Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[C:10]([O:16][CH2:17][CH:18]=[CH2:19])[C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[CH2:17]([O:16][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:4])[C:14]=2[N:13]=[CH:12][C:11]=1[CH3:15])[CH:18]=[CH2:19]
Reactant: C=CCOc1c(C)cnc2c1CCCC2OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1c(C)cnc2c1CCCC2O

Procedure:
5.0 Grams of 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 20 ml of methanol. Then a solution prepared by dissolving 2.3 g of sodium hydroxide in 20 ml of water was added thereto, and the mixture was refluxed for 1 hour. After the reaction was completed, methanol was removed by evaporation, and to the residue thus obtained was added water, and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation to obtain 3.5 g of 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline in the form of brown oily substance.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[S:31]1[CH:35]=[C:34]([C:36]([NH:38][NH2:39])=O)[N:33]=[N:32]1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:36]([C:34]3[N:33]=[N:32][S:31][CH:35]=3)=[N:38][N:39]=[C:26]2[CH2:25]1)=[O:23]
Reactant: NNC(=O)c1csnn1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2csnn2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethyloxonium tetrafluoroborate (363 mg, 1.908 mmol) was added to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(505 mg, 1.735 mmol) in dry dichloromethane (DCM) (4.2 ml). The reaction mixture was stirred at room temperature 45 mins—until everything was dissolved. 1,2,3-Thiadiazole-4-carbohydrazide (300 mg, 2.082 mmol, commercially available from e.g. Apollo) was added and the resulting mixture was stirred at room temperature for 3 h. DCM was evaporated and the residue was dissolved into 1-butanol (4.2 ml). The reaction mixture was stirred at reflux for 19 h. The mixture was washed with ethyl acetate and washed with water (2×25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and dried under reduced pressure. The crude product was purified by flash chromatography (DCM−10% MeOH in DCM). The residue was triturated with Et2O and then dried under vacuum at 50° C. for 2 days. The resulting solid was triturated with n-hexane and dried at 50° C. under vacuum 20 h to afford the desired product in 4.71 mg, as a white solid.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([NH:35][C:2]2[C:15]3[C:14](=[O:16])[N:13]([C:17]4[CH:18]=[C:19]([C:23]5[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=5)[CH:20]=[CH:21][CH:22]=4)[CH2:12][C@H:11]4[N:7]([CH2:8][CH2:9][CH2:10]4)[C:6]=3[N:5]=[C:4]([S:30][CH3:31])[N:3]=2)[CH2:34][CH2:33]1
Reactant: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Reactant: NC1CC1
Solvent: C1CCOC1
Product: CSc1nc(NC2CC2)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(S)-5-[3-(7-Chloro-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (30.0 mg, 0.0654 mmol) obtained in Step 8 of Example 156 was dissolved in THF (3 mL), and the mixture was stirred at room temperature for 17 hours after adding cyclopropylamine (0.023 mL, 0.327 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(7-cyclopropylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2 (3H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.CO[CH2:21][CH2:22]OC.C(=O)([O-])[O-].[Na+].[Na+]>[OH-].[Na+]>[N:5]1[CH:22]=[CH:21][CH:2]=[C:3]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)[CH:3]=2)[CH:4]=1
Reactant: COCCOC
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: c1cncc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c1
Temperature: 200 °C

Procedure:
To a 5 mL, microwave vial containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (0.30 g, 1.2 mmol) and ethylene glycol dimethyl ether (2 mL) was added 3-diethyl (3-pyridyl)borane (0.21 g, 1.5 mmol, Aldrich), 1 N sodium carbonate (1.8 mL), and palladium(0)-tetrakis-triphenylphosphine (0.14 g, 0.15 mmol, Strem Chemical). The vial was sealed and heated at 200° C. for 20 min in a microwave synthesizer, allowed to cool to room temperature, and the reaction mixture was diluted with 1 N sodium hydroxide (25 mL) and extracted with dichloromethane (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated onto silica gel. The crude material was purified by silica gel chromatography (gradient: 1–2% 2 N ammonia in methanol/dichloromethane) to obtain the title compound as an off-white solid. Mp: 155–158° C. MS (ESI, pos. ion.) m/z: 301 (M+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][C:26]=2[F:36])=[CH:21][CH:20]=1.C(OC1(C2C=CC(CCCCC)=CC=2)C(F)=CC(C2C=CC=CC=2)=C(F)C1)CCCCC>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][C:26]=3[F:36])=[CH:23][CH:24]=2)=[CH:10][C:9]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)c(F)c1
Reactant: CCCCCCOc1ccc(B(O)O)cc1F
Agent: CCCCCCOC1(c2ccc(CCCCC)cc2)CC(F)=C(c2ccccc2)C=C1F
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(CCCCC)cc3F)cc2)cc1F

Procedure:
4-n-Hexyloxy-3-fluorophenylboronic acid is coupled with 4'-bromo-2-fluoro-4-n-pentylbiphenyl in an analogous manner as described for 1G.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:13])[C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:14]1([C@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([NH:5][C:6](=[O:13])[C:7](=[N:22][C@@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(=O)C(C)(C)C
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](N=C(C(=O)NC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 58.2 %

Procedure:
The procedure described under l) was carried out using 7.5 g of N-tert-butyl-3,3-dimethyl-2-oxo-butyramide and 15 g of (R)-1-phenylethylamine. There were isolated 6.8 g (58%) of (R)-N-tert-butyl-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of boiling point 120° at 0.2 mbar. [α]=+40.9 (c=1.0, CHCl3).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethoxy-phenyl)-propionic acid (0.16 g, 0.52 mmol) in methylene chloride (5.3 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.29 mL, 0.58 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (0.11 g, 1.16 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.27 mmol) in tetrahydrofuran (2.65 mL). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide (203.8 mg, 100%) as a white solid: mp 168–170° C.; EI-HRMS m/e calcd for C18H19F3N2O2S (M+) 384.1119, found 384.1118.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:30][N:29]=[CH:28]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cnco2)cc1
Yield: 79.9 %

Procedure:
Methyl 4-formylbenzoate (Aldrich Chemical Co., St Louis, Mo.) (5.0 g, 30.5 mmol), anhydrous potassium carbonate (4.55 g, 33 mmol) and p-toluenesulfonylmethyl isocyanide (TOSMIC, Aldrich Chemical Co.) (6.83 g, 30.5 mmol) were refluxed in methanol (100 ml) for 3.5 hours. The mixture was then concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed twice with water, dried and concentrated in vacuo to give methyl 4-(1,3-oxazol-5-yl)benzoate as a beige solid (4.95 g). (NMR (300 MHz, CDCl3: 8.10 (d, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.48 (s, 1H), 3.94 (s, 3H)).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].O[C:17]([C:20](O)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OCC)C.O>O1CCOCC1>[CH3:18][C:17]1([CH3:19])[C:20]([CH3:22])([CH3:21])[O:11][B:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:5]=2)[O:10]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: CSc1ccc(B(O)O)cc1C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F

Procedure:
The product of step b) (0.25 g) was heated in dioxan (2 ml) with pinacol (2 equiv) for 3 h. The solution was treated with diethyl ether and water. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. Yield 85 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[F:18][C:15]([F:16])([F:17])[C:13]1[NH:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1

Procedure:
A solution of 104 mg (0.4 mmol) of 5-(4-nitrophenyl)-2-(trifluoromethyl)-1H-imidazole in 10 ml of ethanol was hydrogenated in the presence of 15 mg of palladium (10% on activated carbon) at RT and standard pressure. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure and dried. Yield: 98 mg (quant.)
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[CH:27][CH:28]=[C:29](F)[C:23]=4[S:22](=[O:32])(=[O:31])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:5][O:4][CH2:3]1.[CH3:33][O-:34].[Na+]>CO>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[CH:27][CH:28]=[C:29]([O:34][CH3:33])[C:23]=4[S:22](=[O:32])(=[O:31])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: C[O-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4c(F)cccc4C3)cc(NCC3(N)COC3)c2c1
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3cc(C)ccc3n1)C2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 29.1 %

Procedure:
A mixture of N-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (20 mg, 0.044 mmol, prepared in analogy to Example 1-4) and sodium methoxide (24 mg, 0.44 mmol) in methanol (2 mL) was heated with stirring in a sealed 5 mL of microwave process via for 20 minutes at 100° C. under microwave irradiation. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 6 mg of the product (yield was 29%). MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, CD3OD) δ ppm 7.67 (s, 1 H), 7.62-7.52 (m, 1 H), 7.47 (d, J=8.59 Hz, 1 H), 7.41 (d, J=7.07 Hz, 1 H), 7.31 (dd, J=8.46, 1.89 Hz, 1 H), 7.16 (d, J=7.83 Hz, 1 H), 5.99 (s, 1 H), 5.08 (s, 2 H), 4.63-4.49 (m, 4 H), 4.31 (t, J=5.56 Hz, 2 H), 3.98-3.81 (m, 5 H), 3.54 (s, 2 H), 2.43 (s, 3 H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]#[N:15].[OH-].[K+]>>[C:1]1(=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH3:16])[C:14]#[N:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1CC#N
Reactant: O=C1CCCC1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1C(C#N)=C1CCCC1
Yield: 11.7 %

Procedure:
The procedure outlined in example 1 is repeated with cyclopentanone (14.3 g, 0.17 mol), o-tolylacetonitrile (13.1 g, 0.10 mol) and KOH (1.12 g, 0.02 mol). Short path distillation of the crude at 0.05 mbar/124-130° C. yields 5.30 g (27% yield). The product is contaminated with α,α′-dicyclopentylidenecyclopentanone. It is further purified by FC on SiO2 to yield 2.3 g of oily product (10% yield).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([OH:16])=O>>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][CH2:13][C:14]2=[O:16]
Reactant: O=C(O)CCc1ccccc1Br
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(Br)cccc21
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Thionyl chloride (85 ml) was added to 3-(2-bromophenyl)propionic acid (16.88 g), and the mixture was stirred under reflux for 2 hours. After the mixture was left standing for cooling, the excessive amount of the thionyl chloride was removed by distillation under reduced pressure, and the residual mixture was distilled azeotropically once with toluene and once with carbon tetrachloride. The residual concentrate was dissolved in carbon tetrachloride (30 ml) and added at a temperature of 5°-10° C. dropwise to a suspension of aluminum chloride (14.74 g) in carbon tetrachloride (100 ml). The mixture was stirred at the same temperature for 40 minutes, then at room temperature for 30 minutes and further under reflux for 1 hour. After left standing for cooling, the mixture was poured into ice-hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residual concentrate was purified by chromatography on a silica gel column to give the title compound (13.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[O:24]C(C)=O>CC(O)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=[O:24])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
4-Allyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.97 g, 10 mmol) was dissolved in iPrOH (50.0 mL) and H2O (10.0 mL). To this was added a aqueous solution of NaIO4 (4.68 g, 21.8 mmol) in water (40.0 mL), followed by addition of OsO4 (8.4 mg, crystals, in one portion) at rt. The solution was stirred at rt. After 30 min, milky cloudy formed. Stirring was continued overnight. TLC and LC/MS did not detect the SM, but it is still very milky. The reaction mixture was poured into ice water (20 mL) and EtOAc (30 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined extracts were washed with brine, and concentrated to dryness to get a liquid. The liquid was subject a reduced distillation to remove isopropanol. The remaining liquid was purified on a 50-g silica gel column, eluted with MeOH in DCM (0-5%). Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield 1.03 g (34% yield) of the title compound as a liquid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2.[OH:27]O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)=[O:27]
Reactant: O=C1CCc2cc(OCCCCSc3nc4ccccc4s3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3nc4ccccc4s3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-benzthiazolyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][C:37](=[O:39])[CH2:36][C:35]1=[O:40]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[C:35](=[O:40])[CH2:36][C:37](=[O:39])[CH:38]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC(=O)C(=O)C1
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3=O)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(tri-fluoromethyl)Phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 6) and cyclopentane-1,2,4-trione according to the procedure of Example 7. MS: (MH)+570.0
Reaction SMILES: [CH2:1]1[CH:6]2[CH:7]3[CH:13]4[CH2:14][CH:2]1[CH2:3][CH:4]1[CH:12]4[CH2:11][CH:9]([CH2:10][CH:5]12)[CH2:8]3.[Br-:15].[Al+3].[Br-:17].[Br-]>BrBr>[CH2:14]1[C:2]2([Br:15])[CH2:1][CH:6]3[CH:5]4[CH2:10][C:9]5([Br:17])[CH2:11][CH:12]([CH:4]4[CH2:3]2)[CH:13]1[CH:7]3[CH2:8]5
Reactant: [Br-]
Reactant: C1C2CC3C4CC5CC(C14)C(C2)C3C5
Agent: BrBr
Agent: [Al+3]
Product: BrC12CC3C4CC5(Br)CC3C(C1)C(C5)C4C2
Temperature: 0 °C
Reaction time: 16 h
Yield: 650.1 %

Procedure:
Diamantane (50 g, 0.26 mol) was added over 1 h to bromine (200 mL) at 0° C. Aluminum bromide (5.4 g, 0.02 mol) was added and the mixture was stirred at 0° C. for 3 h and at ambient temperature for 16 h. When glc showed less than 5% monobrominated diamantanes, the bromine was removed under reduced pressure and the residue was triturated with pentane (300 mL). The precipitate was filtered, and was washed with pentane (2×150 mL) and methanol (3×100 mL). The residue was recrystallized from toluene to give 45 g (50%) of 4,9-dibromodiamantane, a white solid: mp 328° C. (lit. mp 324°-326° C.); 1H NMR (CDCl3) δ1.97 (s, 6H) 2.31 (s, 12H); 13C NMR (CDCl3) δ39.64, 48.45, 62.81.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:26][C:27]1[O:31][C:30]([C:32]2([CH3:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:29][C:28]=1[CH2:39][CH2:40][O:41]S(C1C=CC(C)=CC=1)(=O)=O>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:41][CH2:40][CH2:39][C:28]4[N:29]=[C:30]([C:32]5([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)[O:31][C:27]=4[CH3:26])=[CH:9][CH:8]=3)[C:4]([OH:25])=[O:3])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 6.65 (d, 1H, J=8.21 Hz), 6.47 (d, 1H, J=2.35 Hz), 6.37 (dd, 1H, J=8.21 Hz, J=2.35 Hz), 5.92 (d, 2H, J=0.78 Hz), 4.14 (t, 2H, J=6.25 Hz), 3.19 (d, 1H, J=14.08 Hz), 3.07 (d, 1H, J=14.08 Hz), 2.98 (t, 2H, J=6.25 Hz), 2.31 (s, 3H), 2.17-2.08 (m, 2H), 1.62-1.35 (m, 8H), 1.34 (s, 3H), 1.31 (s, 3H); MS (ES+) calcd for C30H35NO7: Found m/e 522.3 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[CH3:17]I.[H-].[Na+]>CN(C=O)C>[CH3:16][O:15][C:13]([C:10]1([CH3:17])[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)=[O:14]
Reactant: COC(=O)C1CCCc2ccc(OC)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
7-Methoxytetralin-1-yl-carboxylic acid, methyl ester (0.4 g; 1.8 mmol; from step (i) above) and MeI (0.13 mL, 2.0 mmol) were added to a slurry of NaH (55% in oil; 87 mg; 2.0 mmol) in DMF (5 mL) and the mixture was stirred at RT overnight. The resultant mixture was poured onto water, and the water mixture was extracted with EtOAc:toluene 3 times. The combined organic layer was washed with water, dried (Na2SO4), and concentrated. Flash chromatography (Si-gel; heptane:EtOAc; 4:1) yielded 0.18 g (42%) of the sub-title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@@H:9]1[CH2:16][O:17]C(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(OC[C@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H]1CO
Reaction time: 12 h

Procedure:
(2R,4S)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl)oxymethyl-4-azido-pyrrolidine 40 (2.72 g, 5 mmol) in methanol (75 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.3 g) at room temperature and 5 atm pressure. After 12 h, the catalyst was filtered, washed with methanol (20 ml) and the solvent removed under vacuum. Yield 1.0 g (93%). 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H) and 4.44 (m, 1H).