Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21]O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.OS(O)(=O)=O>CN(C=O)C>[S:17]([CH2:20][CH2:21][S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([C:14]1[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=C(O)c1cccnc1S
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CCSc2ncccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A solution of 7.3 g (47 mmol) of 2-mercaptonicotinic acid and 9.6 g (48 mmol) of 2-(p-toluenesulfonyl)-ethanol was dissolved in DMF (80 ml). 0.5 ml of conc. H2SO4 was then carefully added dropwise, and stirring was carried out overnight under reflux. The reaction mixture was concentrated using a Genevac (EZ2). The residue was dissolved in acetonitrile and the solid was separated off. The mother liquor was concentrated, and MeOH was added. The resulting solid was filtered off and dried. 2.35 g (7 mmol, 14.8%) of 2-(2-tosylethylthio)nicotinic acid were obtained as solid.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[SH2:15].[Na]>CO>[NH2:12][C:11]1[C:2]([SH:15])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: S
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cnc(S)c(N)c1
Yield: 484 %

Procedure:
To a solution of 6 g of methyl 6-chloro-5-nitronicotinate in methanol (100 ml) was added 6.7 g of sodium hydrogensulfide and the resulting mixture was heated under reflux for 2 hours. After distilling off the solvent under reduced pressure, dilute hydrochloric acid was added to the residue followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 24.7 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2([CH2:46][OH:47])[CH2:45][CH2:44]2)=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:38]3[CH:39]=[C:40]([C:43]4([CH2:46][OH:47])[CH2:44][CH2:45]4)[CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C2(CO)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2(CO)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 28 mg; 0.046 mmol) was treated with {1-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}methanol (Intermediate 28; 18 mg; 0.060 mmol), 1-1′-bis(di tert-butylphosphino) ferrocene palladium dichloride (3.0 mg; 0.0046 mmol), 1 N K2CO3 (2 mL) and THF (2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-[1-(hydroxymethyl)cyclopropyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=662.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.82 (m, 2H), 7.76 (s, 1H), 7.66-7.61 (m, 2H), 7.40-7.37 (m, 1H), 7.27-7.24 (m, 2H), 6.96-6.93 (m, 1H), 5.40 (d, J=15.6 Hz, 1H), 4.91 (d, J=10.5 Hz, 1H), 4.11 (d, J=15.6 Hz, 1H), 3.91 (s, 3H), 3.68-3.56 (m, 2H), 3.39-3.32 (m, 1H), 2.24-2.16 (m, 1H), 1.80-1.64 (m, 1H), 1.05 (d, J=6.2 Hz, 3H), 0.88-0.74 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N[CH2:13][CH:14]([OH:41])[CH2:15][NH:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:29]1)=[CH:22]2)=[O:18])CC>>[CH:1]1([CH2:7][NH:8][CH2:13][CH:14]([OH:41])[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([N:28]2[CH2:29][CH2:30][CH:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:32][CH2:33]2)=[CH:22]3)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCNCC(O)CNC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Reactant: NCC1CCCCC1
Product: O=C(NCC(O)CNCC1CCCCC1)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1

Procedure:
substituting propylamine for cyclohexylmethylamine, N-{3-n-propylamino-2-hydroxypropyl}-4-benzylpiperidinyl indole-5-carboxamide:
Reaction SMILES: [SH:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:29](#[N:32])[CH:30]=[CH2:31]>CCO.CN(C)C(N(C)C)=N>[C:29]([CH2:30][CH2:31][S:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:32]
Reactant: C=CC#N
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CN(C)C(=N)N(C)C
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CSCCC#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 92 %

Procedure:
A solution of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1, 4-dihydropyridine (5 g), acrylonitrile (0.66 g) and 1,1,3,3-tetramethylguanidine (0.1 g) in EtOH (60 ml) is stirred at room temperature for 18 hours and then evaporated to dryness. After the usual work-up, the residue is recrystallized from Et2O to give 5.2 g of 2-[(2-cyanoethyl)thio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine m.p. 102°-104° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccccc1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[CH2:9][O:8][C:7]3[N:12]=[C:13]([C:22]4[CH:36]=[CH:35][C:25]([CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:24][CH:23]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:6]2=3)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[NH2:27][CH2:26][C:25]1[CH:35]=[CH:36][C:22]([C:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:10](=[O:11])[CH2:9][O:8][C:7]=3[N:12]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC2CC2)C(=O)CO3)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC2CC2)C(=O)CO3)cc1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 70.8 %

Procedure:
tert-Butyl 4-(1-(cyclopropylmethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (80 mg, 0.165 mmol) was dissolved in TFA (1 mL). The resulting mixture was stirred for 30 seconds at room temperature and evaporated under reduced pressure. The deprotected compound was taken back twice into diethyl ether and the solid formed was washed twice with diethylether. The remaining solvent was removed under reduced pressure and dried to afford the title compound (45 mg, 70.9%) as white solid. LCMS: RT=0.84 min, M+H+=386. 1H NMR (500 MHz, CDCl3): 8.33 (2H, br), 7.41 (1H, s), 7.27-7.26 (4H, m), 7.18 (3H, m), 7.13-7.12 (2H, m), 4.82 (2H, s), 3.94 (2H, s), 3.87-3.85 (2H, d), 1.16-1.14 (1H, m), 0.60-0.57 (2H, m), 0.48-0.45 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:10]1[C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a stirred solution of 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (5.5 g, 0.025 mol) in CHCl3 (100 mL) was added NBS (6.733 g, 0.038 mol) portion wise at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via by flash column chromatography using 25% ethyl acetate in hexane and silica gel (230-400 Mesh) to afford 4-bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (4.6 g, 65%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (from example 55d), (100 mg) was dissolved in MeOH (1 ml) prior to the addition of 5% Pd/BaSO4 (120 mg). A hydrogen balloon was added and the solution was stirred for 1.5 h. The palladium was filtered off and the solution was concentrated to give ±(1S*,2R*,4R*)-[4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (94 mg). MS found: (M+H)+=415.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[S:11])[N:12]=[N:13][NH:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2[nH]nnc2=S)cc1
Yield: 59.5 %

Procedure:
4-Methoxyphenylisothiocyanate (2 g) and 1 g of sodium azide in 50 mL of ethanol is refluxed for 5 hours, cooled and concentrated as described (Canadian Journal of Chemistry 1959, p 101). The precipitate is collected by vacuum filtration and dried to give 1.5 g of 1-(4-methoxyphenyl)tetrazol-5-thione as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (320 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:25].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (104) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Reactant: CCNCC
Product: CCN(CC)CC(O)COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and diethylamine.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][C:22]=3[O:31][CH2:32][O:33][CH3:34])=[CH:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([Si:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][C:22]=3[O:31][CH2:32][O:33][CH3:34])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2=CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Reaction time: 17 h
Yield: 101 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added tert-butyl (4-{4-[2,4-bis(methoxymethoxy)phenyl]-3-cyclohexen-1-yl}phenoxy) dimethylsilane (118 mg, 0.24 mmol) and ethanol (15 ml). To the stirred solution, palladium (catalytic amount, 10% on activated carbon) was added in one portion. The reaction vessel was then evacuated and placed under an atmosphere of hydrogen. This process was repeated for 10 cycles before leaving under a hydrogen atmosphere. The reaction mixture was stirred vigorously for 17 hr then filtered through celite, washing with ethyl acetate. The filtrate was concentrated in vacuo affording the title compound as a colourless oil (118 mg, 100%) and a mixture of diastereoisomers. δH(CDCl3) 0.15 (6H, s), 0.92 (9H, s), 1.51 (2H, m), 1.63 (2H, m), 1.81 (2H, m), 1.94 (2H, m), 2.43 and 2.90 (1H, m), 2.84 and 3.02 (1H, m), 3.38 and 3.39 (3H, s), 3.40 (2×1.5H, s), 5.04 and 5.06 (2H, s), 5.08 and 5.10 (2H, s), 6.56 and 6.61 (1H, m), 6.70 (3H, m), 7.03 (2H, m), 7.11 (1H, d).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([C:5]#[N:6])[C:3]#[N:4].[C:8](#[N:10])[CH3:9].O>C1(C)C=CC=CC=1>[NH2:4][C:3]([C:2]([CH3:7])([CH3:1])[C:5]#[N:6])=[CH:9][C:8]#[N:10]
Reactant: CC(C)(C#N)C#N
Reactant: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C#N)C(N)=CC#N
Temperature: 40 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of potassium tert amylate in toluene (25%, 11.8 mL, 23 mmol) is added slowly to a solution of 2,2-Dimethyl-malononitrile (2.0 g, 21 mmol) and acetonitrile (1.2 mL, 23 mmol) in toluene (20 mL) at 40° C. under argon. The reaction mixture is stirred at 40° C. for 2 h and then cooled to 12° C. Water (5 mL) is added and the mixture is stirred at 20° C. for 15 min and at 2° C. for 30 min. Filtration, washing with cold water (10 mL) and drying under vacuum provides 2.30 g 3-Amino-4,4-dimethyl-pent-2-endinitrile. Yield: 80%: ESI-MS: 136 [M+H]+; 1H-NMR (DMSO-d6): 1.5, 4.1, 6.8 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>C(Cl)Cl.O>[CH3:21][CH:20]([CH3:22])[CH2:19][O:18][C:16](=[O:17])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cccc(F)c1
Reaction time: 2.5 h

Procedure:
To a mixture of 3-fluoroaniline (I, 29.058 g, 261.5 mmol) in methylene chloride (116 ml) is added a mixture of potassium carbonate (27.26 g, 197.3 mmol, 0.75 eq) in water (116 ml) at 20-25°. The mixture is warmed to 32°, and isobutyl chloroformate (38.5 g, 282 mmol, 1.08 eq) is added over 13 min while maintaining 30-35° with mild cooling. The mixture is stirred at 30-35° for 2.5 hr until the reaction is complete to give 2-methylpropyl-(3-fluorophenyl)carbamate as determined by GC [GC method A, <0.1 area % 3-fluoroaniline; RT (3-fluoroaniline)=3.97 min, RT=14.2 min]. Aqueous ammonia (29.3 wt %, 4.20 ml, 65.0 mmol, 0.25 eq) is added and the mixture stirred at 30-35° for 15 min. The mixture is cooled to 20-25° and the pH adjusted from 8.7 to 1.9 with hydrochloric acid (37 wt %, 6.36 g, 64.5 mmol, 0.25 eq). The phases are separated and the aqueous washed with methylene chloride (58 ml). The combined organics are washed with water (118 ml) and the water wash back extracted with methylene chloride (58 ml). [In a prior experiment crystallization at this point from heptane at −30° gave 2-methylpropyl-(3-fluorophenyl)carbamate analytically pure in 98.1% yield.]. Dibromantin (57.37 g;, 200.6 mmol, 0.767 eq) and water (174 ml) are added to the combined organics and the mixture stirred at 40° for 12 hr until complete as measured by HPLC (<0.1 2-methylpropyl-(3-fluorophenyl)carbamate). The mixture is cooled to 20-25° and clarified on a “C” frit by vacuum filtration. The phases are separated and the organic (lower) phase added to a mixture of sodium sulfite (33.06 g, 262.3 mmol, 1.00 eq) in water (220 ml) with good agitation. The phases are separated and the organic phase washed with water (150 ml). Serial back-extracted the clarified solids and all aqueous with a single portion of methylene chloride (150 ml). Added heptane (520 ml) to the combined organic phases and concentrated under reduced pressure. Heptane (240 ml) is added, the mixture cooled to −30°, the precipitate is collected by vacuum filtration, washed with cold heptane (150 ml) and dried in a nitrogen stream to give the title compound; mp=79-82°; TLC Rf=0.41 (ethyl acetate/hexanes, 5/95); HPLC (method A) rt=6.75 min; NMR (CDCl3, 400 MHz) d 7.41, 6.96, 6.87, 3.96, 1.97 and 0.96; CMR (CDCl3, 75 MHz) d 159.2, 153.4, 139.0, 133.3, 115.1, 107.1, 102.0, 71.8, 27.9 and 19.0; MS (CI, NH3) m/Z (relative intensity) 310 (9.3), 309 (100), 308 (6.1), 307 (100), 292 (11), 291 (18), 290 (7.5) and 289 (19)
Reaction SMILES: [C:1](Cl)(=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:9]1([C:15]#[C:16][C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:9]1([C:15]#[C:16][C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:31][C:1](=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH3:6])(=[O:33])=[O:32])=[O:22])=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CC=CC=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC=C/C=C/C(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
In a stream of nitrogen and at 0° C., 0.10 ml (0.96 mmol) of 2,4-hexadienoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.80 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 195 mg (1.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus formed crude crystals were recrystallized from methanol to obtain 180 mg (yield: 48.0%) of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1>C(O)(=O)C>[C:5]([NH:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C#Cc1cccc(NC(C)=O)c1
Yield: 79 %

Procedure:
To a 250 ml 3-neck flask fitted with a condenser, nitrogen inlet and outlet, and magnetic stirrer was added 150 ml of acetic acid and 35 ml of acetic anhydride. The mixture was heated to reflux under nitrogen and cooled under nitrogen. To the cooled mixture was added 15 g (0.114 mole) of 3-aminophenylacetylene and the homogeneous solution was refluxed overnight. The cooled reaction mixture was transferred to a 500 ml one-neck flask, and the acetic acid was removed by a rotor-evaporator under high vacuum. Water (200 ml) was added to the residual oil to crystallize the solid product. The material was isolated by filtration and washed with water and then air dried. Recrystallization from carbon tetrachloride with 200 g/10 g solid plus charcoal yielded 14.4 g (79% yield) of a white crystalline product (m.p. 94°-96° C.).
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[Si:1]([C:8]1[S:9][C:10]([C:19]2([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:23][CH2:24]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 100 mL 3-necked round-bottom flask, was placed a solution of 2-(tert-butyldimethylsilyl)thiazole (1.58 g, 7.94 mmol, 1.00 equiv) in tetrahydrofuran (40 mL). This was followed by the addition of n-BuLi (3.7 mL, 1.20 equiv) dropwise with stirring at −78° C. in 1 hr. After half-hour, the benzyl 4-oxopiperidine-1-carboxylate (1.85 g, 7.94 mmol, 1.00 equiv) was added dropwise with stirring at −78° C. in 0.5 hr. The reaction mixture was stirred for 2 h at −78° C. in a liquid nitrogen bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate, and the combined organic layers washed with 2×100 mL of brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 2 g (58%) of benzyl 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)-4-hydroxypiperidine-1-carboxylate as yellow oil.