Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20]Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CN(C)C=O>[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20][O:8][CH2:7][CH:3]1[C:4]([CH3:6])([CH3:5])[C:2]1([CH3:9])[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)C(CO)C1(C)C
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(C)C(COCc2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.9 g of 2,2,3,3-tetramethylcyclopropylmethanol and 4.2 g of 3-phenoxy-4-fluorobenzyl bromide in 20 ml of a 1:1 mixture of toluene/dimethylformamide is added dropwise at 0°-5° C. to 0.9 g of sodium hydride (50% dispersion in mineral oil) in 60 ml of a 1:1 mixture of toluene/dimethylformamide. When the reaction has subsided, the batch is stirred for 16 hours at room temperature and, after the dropwise addition of a saturated solution of ammonium chloride, extracted with toluene. The combined toluene extracts are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The crude product is chromatographed through a column of 300 g of silica gel (elution with a 95:5 mixture of hexane/ether), affording the title compound of formula ##STR9## in the form of a clear oil with a refractive index of nD24 =1.5300 (compound 1).
Reaction SMILES: C([O:8][C@@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[C:35]2[CH:36]=[C:37]([Cl:42])[C:38]([Cl:41])=[C:39]([Cl:40])[C:34]=2[N:33]=[C:32]1[Cl:43])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl.CO>C(Cl)Cl.CCOC(C)=O>[C@@H:10]1([N:31]2[C:35]3[CH:36]=[C:37]([Cl:42])[C:38]([Cl:41])=[C:39]([Cl:40])[C:34]=3[N:33]=[C:32]2[Cl:43])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]1[OH:8]
Reactant: Clc1cc2c(nc(Cl)n2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(Cl)c1Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Cl)c(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 0.565 g (0.858 mmol) of 91a in 8 mL of CH2Cl2, was added dropwise 8.58 mL of 1M BCl3 /CH2Cl2 at -78° C. The reaction mixture was stirred at -78° C. for 2 hr and then at -40° C. for 2 hr. MeOH (2.5 mL) was added dropwise and stirring was continued at -40° C. for 10 min. The reaction mixture was diluted with EtOAc (75 mL). The EtOAc solution was washed with H2O (50 mL), sat. NaHCO3 solution (50 mL), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was suspended in a small amount of CHCl3 and then filtered. The solid product was washed with portions of CHCl3 and recrystallized from MeOH to give 0.271 g (81%) of 92 as white crystals. MP: 172°-175° C. (dec). 1H NMR (DMSO-d6): d 8.62 (s, 1, 7-H), 5.89 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.52 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.46 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.31 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.39 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.04 (m, 1, 4'-H, J4'-5' =J4'-5" =2.5 Hz), 3.72 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 142.44 (C2), 138.56 (C3a), 131.95 (C7a), 126.91 (C4), 124.52, 122.39 (C5 and C6), 113.55 (C7), 89.58 (C1'), 86.44 (C4'), 71.95 (C2'), 69.53 (C3'), 60.82 (C5'). Anal. Calcd. for C12H10Cl4N2O4 : C, 37.14; H, 2.60; N, 7.22. Found: C, 37.01; H, 2.60; N, 7.01.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[OH:18][CH2:17][C:16]([NH:15][C:12]([C:10]1[CH:9]=[N:8][NH:7][CH:11]=1)=[O:14])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CC(C)(N)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of DMF (2 drops) and oxalyl chloride (0.88 g, 4.5 mmol) in methylene chloride (4 ml) was added to a suspension of 4-pyrazolecarboxylic acid (0.50 g, 4.5 mmol) in methylene chloride (6 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried under a reduced pressure. To a suspension of the obtained solid in methylene chloride (5 ml) cooled in an ice-bath, 2-amino-2-methyl-1-propanol (1.33 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 hour, added saturated aqueous NaHCO3 to, and concentrated and dried under a reduced pressure. The residue was extracted with warm chloroform and the solvent was evaporated under a reduced pressure. The residue was subjected to silica gel chromatography (chloroform/methanol/triethylamine=100/10/1) to give the title compound (0.37 g, 45%).
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@@H:8]([CH2:18][C:19]#[N:20])[CH2:7][N:6]1[CH2:21][CH2:22][CH3:23].N.C(OCC)(=[O:27])C>Br.C(O)(=O)C>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@@H:8]([CH2:18][C:19]([NH2:20])=[O:27])[CH2:7][N:6]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCN1C[C@H](CC#N)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Reactant: CCOC(C)=O
Agent: Br
Agent: N
Solvent: CC(=O)O
Product: CCCN1C[C@H](CC(N)=O)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
922 mg of (2-methyl-6-n-propyl-8beta-ergolinyl)-acetonitrile (3 mmol) is dissolved in 15 ml of a 30% solution of HBr in glacial acetic acid and stirred for 3 hours at room temperature. The mixture is mixed with ice, made alkaline with ammonia and shaken with ethyl acetate. The organic phases are dried and concentrated by evaporation. The residue is chromatographed on silica gel with acetone/methanol and crystallized from ethyl acetate, yield 421 mg (43% of theory), [α]D =-67° (0.5% in pyridine).
Reaction SMILES: C([C@H:4]1[CH2:7][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][C:17]=3[F:30])=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[CH:35][N:36]=[C:9]23)[CH2:5]1)(=O)C.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:30][C:17]1[CH:18]=[C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]=1[CH2:15][C:12]1[C:13](=[O:14])[N:8]([C@H:6]2[CH2:5][C@H:4]([OH:42])[CH2:7]2)[C:9]2[N:10]([N:34]=[CH:35][N:36]=2)[C:11]=1[CH2:31][CH2:32][CH3:33]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a mixture of 4′-{[4-(trans-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.49 g), 30% hydrogen peroxide (8.3 mL) and chloroform (10 mL) was gradually added dropwise trifluoroacetic acid anhydride (5.6 mL), and the mixture was heated under reflux for 14 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were gradually added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was mixed with tetrahydrofuran (5 mL), methanol (5 mL) and 1 M aqueous sodium hydroxide solution (5 mL). The mixture was stirred at room temperature for 4 hr, and the reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 62%).
Reaction SMILES: Cl.F[C:3]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:4]=1[C:5](=[N:12][OH:13])[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[K+]>O>[F:18][C:16]1[CH:15]=[CH:14][C:4]2[C:5]([CH:6]3[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)=[N:12][O:13][C:3]=2[CH:17]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)noc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A suspension of 11 g of 4-(2,4-difluoro-benzoyl)piperidine-oxime hydrochloride and 25 g of potassium hydroxide in 25 ml of water is heated to boiling with stirring for 2 hours. The reaction mixture is cooled to room temperature and extracted with toluene. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residual crude product is recrystallized from petroleum ether. Thus 7.1 g of the title compound are obtained. According to HPLC MS analysis the product contains 5% of 4-{6-[4′-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-piperidine-1′-yl]-1,2-benzisoxazol-3-yl}-piperidine, as a contamination (compound of the Formula VI).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH2:25][CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:6]=1[CH3:27])([CH3:4])([CH3:3])[CH3:2].IB1C2CCCC1CCC2>ClCCl>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH2:25][CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:6]=1[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(c1ccc(OC)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C
Agent: IB1C2CCCC1CCC2
Solvent: ClCCl
Product: CCN(c1ccc(O)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C

Procedure:
Following general procedure M and using 7-t-butyl-5-[ethyl-(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 56, 0.12 g, 0.3 mmol) and 1M solution of 9-iodo-9-borabicyclo[3.3.1]nonane (B-iodo-9-BBN) in hexanes (0.44 mL, 0.44 mmol) in 2 mL of anhydrous dichloromethane, the title compound was obtained as a brown oil that was used in the next step without further purification.
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=3)[N:9]2[CH:25]=1)=O)C.[CH2:26]([CH:28]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][SH:34])[CH3:27].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:26]([CH:28]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][S:34][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:8]3[N:9]2[CH:25]=[CH:6][N:7]=3)=[CH:14][CH:13]=1)[CH3:27]
Reactant: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(I)cc32)n1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nccn3c2c1
Temperature: 60 °C

Procedure:
1v (900 mg, 2.4 mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (660 mg, 3.0 mmol), Pd2dba3 (69 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol), and iPr2NEt (1.1 mL, 6.0 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The mixture was heated at 60° C. for 1.5 hours, then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 1x.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1cc(-c2nnn[nH]2)oc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12
Reaction time: 18 h

Procedure:
1.59 g of the nitro compound obtained in Example 36, Step 3, above, is suspended in 46 ml of methanol to which 1 ml of concentrated hydrochloric acid, and 0.17 g of 5% palladium on carbon are added. The mixture is stirred under hydrogen at atmospheric pressure for 18 hours, filtered, and the filtrate concentrated in vacuo to 1.10 g 5-(8-amino-4-oxo-4H-1-benzopyran-2-yl)tetrazole.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1nc(-c2ccccc2)cs1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of 3-(4-phenylthiazol-2-yl)propan-1-ol (0.4 g, 1.82 mmol) in dry pyridine (8 mL) was cooled to 0° C. and methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature, stirred for 1 h, and quenched with ice water. The organic product was extracted with EtOAc and organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, yield 74%) as a pale yellow liquid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.46-7.40 (m, 2H), 7.37-7.31 (m, 2H), 4.42-4.38 (t, J=6.1 Hz, 2H), 3.24-3.19 (t, J=7.2 Hz, 2H), 3.04 (s, 3H), 2.39-2.30 (m, 2H). MS (ESI) m/z: Calculated for C13H15NO3S2: 297.05. found: 298.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[C:6]([CH:32]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:8].[CH3:40]N1C(=O)N(C)CCC1.[H-].[Na+].CI>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:33]([CH3:40])[C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[C:6]([CH:32]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31]2)=[CH:25][CH:24]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:8]
Reactant: CN1CCCN(C)C1=O
Reactant: O=C(c1cc(Cl)ccc1NC(=O)C(F)(F)F)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
50 mg of 5-chloro-N-(4-cyclopropyl-benzyl)-2-(2,2,2-trifluoro-acetylamino)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (0.09 mmol) were dissolved in 1 ml DMF and 0.1 ml DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2-pyridinon) under argon and cooled down to 0° C. 6 mg of sodium hydride (55% dispersion in oil, 0.135 mmol) were then added and after 15 min stirring at RT the reaction mixture was again cooled down to 0° C. 0.008 ml of methyl iodide (0.135 mmol) were added and after 4 h stirring at RT a second portion of the same amount was added. After 20 hours stirring at RT the reaction mixture was diluted with ethyl acetate and washed with water and brine. The aqueous phases were reextracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/EtOAc 9:1) to give 36 mg (70%) 5-chloro-N-(4-cyclopropyl-benzyl)-2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a colorless viscous oil. MS (ISP) 583.2 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:3]2=[N:1][N:2]=1
Reactant: NNc1ncccc1-c1cccnc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2c(-c3cccnc3)cccn12
Temperature: 130 °C

Procedure:
A mixture of 0.27 g of 2'-hydrazino-3,3'-bipyridine and 5 ml of triethyl orthoacetate was heated at 130° C. for 1.5 hours and the solvent removed. The residue was chromatographed on silica gel and eluted first with ethyl acetate:methanol (9:2), then with methanol to elute the product. This solid was recrystallized from methylene chloride-hexane giving the desired product as tan crystals, mp 112°-115° C.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][C:12]#[CH:13])(C(O)=O)[C:3]([OH:5])=[O:4]>C(#N)C>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[C:3]([OH:5])=[O:4]
Reactant: C#CCCCC(C)(C(=O)O)C(=O)O
Solvent: CC#N
Product: C#CCCCC(C)C(=O)O
Yield: 83 %

Procedure:
A mixture of 2-methyl-2-(pent-4-ynyl)malonic acid (5.7 g) and cuprous oxide (0.22 g) in acetonitrile (150 ml) was heated to reflux, under a nitrogen atmosphere, for 4.25 hours. The solvent was removed under reduced pressure and water (50 ml) was added to the residue followed by sufficient concentrated hydrochloric acid to hydrolyse the copper salts. The resulting aqueous phase was extracted with diethyl ether and the organic extracts were washed with water and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. 2-Methylhept-6-ynoic acid (3.6 g) was obtained as a colourless oil after distillation (b.p. 150°-165°, 0.5 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 89.2 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 156 (4.2 g), 1 mol/L of an aqueous sodium hydroxide solution (17 mL), and methanol (170 mL), to give the captioned compound (3.6 g, 88%) as crystals.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](O)[C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([Cl:20])[C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Yield: 55.7 %

Procedure:
A mixture of 15 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropanol (crude oil), 12 g of thionyl chloride and 80 ml of anhydrous benzene is refluxed for 3 hours. After the reaction, the reaction mixture is evaporated to remove solvent and thionyl chloride. The residue is purified by silica gel chromatography (Solvent: benzene). 9.0 g of 1-(3,4-methylenedioxyphenyl)-1-chloro-2-methyl-2-nitropropane are thereby obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:17]([O-:19])=[O:18])[C:6]([CH:11](O)[CH2:12][N+:13]([O-:15])=[O:14])=[N:7][C:8]=1[O:9][CH3:10].CC([O-])=O.[Na+].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:11]=[CH:12][N+:13]([O-:15])=[O:14])[N:7]=1
Reactant: COc1cc([N+](=O)[O-])c(C(O)C[N+](=O)[O-])nc1OC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])c(C=C[N+](=O)[O-])nc1OC
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
Bring 1-(5,6-dimethoxy-3-nitropyridin-2-yl)-2-nitroethanol, 7 (173 mg, 0.63 mmol) and NaOAc (208 mg, 2.53 mmol) to reflux in Ac2O (5.0 mL), following the reaction by LC-MS. After 45 min, pour the reaction mixture onto an ice/H2O mixture, neutralize with NaHCO3, extract with EtOAc, wash with saturated NaHCO3, dry (MgSO4) and concentrate. Purify the raw product by flash chromatography (EtOAc at 20%/heptane) to give 8 (144 mg, 89.2%) as an ivory-colored solid, which is an 8:2 mixture of isomers: 1H NMR (CDCl3) δ 8.68 (d, 0.8 H, J=12.9 Hz), 8.57 (d, 1.6 H, J=13 Hz), 7.99 (d, 0.83 H, J=12.9 Hz), 7.72 (d, 1H, J=11.7 Hz), 7.3 (d, 0.15 H, J=12 Hz), 4.18 (s, 2.6 H), 4.15 (s, 0.56 H), is 4.05 (s, 2.8 H), 3.97 (0.54 H); Rf (EtOAc at 40%/heptane, two spots)=0.4 and 0.42; m/z obs.=256 (M+1).
Reaction SMILES: C(O[C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH2:8]Cl)C.Cl.Cl.[F:28][C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.O>[F:28][C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([N:38]2[CH2:8][CH2:7][CH2:6]/[C:5](=[CH:10]\[C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)/[C:4]2=[O:25])[CH2:34]1
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCl
Reactant: N[C@H]1CCN(Cc2ccc(F)c(F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: COc1cc(/C=C2\CCCN([C@H]3CCN(Cc4ccc(F)c(F)c4)C3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid ethyl ester (200 mg) and ((3S)-1-(3,4-difluorobenzyl)pyrrolidine-3-yl)amine dihydrochloride (315 mg) in acetonitrile (8 mL) and water (2 mL), potassium carbonate (228 mg) and sodium iodide (831 mg) were added. After carrying out heat-refluxing of the reaction solution for 12 hours, the reaction solution allowed to be cooled to room temperature and concentrated under reduced pressure. A 2N sodium hydroxide solution (1 mL) in ethanol (5 mL) was added to the obtained residue. After agitating the reaction mixture at room temperature for 12 hours, it was neutralized with a 5N hydrochloric acid solution, and the reaction solution was extracted with ethyl acetate. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 200 mg of the title compound was obtained by purifying the residue by silica gel chromatography (Carrier: Chromatorex™ NH; elution solvent: ethyl acetate). The physical properties of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C1(CCc2ccccn2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccn3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-14; 0.8 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9 mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product was triturated from Et2O, mp 100-110° C. MS (APCI): 470 (M+H).