Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:11]=1.[C:27](=O)([O:30]C)[O:28][CH3:29]>>[CH3:29][O:28][C:27](=[O:30])[CH2:16][C:14]1[CH:13]=[C:12]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[N:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 3.0 mL, 5.4 mmol) was added slowly to a stirred solution of 2-Chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (545 g, 2.0 mmol) under N2 at −78° C. After 30 minutes dimethyl carbonate (400 μL, 4.0 mmol) was added. After stirring at −78° C. for an additional 30 minutes, the solution was allowed to warm up slowly and stirred at 0° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (4 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (40-80% CH2Cl2 in heptane) to give the product as an off white solid (520 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.29 Hz, 2H), 7.72 (d, J=8.29 Hz, 2H), 7.62 (s, 1H), 7.28 (s, 1H), 3.76 (s, 3H), 3.71 (s, 2H). MS m/e 330.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[C:13](=[O:14])[N:12]=[CH:11][C:10]([C:15]([OH:17])=O)=[C:8]3[S:9][C:5]=2[CH:4]=1.O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>CN(C)C=O>[NH:23]1[C:22]([NH:21][C:15]([C:10]2[CH:11]=[N:12][C:13](=[O:14])[N:7]3[C:6]4[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[S:9][C:8]=23)=[O:17])=[N:26][N:25]=[N:24]1
Reactant: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)sc1c(C(=O)Nc3nnn[nH]3)cnc(=O)n12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.52 g. 7-Methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid (prepared according to Example 1) in 150 ml. dimethylformamide are mixed with 7.14 g. N,N'-carbonyldiimidazole. The reaction mixture is subsequently stirred for 90 minutes at 100° C. and for 1 hour at ambient temperature, then mixed with 2.26 g. 5-aminotetrazole monohydrate and again heated for 3 hours at 100° C. The solvent is substantially removed in vacuo and the residue stirred with water. The precipitate consists of 5.2 g. N-(5-tetrazolyl)-7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxamide (75.7% of theory); m.p. 234°-235° C. (recrystallized from nitromethane).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>>[CH2:5]([O:4][CH2:3][CH2:2][N:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:21]([CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)=[O:22])[CH:6]=[CH2:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: C=CCOCCO
Product: C=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 4 using allyl hydroxyethyl ether and 1-(t-butoxycarbonyl)-4-(1 H-benzoimidazole-2-carbonyl)-piperidine to give the title compound.
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10][N:9]2C(=N[CH2:6][CH2:7][CH2:8]2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl.ClCC1C=NC=CC=1>C1C=CC=CC=1.C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH:26]([CH2:1][C:11]3[CH:10]=[N:9][CH:8]=[CH:7][CH:6]=3)[C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cl
Agent: ClCc1cccnc1
Solvent: c1ccccc1
Solvent: CC#N
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3cccnc3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.7 %

Procedure:
DBU (55 ul, 0.367 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (58.6 mg, 0.167 mmol) in benzene (16.0 ml) and acetonitrile (3 ml), under an atmosphere of argon. 3-(chloromethyl)pyridine hydrochloride (27.4 mg, 0.167 mmol) was then added. The reaction mixture was stirred at room temperature for 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (8.60 mg). 1H NMR (CDCl3): δ 1.40-1.80 (bm, 8H), 1.90 (m, 2H), 2.30 (m, 1H), 2.51 (m, 3H), 2.74 (d, J=17.27 Hz, 1H), 3.74 (m, 3H), 3.85 (s, 3H), 6.73 (d, J=8.32 Hz, 1H), 6.89 (m, 1H), 7.02 (s, 1H), 7.30 (m, 1H), 7.92 (m, 1H), 8.26 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(/C=C/C(=O)O)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/C(=O)NOC2CCCCO2)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid (338 mg, crude) in DMF (4 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (153 mg), HOBt (203 mg), and EDCI (233 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=90:10) to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) as pale yellow form.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[N:17]=[CH:18][N:19]2[C:24](=[O:25])[N:23]([CH2:26][S:27][CH3:28])[N:22]=[N:21][C:20]=12>CN(C=O)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[N:17]=[CH:18][N:19]2[C:24](=[O:25])[N:23]([CH2:26][S:27]([CH3:28])=[O:1])[N:22]=[N:21][C:20]=12
Reactant: O=S([O-])OO
Reactant: CSCn1nnc2c(-c3nc4ccccc4o3)ncn2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)Cn1nnc2c(-c3nc4ccccc4o3)ncn2c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
An aqueous solution (250 μL) of Oxone™ (54 mg, 0.195 mmol) was added to a stirred solution of 8-(benzo[d]oxazol-2-yl)-3-(methylthiomethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (25 mg, 0.0795 mmol) in DMF (1 mL) and the resulting suspension was stirred overnight. The mixture was poured into ice (10 g) and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give 19 mg of the title compound as a bright yellow solid (73% yield). δH (DMSO d6): 9.12 (1H, s), 7.89-7.94 (2H, m), 7.47-7.55 (2H, m), 5.66 (1H, d, J=13.2), 5.53 (1H, d, J=13.2), 2.80 (3H, s). LCMS: 97% pure at 4.63 min., m/z (ES+): 331.1 (MH+).
Reaction SMILES: [Na+].[S:2]1[C:6]2[CH:7]=[C:8]([S:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.N1C=CC=CC=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]([S:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[CH:3][S:2][C:6]=2[CH:7]=1)(=[O:13])=[O:12])([CH3:28])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=S([O-])c1ccc2ncsc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
The crude 1,3-benzothiazol-6-sulfinic acid sodium salt (1.1 g, 4.97 mmol) is suspended in DMF (15 mL). Pyridine (0.33 mL) and ethyl α-bromoisobutyrate (0.61 mL) are added. The reaction is stirred at 50° C. under nitrogen for 2 h. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with 2M aqueous HCl solution (20 mL). The acidic aqueous layer is back-extracted with ethyl acetate (2×20 mL). The combined organic extracts are washed with brine (20 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography of the residue (silica, eluent DCM, 30-40% ethyl acetate) afforded 0.85 g of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid ethyl ester. Yield: 66%, ES-MS: m/z 314 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.19 (3H, t, J=7.16 Hz), 1.67 (6H, s), 4.15 (2H, q, J=7.13 Hz), 7.99 (1H, dd, J=8.68, 1.79 Hz), 8.28 (1H, d, J=8.68 Hz), 8.54 (1H, d, J=1.48 Hz), 9.26 (1H, s);
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[CH2:4][N:3]1[CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl.[NH2:24][CH2:25][C@H:26]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[C@@H:26]([NH:34][S:35]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH2:25][NH:24][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][N:3]([CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:2]2=[O:1])=[O:12])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2)NS(=O)(=O)c1ccccc1

Procedure:
A DMF solution (10 mL) of acid 6-4 (382 mg, 1.28 mmol) 1-4 (517 mg, 1.54 mmol), HOBT (264 mg, 1.13 mmol) NMM (563 μl, 5.1 mmol) and EDC (331 mg, 1.73 mmol) was stirred under ambient conditions for 18 h. The DMF was removed at 50° C. and the residue partitioned between EtOAc and H2O. The organic layer was washed with sat. NaHCO3 solution, brine, and dried (MgSO4). Evaporation gave a yellow foam which was purified by flash chromatography (silica, 3:1 acetone/CH2Cl2) to provide 6-5 as a colorless foam.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1.[NH:21]([C:28]1[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([N:21]([C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=3[C:30]([O:32][CH3:33])=[O:31])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[O:13]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1Nc1ccccc1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Product: COC(=O)c1ccccc1N(c1ccccc1)C1(c2ccc(N(C)C)cc2)OC(=O)c2ccccc21
Yield: 28.1 %

Procedure:
Following a procedure similar to that described in Example 4 but employing 2.6 g of 2-[4-(dimethylamino)benzoyl]benzoic acid and 2.3 g of methyl 2-anilinobenzoate there was obtained 1.3 g of 3-[4-(dimethylamino)phenyl]-3-{[2-(methoxycarbonyl)phenyl]phenylamino}phthalide, m.p. 92.5°-102° C. A toluene solution of the product contacted with acidic clay developed a yellow-colored image.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[CH:28]=[C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:26]=[CH:25][C:22]=3[C:23]#[N:24])=[C:3]([CH3:19])[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (150 mg, 0.55 mmol), 2-amino-4-morpholinobenzonitrile (112 mg, 0.55 mmol) and a 4.0M solution of HCl in dioxane (0.028 mL, 0.11 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-((7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinyl)amino)-4-(4-morpholinyl)benzonitrile was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 8.87 (1H, dd, J=2.0, 0.5 Hz), 8.73 (1H, dd, J=4.9, 1.7 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.92 (1H, dd, J=9.3, 5.9 Hz), 7.80 (1H, dd, J=9.8, 2.4 Hz), 7.44-7.51 (2H, m), 7.33 (1H, ddd, J=9.2, 8.0, 2.6 Hz), 6.46 (1H, s), 6.43 (1H, dd, J=8.9, 2.3 Hz), 5.72 (1H, d, J=2.2 Hz), 3.63-3.76 (4H, m), 2.95-3.09 (4H, m), 2.35 (3H, s). Mass Spectrum (ESI) m/e=440.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[N:11]=1)([CH3:5])[CH3:4].BrCC(C1C=CC([C:28]#[N:29])=CC=1)=O.C1N=CN(C(N2C=NC=C2)=N)C=1>O1CCCC1>[NH:29]=[C:28]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[N:11]=2)[C:3]([CH3:5])([CH3:4])[CH2:2][O:1]1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: N=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Yield: 19 %

Procedure:
A mixture of 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.00 g, 7.31 mmol), prepared in the same manner as described in step 3 of Example 3, and replacing 3-(2-bromoacetyl)benzonitrile with 4-(2-bromoacetyl)benzonitrile, and C-(di-imidazol-1-yl)-methyleneamine (1.30 g, 8.07 mmol) in 35 mL of tetrahydrofuran was refluxed under nitrogen for three days. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of hexane in methylene chloride as the eluent gave the title compound (417.2 mg, 19%) as an off-white solid, mp 158-161° C.; MS (ES) m/z 299.0 [M+H]+. Anal. Calcd for C15H14N4OS: C, 60.38; H, 4.73; N, 18.78. Found: C, 60.38; H, 4.82; N, 18.67.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][C:6]#[CH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C1COCC1.CCCCCC>[Si:9]([O:8][CH2:3][CH2:4][CH2:5][C:6]#[CH:7])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a suspension of 18.0 g (749 mmol, 1.05 equiv.) of sodium hydride in 500 mL of THF at 0° C. was added a solution of 60.0 g (713 mmol, 1.00 equiv.) of 4-pentyne-1-ol in 150 mL of THF. When the addition was complete the reaction was allowed to warm to room temperature over one hour. To this mixture was added 113 g (749 mmol, 1.05 equiv.) of t-butyldimethylsilyl chloride in 150 mL of THF. The reaction was allowed to stir for 16 hours at room temperature then diluted with 1200 mL of hexane. The organic layer was washed with 500 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting liquid was distilled at 39°-42° C. at 0.05 mm Hg to yield 135 g (96%) of 1-t-butyldimethylsilyloxy-4-pentyne
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[Cl:16].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[CH3:17][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([Cl:16])[CH:4]=1
Reactant: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.5 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide (Example I13) (4.43 g) in butanone (80 ml) was added potassium carbonate (2.73 g) and methyl iodide (1.02 ml). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:5) to give of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (2.56 g). 1H-NMR (400 MHz, CDCl3): 7.55-7.15 (m, 3H), 3.55 (s, 2H), 1.98 (s, 3H), 0.00 (s, 9H) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:25][CH2:26][C:27]1[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33]>ClCCl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:25][CH2:26][C:27]2[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Cc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture of 4-benzoylbenzoic acid (106 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (152 mg, 1.5 mmol) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL). The organic phase was separated, dried over sodium, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-benzyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (50 mg, 29%). LRMS (M+H+) m/z: 346.17. found 346. HPLC purity (214 nm): 97%. 1H NMR (300 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.29 (t, J=4.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.28-7.13 (m, 7H), 5.85 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.96 (s, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1>CN(C=O)C.O>[CH:14]1([CH2:17][O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:16][CH2:15]1
Reactant: OCc1ccc2occc2c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc2cc(COCC3CC3)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzofuran-5-ylmethanol (1.0 g, 6.8 mmol), and sodium hydride (0.25 g, 10.0 mmol) in DMF (20 mL) was stirred at 0° C. for 30 minutes. Cyclopropylmethyl bromide (0.97 g, 7.0 mmol) was the added and resultant reaction mixture was slowly warmed to room temperature and left stirring over night. Reaction mixture was diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield the desired product after purification on silica (4/1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H), 7.44 (d, 1H), 7.27 (d, 1H), 6.76 (s, 1H), 4.62 (s, 2H) 3.37 (d, 2H), 1.41 (m, 1H), 0.58 (m, 2H), 0.21 (m, 2H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(C(C)=O)C(C)C.O>[C:19]1([CH2:18][N:3]2[CH2:4][CH2:5][S:1][C:2]2=[O:6])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCS1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1SCCN1Cc1ccccc1
Yield: 55.2 %

Procedure:
A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g of potassium carbonate, 1.8 g of potassium hydrogen carbonate, 0.5 ml of water, 30 ml of methyl isobutyl ketone and 3.0 ml (0.033 mol) of benzyl bromide is refluxed for 7 hours. After cooling down, the reaction mixture is washed twice with 30 ml of water each, the organic phase is dried and evaporated. The yellow oily product (which solidifies on standing) may be purified by column chromatography (by using Kieselgel 60 of 230-400 mesh as sorbent and chloroform as eluent) to give 3.2 g (55.2%) of the title compound, m.p.: 50°-51° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[NH:17][CH3:18])([O-])=O.C(O)(=O)C>[Fe].C(O)C>[CH3:18][NH:17][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([C:10]([F:11])([F:13])[F:12])=[CH:7][C:6]=1[NH2:14]
Reactant: CNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1c(N)cc(C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80.1 %

Procedure:
To a mixture of (2,6-dinitro-4-trifluoromethyl-phenyl)-methyl-amine (5.0 g), acetic acid (11 mL), ethanol (100 ml), and ice (20 g), iron powder (6.4 g) was added under ice-cooling. The reaction mixture was stirred at 0° C. for 3.5 hours, and filtered through Celite®. The resulting filtrate was concentrated under reduced pressure, and diluted with 1N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 3.1 g of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine. N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pt](=O)=O>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH:20]([CH3:38])[CH2:19][CH2:18][CH:17]([CH3:39])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: [H][H]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Solvent: C1COCCO1
Product: CC(CCC(C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 99.6 %

Procedure:
A solution of 593 mg (1.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl- 6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 15 ml dioxane was stirred with 25 mg (0.11 mmol) platinum (IV) oxide under 1 atm of hydrogen for 72 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and azeotroped three times with chloroform on a rotary evaporator to remove last traces of dioxane, then triturated in ether to afford 400 mg (100%) of the title compound as a white foam. MS m/e (%): 369 (M+H+, 100).