Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH:13]=[CH2:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH:26]2[CH2:27][CH2:28][CH:21]1[CH2:22][NH:23][CH2:24][CH2:25]2>>[CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:23]3[CH2:24][CH2:25][CH:26]4[N:20]([CH3:19])[CH:21]([CH2:28][CH2:27]4)[CH2:22]3)[CH:10]=2)[C:5](=[O:18])[C:6]([C:15]([OH:17])=[O:16])=[CH:7]1)=[CH2:14]
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CN1C2CCNCC1CC2
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4CCC(C3)N4C)cc21
Yield: 44.7 %

Procedure:
The title compound was prepared in 44.7% yield according to example 8 by reacting 6,7-difluoro-1-vinyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with 9-methyl-3,9-diazabicyclo[4.2.1 ]nonane, m.p. 214°-215° C.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>>[C:2]([C:3](=[CH:15][O:16][CH2:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Temperature: 135 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
A mixture of ethyl 3-oxo-3-phenylpropanoate (17.2 mL, 100 mmol), triethyl orthoformate (24.5 mL, 150 mmol), and acetic anhydride (38 mL, 400 mmol) was stirred at 135° C. for 5 hr. Distillation under reduced pressure gave ethyl 2-benzoyl-3-ethoxyacrylate (14.7 g, 59 mmol, 59% yield) as a yellow liquid.
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7]>CN(C)C=O>[Cl:15][C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:5]2[C:4]=1[CH2:3][NH:1][C:6]2=[O:7]
Reactant: N
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1CBr
Solvent: CN(C)C=O
Product: O=C1NCc2c1ccc(Cl)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ammonia was bubbled through a solution of ethyl 2-bromomethyl-3,4-dichlorobenzoate (25 g, 0.08 mol.) in 250 ml. of dimethylformamide for 1/2 hour at 0° C. The mixture was stirred for one hour at 25° C., poured on crushed ice and filtered. The solid was chromatographed on silica gel eluted ether, ethyl acetate and then acetone to give 4,5-di-chloro-2,3-dihydro-1H-isoindol-1-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:2]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:15][C:16]3[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 250 mL round-bottomed flask was added 4-(pyridin-3-yl)benzaldehyde (4 g, 21.8 mmol), methyl 2-aminothiazole-5-carboxylate (3.45 g, 21.83 mmol) and acetic acid (0.375 ml, 6.55 mmol) in toluene (109 ml). The reaction mixture was heated at reflux under Dean-Stark conditions for 3 hours, cooled to room temperature, and the volatiles were removed by rotary evaporation. Methanol was added, the solution was cooled to 0° C., and sodium borohydride (1.322 g, 34.9 mmol) was carefully added. The reaction was stirred at 0° C. for 15 minutes and allowed to warm to room temperature while stirring for an additional 2 hour. The solids were filtered off, washed with water and dried under high vacuum to give the title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([NH:23][C:24]1[S:28][C:27]2[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[C:33]([NH2:35])=[O:34])=[O:22]>CN(C=O)C.CO>[OH:10][CH2:9][CH2:8][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][N:5]([CH2:20][C:21]([NH:23][C:24]2[S:28][C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[C:33]([NH2:35])=[O:34])=[O:22])[CH:6]=1
Reactant: OCCc1c[nH]nc1C(F)(F)F
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1c(NC(=O)Cn2cc(CCO)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 60 °C
Yield: 40 %

Procedure:
To a solution of 2-(3-trifluoromethylpyrazol-4-yl)-ethanol (18 mg, 0.1 mmol) in DMF (0.5 mL) was added potassium carbonate (16 mg, 0.12 mmol). The reaction mixture was stirred at 60° C. for 25 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (32 mg, 0.1 mmol) was added. Heating at 60° C. was maintained for 4 h before the reaction mixture was allowed to cool to RT. The whole was diluted with MeOH (0.5 mL), and filtered before being purified by preparative reverse phase HPLC to give the desired product as a white solid (17 mg, 0.04 mmol, 41%).
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]=[C:10]([CH3:12])[CH3:11].C(OOC(C)(C)C)(C)(C)C>>[CH2:1]([O:3][P:4]([CH2:9][CH:10]([CH3:12])[CH3:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: C=C(C)C
Agent: CC(C)(C)OOC(C)(C)C
Product: CCOP(=O)(CC(C)C)OCC
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
In a 10-liter flask with stirrer, internal thermometer, reflux condenser (-80° C.) and a cooled dropping funnel, 2070 g of diethylphosphite is heated to 150° C. Then over a period of about 90 minutes a mixture of 2070 g of diethylphosphite, 1680 g of isobutene and 44 g of ditertiarybutyl peroxide is added drop by drop. The reaction heat that develops is removed by external cooling. Then heating at 150° C. continues for about 30 minutes. Vacuum distillation through a 12-tray column delivers an 81% yield of pure product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH:14]=O)[C:4](=[O:16])[CH:3]=1.[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=3)[C:2]([Cl:1])=[CH:3][C:4]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(Cl)c2ccc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To 3 mL of a chloroform solution containing 69 mg of (4,7-dichloro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 94 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 24 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 86 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 109 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4,7-dichloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]#[N:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N#C/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: N#CCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
The mixture of (2E)-3-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)-2-propenenitrile (18.0 g, 55.6 mmol) and Pd/C (2.00 g, 1.88 mmol) in THF (150 mL) was stirred at 25° C. under H2 overnight, filtered through a pad of Celite, and concentrated. Purification via a column chromatography afforded the title compound as a white solid (15 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C:10]([CH:12]1[CH:16]([CH:17]=[C:18]([F:20])[F:19])[CH2:15][N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13]1=[O:32])=[O:11])C>O.CO>[F:20][C:18]([F:19])=[CH:17][CH:16]1[CH2:15][N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13](=[O:32])[CH:12]1[C:10]([OH:11])=[O:9]
Reactant: CCOC(=O)C1C(=O)N(Cc2ccc(OC)cc2OC)CC1C=C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(CN2CC(C=C(F)F)C(C(=O)O)C2=O)c(OC)c1
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of potassium carbonate (581 g, 4.20 mol) in water (4 L) is added to a stirred refluxed solution of (H) in methanol (1 L). The mixture is stirred for 18 h, washed with toluene (2×5 L) and acidified to a pH<2 with concentrated HCl (750 mL). The aqueous layer is extracted with ethyl acetate. This organic layer is washed with water, dried over anhydrous MgSO4 and concentrated to give 615 g of (K) (yield=89%)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9]([CH2:12][S:13][C:14]2C=CC=C[C:15]=2[O:20]C)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:24]1C(OC)=C(C(CBr)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:22][CH3:24])=[C:4]([C:9]([CH2:12][S:13][CH2:14][CH2:15][OH:20])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSCCO)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-mercaptolethanol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:22])([CH3:21])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].Cl>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:21])([CH3:22])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c(N)c1C(=O)O
Temperature: 90 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a solution of ethyl 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate (Example 1a, 14.0 g, 36.2 mmol) in EtOH (140 mL) was added aqueous NaOH solution (2.0 N, 46 mL) at room temperature. The reaction mixture was stirred at 90° C. for 4 hrs. The resulting solution was neutralized at 0° C. to pH 7 with 6 N HCl, and concentrated under reduced pressure. The residue was re-dissolved in EtOH (400 mL) and water (25 mL), and treated with charcoal (200 mg) at 65° C. for 30 minutes. After removal of the charcoal by filtration, the filtrate was concentrated, and the resultant white solid was purified by re-crystallization from EtOH/H2O and dried under vacuum at 70° C. to give the title compound as a white solid (11.5 g, 89%). M.p.: 216-218° C. 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.24 (s, 6H), 2.75 (s, 3H), 3.86-3.93 (m, 1H), 4.17 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 8.83 (brs, 1H), 12.34 (brs, 1H), 12.78 (brs, 1H). MS 360 (MH+).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].CO[C:36]([C:38]1(SC2SC(N)=NC=2)CCCC[CH2:39]1)=O.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:33][C@H:30]1[CH2:29][CH2:28][C@H:27]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]3([C:3]([OH:5])=[O:4])[CH2:1][CH2:39][CH2:38][CH2:36][CH2:6]3)=[CH:9][N:10]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: COC(=O)C1(Sc2cnc(N)s2)CCCCC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SC3(C(=O)O)CCCCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-amino-thiazol-5-ylsulfanyl) -cyclohexanecarboxylic acid methyl ester prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[C:28]([C:36](O)=O)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[N:29]=[C:28]([C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.14 g, 0.65 mmol) and 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.9) (0.175 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.147 g, 56%). MS (ISN) 528.3 [(M−H)−]; mp 261° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]1([CH:30]2[O:35][CH2:34][CH:33](O)[CH2:32][O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:33]3[CH2:32][O:31][CH:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:35][CH2:34]3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OC1COC(c2ccccc2)OC1
Product: CC1(C)c2cc(OC3COC(c4ccccc4)OC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-phenyl-[1,3]dioxan-5-ol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:19]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1nc(-c2ccccc2)no1
Product: c1ccc(-c2noc(COc3ccc(CCCn4ccnc4)cc3)n2)cc1
Yield: 51 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 5-chloromethyl-3-phenyl-1,2,4-oxadiazole to obtain 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-3-phenyl-1,2,4-oxadiazole. The yield was 51%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 124-125° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH3:25][C:26]1[N:30]=[C:29]([C:31]2[N:32]=[N:33][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:35][CH:36]=2)[S:28][N:27]=1.O>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:40]1[CH2:39][CH2:38][N:37]([C:34]2[N:33]=[N:32][C:31]([C:29]3[S:28][N:27]=[C:26]([CH3:25])[N:30]=3)=[CH:36][CH:35]=2)[CH2:42][CH2:41]1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1nsc(-c2ccc(N3CCNCC3)nn2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nsc(-c2ccc(N3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)nn2)n1
Yield: 45.5 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)-benzoyl chloride (1.1 g) and triethylamine (0.4 g) in DCM (40 ml) was stirred. 3-(3-methyl-1,2,4-thiadiazol-5-yl)-6-(1-piperazinyl)-pyridazine (1.1 g) was added portionwise. The mixture was stirred at room temperature for 3 hours. Triethylamine was added. The mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted three times with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from methanol. The precipitate was filtered off and dried, yielding 0.91 g (45%) of 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[6-(3-methyl-1,2,4-thiadiazol-5-yl)-3-pyridazinyl]piperazine (compound 131).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([O:16][CH2:17][CH2:18]Br)[NH:14][C:13]1=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:13](=[O:20])[N:14]2[C@@H:15]1[O:16][CH2:17][CH2:18]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1OCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1C(=O)N2CCO[C@H]12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of (3S,4R)-3-benzyloxycarbonylamino-4-bromoethoxy-azetidin-2-one (2.04 g, 5.945 mmole) and powder K2CO3 (903 mg, 6.54 mmole) in DMSO (20 ml) was stirred at room temperature overnight and then diluted with ethyl acetate, washed with cold water, brine, and dried over sodium sulfate. After removal of the solvent, 1.43 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[C:3](=[O:43])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[CH:26]([C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH2:25][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8].[H][H]>[Pd].CO>[CH3:1][C:2]([CH3:45])([CH3:44])[C:3](=[O:43])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[CH:26]([C:27]([OH:29])=[O:28])[CH2:25][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)O

Procedure:
The diester product from part (d) (2.0 g.) is dissolved in 50 ml. of methanol containing 0.5 g. of 5% palladium on carbon catalyst and hydrogenated at 50 psi on a Parr apparatus until cessation of hydrogen uptake (2-4 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is triturated with acetonitrile or purified by flash chromatography to give (+)-4,5-dihydro-1-[[[(2,2-dimethyl-1-oxopropoxy)methoxy] (4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:10]1[CH2:11][CH2:1][O:2][CH:3]1[CH2:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: COC(CNC(=O)CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: OCCO
Product: O=C(CCl)NCC1OCCO1
Temperature: 25 °C

Procedure:
N-(2,2-Dimethoxyethyl)-2-chloroacetamide (18.1 grams; 0.10 mole) ethylene glycol (6.82 grams; 0.11 mole) and 10 drops of a solution of one gram of p-toluenesulfonic acid in 100 ml of diethyl ether were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distillation heat and condenser. The mixture was stirred and heated to about 95° C. to 100° C. Byproduct methanol was distilled off. When no further methanol was evolved, the mixture was cooled to room temperature, sodium carbonate (2 grams) was added and the slurry was stirred for a period of about 1 hour. The slurry was then filtered and the filtrate fractionally distilled under reduced pressure the desired product N-(1,3-dioxolan-2-ylmethyl)-2-chloroacetamide was obtained as a fraction boiling at 109° C.-110° C. at 0.15 mm Hg which, when cooled, solidified. The solid had a melting point of 61° C.-63° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9]P(=O)(OCC)OCC)([O-:5])=[O:4].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>O1CCCC1>[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH:9]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)([O-:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A suspension of sodium hydride (10.98 mmol, 0.439 g) in tetrahydrofuran (40 mL) was added to a stirred solution of diethyl 3-nitrobenzylphosphonate (7.32 mmol, 2 g) in tetrahydrofuran (40 mL) at 0° C. and the reaction stirred for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (7.32 mmol, 1.459 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and water. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: 0-2% methanol in dichloromethane) to afford the intermediate tert-butyl 4-(3-nitrobenzylidene)-piperidine-1-carboxylate (2 g).
Reaction SMILES: C(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)C(C)=C.[C:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[C:18]([CH3:20])=[CH2:19].CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[C:17]([O:22][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[CH:7][CH:8]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19].[C:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Oc1ccc2ccccc2c1
Agent: C=C(C)C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Oc1cccc2ccccc12
Temperature: 70 °C

Procedure:
0.3 mol of 2-naphthyl methacrylate and 0.7 mol of tert-butyl methacrylate were mixed with 200 g of toluene, and 2 g of azoisobutylonitrile (AIBN) was added thereto. The mixed system was heated at a temperature of 70° C. for 8 hours and then purified by dropping it into acetone-methanol solvent, to obtain a copolymer of naphthyl methacrylate and tert-butyl methacrylate (Resin A).