Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=4[O:25][CH2:34]3)[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 193-195° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.38-7.32 (m, 10H), 7.14-6.92 (m, 4H), 6.75-6.78 (m, 1H), 6.55-6.50 (m, 1H), 6.37-6.31 (m, 1H), 4.99-4.94 (m, 1H), 4.73-4.65 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.9, 159.0, 141.7, 138.4, 137.7, 137.4, 132.8, 129.4, 128.6, 128.4, 128.1, 127.9, 127.8, 126.3, 123.8, 123.0, 112.2, 111.4, 79.7, 58.7, 57.8, 20.3, 19.3; MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A solution of 7.31 g of Methyl 4'-methylbiphenyl-3-carboxylate, 5.75 g of N-bromosuccinimide, 0.125 g of azo(bisisobutyronitrile), and 500 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 9.90 g of crude methyl 4'-bromomethylbiphenyl-3-carboxylate which was used in a subsequent reaction without further purification; NMR (200 MHz, CDCl3): δ 8.28 (s, 1H); 8.05 (d, 1H); 7.79 (d, 1H); 7.67-7.48 (m, 5H); 4.55 (s, 2H); 3.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17](N(C)OC)=[O:18])(=[O:11])=[O:10])[O:4][N:3]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][Mg]Cl)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17](=[O:18])[CH2:23][C:24]2[CH:32]=[CH:31][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: Cc1ccc(C[Mg]Cl)cc1
Product: Cc1ccc(CC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)cc1
Yield: 65 %

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetyl)thiophene-3-sulfonamide was prepared, as described in Example 93B, by reacting N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamide with 4-methylbenzylmagnesium chloride, resulting in a 65% yield, m.p. 95-100° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[O:11][N:10]=[C:9]([CH3:12])[N:8]=2)=[C:5]([CH3:13])[N:4]=[CH:3]1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[O:11][N:10]=[C:9]([CH3:12])[N:8]=2)=[C:5]([CH3:13])[N:4]=1
Reactant: BrBr
Reactant: Cc1noc(-c2c(C)ncn2C)n1
Solvent: ClC(Cl)Cl
Product: Cc1noc(-c2c(C)nc(Br)n2C)n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 51.5 %

Procedure:
To a stirred solution of 5-(3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazol (0.7 g, 3.93 mmol) in chloroform (7 ml) was added dropwise at RT a solution of bromine (0.94 g, 0.30 ml, 5.89 mmol) in chloroform (7 ml). The reaction mixture was stirred at RT for 26 h, evaporated, poured into sat. NaHCO3 solution (40 ml) and extracted with dichloromethane (2×30 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated to give the crude product as yellow oil (0.84 g). Purification by column chromatography on silica gel (ethyl acetate/MeOH 98:2) gave the title compound (0.52 g, 51%) as a white solid, m.p. 89° C. and MS: m/e=256, 258 (M+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:34])[C@@H:14]([NH:16][C:17](=[O:33])[C@@H:18]([NH:20][C:21](=[O:32])[C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])[CH3:19])[CH3:15])=[N:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CCO.O>[OH:2][CH2:1][C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:34])[C@@H:14]([NH:16][C:17](=[O:33])[C@@H:18]([NH:20][C:21](=[O:32])[C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH3:23])[CH3:19])[CH3:15])=[N:5][CH:4]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(CO)s1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Following the procedure as described in Example 32, except using material from Example 73 (2.5 mg, 5.01 μmol), EtOH/H2O (4:1) (500 μlit), sodium borohydride (1.1 mg, 29.0 μmol) and stirring at room temp for 40 min, the title compound is isolated (quantitative yield) and is used crude in the next step. LC/MS (Condition A): ret. T=2.22 min, (M+H)+ 501.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.[C:10]1([CH3:33])[CH:15]=[CH:14][C:13]([S:16]([O:19][CH2:20][CH2:21][O:22]S(C2C=CC(C)=CC=2)(=O)=O)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:33])[CH:11]=[CH:12][C:13]([S:16]([O:19][CH2:20][CH2:21][O:22][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1
Reactant: COc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1cccc(OCCOS(=O)(=O)c2ccc(C)cc2)c1

Procedure:
Analogously to Method I, 0.500 g of methoxyphenol and 4.385 g of ethylene di(p-toluenesulphonate) are reacted. The title compound is obtained as a colourless solid. Rf=0.51 (1:1 EtOAc-heptane); Rt=4.68.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:13]=[C:14]=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:18]>CCOCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:13][C:14]([NH2:18])=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: N
Reactant: Cc1ccc(C(N=C=S)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1ccc(C(NC(N)=S)c2ccccc2)cc1

Procedure:
A solution of 22 g (0.092 mole) of 4-methylbenzhydrylisothiocyanate in 250 ml of dry ether at 0° is treated with anhydrous NH3 for 3 hours while stirring. The mixture is stirred an additional 1.5 hours at 0° to 10° C during which time the crude product precipitates as a white solid. Filtration and washing with Et2O affords the product; mp 167°-8° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:27][C:28]1[CH:32]=[C:31](Br)[N:30]([S:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:25]([CH2:27][C:28]1[CH:32]=[C:31]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[N:30]([S:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=1)[C:24](=[O:43])[O:23][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2cccs2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of crude tributyl(2-thienyl)stannane (1.1 g) and tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg) in toluene was added tetrakis(triphenylphosphine)palladium (116 mg), and the mixture was stirred under a nitrogen atmosphere at 120° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a pale-yellow oil (yield 315 mg, 73%).
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>N1C=CC=CC=1>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:2][NH:3][CH2:4][CH2:5]2)([CH3:20])[CH3:19]
Reactant: Oc1cc2c(cc1O)CNCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Yield: 100 %

Procedure:
A mixture of 1.0 g of 1,2,3,4-tetrahydro-6,7-isoquinolinediol hydrobromide and 2.45 g of t-butyl dimethylsilyl chloride in 25.0 mL of pyridine is heated under reflux for 4.5 hours, cooled, poured into water and extracted with diethyl ether. The diethyl ether extract is washed with brine, dried, filtered. The filtrate is evaporated to yield a brown oil. This oil is purified by Kugelrohr distillation to yield 1.6 g of the desired product as a yellow solid, b.p. 155° C., 350 torr.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:15]C[CH:13](O)[CH2:12]1.C(OC(C)C)(C)C.O1CCOCC1>>[C:1]([O:9][CH:10]1[CH2:13][CH2:12][NH:11][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNC1
Reactant: COC(=O)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: O=C(OC1CCNC1)c1ccccc1
Yield: 66 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), pyrrolidin-3-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether/1,4-dioxane (3/1) (5.0 ml) was heated to reflux for 46 hours, and as a result, pyrrolidin-3-yl benzoate was obtained at a yield of 66%. The yield of N-benzoylpyrrolidin-3-yl benzoate was 34%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[Cu][C:15]#[N:16]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([C:15]#[N:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)ccc1N
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C#N)ccc1N
Yield: 26.6 %

Procedure:
A solution of 3-amino-6-bromo-pyridine-2-carboxylic acid ethyl ester (40 mg, 163 μmol) and copper(I) cyanide (29.2 mg, 326 μmol) in DMF (800 μL) was heated in the microwave at 220° C. for 8 min. The reaction mixture was filtered through diatomaceous filter-aid and the crude product was purified by preparative HPLC to afford the title compound as off-white solid (8.3 mg, 26.6%).
Reaction SMILES: CN[C:3]([C:5]1[S:6][C:7]([CH3:19])=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[OH-:20].[K+]>CO.O>[C:10]([C:9]1[C:8]([CH3:18])=[C:7]([CH3:19])[S:6][C:5]=1[C:3]([OH:20])=[O:4])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)c1sc(C)c(C)c1C(=O)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1sc(C(=O)O)c(C(=O)c2ccccc2)c1C

Procedure:
A solution of 16a (0.281 g, 1.03 mmole) in methanol-water 1:1 containing 10% KOH was heated at reflux for 12 hours, neutralized and extracted with ethyl acetate. The solid after evaporation was crystallized from ethanol. Yield 0.19 g, 71%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[C:7]([OH:10])[C:8]=1[OH:9])#[N:2].[NH2:17][C:18]1C(O)=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=1>CN(C)C=O.O>[OH:9][C:8]1[C:7]([OH:10])=[CH:6][C:5]([C:11]2[C:12](=[O:13])[O:14][C:15]3[CH:22]=[CH:21][C:20]([CH3:25])=[CH:19][C:18]=3[N:17]=2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COC(=O)C(=O)c1cc(O)c(O)c(C#N)c1
Reactant: Cc1ccc(O)c(N)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)c(-c3cc(O)c(O)c(C#N)c3)nc2c1
Temperature: 25 °C

Procedure:
1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl)-glyoxylate and 0.60 g of 2-amino-p-cresol are stirred at 120° for 70 minutes in 2 ml of dimethylformamide. The mixture is subsequently cooled to room temperature and diluted with 15 ml of water. The precipitate is filtered and dried in a water-jet vacuum at 80° for 6 hours. After recrystallization from acetonitrile there is obtained 2,3-dihydroxy-5-(6-methyl-2-oxo-2H-1,4-benzoxazin-3-yl)-benzonitrile of m.p. 278°-280°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1COCC1.C[Mg]Br.O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]([OH:12])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccc1OCc1ccccc1

Procedure:
2-Benzyloxy-5-bromobenzaldehyde (5 g) was dissolved in anhydrous diethyl ether (20 mL) and THF (20 mL) and stirred at ambient temperature under argon while a solution of methyl magnesium bromide in ether (7.4 mL, 3M solution in ether) was added dropwise over 5 minutes. A white precipitate formed. After 30 minutes the mixture was poured onto a mixture of ice and water (300 mL). The aqueous mixture was extracted with ethyl acetate (3×250 mL), the organic extracts were washed with brine (100 mL) and dried (MgSO4). After removal of the solvent the residual pale yellow oil was purified by MPLC (eluting with dichloromethane on silica) to give 1-(2-benzyloxy-5-bromophenyl)-ethanol, (5.19 g, mp 76.7° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](Cl)[N:3]=1.[CH3:13][O-:14].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)c(C(=O)O)cc1F
Yield: 65 %

Procedure:
A solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (51.12 g, 243 mmol) in methanol (400 ml) was treated with sodium methoxide in methanol (25% w/v, 100 ml, 535 mmol) and the mixture heated to reflux for 4 hours. The cooled mixture was treated with water (400 ml) and acidified to pH2 with aqueous hydrochloric acid (2M) then concentrated to ca 400 ml. Filtration, washing with water and drying in vacuo over P2O5 for 18 h afforded the product as a white solid (32.65 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Br.[C:12]([O:16][C:17](=[O:30])[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([N:25]=[CH:26]N(C)C)=[S:24])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>C(O)C>[C:12]([O:16][C:17](=[O:30])[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[S:24][C:5]([C:4](=[O:7])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])=[CH:26][N:25]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Reactant: Cc1ccccc1C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(NCCCNC(=O)OC(C)(C)C)s1
Temperature: 100 °C
Yield: 76.9 %

Procedure:
A mixture of 613 mg (2.9 mmol) 2-methyl phenacylbromide (literature: WO9907666), 691 mg (2.4 mmol) [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 1 ml (7.2 mmol) NEt3 in 20 ml ethanol was heated to 100° C. for 16 h. The mixture was concentrated and purified by flash column chromatography on silica eluting with ethyl acetate/n-hexane 1/1. The combined product fractions were evaporated and 693 mg (77%) of the title compound (MS (m/e): 375.9 (MH+, 100%)) were obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=[O:4])=[O:3].[F:41][C:42]1[C:43]([S:52][CH3:53])=[C:44](B(O)O)[CH:45]=[C:46]([F:48])[CH:47]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[F:41][C:42]1[C:43]([S:52][CH3:53])=[C:44]([C:11]2[C:12]([C:16](=[O:32])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:19][CH:18]=3)=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]3)[CH:45]=[C:46]([F:48])[CH:47]=1
Reactant: CSc1c(F)cc(F)cc1B(O)O
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1c(F)cc(F)cc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (8.8 g, 14.6 mmol) and 3,5-difluoro-2-methylsulfanyl-benzene boronic acid (9.0 g, 42 mmol) and flush with nitrogen. Dissolve solids in degassed dioxane (240 mL). Add 2M sodium carbonate (120 mL) and Pd(PPh3)4 (6.7 g, 5.9 mmol). Plunge into 110° C. oil bath and stir vigorously. After 30 minutes, cool the reaction to room temperature and filter off solids. Partition the filtrate between water and methylene chloride. Wash the organic layer with water twice, dry over sodium sulfate, filter and concentrate. Purify the residue over silica gel, eluting with 1 to 2% methanol in methylene chloride, to yield 8.0 g (90%) of the title compound. LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=3.18 mm (99%); mass spectrum (ion spray): m/z=612.3 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16]>O>[OH:3][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccs1
Yield: 48.2 %

Procedure:
A cooled solution of hydroxylamine hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0°) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the oxime (syn-isomer) (1.05 g; 51%), m.p. 132°, λmax. (ethanol) 284 nm (ε 9,500), λmax. (Nujol) 2590 and 1706 (CO2H) and 1655 cm-1 (C=N), τ (DMSO-d6), -2.5 to -0.5 (broad multiplet; N--OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[H][H]>C1COCC1.C(O)C.[Rh]>[OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:13][CH2:12][CH:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc(OCCO)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCC(OCCO)CC1

Procedure:
1.00 g (5.49 mmol) of 4-(2-hydroxyethoxy)benzoic acid is dissolved in 30 ml of dry THF and 30 ml of dry ethanol, and 1.13 mg (0.55 mmol) of rhodium on alumina are added. The reaction mixture is hydrogenated at +50° C. at a hydrogen pressure of 50 bar for 12 h. The mixture is then hydrogenated at +60° C. at a hydrogen pressure of 80 bar for a further 48 h. After filtration, the filtrate is concentrated on a rotary evaporator. The residue is directly used in the next reaction without further purification.
Reaction SMILES: O[CH:2]1[CH2:7]SC(O)C[S:3]1.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10]>C(O)C.C(N(CC)CC)C>[NH2:10][C:9]1[S:3][CH:2]=[CH:7][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(N)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)c1ccsc1N
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
To a solution of 2,5-dihydroxy-1,4-dithiane (10 g, 65.78 mmol) in ethanol (200 mL) and triethylamine (2 mL) was added cyanoacetamide (5.52 g, 65.78 mmol) at rt for 5 min. The reaction mixture was refluxed for 3 h and attained to rt. Ethanol (appr. 150 mL) was removed under reduced pressure and poured the contents into ice cold water and stirred for 15 min. The solution was extracted with ethyl acetate (3×100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale yellow color solid (4.9 g, 53%), mp 150-152° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H].C(OC(C)C)(C)C>[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 66.4 %

Procedure:
A Parr bottle was charged with (4-nitrobenzyl)-methy-carbarnic acid tert-butyl ester (30.0 g, 113 mmol), 150 mL EtOAc, and 10% Pd/C (3.0 g, 10 wt %), and shaken under 40 psi hydrogen for 90 min. When hydrogen uptake ceased, the reaction vessel was purged with nitrogen, filtered through celite, and concentrated to provide a tan solid, which was granulated with 300 mL of isopropyl ether to provide the title compound as an off-white solid (17.7 g in two crops, 75 mmol, 66% yield):
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(=O)OC)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), methyl 4-(bromomethyl)benzoate (3.7 mL), potassium carbonate (2.3 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then 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 (2.8 g, 40%).