Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[CH:22]1([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Sn](Cl)(Cl)(Cl)Cl>C(=S)=S>[CH:22]1([CH2:27][C:28]([C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Reactant: O=C(Cl)CC1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC3CCCC3)ccc2c1
Yield: 59.1 %

Procedure:
Following the procedure described in Step 2 of Example 1, 2-(6-methoxy-2-naphthyl)-1-benzofuran (6.00 g, 21.9 mmol) was acylated with 2-cyclopentylacetyl chloride (3.51 g, 23.9 mmol) using tin (IV) chloride (2.8 mL, 24 mmol) in carbon disulfide (120 mL). Purification by flash chromatography (Biotage apparatus) using 10-25% chloroform in hexane and 0.5-1% ethyl acetate in hexane as eluants furnished the title compound as a yellow gum (4.98 g); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (d, 3H, J=8.7 Hz), 7.8 (d, 1H, J=8.7 Hz), 7.7-7.8 (m, 1H), 7.35-7.5 (m, 3H), 7.2-7.35 (m, 1H), 3.95 (s, 3H), 2.75 (d, 2H, J=7.7 Hz), 2.1-2.3 (m, 1H), 1.5-1.75 (m, 2H), 1.3-1.5 (m, 4H), and 0.8-1.1 ppm (m, 2H).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](O)[C:31]#[CH:32]>>[C:1]([NH:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:11]([O:13][CH2:32][C:31]#[CH:30])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: O=C(NC(Cc1ccc(OC(=O)c2ccccc2)cc1)C(=O)O)c1ccccc1
Product: C#CCOC(=O)C(Cc1ccc(OC(=O)c2ccccc2)cc1)NC(=O)c1ccccc1

Procedure:
Proceeding in a similar manner, but substituting for 2-(benzoylamino)-3-(4-benzoyloxyphenyl)propanoic acid, and using propargyl alcohol or another appropriate acetylenic alcohol, the mono-acids prepared by Example 1 and 2 may be converted to the corresponding ester, to obtain, for example:
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]2[C:26]3[C:21](=[C:22]([O:27]C)[N:23]=[CH:24][CH:25]=3)[N:20]([CH3:29])[CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCOCC1.Cl>[CH:1]1([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[C:18]2[C:26]3[CH:25]=[CH:24][NH:23][C:22](=[O:27])[C:21]=3[N:20]([CH3:29])[CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CCCC3)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NCC2CCCC2)c2cc[nH]c(=O)c21
Yield: 34.5 %

Procedure:
The product from Example 68A, (0.021 g) in dioxane (0.5 mL) and 4N HCl in dioxane (0.5 mL) was heated at 70° C. for 24 hours, cooled, and concentrated. Purification by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.007 g, 27%) as the TFA salt. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.64 (dd, J=8.70, 2.29 Hz, 1H) 7.44-7.46 (m, 2H) 6.93 (d, J=7.02 Hz, 1H) 6.83 (d, J=8.85 Hz, 1H) 6.24 (d, J=6.71 Hz, 1H) 4.12 (s, 3H) 3.09 (s, 3H) 3.06 (d, J=7.32 Hz, 2H) 2.10-2.17 (m, 1H) 1.61-1.69 (m, 2H) 1.51-1.58 (m, 2H) 1.44-1.50 (m, 2H) 1.15-1.24 (m, 2H). MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>CC(C)=O.CN(C=O)C>[N:19]1([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: c1ccc2c(c1)CCN2
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1nc(N2CCc3ccccc32)sc2ncccc12
Yield: 79.4 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.728 mg (10.97 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 913 mg of ammonium thiocyanate, 15 ml of acetone, 1.31 g of indoline and 10 ml of acetone were used. As a result, 2.45 g of 2-(indolin-1-yl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].[CH3:23][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:23][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][N:21]=[CH:22][C:14]=1[C:10]1[CH:11]=[N:12][C:13]2[N:4]([C:1](=[O:3])[NH2:2])[CH2:5][CH2:6][CH2:7][C:8]=2[CH:9]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(=O)N1CCCc2cc(-c3cnccc3C(=O)O)cnc21
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a solution of 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid (80 mg, 0.27 mmol) in 8.0 mL of toluene/MeOH 1:1 mixture is added 2.0 M trimethylsilyl-diazomethane (0.20 mL, 0.40 mmol) under N2 atmosphere. The reaction solution is stirred at room temperature for 16 hrs. The solvent is removed and the residue is purified by preparative HPLC to give 33 mg of the titled product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17][CH:16]2[C:36](O)=[O:37])[CH:12]=[CH:13][CH:14]=1.[NH2:40][C:41]1[CH:45]=[CH:44][N:43]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[N:42]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[OH:49][C:47]([CH3:50])([CH3:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:41]([NH:40][C:36]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:39])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17]2)=[O:37])=[N:42]1
Reactant: CC(C)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)Cn1ccc(NC(=O)C2NC(CC(C)(C)CO)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 19.3 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (0.55 g, 0.92 mmol) was reacted with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (0.17 g, 1.1 mmol), EDCI (0.26 g, 1.38 mmol), HOBT (0.19 g, 1.4 mmol) and NEt3 (0.26 mL, 1.8 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.11 g, 20%).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH2:4][CH2:3]1.C(#N)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.Cl>CCOCC.CCCCCC>[ClH:19].[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]([O:14][C:27](=[O:28])[NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[C:10]([F:13])([F:11])[F:12])[CH2:6][CH2:7]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=S1(=O)CCN(C[C@H](O)C(F)(F)F)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCS(=O)(=O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
In a 10 mL round-bottomed flask, (S)-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-1,1,1-trifluoro-propan-2-ol (120 mg, 485 μmol) was combined with acetonitrile (5.00 ml) to give a colorless solution. 1-Chloro-4-isocyanatobenzene (74.5 mg, 485 μmol) was added and the resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and purified on a silica column (hexane to 60% EtOAc/hexane gradient) to afford an oil. This oil was dissolved in ether and hexane and a 4N HCl solution (0.2 ml) was added and the mixture concentrated to afford 50 mg of (4-chlorophenyl)-carbamic acid (S)-1-(1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl)-2,2,2-trifluoroethyl ester hydrochloride as a white solid. (M+H)+=401 m/e.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[O:9][C:8]1=[O:23]>O1CCOCC1.CN(C)C=O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[O:9][C:8]1=[O:23]
Reactant: O=C1OC(COc2ccc([N+](=O)[O-])cc2)CN1c1ccccn1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nc1ccc(OCC2CN(c3ccccn3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
To a solution of 4.64 g of 4-[3-(2-pyridyl)-2-oxooxazolidin-5-yl]methoxynitrobenzene in 50 ml of 1,4-dioxane and 150 ml of N,N-dimethylformamide, 0.47 g of 10% palladium carbon was added, followed by stirring for 2.5 hours at room temperature and 5 atm. pressure under a hydrogen stream. The reaction mixture was filtered and the filtrate was then concentrated under reduced pressure. Methanol was added to the residue and the crystals so precipitated were collected by filtration, whereby 3.41 g of the title compound were obtained (yield: 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:18])=[O:10])[CH2:6]1
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1OC1CN(C(N)=O)C1
Reaction time: 72 h
Yield: 77.6 %

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 2.8 mL (0.045 mole) of 57% ammonium hydroxide. After stirring for 72 h the reaction mixture was diluted with 200 mL of water and the precipitated product collected by filtration (3.6 g of pale yellow product). Recrystallization from benzene yielded 2.8 g (69.2%) of fine white crystals, mp 256°-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]1([NH:65][CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:63][CH2:62]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:65]([CH2:66][CH2:67][C:68]#[N:69])[CH:61]2[CH2:64][CH2:63][CH2:62]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: N#CCCNC1CCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.2 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 3-(cyclobutylamino)propionitrile (0.038 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.042 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C([CH:3]([C:9]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[S:11][N:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.C(Cl)(=O)C>C(O)C.C(OCC)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]2[S:11][N:10]=[C:9]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:13]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)C(C#N)c1nsc2ccc([N+](=O)[O-])cc12
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: CCOC(=O)Cc1nsc2ccc([N+](=O)[O-])cc12
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate (6.67 g, 0.0229 mol) is added to a solution of acetyl chloride (67.0 mL) in ethanol. The reaction mixture is refluxed overnight, cooled, and filtered to remove solids. The resultant filtrate is concentrated in vacuo to obtain a brown semi-solid. A mixture of the semi-solid in diethyl ether is stirred for two hours and filtered to obtain a solid. The solid is washed with diethyl ether and air-dried to give the title product as yellow crystals (1.04 g, mp 91-92° C.).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[CH:1]1([NH:6][C:21]([C:20]2[CH:24]=[CH:25][N:26]=[CH:27][C:19]=2[NH:18][C:16]([C:14]2[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=[C:10]([CH:7]3[CH2:9][CH2:8]3)[N:15]=2)=[O:17])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 18 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclopentylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (18%) as amorphous yellow solid.
Reaction SMILES: [C:1](C1C=C2C(=CC=1)C(=O)CCC2(C)C)#[CH:2].Br[C:17]1[CH:26]=[C:25]2[C:20]([C:21]([CH3:33])([CH3:32])[CH2:22][CH2:23][C:24]2=[C:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:19][CH:18]=1>>[C:1]([C:17]1[CH:26]=[C:25]2[C:20]([C:21]([CH3:33])([CH3:32])[CH2:22][CH2:23][C:24]2=[C:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:19][CH:18]=1)#[CH:2]
Reactant: CCC(CC)=C1CCC(C)(C)c2ccc(Br)cc21
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Product: C#Cc1ccc2c(c1)C(=C(CC)CC)CCC2(C)C

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 384 mg (1.25 mmol) of 7-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound R) was converted into the title compound using 2.1 g (21 mmol) of trimethylsilylacetylene, 12 mg (0.06 mmol) of cuprous iodide, 43 mg (0.06 mmol) of bis(triphenylphosphine)palladium(II) chloride and 70 mg (0.5 mmol) of potassium carbonate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[C:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)#[N:13]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(-c2ccccc2C#N)c1

Procedure:
In the same manner as in Example 2, 3-bromotoluene and 2-chlorobenzonitrile were reacted at 85° C. for 3 hours, and the reaction solution was analyzed by gas chromatography. The results are shown in Table 1.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: COC(=O)CS
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Methyl thioglycolate was dissolved in DMF (10 ml) and this mixture was cooled to 0° C. under an atmosphere of nitrogen. NaH (750 mg of 60% mineral oil dispersion, 18.1 mmol) was then added in one portion. After 5 min., the ice bath was removed and p-fluoroacetophenone (1 ml, 8.2 mmol) was added in one portion. The reaction mixture stirred at ambient temperature for 1 hr then diluted with ethyl acetate (50 ml) and washed with water. The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organics dried over MgSO4 and concentrated in vacuo to yield (4-acetyl-phenylsulfanyl)-acetic acid methyl ester, as a white waxy solid (1.48 g, 80%). 1H NMR (250 MHz, CDCl3): δ 7.80 (d, 2H, J=9.4), 7.32 (d, 2H, J=9.4), 3.71 (s, 2H), 3.67 (s, 3H), 2.50 (s, 3H). MS [EI+] 225 (M+H)+.
Reaction SMILES: ClC[Si:3](C)(C)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1.[C:15]([O-:18])(=O)[CH3:16].[K+].[CH3:20]S(C)=O>O>[CH3:20][C:15]([CH3:16])([SiH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)[OH:18]
Reactant: CS(C)=O
Reactant: CCOc1ccc([Si](C)(C)CCl)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCOc1ccc([SiH2]C(C)(C)O)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of chloromethyldimethyl(4-ethoxyphenyl)silane (0.55 gram), potassium acetate (0.47 gram) and 3 ml of DMSO was stirred for 1.5 hours at 90° C. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl ether. The ether extract was washed with saturated sodium chloride solution, dried, and concentrated. The residue (0.55 gram) was dissolved in 5 ml of ethyl ether. Lithium aluminum hydride (100 mg) was added to the resulting solution at 0° C. with stirring and the solution was stirred for 2 hours at the same temperature. After addition of a minimun amount of saturated ammonium chloride solution, the mixture was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography over silica gel (15 gram) using n-hexane:ethyl acetate (100:30) as the eluent to give the title compound as a white crystal. Yield 0.50 gram. Physicochemical data of the product is given in Table 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1.Cl.[N:16](OCCC(C)C)=[O:17].[OH-].[NH4+]>CCOC(C)=O.CCO.CC(O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:13]([NH2:14])=[C:12]([N:16]=[O:17])[CH:11]=[N:10]1
Reactant: CC(C)CCON=O
Reactant: Nc1ccnn1-c1c(F)cccc1F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Nc1c(N=O)cnn1-c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
To a solution of (2,6-difluorophenyl)-1H-pyrazol-5-amine (2.60 g, 13.3 mmol) in 8 mL of EtOAc and 4 mL of EtOH was added 8 mL of HCl in 2-propanol (5-6 N). The heterogeneous mixture was cooled with an ice-NaCl bath, and isopentyl nitrite (1.83 mL, 13.6 mmol) was added drop wise (within 10 min) to prevent the temperature from exceeding 10° C. After stirring for 15 min, the reaction mixture became homogeneous. Stirring was continued for a total of 40 min. The brown homogeneous solution was diluted with 150 mL of EtOAc, and neutralized with ammonium hydroxide. The EtOAc layer was separated and washed with brine to afford a rusty crystalline solid which was triturated with 15 mL Hexanes. The rusty solid was collected and dried in a vacuum oven at 45° C. for 2 h to afford 1-(2,6-difluorophenyl)-4-nitroso-1H-pyrazol-5-amine This crude material was used without further purification. MS (ES+): 225.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:14])([CH3:13])[C:8](=O)[CH2:9][C:10]#[N:11]>>[CH2:1]([N:4]1[C:10]([NH2:11])=[CH:9][C:8]([C:7]([CH3:14])([CH3:13])[CH3:6])=[N:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: C=CCNN
Product: C=CCn1nc(C(C)(C)C)cc1N

Procedure:
Allylhydrazine (70% in water, Wako) and 4,4-dimethyl-3-oxopentanenitrile (Aldrich) were processed as described for Example 30A to obtain the title compound. MS (ESI+) m/z 180 (M+H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[OH:13].[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCOC(C)=O>C1COCC1>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[O:13][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)ccc1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a ice cooled suspension of sodium hydride (60%, 1.3 g, 78.3 mmol) in THF (100 mL) is added a solution of 2-hydroxy-5-methylbenzoic acid methyl ester (10 g, 60 mmol) in THF (20 mL) and it is stirred at 0° C. Then a solution of methanesulfonyl chloride (8.2 g, 72 mmol) in THF (20 mL) is added dropwise. The reaction mixture is stirred at RT for 18 h. Then the reaction mixture is cooled in an ice bath and slowly ice is added to quench the reaction. EtOAc is used to extract. Brine is added to the aqueous phase and re-extracted with EtOAc. The combined organic phase is washed with water, brine, dried over NaSO4 and MgSO4, and concentrated to give the title compound as an oil. It is used directly in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N+:17]2[CH:18]=[CH:19][C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=3[CH:16]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(CCCCBr)cc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CC#N
Product: CCCCc1ccc(CCCC[n+]2ccc3c(c2)CCCC3)cc1
Product: [Br-]
Yield: 72 %

Procedure:
1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of tetrahydroisoquinoline (2 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no tetrahydroisoquinoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (72%). 1HNMR (300 MHz, CDCl3, ppm), 9.12 (s, 1H), 8.85 (d, J=6.0, 1H), 7.61 (d, J=6.0, 1H), 7.02-7.08 (m, 4H), 4.83 (t, 7.5, 3H), 2.92-2.94 (m, 4H), 2.61 (t, J=7.5, 2H), 2.54 (t, J=7.5, 2H), 1.90-2.04 (m, 2H), 1.80-1.90 (m, 4H), 1.62-1.69 (m, 2H), 1.53-1.62 (m, 2H), 1.29-1.37 (m, 2H), 0.90 (t, J=7.2, 3H). 13CNMR, 157.94, 144.18, 140.82, 140.64. 138.96, 138.37, 128.65, 128.48, 127.99, 61.16, 35.54, 34.99, 34.05, 31.56, 29.92, 27.98, 26.69, 22.74, 21.37, 14.33.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[I:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:12][CH:11]=1
Reactant: Cc1occc1CO
Reactant: Oc1ccc(I)cc1
Product: Cc1occc1COc1ccc(I)cc1

Procedure:
3-(4-Iodo-phenoxymethyl)-2-methyl-furan was prepared from (2-methyl-furan-3-yl)-methanol and 4-iodo-phenol in an analogous manner to that described in Example 14(a).