a holding time 18 hours. The resulting precipitate was collected by filtration to obtain 15.9 Kg of wet Gatifloxacin (11.6 Kg dry, 76% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)C.Cl[C:11]1[C:16]([I:17])=[CH:15][N:14]=[C:13]([S:18][CH3:19])[N:12]=1.[CH3:20][NH:21][NH2:22]>O>[I:17][C:16]1[C:11]([N:21]([CH3:20])[NH2:22])=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=1
Reactant: CSc1ncc(I)c(Cl)n1
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CSc1ncc(I)c(N(C)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
603 mg of potassium carbonate was added to ethanol (15 mL) solution of 1.25 g of 4-chloro-5-iodo-2-(methylthio)pyrimidine, and with cooling with ice, 0.28 mL of methylhydrazine was dropwise added thereto. This was stirred overnight at room temperature, then water was added thereto, and the precipitated crystal was taken out through filtration and dried to obtain 851 mg of the entitled compound as a white solid.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH3:23])[CH3:2].CO.Cl>O1CCCC1.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH3:23])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2OC)CC(OC)=CC4
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC
Yield: 26.2 %

Procedure:
Add 13β-ethyl-3, 17β-dimethoxy-gona-2,5(10)-diene (0.8 g.) in tetrahydrofuran (5 cc.) to methanol (72 cc.) in an atmosphere of nitrogen and add a mixture of hydrochloric acid (4.8 cc.) and water (3.2 cc.). Add a further 10 cc. of tetrahydrofuran and after 1 hour dilute the solution with water and extract with ether. Wash, dry and evaporate the ethereal extracts and chromatograph the residue on neutral alumina. Remove impurities by elution with benzene. Wash the column with ether, evaporate the eluate and recrystallize the residue from hexane to obtain the title compound (0.2 g.), m.p. 117°-119°; ultraviolet absorption ξ max. 240 mμ (ε15,800); infrared spectrum (KBr disc) 6.0, 6.2, 8.8, 9.05 μ.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(Br)cc1
Product: CCOP(=O)(Cc1ccc(Br)cc1)OCC

Procedure:
40.69 g (1 molar equivalent, 163 mmol) of 4-bromobenzyl bromide 1 are heated at 160° C. in 28.3 ml (1 molar equivalent, 163 mmol) of triethyl phosphite until the evolution of gas is complete. The batch is distilled in vacuo, and the residue remaining in the form of an oil 2 (48.87 g, 98%) is employed in the subsequent reaction without further purification.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([O-:16])(=[O:15])C.[K+].[C:18](OC(=O)C)(=O)C>>[C:1]1([C:11](=[CH2:18])[C:13]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [K+]
Product: C=C(C(=O)O)c1cccc2ccccc12
Yield: 58 %

Procedure:
1-Naphthaldehyde (30.5 g), potassium acetate (38.3 g) and acetic anhydride (36.9 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 14(a) to obtain the title compound (22.4 g, 58%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Cl:8][C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].Br.NCCBr>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:9]1[C:18]([C:19]2[O:20][CH2:2][CH2:1][N:3]=2)=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Reactant: CCN(CC)CC
Agent: Br
Agent: NCCBr
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NCCO2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
At room temperature, 41.8 g (0.41 mol) of triethylamine and then 31.1 g (0.10 mol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate in 150 ml of toluene were added dropwise to 26.6 g (0.13 mol) of 1-amino-2-bromoethane hydrobromide in 5.00 ml of toluene. The mixture was heated under reflux for 5 hours and then stirred at room temperature for 12 hours, another 5.0 g (0.02 mol) of 1-amino-2-bromoethane hydrobromide were added and the mixture was heated under reflux for 7.5 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried and concentrated. The residue was then recrystallized from methyl tert-butyl ether/ethyl acetate. 14.5 g (46% of theory) of methyl 2-chloro-4-methylsulfonyl-3-(4,5-dihydrooxazol-2-yl)benzoate were obtained.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1>CN(C)C=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:41])=[CH:35][CH:34]=1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N(N=C(c2ccccc2)c2ccccc2)C(=O)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-chilled solution of 1-(diphenylmethylene)-2-p-tolylhydrazine (270 mg, 0.94 mmol; Example 36A) and N,N-diisopropyl-N-ethylamine (120 mg, 0.94 mmol; Aldrich) in N,N-dimethylformamide (2.0 mL) was added 2-(4-chlorophenyl)acetyl chloride (178 mg, 0.94 mmol; Alfa Aesar). After 10 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight (18 hours). The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was carried on to the next step without further purification: LC/MS m/z 439 (M+H)+.
Reaction SMILES: [C:1]([C@H:5]([NH:27][CH2:28][C:29]([O:31]CC)=O)[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35]>C1COCC1>[C:1]([C@H:5]([NH:27][CH2:28][C:29]([NH:36][CH2:34][CH3:35])=[O:31])[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C

Procedure:
A solution of ethyl({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)acetate (30-1, 50 mg, 0.11 mmol) in a solution of ethylamine in THF (2 M, 2 mL) was heated in a sealable tube at 100° C. for 16 hours. The reaction mixture was concentrated and the residue purified by flash column chromatography (EtOAc) to give 2-({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)-N-ethylacetamide (30-2) as a white solid. 1H NMR (500 MHz, CDCl3) showed a 1:1 mixture of rotamers; one rotamer: δ 7.43-7.22 (m, 5H), 7.11-6.96 (m, 3H), 6.89 (br m, 1H), 6.38 (br s, 1H), 5.94 (m, 1H), 4.92 (ddd, 1H, J=14.9, 4.4, 1.7 Hz), 4.87 (br d, 1H, J=15.3 Hz), 3.42 (d, 1H, J=16.8 Hz), 3.35 (m, 2H), 3.03 (s, 1H), 2.88 (d, 1H, J=16.8 Hz), 2.34 (br s, 1H), 1.18 (t, 3H, J=7.3 Hz), 1.06 (s, 9H). LRMS m/z (M+H) 456.5 found, 456.2 required.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[S:3][C:4]([CH:7]=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[N:5][N:6]=1)(=[O:21])[CH3:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nnc(N)s1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nnc(C=Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 49.4 %

Procedure:
A mixture of 21.4 g (0.186 m) of 2-amino-5-methyl-1,3,4-thiadiazole and 380 ml of acetic anhydride was refluxed 1 hr., after which 28.0 g (0.186 m) of p-nitrobenzaldehyde was added and the reaction mixture was refluxed for an additional 16 hrs. After cooling, the solid product was collected on a Buchner funnel, washed in acetone, and air-dried to yield 26.6 g (0.092 m, 49.4%) of the acetamide as a light yellow powder. Purification by washing in hot acetone/dimethylformamide (50/50) yielded small yellow crystals, MP. 341.5°-342.5° C. (dec).
Reaction SMILES: Cl.[NH2:2][C:3]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10](N(CC)CC)C.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>C1(C)C=CC=CC=1>[CH2:10]=[C:6]1[CH2:7][CH2:8][CH:3]([N:2]2[C:20](=[O:21])[C:19]3[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]2=[O:22])[CH2:4][CH2:5]1
Reactant: NC1(O)CCCCC1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: Cc1ccccc1
Product: C=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 125 °C
Yield: 84.7 %

Procedure:
Aminocyclohexanol hydrochloride (6.3 g, 41.6 mmol) and triethylamine (11.6 mL, 83.1 mmol) were stirred in toluene (150 mL) at room temperature for 1 hour. To this was added phthalic anhydride (7.4 g, 49.9 mmol) and the reaction mixture was stirred at 120-130° C. The by-product water was removed from the reaction mixture. Toluene was concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography using ether in hexane solvent mixture (2:1) as eluent to furnish the title compound (8.5 g, 84%).