Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4](C)[C:5]([C:7]1[N:8]=[C:9]([CH3:19])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:6].C(N(CC)CC)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>C1COCC1>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([CH3:19])[S:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[O:6]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1nc(C(=O)N(C)CCN)c(-c2ccc(F)cc2)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)NCCNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (2-amino-ethyl)-methyl-amide, D5 (120 mg, 0.41 mmol) in THF (7 ml) was treated with triethylamine (0.057 ml) and 2-chlorobenzoxazole (0.047 ml, 0.41 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h then the volatiles removed in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate-pentane) to afford the title compound as a white solid (97 mg, 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cc1
Yield: 5.2 %

Procedure:
2-Chloro-5-(4-trifluoromethoxyphenyl)-pyrimidine (4.22 mmol), 4-formylphenyl boronic acid (5.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol), 2 M potassium carbonate (4.2 mL) and dioxane (21 mL) were combined in a vial and irradiated by microwave for 20 min at 150° C. The organic layer from the reaction mixture was loaded directly onto silica and dried in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (75 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.06 (s, 2H), 8.68 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.C[O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([OH:31])=[O:22])=[CH:11][CH:12]=1)([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: COC(=O)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2C(=O)O)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][C@@H:18]([S:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:40])[N:4]([CH3:41])[C:3]1=[O:42].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[SH:20][C@@H:18]([CH3:19])[CH2:17][N:9]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:42])[N:4]([CH3:41])[C:5]2=[O:40])=[CH:8]1
Reactant: C[C@@H](Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](S)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude (S)-1,3-dimethyl-5-phenyl-6-(2-(tritylthio)propyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 3)(1.35 mg, 1.06 mmol) in DCM (30 ml) was added TFA (4.09 ml, 53.1 mmol) and triethylsilane (1.7 ml, 10.6 mmol) giving a yellow solution. The mixture was stirred at RT overnight. The reaction mixture was evaporated under vacuum. The residue was partitioned between DCM/water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. The solid was dissolved in a minimal volume of DCM and purified via ISCO column chromatography, 40 g silica, liquid load, 0-60% iso-hexane:EtOAc, product eluting at 50% affording 7 pure fractions. Corresponding fractions were reduced in vacuo to yield the title compound as a white solid.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][C:4]=1[F:17].[CH3:18][O:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CCOCC.C1(O)CCCCC1>[CH3:18][O:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:5]2[C:4]([F:17])=[CH:3][C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)=[CH:25][CH:24]=1
Reactant: COc1cc2ncc(F)c(Cl)c2cc1OC
Reactant: COc1ccccc1Oc1ccc(N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: OC1CCCCC1
Product: COc1cc2cc(F)c(Nc3ccc(Oc4ccccc4OC)cc3)nc2cc1OC
Temperature: 110 °C
Yield: 86.2 %

Procedure:
A solution of hydrogen chloride in ether (1 molar, 0.34 ml) was added to a mixture of 4-chloro-6,7-dimethoxy-3-fluoro-quinoline (80 mg) and 4-(2-methoxyphenoxy)-aniline (142 mg) in cyclohexanol (3 ml). The mixture was stirred and heated at 110° C. for 18 hours. The mixture was cooled to ambient temperature and then filtered. The crystals were washed with a small volume of diethyl ether and then dried to give 4-(2-methoxyphenoxy)-anilino-3-fluoro-6,7-dimethoxyquinoline (120 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([C:30]([F:33])([F:32])[F:31])=[CH:18][C:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)=[O:20])[CH:13]=[C:14]([Cl:16])[CH:15]=1.O>N1C=CC=CC=1>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:19](=[O:20])[CH:18]=[C:17]([C:12]3[CH:11]=[C:10]([Cl:9])[CH:15]=[C:14]([Cl:16])[CH:13]=3)[C:30]([F:33])([F:31])[F:32])=[CH:22][CH:23]=2)=[N:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: Nc1ncc(Cl)cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)Nc2ncc(Cl)cn2)cc1
Reaction time: 2.5 h
Yield: 50.5 %

Procedure:
To a solution of 0.5 g of 2-amino-5-chloropyrimidine in 20 mL of pyridine, 0.5 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid chloride was poured at room temperature and the mixture was stirred for 2.5 hours. After that, water was added to the reaction solution that was extracted with ethyl acetate, an organic layer was washed with water and diluted hydrochloric acid and then dehydrated and dried with saturated saline followed by anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (5:2) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 0.31 g of aimed product as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37].CC1(C)C(C)(C)[O:44][B:43](B2OC(C)(C)C(C)(C)O2)[O:42]1.C([O-])(=O)C.[K+].Cl.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH:33]1([C:32]2[C:13]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([B:43]([OH:44])[OH:42])=[C:3]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:4]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:28])[NH:29][CH3:30])[C:16]=3[CH:31]=2)[CH2:35][CH2:34]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(S(C)(=O)=O)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(S(C)(=O)=O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 6.3 %

Procedure:
To a solution of 6-(N-(4-bromo-3-(methylsulfonyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.315 mmol) in 1,4-Dioxane (2 mL) wad added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (400 mg, 1.574 mmol), potassium acetate (154 mg, 1.574 mmol) and Pd(II)(dppf)Cl2 DCM complex (12.85 mg, 0.016 mmol). The mixture was stirred under nitrogen at 80° C. After 4 hours the mixture was cooled to RT and diluted with EtOAc (10 mL). The resulting solution was washed with water, saturated brine, and dried over sodium sulfate. After evaporation of the solvent, the crude residue was dissolved in 10 mL of THF and the resulting solution cooled in an ice water bath. The solution was treated with 1N aqueous HCl (1.574 mL, 1.574 mmol) followed by sodium periodate (135 mg, 0.629 mmol). The mixture was stirred at 0° C. for 20 minutes and then allowed to warm to RT. After 18 hours, the mixture was partitioned between water and EtOAc and the phases separated. The aqueous solution was extracted with EtOAc. The combined EtOAc solutions were washed with 5% aqueous sodium bisulfite, saturated brine, dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue was subjected to HPLC purification (ACN: Water-0.1% Formic acid) to provide the pure product (12 mg, 6.4%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97 (br. s., 2H), 7.87 (d, J=5.37 Hz, 2H), 7.56-7.64 (m, 2H), 7.49 (s, 1H), 7.15-7.24 (m, 2H), 6.15-6.37 (m, 1H), 5.77-5.92 (m, 1H), 3.30 (s, 3H), 3.13 (br. s., 3H), 3.00 (d, J=2.34 Hz, 3H), 1.91-2.10 (m, 1H), 1.18-1.34 (m, 1H), 0.95-1.10 (m, 1H), 0.83-0.93 (m, 1H), 0.69-0.83 (m, 1H), 0.44-0.61 (m, 1H). LCMS (m/z, ES+)=601 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:13].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][N:2]1[C:3]([S:13][CH3:14])=[N:4][N:5]=[C:6]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccncc2)n[nH]c1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nnc(-c2ccncc2)n1C

Procedure:
A mixture of 2,4-dihydro-4-methy-5-(4-pyridyl)-3H-1,2,4-triazole-3-thione (4.19 g, 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1.5 ml, 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated at reduced pressure and the concentrate was treated with water. The aqueous mixture was extracted with EtOAc three times. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:11][C:7]1[C:6]([CH3:12])=[C:3]([C:4]#[N:5])[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:9][C:8]=1[CH3:10]
Reactant: Cc1nc(Cl)c(C#N)c(C)c1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(N2CCNCC2)c(C#N)c(C)c1Cl
Temperature: 120 °C
Yield: 92.7 %

Procedure:
A mixture of 2,5-dichloro-4,6-dimethylnicotinonitrile (200 mg, 0.995 mmol), K2CO3 (275 mg, 1.990 mmol) and piperazine (5141 mg, 59.7 mmol) was heated under microwave heating at 120° C. for 15 minutes. After cooling to room temperature the mixture was partitioned between 1N HCl and DCM. The layers were separated and the aqueous layer was extracted once with DCM, basified with NaOH (4N) and extracted with DCM (4×). The combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure to give 231 mg of a solid (0.922 mmol, yield 93%) MS (multi-mode) m/z=251.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH3:18])[CH3:14]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:18]=[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:19])[N:10]=[N:9]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of para-methoxy benzyl azide (125.0 g, 0.77 mol) in anhydrous DMF (300 mL) was added dropwise propionic acid ethyl ester-(166 g, 1.77 mol) at 0° C. After the addition, the mixture was stirred at RT overnight. The mixture was evaporated in vacuo to yield crude title compound (190.0 g, 95.0%) as yellow oil that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1)#[N:2].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Reactant: C=C(Cl)C#N
Solvent: O
Product: N#Cc1ccc(Cn2cc(C#N)nn2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 4-cyanobenzyl azide (0.8 g) and 2-chloroacrylonitrile (0.88 g) in water (5 ml) is stirred at about 80° C. for 20 hours. Excess 2-chloroacrylonitrile is distilled off in vacuo, the mixture is cooled to room temperature and the precipitated product is isolated by filtration and washed with water. The product (yield 0.92 g; 88% of theory) of m.p. 93.5-94° C. (recrystallization from ethyl acetate/toluene) is obtained after drying.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:15]
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(F)cc2)cc1N
Yield: 67.4 %

Procedure:
Prepared according to the procedure described for Example 7 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 4-fluroaniline (5.0 mL, 52.78 mmol) to afford the product (4.45 g); m.p. 164-167° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>C(Cl)CCl.C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1nncs1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2nncs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 41 %

Procedure:
4-Hydroxy-2-methyl-N-(1,3,4-thiadiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-1,3,4-thiadiazole. Yield: 41% of theory; m.p.217°-219° C (decomp.; from ethylene chloride/ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(NCc3ccccc3)cc2)CC1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.34 g), benzylamine (0.12 g) and sodium tert-butoxide (0.13 g) in toluene (8 mL) were added tris(dibenzylidene acetone)dipalladium (2.2 mg) and Binap (4.6 mg) and the mixture was heated at 80° C. for 16 hours. The solution was then cooled to room temperature, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with petroleum ether/AcOEt (90/10) and the oily residue was crystallized from diisopropyl ether to give the title compound (0.27 g) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12](Br)[CH:11]=2)[CH2:4][CH2:3]1.C(=[NH:31])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([NH2:31])[CH:11]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(NCc2cc(F)cc(Br)c2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCC(NCc2cc(N)cc(F)c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
Combine 1-methyl-4-(N-(3-bromo-5-fluorophenyl)methylamino)piperidine (Preparation 30, 2.90 g, 9.63 mmol), benzophenone imine (1.94 mL, 11.55 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.24 g, 0.39 mmol), sodium t-butoxide (1.26 g, 13.48 mmol), and toluene (60 mL), stir and heat to 80° C. After 10 minutes, add Pd2(dba)3 (0.17 g, 0.19 mmol). After 3 hr at 80° C., cool to ambient temperature. Dilute with ethyl acetate (100 mL) and wash with water (50 mL). Separate organic layer, dry over sodium sulfate, filter and concentrate. Dissolve this material in tetrahydrofuran (120 mL) and treat with 1M aqueous hydrochloric acid solution (40 mL). After stirring at ambient temperature for 1 hr, add 2M sodium hydroxide solution until basic (21 mL). Extract with ethyl acetate (2×100 mL). Wash organic layer with saturated aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate to an oil. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3 in methanol) in CH2Cl2 to obtain 1.96 g (86%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.O[Li].O>CO.O>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1
Reactant: COC(=O)Cc1cccc(OC[C@@H]2COC(C)(C)O2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@H](COc2cccc(CC(=O)O)c2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
To a solution of methyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl-acetate (23 g, 0.08 mol) in methanol (80 mL) and water (5 mL) was added LiOH-H2O (13.8 g, 4 eq.). After stirring the reaction mixture at room temperature for 4 h, the volatiles were removed under vacuo and the residue was partitioned between EtOAc and H20. The aqueous layer was separated, cooled with an ice bath, and then acidified with 10% aq. HCl. The acidic aqueous layer was extracted with EtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na2SO4, and concentrated to give 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenylacetic acid as a white solid (22 g, >99% yield).
Reaction SMILES: [CH:1]([CH:4]1[C:13]2[CH2:12][C:11]([CH3:14])=[CH:10][CH2:9][C:8]=2[C:7]([CH3:16])([CH3:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].P([O-])([O-])(O)=[O:18].[Na+].[Na+].C(OO)(C)(C)C>ClC(Cl)C.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[O:18]1[C:11]2([CH3:14])[CH:10]1[CH2:9][C:8]1[C:7]([CH3:16])([CH3:15])[CH2:6][CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[C:13]=1[CH2:12]2
Reactant: CC1=CCC2=C(C1)C(C(C)C)CCC2(C)C
Reactant: O=P([O-])([O-])O
Agent: [Mo]
Agent: CC(C)(C)OO
Agent: [C-]#[O+]
Solvent: CC(Cl)Cl
Product: CC(C)C1CCC(C)(C)C2=C1CC1(C)OC1C2

Procedure:
105 g of a hydrocarbon mixture containing (according to GC) 56% of 1-isopropyl-4,4,7-trimethyl-1,2,3,4,5,8-hexahydronaphthalene (IIo) are dissolved in 400 ml of dichloroethane and treated in accordance with Example 1, method C, with 1.1 g of molybdenum hexacarbonyl, 0.4 g of disodium hydrogen phosphate and 228 ml of a 2.8 molar tert.butyl hydroperoxide solution. After working-up, 115 g of crude product are obtained. By chromatography there is obtained pure 6,7-epoxy-1-isopropyl-4,4,7-trimethyl1,2,3,4,5,6,7,8-octahydronaphthalene.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:23]([NH:26][C@@H:27]1[C@H:32]([O:33][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=[C:30]([C:51]([O:53]C)=[O:52])[O:29][C@H:28]1[C:55]([O-:57])=O)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.[CH2:67]([CH2:75][CH2:76][CH2:77][NH2:78])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C)C=O>[C:23]([NH:26][C@H:27]1[C@H:28]([C:55](=[O:57])[NH:78][CH2:77][CH2:76][CH2:75][CH2:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:29][C:30]([C:51]([OH:53])=[O:52])=[CH:31][C@H:32]1[OH:33])(=[O:25])[CH3:24]
Reactant: COC(=O)C1=C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](NC(C)=O)[C@H](C(=O)[O-])O1
Reactant: NCCCCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1[C@H](O)C=C(C(=O)O)O[C@H]1C(=O)NCCCCCc1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.42 g) was added to a solution of (2R,3S,4R)-3-acetylamino-4-(tert-butyldiphenylsilanyloxy)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid, 6-methyl ester (2 g) and N,N-diisopropylethylamine (1.4 ml) in dimethylformamide (5 ml), under nitrogen. To this was added N-phenethylpropylamine (722 mg) and the reaction was stirred at 23° C. for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo to give a fawn foam. The foam was chromatographed over silica (Merck 9385, 45 g) using medium pressure (ca 4 psi) and ethyl acetate/cyclohexane (1:2 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white foam (1.1 g). 1H NMR (250 MHz, CDCl3, rotamers) 7.6--7.1 (15H, m), 6.0+5.95 (1H, 2×m), 5.9--5.8 (1H, 2×d, J=6Hz), 5.2 (1H, 2×d, J=5Hz), 4.6 (1H, 2×d, J=3Hz), 4.0--3.7 (1H, m), 3.8 (3H, 2×s), 3.5--2.9 (4H, m), 2.8+2.5 (2H, 2×m), 2.0 (3H, 2×s), 1.5 --1.2 (2H, m), 1.1 (9H, s), 0.9+0.7 (3H, 2×t, J=7Hz).