Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][CH:6]=[C:5]([C:8](O)=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:22][N:23](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN1C(=O)CCC1>[CH3:22][NH:23][C:8]([C:5]1[C:4](=[O:11])[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:2]([CH3:1])[NH:7][CH:6]=1)=[O:9]
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c[nH]c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 5b, 0.800 g, 2.69 mmol), HBTU (1.07 g, 2.81 mmol), DIPEA (0.78 mL, 4.59 mmol) in NMP (5 mL) is stirred for 30 min. Then, methylamine (5.00 mL of 2M solution in THF, 10.0 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is concentrated under reduced pressure and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 0.20 g (24% of theory); ESI mass spectrum: [M+H]+=311; Retention time HPLC: 1.10 min (V003—003).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].[C:9](=O)([O-])[O-:10].[K+].[K+].C[O-].[Na+]>CO>[CH3:9][O:10][CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: C=C(CBr)C(=O)OC
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C=C(COC)C(=O)OC
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred mixture of methyl 2-(bromomethyl)acrylate (239 μl, 2 mmol) in petroleum ether (3 ml) was added potassium carbonate (276 mg, 2 mmol), followed by sodium methoxide (119 mg, 2.2 mmol) and methanol (450 μl). The resulting mixture was stirred overnight, filtered, concentrated to a residue that was purified by column chromatography eluting with 10% ether in hexanes to provide the title compound (150 mg, 58%). (Reference: J. Med. Chem.; 42; 15; 1999; 2760-2773.)
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][C:17]([CH2:24][CH3:25])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>COCCOC.[Cl-].[Na+].O.[Zn]>[CH2:20]([C:17]1([CH2:24][CH3:25])[CH:18]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH2:16]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(C=O)(CC)CSc1ccccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: CCCCC1(CC)C=C(c2ccccc2)c2ccccc2SC1
Temperature: 5 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3 and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5° C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:9]=1.[C:43]1([C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][N:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:52]3[CH:51]=[N:50][C:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:54][CH:53]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Temperature: 100 °C
Yield: 88.1 %

Procedure:
To tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g, 2.7 mmol) in dioxane (22 mL) and H2O (5.5 mL) was added 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 g, 4.1 mmol), PdCl2(dppf).CH2Cl2 (0.3 g, 0.3 mmol) and K2CO3 (1.2 g, 8.2 mmol). The reaction was heated at 100° C. for 15 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, H2O (40 ml) and EtOAc (100 mL) were added and organics were extracted with EtOAc (2×75 ml), dried (Na2SO4) and concentrated in vacuo to crude. Gradient column chromatography on silica eluting with 0 to 50% EtOAc/hexanes gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.8 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-])=[O:16])[C:5]([C:18]([O:20]C)=O)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:14][C:12]1[CH:11]=[CH:10][C:9]2[N:15]([OH:16])[C:18](=[O:20])[C:5]3[C:6](=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]=2[CH:13]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(F)cc1-c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=c1c2ccc(F)cc2c2cc(F)ccc2n1O
Reaction time: 16 h
Yield: 18.3 %

Procedure:
To the product of Example 38a (279.8 mg) was added methanol (7.5 mL) and 10% palladium on carbon (76 mg, 0.071 mmol). The flask was fitted with a hydrogen balloon and the mixture was de-gased and back-filled with hydrogen three times. The mixture was stirred under hydrogen for 16 h, diluted with dimethylformamide and filtered. The filtrate was concentrated to give a red solid. This material was triturated with dichloromethane/hexane (9/1) and filtered to provide the title compound (Example 38b, 43.15 mg, 0.175 mmol, quantitative yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([C:9]2[CH:17]=[C:16]([C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]C)=[CH:21][CH:20]=3)[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:28]([OH:30])=[O:29])=O)=[CH:5][CH:4]=1)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[CH:17]=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:28]([OH:30])=[O:29])=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: CCc1ccc(C(=O)c2cc(C(=O)c3ccc(CC)cc3)c(C(=O)O)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1

Procedure:
A mixture of 21.1 grams of 4,6-bis(4 ethylbenzoyl)isophthalic acid, 350 mL of acetic acid, and 2.10 grams of 5% palladium on carbon (as a catalyst) was heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The resulting filtrate was concentrated in vacuo to give 4,6-bis(4-methylbenzyl)isophthalic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH:4]([CH3:25])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[CH:11]=[CH:10]3)[CH2:7][CH2:6]1.[OH-:28].[Na+].OO>CO>[O:28]1[C@H:15]2[C:14](=[O:24])[CH:13]=[C:12]3[C@:17]([CH3:18])([C@@H:16]12)[C@@H:19]1[C@H:9]([C@H:8]2[C@:22]([CH3:23])([CH2:21][CH2:20]1)[C@@H:5]([CH:4]([CH3:25])[CH:3]([O:2][CH3:1])[O:26][CH3:27])[CH2:6][CH2:7]2)[CH:10]=[CH:11]3
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of 2.00 g (5.4 mmoles) of 21,21-dimethoxy-20-methylpregna-1,4,6-trien-3-one in 70 ml of methanol were added a 10 wt % solution of sodium hydroxide in methanol (0.55 ml) and 3.04 ml of a 30 wt. % aqueous solution of hydrogen peroxide (containing 29.8 mmoles of hydrogen peroxide) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was worked up in the same manner as Example 6 to recover 1.56 g of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one (yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1cc(N)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Methyl 2-methoxycarbonylmethyl-4-nitrobenzoate (1.74 g, 6.87 mmol) was dissolved in a mixed solvent of ethyl acetate and methanol under nitrogen atmosphere, and then 10% palladium ddcarbon (30 w/w %) was added thereto. After replacing nitrogen gas with hydrogen gas, the reaction solution was stirred at room temperature overnight. The palladium catalyst was removed by Celite filtration, followed by washing with ethyl acetate. The filtrate and washing solution were combined together, and concentrated under reduced pressure to give the title compound (1.30 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccccc1N1CCOCC1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccccc2N2CCOCC2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Morpholin-4-yl-benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]1[C:9]2=[C:10]([S:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:11]3[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO.CC(O)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][C:10]2[C:11]3[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:31])=[O:2])[C:9]=23)=[CH:25][CH:26]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(S(C)(=O)=O)c2c(Sc3ccc(Cl)cc3)c3n(c2c1)CCC3CC(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.4 %

Procedure:
To a solution of the ester from Step 7 (23 mg, 0.048 mmol) in THF (3 mL) and MeOH (1 mL) at RT was added 1M LiOH (0.24 mL, 0.24 mmol). After stirring at r.t. for 4.5 hours, HOAc (10 drops) was added and the solvent was evaporated. The residue was taken up in EtOAc/H2O and the organic phase was washed with brine, dried (MgSO4), and filtered. Upon removal of the solvent, the resulting solid was stirred with 1:5 EtOAc:hexane to give a beige solid (20 mg).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:21][OH:22])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[O:14]([C:10]1[CH:9]=[C:8]([C:5]2([CH2:21][OH:22])[CH2:4][CH2:3][C:2]3([O:31][CH2:1]3)[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C1CCC(CO)(c2cccc(Oc3ccccc3)c2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCC1(c2cccc(Oc3ccccc3)c2)CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (4-methylene-1-(3-phenoxyphenyl)cyclohexyl)methanol (53 mg, 0.180 mmol) in CH2Cl2 (0.9 mL) at 0° C. was added m-chloroperbenzoic acid (43.5 mg, 0.252 mmol). The solution was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc, washed successively with 1 N aqueous NaOH, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (56 mg, 100% yield) as a colorless oil. LCMS, [M+H]+=311.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[C:14]([N:17]4[CH2:21][CH:20]5[CH2:22][N:23](C(OCCCC)=O)[CH2:24][CH:19]5[CH2:18]4)[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:5]=[CH:4][N:3]=1.Cl>ClCCl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][CH:20]5[CH:19]([CH2:24][NH:23][CH2:22]5)[CH2:18]4)=[N:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:33][CH:34]=1
Reactant: CCCCOC(=O)N1CC2CN(c3ccc4nc(-c5ccc(Cl)cc5)c(-c5ccnc(N)c5)n4n3)CC2C1
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(N4CC5CNCC5C4)nn23)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.16 g (0.29 mmol) of tent-butyl 5-[3-(2-aminopyrid-4-yl)-2-(4-chlorophenyl)-imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 3 mL of dichloromethane are added 1.5 mL (18 mmol) of concentrated hydrochloric acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the oily residue is taken up with aqueous ammonia and the product is extracted with dichloromethane. The organic phase is filtered on a hydrophobic cartridge and concentrated under reduced pressure. The solid obtained is triturated with diisopropyl ether to give 0.091 g of solid after filtering off and drying under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.CN1CCOCC1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:34][C@H:35]([C:39]([N:41]1[CH2:61][CH2:60][CH2:59][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([C:52]([C:55]([F:58])([F:57])[F:56])([F:54])[F:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])=[O:40])[CH:36]([CH3:38])[CH3:37].Cl>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([NH:34][C@H:35]([C:39]([N:41]2[CH2:61][CH2:60][CH2:59][C@H:42]2[C:43]([NH:45][CH:46]([CH:47]([CH3:48])[CH3:49])[C:50](=[O:51])[C:52]([F:53])([F:54])[C:55]([F:56])([F:57])[F:58])=[O:44])=[O:40])[CH:36]([CH3:37])[CH3:38])=[O:11])[CH:2]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Reactant: O=C(O)CCc1cccnc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
Suspend 3-(3-pyridyl)propionic acid (174 mg, 1.15 mmol, Walker, F. A. et al., J. Amer. Chem. Soc., 102, 5530-5538 (1980)) in methylene chloride (15 mL). Add N-methylmorpholine (0.38 mL, 3.45 mmol) and triethylamine (0.32 mL, 2.30 mmol), and cool the resulting clear, colorless solution to -18° C. Add isobutylchloroformate (0.15 mL, 1.15 mmol) and stir for 20 minutes. Subsequently add N-methylmorpholine (0.13 mL, 1.15 mmol) and H-Val-Pro-Val-CF2CF3.hydrochloride (520 mg, 1.15 mmol) and stir at -20° C. for 1 hour. Allow reaction mixture to warm to room temperature, dilute the reaction mixture with additional methylene chloride (35 mL) and successively wash with 1N HCl (3×20 mL), saturated NaHCO3 (2×20 mL), and brine (1×20 mL). Dry and concentrate the crude product. Purify the crude product by flash chromatography (75:25::acetone:EtOAc) to give the title compound as a white solid foam. (Yield: 470 mg, 74%, 3:1::LLL:LLD).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:10][C:11](=[O:23])[CH:12]=[C:13]([CH2:21][CH3:22])[CH:14]([CH3:20])[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:7][CH2:8][CH3:9]>C(O)=O>[CH2:6]([O:10][C:11]([CH:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]([CH3:20])=[C:13]1[CH2:21][CH3:22])=[O:23])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)C=C(CC)C(C)CC=C(C)C
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: CCCCOC(=O)C1C(CC)=C(C)CCC1(C)C
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 81 ml of concentrated formic acid and 9 ml of concentrated sulphuric acid is cooled to 5°-10° C and there are cautiously added at this temperature 10 g (39.7 mmol) of 3-ethyl-4,7-dimethyl-2,6-octadienoic acid n-butyl ester. The mixture is left to come to room temperature and then stirred at room temperature for ca 1 hour. The mixture is then poured on to ice and extracted three times with hexane. The combined hexane solutions are washed once with water, twice with sodium bicarbonate solution and three times with water, dried over sodium sulphate and concentrated. The crude product (9.1 g) is fractionally distilled. There are obtained 6.9 g (69%) of pure 2-ethyl-3,6,6-trimethyl-2-cyclohexene-1-carboxylic acid n-butyl ester of boiling point 75°-74° C/0.03 mm Hg; nD 20 = 1.4663. The ester has a powerful balsamic and spicy odor with a slight buttery undertone.
Reaction SMILES: C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+].C([N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:27])[C:21]=2[N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:19]1=[O:35])C=C>O.O1CCOCC1.O=[Os](=O)(=O)=O>[CH2:28]([N:20]1[C:21]2[C:22]([Cl:27])=[N:23][CH:24]=[CH:25][C:26]=2[NH:18][C:19]1=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=CCn1c(=O)n(Cc2ccccc2)c2c(Cl)nccc21
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccnc(Cl)c2n1Cc1ccccc1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
Water (1.5 mL), 4-methylmorpholin-N-oxide (1.06 g), 2% aqueous osmic acid solution (3 mL), and a solution of sodium periodate (1.94 g) in water (6 mL) were added to a solution of 1-allyl-3-benzyl-4-chloro-1,3-dihydroimidazo[4.5-c]pyridin-2-one (0.75 g) in 1,4-dioxane (15 mL). This was then heated at 60° C. for 18 hours. Water (200 mL) was added, and this was extracted with ethyl acetate (100 mL). The obtained organic layer was washed twice with 50 mL of water and then once with 50 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted by ethyl acetate-hexane (1:1) gave the title compound (0.38 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:27][C:28]([SH:31])([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:31][C:28]([CH3:30])([CH3:29])[CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: CC(C)(C)S
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 2-methyl-2-propanethiol.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[O:19].[CH3:20][Mg]Br.CCOCC.O>C1COCC1>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([OH:19])[CH3:20]
Reactant: C[Mg]Br
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=O)C(=O)N2
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(O)C(=O)N2
Reaction time: 8 h
Yield: 28 %

Procedure:
1 g (3,6 mmol) 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1H-indole-2,3 dione (Example 12) were dissolved under argon in 25 ml dry THF in a flame dried flask. 12 ml 3M methyl magnesium bromide in ether (10 eq) were added dropwise at 0°-5° C. The mixture was stirred overnight. 50 ml water were added, and extracted with ethyl acetate. The organic layers were washed with water and dried over magnesium sulfate. Purification by chromatography on silica (eluent:methylene chloride/ethyl acetate: 2/1), yielded 300 mg (28%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[CH2:11][S:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[ClH:14]>>[ClH:14].[O:13]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:12]=2[CH2:11][S:10]1
Reactant: O=C1SCc2c1cccc2[N+](=O)[O-]
Agent: Cl
Product: Nc1cccc2c1CSC2=O
Temperature: 25 °C

Procedure:
4-Nitrobenzo[c]thiophene-1(3H)-one (38.1 g) was added portionwise to a solution of 146.0 g of stannous chloride dihydrate in 325 ml concentrated hydrochloric acid. A slow exotherm from 18° to 42° occurred and the reaction mixture was maintained at 40°-45° by cooling. When the exotherm subsided, the suspension was stirred while cooling to ambient temperature (3.5 hours). The solid was collected, washed with a small volume of cold concentrated hydrochloric acid, then dried under nitrogen to give 57.7 g of crude 1,3-dihydro-1-oxobenzo[c]thiophene-4-amine hydrochloride, m.p. 205°(d).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 mL round bottom flask, quinoline-3-carbaldehyde (1.57 g, 10 mmol) was dissolved anhydrous ethanol (20 mL) The solution was cooled to 0° C. under nitrogen. NaBH4 (420 mg, 11 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, and quenched by addition of water (3 mL). Na2SO4 (15 g) was added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide quinolin-3-ylmethanol.