Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([CH3:18])[N:17]=1>C(O)C>[CH3:18][C:16]1[N:17]=[C:12]([CH3:11])[C:13]2[N:14]([CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=2)[CH:15]=1
Reactant: Cc1cnc(N)c(C)n1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1cn2cc(C)nc(C)c2n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A 75 mL pressure vessel was charged with ethyl 4-chloro-3-oxo-butyrate (4 g, 24.4 mmol), 3,5-dimethylpyrazin-2-amine (3 g, 24.4 mmol) and 200 proof ethanol (24 mL). After stirring at 100° C. in an oil bath for 16 hours, the reaction mixture was concentrated, diluted with dichloromethane and a saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with a gradient mixture of dichloromethane and methanol yielded ethyl 2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)acetate as a light brown solid (5 g). MS m/z 234 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:15]O.S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15]
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C=NO)c1=O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CC(C)[C@H](C)n1ccc(Cl)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-((2S)-3-methylbutan-2-yl)pyridin-2(1H)-one obtained in Step D (23.2 g) in acetonitrile (300 mL) was added dropwise thionyl chloride (13.9 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and to the residue were added diisopropyl ether/ethyl acetate/hexane. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (14.6 g).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:12])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH3:11]
Reactant: CCCCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Product: CCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (15.2 g, 0.17 mol), 2-hexanone (30 g, 0.3 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 0.88, t J 7.2 Hz, 3H, CH3; 1.44, m, 2H, CH2; 2.41, s, 3H, CH3; 2.78, t J 7.5 Hz, 2H, CH2; 6.51, s, CH 13C n.m.r. δ (CDCl3): 14.0, CH3; 22.5, 26.5, CH2; 28.6, CH3; 124.5, C2; 157.3, C3; 170.4, COOH; 199.8 C2.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1)#[N:8]
Reactant: COC(=O)C1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (26.7 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.53 mL, 0.0280 mol) in tetrahydrofuran (50 mL, 0.6 mol). The reaction was warmed to rt and then cooled at 0° C. again. To the reaction mixture was a solution of methyl 3-oxocyclobutanecarboxylate (3.26 g, 0.0254 mol) in tetrahydrofuran (20 mL, 0.3 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (3.12 g, 81.12%). LCMS calculated for C8H10NO2(M+H)+: 152.1. Found: 152.3.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23]2>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)CCC2)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-aminoindan (Aldrich) according to the method described in Example 1c. Melting Point: 106-109° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27]O)[C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:60]([CH2:27][C:26]1[C:21]2[S:20](=[O:29])(=[O:30])[N:19]=[C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)[NH:23][C:22]=2[S:24][CH:25]=1)=[N+:61]=[N-:62]
Reactant: O=C1C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-hydroxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.38 g, 0.76 mmol) in dichloromethane (9 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.60 mL, 4.03 mmol) and diphenylphosphoryl azide (0.84 mL, 3.88 mmol). The reaction was stirred at 25° C. overnight. The reaction was quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-1% methanol in dichloromethane) to afford the desired product, (1R,2S,7R,8S)-5-(7-azidomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.21 g, 0.40 mmol, 52%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.56-2.57 (1H, m), 2.82-2.87 (2H, m), 3.47 (1H, d, J=9.6 Hz), 4.21 (1H, d, J=14.8 Hz), 4.67 (2H, s), 5.15 (1H, d, J=14.4 Hz), 7.00-7.07 (2H, m), 7.19-7.23 (2H, m), 7.32-7.36 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:24]3[CH2:25][CH2:26][N:21]([CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:22][CH2:23]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: O=C(O)C1Cc2cc(F)ccc2O1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1

Procedure:
0.03 mol of 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl)carbonyl]-4-benzylpiperazine (resulting from the condensation of 5-fluoro-2,3-dihydrobenzofuran-2-carboxylic acid with N-benzylpiperazine) is dissolved in 150 ml of anhydrous tetrahydrofuran (T.H.F.). Two times 0.03 mol of lithium aluminum hydride are added in the form of pellets. The mixture is stirred at room temperature. The title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[Br:23][CH2:24][C:25](Cl)=[O:26]>ClCCl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[Br:23][CH2:24][C:25]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:26]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Reactant: O=C(Cl)CBr
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2
Reaction time: 8 h

Procedure:
A mixture of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (0.19 g, 0.91 mmol) and triethylamine (0.5 mL, 3.7 mmol, Aldrich) in dichloromethane was treated with dropwise addition of bromoacetyl chloride (0.33 mL, 4.0 mmol, Fluka). A catalytic amount of 4-dimethylaminopyridine was added and the reaction stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-(bromoacetyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline which was taken directly to the next step without determination of yield. RF=0.3 (50% EtOAc/hexanes).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[CH:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (example 280) (0.110 g, 0.19 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.092 g, 93%). MS (ISP) 513.4 [(M+H)+]; mp>266° C.
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[C:22]([CH2:23][OH:24])=[CH:21][C:20]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:19]([F:33])[C:18]=2[F:34])[CH2:11]1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:16][C@H:14]1[O:15][C@@H:10]([CH3:9])[CH2:11][N:12]([C:17]2[C:18]([F:34])=[C:19]([F:33])[C:20]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:21][C:22]=2[CH:23]=[O:24])[CH2:13]1
Reactant: C[C@@H]1CN(c2c(CO)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(C=O)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NMO (295 mg, 0.0025 mmol) and TPAP (44 mg, 0.0001 mmol) were added to a stirred solution of {4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluoro-5-(hydroxymethyl)phenyl}(phenyl)methanone (Intermediate 23, 450 mg, 0.001 mmol) in anhydrous CH2Cl2:CH3CN (1:1, 10 mL) at 0° C., and the mixture was stirred for 12 hours with warming to room temperature. The solvents were removed and the residue was purified over a silica gel chromatography column using ethyl acetate-pet. ether gradient, providing the title compound. Yield: 340 mg, (76%)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: NCc1cccc(F)c1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-fluorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a graded solvent mixture of 40% ethyl acetate in heptane to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=369.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OC([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])=O)(C)(C)C>>[C:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:23])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O
Product: CC(C)(C)OC(=O)CCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Yield: 132.2 %

Procedure:
Octanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (1.13 g, 3.45 mmol) and N-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethyl}-succinamic acid (1 g, 2.874 mmol) were reacted as described above. 1.75 g crude product was isolated and used without further purification. LCMS (Method 6): Rt 3.86 min; m/z (M+1) 461; Calcd.: 461.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[N:25]=2)=[N:10]1.C1C(=O)N([Br:38])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:38])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Yield: 54.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(4-(2-(methylamino)-2-oxoethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.63 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1[C:24]([O:25][C:26](Cl)=[O:27])=[CH:23][CH:22]=[C:21]([Cl:29])[CH:20]=1>C(Cl)(Cl)Cl>[Cl:29][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]([N:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8](=[O:18])[NH:9]2)=[O:27])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1NN(C(=O)Oc2ccc(Cl)cc2)C(c2ccccc2)C1c1ccccc1
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A solution of 4,5-diphenyl-3-pyrazolidinone (1.25 g, 5.26 mmol) in 50 mL CHCl3 was treated with a solution of 4-chlorophenylchloroformate (1.0 g, 5.26 mmol) in 10 mL CHCl3 and stirred overnight. The solvent was removed in vacuo and the residue recrystallized from EtOAc:hexane to give 1.6 g (58%) white solid: mp 175°-7° C.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:23])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.C1C[O:33][CH2:32]C1>>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:19]2[O:20][C:32](=[O:33])[NH:22][N:21]=2)=[O:23])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(=O)NN
Reactant: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 24, (200 mg, 0.50 mmol) in THF (10 mL) is added CDl (86 mg, 0.53 mmol). The crude is stirred at room temperature for 4 hrs. The crude is heated to 60 deg C. for 30 mins. This reaction is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude residue is purified via HPLC MeCN/water (0.1% TFA) to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (69 mg). HPLC retention time=1.79 minutes (condition A), MS 424.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=7.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.66 (ddd, J=14.3, 10.2, 3.8 Hz, 1H), 2.02 (ddd, J=14.2, 10.0, 3.8 Hz, 1H), 2.59 (m, 1H), 2.89 (dd, 1H), 2.96 (dd, 1H), 4.03-4.19 (q, 2H), 4.37-4.47 (m, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.25 (d, 1H), 7.28-7.35 (m, 1H), 7.40 (t, J=7.6 Hz, 2H), 7.49-7.60 (m, 4H), 10.51 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)[S:5][CH:6]=1.O.[NH2:15]N>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][NH:10][N:15]=2)[S:5][CH:6]=1
Reactant: CN(C)C=CC(=O)c1cc(Br)cs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Brc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 1-(4-bromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (43.5 mmol) and hydrazine hydrate (86.9 mmol) in 50 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated to afford 9.74 g (94% yield) 3-(4-bromo-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:13]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:34](=[O:37])[CH:35]=[CH2:36])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:17]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)OCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Temperature: 27.5 °C
Yield: 88.8 %

Procedure:
22.1 g (0.05 mol) of 2-(2-hydroxy-4-hydroxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine (prepared as described in U.S. Pat. No. 3,244,708, Example 18), are dissolved in 300 ml of tetrahydrofurane at 40° C. and 21 ml (0.15 mol) of triethylamnine are added. A solution of 5.05 ml (0.053 mol) of acrylic acid chloride in 20 ml THF is added dropwise with stirring and with cooling the reaction mixture to 25-30° C. After further stirring of two hours the precipitated ammonium salt is filtered off, the filtrate is evaporated and the residue recrystallized from toluene-hexane mixture to obtain 22 g (88.7% yield) of 2-(2-hydroxy-4-acryloyloxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine as slightly yellow crystals (compound No. 25), m.p. 128-129° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH3:30])=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:36][CH:37]=3)[CH3:30])=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: COC(=O)C(Oc1ccc(Oc2ccccc2)cc1)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
As described in Example 35, 4.66 of p-phenoxyphenol is reacted with methyl bromo{p-[2-(α,α,α-trifluoro-p-tolyloxy)propoxy]phenyl}acetate (0.02 mole) in refluxing methanol-benzene for 24 hrs to give the product as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:17]([O-])=O)=[C:13]([CH:16]=2)[NH:14][CH3:15])=[C:4]([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:17])=[C:13]([NH:14][CH3:15])[CH:16]=2)=[C:4]([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:3]=1
Reactant: CNc1cc(Sc2ccc(Cl)cc2Cn2cncn2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNc1cc(Sc2ccc(Cl)cc2Cn2cncn2)ccc1N

Procedure:
5-[4-Chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenylthio]-N-methyl-2-nitroaniline (0.14 g) from Example 70 was dissolved in acetic acid (2ml), followed by gradual addition of zinc powder (120 mg) at room temperature. After the addition, ethyl acetate was added to filter off insoluble materials, and to the filtrate was added saturated sodium hydrogen carbonate solution carefully for separation. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, 4-[4-chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenylthio]-2-methylaminoaniline was obtained as is the crude product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O>O>[NH2:6][C:7]1[N:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][N:8]=1
Reactant: Nc1ncccn1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: Nc1ncc(S(=O)(=O)Cl)cn1
Temperature: 0 °C
Yield: 27.4 %

Procedure:
21 ml (0.316 mol) of chlorosulfonic acid was cooled in ice-water and 3 g (0.032 mol) of 2-aminopyrimidine was added thereto little by little under stirring. 9.2 ml (0.126 mol) of thionyl chloride was further added thereto, followed by stirring at 150° C. for 70 hours. The reaction solution was returned to room temperature, poured into water and extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated to dryness, to give 1.7 g of the title compound.