Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]([F:28])([F:27])[F:26])=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[C:4]([C:25]([F:27])([F:28])[F:26])=[N:5][N:6]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[C:7]=1[NH:8][CH3:9])#[N:2]
Reactant: CCOC=Nc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethyleneamino-3-trifluoromethylpyrazole (1.0 g) in methanol (10 ml) stirred at room temperature was added sodium borohydride (0.17 g). After 2 hours an additional 0.17 g of sodium borohydride was added, and another 0.34 g added after 1 hours. One hour later the mixture was poured onto water (80 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. The white solid thus obtained was purified by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm-2) with dichloromethane as eluent, to furnish 4-cyano-5-methylamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole as a white solid )0.6 g), m.p. 200-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]=[C:17]([O:20][CH2:21][CH3:22])[CH2:18][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CCOC(CBr)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Solvent: ClCCl
Product: CCOC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of a solution of 0.38 part of 5-chloro-2-(2-bromo-1-ethoxyethylideneamino)benzophenone in 8 parts by volume of methylenechloride and 2 parts by volume of liquid ammonia is stirred in a sealed vessel at room temperature for 1 hour, followed by evaporation at room temperature to remove the ammonia. The resultant is shaken well with a mixture of 10 parts by volume of methylenechloride and 5 parts by volume of water. The methylene chloride layer is washed with water and dried over sodium sulfate, followed by evaporation of the solvent gives 7-chloro-2-ethoxy-5-phenyl-3H-1,4-benzodiazepine as an oily substance.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][NH:22][CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCc3nc(C(=O)Nc4ccccc4N)sc3C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethyl amine (1.0 eq) was added to solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I (1.0 mmol) in 10 mL THF. The solution was cooled to 0° C. 4-Methyl-benzenesulfonyl chloride (1.0 mmol) was added slowly with continuous stirring. Reaction mixture was brought to room temperature and stirred for 2 h Reaction mixture was concentrated, diluted with water, extracted dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to yield the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2.C[N:16](C=O)C>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:16])[C:9]([CH3:14])=[CH:8]2
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)cc(C)n2N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (1.25 g, 51 mmol, 60% in mineral oil) in DMF (47 mL) at 0° C. is treated with 5-methoxy-2-methylindole (500 mg, 3.1 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (1.92 g, 17.0 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5-methoxy-2-methyl-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[N+:28]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35])([O-:30])=[O:29]>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:35])([O-:30])=[O:29]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc([N+](=O)[O-])c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 3-nitrobenzoyl chloride (1.3 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][CH2:32][C@H:33]([OH:38])[C@@H:34]([OH:37])[CH2:35][OH:36]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:31][CH2:32][C@H:33]([OH:38])[C@@H:34]([OH:37])[CH2:35][OH:36])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC[C@H](O)[C@@H](O)CO
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC[C@H](O)[C@@H](O)CO)nc3N(C3CCCC3)C2=O)c1

Procedure:
1-Cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-([S,S]-2,3,4-trihydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.40 g (0.92 mmol) 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.33 g (2.76 mmol) (S,S)-4-amino-1,2,3-butanetriol. The final product was purified by column chromatography (20:1 dichloromethane/methanol) to get 0.05 g (11%) as a white solid: mp 86° C.–88° C.; MS (APCI) m/z 492.2, 493.2.
Reaction SMILES: C(OC(=O)NC1C=CC(N2C=[C:20]([S:22][CH3:23])[N:19]=N2)=C(F)C=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:36][C:37]1[CH:38]=[C:39]([N:49]2[CH2:53][C@H:52]([CH2:54][OH:55])[O:51][C:50]2=[O:56])[CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=NC(C)=[N:44]1>>[F:36][C:37]1[CH:38]=[C:39]([N:49]2[CH2:53][C@H:52]([CH2:54][OH:55])[O:51][C:50]2=[O:56])[CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:20]([S:22][CH3:23])[N:19]=[N:44]1
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)n1
Reactant: CSc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CSc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1

Procedure:
[3-Fluoro-4-[4-(methylthio)-1H-1,2,3-triazol-1-yl]phenyl] carbamic acid benzyl ester (Intermediate 49) (27.4 g, 76.5 mmol), LiHMDS (1M in THF, 91 ml) and R-(−)-glycidyl butyrate (11.5 g, 79.7 mmol) were reacted following the procedure for Intermediate 25 to give the crude title compound (19.4 g), which was used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[S:9][C:10]=1[C:11]([C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1)=[O:12].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[O:20])[S:9][C:10]=1[C:11]([C:13]1[CH:17]=[CH:16][N:15]([CH3:29])[CH:14]=1)=[O:12]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cc[nH]c2)s1)c1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Compound 353 (105 mg, 0.288 mmol) was dissolved in DMF (1.4 mL), and 55% sodium hydride (25.3 mg, 0.576 mmol) and methyl iodide (0.0179 mL, 0.288 mmol) were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 354 (97.0 mg, 89%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[OH:1])=[O:14])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc2ccccc2c1O
Yield: 65.5 %

Procedure:
Using 1-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:9][C:10]4[CH:16]=[CH:15][C:14]([NH:17][C:24]([CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[O:25])=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Product: O=C(Nc1ccc(-c2nc3cc(NC(=O)C4CCCCC4)ccc3[nH]2)cc1)C1CCCCC1

Procedure:
2-(N-Cyclohexylcarbanoyl-4′-aminophenyl)-6-(cyclohexylcarbanoylamino)-benzimidazole was prepared by Method A from 2-(4-aminophenyl)-6-aminobenzimidazole (0.195 g, 0.87 mmole) and cyclohexylcarbonyl chloride (0.291 ml, 0.319 g, 2.175 mmole). The resulting solid (76.7 mg) was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH3:31]>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Product: CCCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 38 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-9a) and 1-bromopropane. Yield: 38%. MS M+H calculated 409.19; found 409.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:33])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.4 g) and 4-trifluoromethylbenzenesulfonyl chloride ((0.339 g ) were combined to provide, after trituration with ether, the title sulfonamide (0.198 g) which was obtained as a crystalline solid. mp 169-171° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C1COCC1>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCSCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.00 g, 33.48 mmol) in THF (250 ml) at room temperature was added thiomorpholine (3.45 g, 33.48 mmol) and sodium bicarbonate (3.66 g, 43.52 mmol). The vessel was purged with nitrogen and stirred at room temperature for 48 hours. After removal of solvent under reduced pressure, the mixture was taken up in ethyl acetate and filtered. The organics were washed with water, then brine and dried with magnesium sulfate. Filtration and concentration provided the title compound as a bright orange solid. MS m/z: 293.1 (M+H+); calc MW=292.28.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.F>O>[C:9]([O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:13](=[O:15])[CH3:12])=[CH:17][CH:16]=2)=[O:15])=[CH:3][CH:2]=1)(=[O:8])[CH3:10]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Oc1ccccc1
Agent: F
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)c2ccc(OC(C)=O)cc2)cc1
Yield: 151.5 %

Procedure:
45.5 g (0.52 mole) of phenol, 69.0 g (0.50 mole) of 4-hydroxybenzoic acid, and 500 mL of hydrogen fluoride were heated together for 6 hr under autogenous pressure in an autoclave. Then the contents were mixed in excess water to precipitate a pink solid. Yield was 99 g (92.5%). The crude product was acetylated directly, without purification, by refluxing 2 hr in 3 times its volume of acetic anhydride and about 8 drops of sulfuric acid. Precipitation in excess water yielded 113 g of 4,4'-diacetoxybenzophenone of such high purity that no recrystallization was required (melting point 150-152° C. ).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Cl:23][C:24]1[CH:25]=[C:26]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([N:57]3[CH2:62][CH2:61][CH:60]([C:63]([F:66])([F:65])[F:64])[CH2:59][CH2:58]3)=[O:56])=[CH:51][CH:50]=2)[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C@H:36]2[CH2:41][CH2:40][C@H:39](OS(C)(=O)=O)[CH2:38][CH2:37]2)[C:32]1=[O:47]>C(#N)C>[CH:36]1([N:33]2[CH2:34][CH2:35][C@@H:31]([CH2:30][C:29]3[C:24]([Cl:23])=[CH:25][C:26]([C:49]4[CH:50]=[CH:51][C:52]([C:55]([N:57]5[CH2:58][CH2:59][CH:60]([C:63]([F:66])([F:65])[F:64])[CH2:61][CH2:62]5)=[O:56])=[CH:53][CH:54]=4)=[CH:27][C:28]=3[Cl:48])[C:32]2=[O:47])[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CC=CCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve tetrabutylammonium fluoride trihydrate (0.436 g, 1.36 mmol) in 5 ml of acetonitrile. Add water (0.05 ml. 2.72 mmol) and stir for 10 minutes. Add trans-methanesulfonic acid 4-{(R)-3-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-2-oxo-pyrrolidin-1-yl}-cyclohexyl ester (0.458 g, 0.68 mmol). Stir at 80° C. for 12 hours. Quench with saturated aqueous sodium bicarbonate and extract with ethyl acetate. Wash the extract with brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify by silica gel chromatography recover 0.036 g (9%) of the title compound: MS (m/z): 579 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH3:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Cl)ccc1CBr
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: [K+]
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1Cc1ccccc1
Yield: 18.4 %

Procedure:
1-Bromomethyl-4-chloro-2-methoxy-benzene (50 mg, 0.21 mmol), phenyl boronic acid (28 mg, 0.23 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol) and K2CO3 (87 mg, 0.63 mmol) were combined in dioxane, purged with N2, and heated to reflux for 16 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to provide 9 mg (18%) of the title compound. MS (ESI) m/e 233 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:5][C:6](=[O:37])[CH2:7][NH:8][C:9](=[O:36])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:27])[C@H:13]([CH2:25][OH:26])[NH:14]C(OCC1C=CC=CC=1)=O.[ClH:43]>CO.[Pd]>[ClH:43].[CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:38][CH:39]([CH3:40])[CH3:41])[NH:5][C:6](=[O:37])[CH2:7][NH:8][C:9](=[O:36])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:27])[C@H:13]([CH2:25][OH:26])[NH2:14]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
A mixture consisting of 2.4 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosylglycyl-L-leucine methyl ester, 60 ml. of methanol, 240 mg. of 5% palladium-on-carbon, and 5.4 ml. of 1.26 N hydrogen chloride in methanol is hydrogenated at one atmosphere and 25° C. for one hour. The mixture is then filtered to remove the catalyst, and the filtrate is evaporated to dryness under reduced pressure to give an amorphous solid residue of L-seryl-L-tyrosylglycyl-L-leucine methyl ester hydrochloride; [α]D25 -12.9° (2% in methanol); λmax 278, E11 33.6 (methanol).
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.N[C:19]1[C:23]([C:24]#[N:25])=C[NH:21][N:20]=1>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:21]3[N:20]=[CH:19][C:23]([C:24]#[N:25])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 3.15 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 1.40 g. of 3-aminopyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 6 hours. The mixture is evaporated and the residue is treated as described in Example 1, giving the desired product, m.p. 144°-145° C.
Reaction SMILES: [CH2:1]([CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].N1CCCCC1.C=O>C(O)C>[CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C(=O)O)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(CCCC)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of n-butylmalonic acid (17.2 g, 107 mmol) in ethanol (200 ml) was added piperidine (12.76 ml, 129 mmol) and 37% aq. formaldehyde (40.3 ml, 538 mmol). The solution was heated to 80° C. during which time a precipitate appeared and gradually redissolved over 1 hour. The reaction mixture was stirred at 80° C. overnight then cooled to room temperature. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate (200 ml), washed successively with 1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a clear oil (13.37 g, 97%). 1H-NMR; δ (CDCl3), 6.29 (1H, s), 5.65 (1H, s), 2.34-2.28 (2H, m), 1.54-1.26 (4H, m), 0.94 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[N:9]2[C:17](=[O:46])[C:18]3[N:19]([CH:21]=[C:22]([C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=4[F:45])=[O:35])[C:23](=[O:33])[C:24]=3[O:25]CC3C=CC=CC=3)[CH2:20][CH:8]12)(=[O:3])[CH3:2]>[Pd]>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[N:9]2[C:17](=[O:46])[C:18]3[N:19]([CH:21]=[C:22]([C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=4[F:45])=[O:35])[C:23](=[O:33])[C:24]=3[OH:25])[CH2:20][CH:8]12)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCN1CC2CCCCC2N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Agent: [Pd]
Product: CC(=O)NCCN1CC2CCCCC2N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12

Procedure:
racemic-4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide. In a manner similar to that described in example Z-35, from racemic-N-[2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethyl]acetamide hydrochloride (82 mg, 0.849 mmol) and 16a (50 mg, 0.106 mmol) was prepared the title compound (24 mg, 86%). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic (4aS,6aS,14aS)-6-[2-(acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (24 mg, 0.0379 mmol) and 10% Pd/C (1 mg) was prepared the title compound as a white solid after purification by HPLC. 1H NMR (CDCl3) 12.50 (s, 1H), 10.44 (s, 1H), 8.35 (s, 1H), 7.32 (m, 1H), 6.79 (m, 2H), 5.86 (s, 1H), 4.78 (m, 1H), 4.61-4.50 (m, 3H), 4.30 (m, 1H), 8.35 (m, 1H), 3.18 (m, 1H), 2.96 (m, 1H), 2.76 (m, 2H), 2.48 (m, 1H), 2.19 (m, 1H), 1.89-1.28 (m, 12H): ES+MS: 544 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:25][CH:24]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-methoxyphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 267.1. HRMS: calcd for C18H18O2+H+, 267.13796; found (ESI, [M+H]+), 267.1373.