Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[N:34]=[N:35]/[C:36]2[CH:41]=[CH:40][C:39](/[N:42]=[N:43]/[C:44]3[CH:49]=[CH:48][C:47](/[N:50]=[N:51]/[C:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[C:55]([OH:62])=[CH:54][CH:53]=4)=[CH:46][CH:45]=3)=[CH:38][CH:37]=2)=[CH:26][CH:25]=1.[OH2:63]>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:62][C:55]2[C:56]3[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:52](/[N:51]=[N:50]/[C:47]3[CH:46]=[CH:45][C:44](/[N:43]=[N:42]/[C:39]4[CH:38]=[CH:37][C:36](/[N:35]=[N:34]/[C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:24]([O:23][C:18](=[O:19])[C:17]6[CH:21]=[CH:22][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:16]=6)=[CH:25][CH:26]=5)=[CH:41][CH:40]=4)=[CH:49][CH:48]=3)=[CH:53][CH:54]=2)=[O:19])=[CH:21][CH:22]=1)(=[O:63])[C:2]([CH3:4])=[CH2:3]
Reactant: Oc1ccc(/N=N/c2ccc(/N=N/c3ccc(/N=N/c4ccc(O)c5ccccc45)cc3)cc2)c2ccccc12
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(/N=N/c3ccc(/N=N/c4ccc(/N=N/c5ccc(OC(=O)c6ccc(OCCCCCCOC(=O)C(=C)C)cc6)c6ccccc56)cc4)cc3)c3ccccc23)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1.28 g of 4-{[6-(methacryloyloxy)hexyl]oxy}benzoic acid (4.20 mM) were dissolved in 30 ml of THF and 4.00 g of triethylamine (40.00 mM). The solution was cooled to −30° C. and 0.48 g of methansulfochloride (4.20 mM) were added. The mixture was stirred for 0.5 h at this temperature, then 1.04 g of bis{4-[(E)-(4-hydroxy-1-naphthyl)diazenyl]phenyl}-(E)-diazene (2.00 mM) were added at once, followed by 50 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, the reaction mixture was poured onto 200 ml of water, the resulting suspension was stirred for 10 min. and the solids were filtered off, washed with water and dried. The resulting orange powder was boiled for 1 h in 25 ml of ethanol, cooled to room temperature and the solid was filtered off, washed with ethanol and dried to give 1.60 g (1.46 mM, 73%) of bis{4-((E)-{4-[(4-{[6-(methacryloyloxy)hexyl]oxy}benzoyl)oxy]-1-naphthyl}diazenyl)-phenyl}-(E)-diazene as orange crystals; λmax=428 nm, ε=52000 (THF).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][C@H:16]([CH3:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][C@H:16]([OH:15])[CH3:30])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:17].[Na+].C(Cl)(Cl)Cl.Cl>CC(C)=O.O>[CH3:4][C:5]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=2)=[O:7])=[CH:13][CH:12]=1)([C:6]([OH:7])=[O:17])[CH3:15]
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.6 %

Procedure:
A mixture of 4-chloro-4′-hydroxybezophenone (116 g, 0.500 mole) and sodium hydroxide (120 g, 3.00 mole) in acetone (1 L) was heated to reflux for 2 hours. The heating was stopped and the heating source was removed. A mixture of chloroform (179 g, 1.50 mole) in acetone (300 mL) was added drop-wise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and was acidified (to pH=1) with 1N hydrochloric acid. The precipitate, which formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL toluene each). After filtration and drying under high vacuum, the experiment produced fenofibric acid (116 g, 73% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:5])=[O:4].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:20])=[O:10])(=[O:4])=[O:5]
Reactant: CO
Reactant: CNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CNS(=O)(=O)c1cccc(C(=O)OC)c1
Yield: 53.5 %

Procedure:
3-(N-methylsulfamoyl)benzoic acid (200 mg, 0.929 mmol) was refluxed in the presence of concentrated sulfuric acid (6.01 mg, 0.046 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-(N-methylsulfamoyl)benzoate (120 mg, 0.497 mmol, 53.5% yield). 1H NMR (CDCl3, 400 MHz): δ 8.51 (m, 1H), 8.25 (m, 1H), 8.06 (dt, 1H, J=1.2 & 8.0 Hz), 7.63 (t, 1H, J=7.6 Hz), 3.96 (s, 3H), 2.69 (s, 3H). Mass [M+H]+: 230.1
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]([C:8](=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)s1
Reactant: O=Cc1cccc(F)c1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cccc(F)c1)C(=O)c1ccc(Br)s1
Yield: 98.1 %

Procedure:
A solution of ethyl 3-(5-bromothiophen-2-yl)-3-oxopropanoate (2.456 g, 8.86 mmol, from Preparation 1, Step 1), 3-fluorobenzaldehyde (1.034 ml, 9.75 mmol), piperidine (0.088 ml, 0.886 mmol) and acetic acid (0.389 ml, 6.8 mmol) in benzene (50 ml) was heated at 85° C. for 6 h using a Dean-Stark trap to remove the formed water. The reaction solution was concentrated. The crude product was dissolved in a small amount of toluene and charged to 80 g silica gel cartridge which was eluted with a 15 min gradient from 0-5% ethyl acetate in hexane to give ethyl 2-(5-bromothiophene-2-carbonyl)-3-(3-fluorophenyl)acrylate as a viscous yellow oil (3.33 g). HPLC: Rt 3.728 min (Method A); LCMS m/z 407.02, 405.02 (M+23)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].N1CCCC1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].CN(C=O)C>C(OCC)(=O)C>[CH3:23][N:24]([CH:26]=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CN(C)C=Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 19 h

Procedure:
Combine 1-methyl-2-nitro-4-trifluoromethoxybenzene (3.73 g, 16.86 mmol), pyrrolidine (1.32 g, 18.55 mmol), N,N-dimethylformamide dimethyl acetal (6.03 g, 50.58 mmol), and dry DMF (35 ml). Heat to about 105°. After 19 hours, remove the DMF under reduced pressure to give an oily residue. Combine the residue and ethyl acetate, wash with brine, dry (Na2SO4), then concentrate to give N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH2:19])[CH3:18])=[CH:7]2.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH:19][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:18])=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cscn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cscn1

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(thiazol-4-yl)-quinolin-3-yl)ethanamine (0.045 g, 0.155 mmol), 6-chloropurine (0.029 g, 0.19 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(8-chloro-2-(thiazol-4-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=16 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1H), 8.63 (s, 1H), 8.44-8.46 (m, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.88-7.93 (m, 2H), 7.56 (t, 1H), 1.77 (d, 3H), Mass Spectrum (ESI) m/e=408 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[S-:7][C:8]#[N:9].[K+].CC(C)=[O:13]>>[N-:9]=[C:8]=[S:7].[CH2:1]([O:3][C:4](=[O:5])[OH:13])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)Cl
Reactant: N#C[S-]
Agent: [K+]
Product: CCOC(=O)O
Product: [N-]=C=S
Reaction time: 2 h
Yield: 32 %

Procedure:
218 g of freshly distilled chloroformic acid ethyl ester were added to 200 g (2 mols) of potassium thiocyanate in 800 ml of acetone at 60°-70° C and the mixture was stirred for 2 hours. The solids which had been separated out were then filtered off, the solvent was evaporated off and the residue was distilled at 55° C and 12 mm Hg. 84 g (32% of theory) of carbonic acid ethyl ester isothiocyanate were obtained.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:16][C:17]1[CH:26]=[CH:25][C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=1>C(Cl)Cl.CCN(CC)CC.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:26]=[CH:25][C:20]([N:21]([CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)=[CH:5][CH:4]=2)[CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=1
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: O=Cc1ccc(-c2ccc(CO)s2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(Cc1ccc(-c2ccc(C=O)cc2)s1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 20 %

Procedure:
To a stirred solution of the product of Step A (0.436 g, 2 mmol) in anhydrous CH2Cl2 (10 ml) and Et3N (0.3 ml) mesyl chloride (0.4 ml) was added at 0° C. and stirring was continued for 1 h. The solvents were evaporated to dryness under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to give the crude product (0.63 g) as pale paste, which was taken up in anhydrous toluene and 4-fluoro-N-isopropylaniline (0.5 ml) was added to it. The mixture was stirred overnight at reflux and the solvent was evaporated. The residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.14 g, 20%), as light creamy paste. 1H-NMR (CDCl3) 9.98 (s, 1H); 7.82 (d, 2H, J=8.31 Hz); 7.66 (d, 2H, J=8.31 Hz); 7.28 (d, 1H, J=3.69 Hz); 6.93-6.86 (m, 3H); 6.81-6.76 (m, 2H); 4.79 (s, 2H); 4.08-3.99 (m, 1H); 1.22 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:32]=[C:33]([F:39])[C:34]=1[O:35][CH2:36][C:37]#[CH:38])[C:23]([N:25]1[CH:31]2[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:24].[Cl-].[NH4+]>O1CCCC1>[F:1][CH:31]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:25][C:23](=[O:24])[C:22]1[CH:21]=[C:20]([F:19])[C:34]([O:35][CH2:36][C:37]#[CH:38])=[C:33]([F:39])[CH:32]=1
Reactant: [F-]
Reactant: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At room temperature, 1.2 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added dropwise to a mixture of 4 ml of tetrahydrofuran and 291 mg of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane. This mixture was stirred at room temperature for 1 hour. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.13 g of N-(2-fluorocyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 114 of the present invention) represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][C:44]2[O:45][C:41]3[C:40]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=3[N:43]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCOCC2)c2oc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2oc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-morpholin-4-yl-benzooxazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 372 (M+H+, 100).
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl>>[N+:18]([C:14]1[CH:13]=[C:12]([CH:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)NC(=S)NC(CO)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: NC1=NC(c2cccc([N+](=O)[O-])c2)CS1
Temperature: 100 °C
Yield: 90.3 %

Procedure:
The process is performed as in Example 2, starting with 1.49 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea in 14 cm3 of aqueous 6 N hydrochloric acid by heating to a temperature in the region of 100° C. for 2 h 30 min. By means of an identical work-up, 1.01 g of 4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of a cream-colored solid melting at 232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([O:13][CH3:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.C([O-])(=O)C.[Na+].[I:22]Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([I:22])=[C:9]([O:13][CH3:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.25 h

Procedure:
To a suspension of 8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (3.00 g) in glacial acetic acid (250 mL) was added sodium acetate (2.07 g) followed by iodine monochloride (15.2 mL). The mixture was heated to reflux for 1.5 hours, was allowed to cool, and the acetic acid was evaporated from the reaction mixture. The solid residue was suspended in tetrahydrofuran and stirred for 15 minutes. The solution was filtered and the resulting filtrate evaporated. The yellowish solid was recrystallized from refluxing toluene (700 mL) to afford the title compound (3.8 g); 250 MHz NMR: 11.60 (broad s, 1), 7.59 (d,1, J=7.1), 7.30 (d,1, J=1.4), 7.23 (dd,1, J=7.1, 1.6), 3.90 (s,3). Analysis for C11H7ClINO3 : Calculated: C, 36.34; H, 1.94; N, 3.85; Found: C, 36.35, H, 1.87; N, 3.82.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][C:21]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)cc2)[nH]1
Reactant: ClSc1ccc(Cl)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Sc2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
A solution of p-chlorophenylsulfenyl chloride (0.80 g, 4.48 mmol) in methylene chloride is added dropwise over 20 minutes to a stirred solution of 2-(p-chlorophenyl)-5-trifluoromethylpyrrole (1.0 g, 4.07 mmol) in methylene chloride. The reaction mixture is stirred at room temperature for 90 minutes, diluted with methylene chloride, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.96 g, mp 39°-54° C.).
Reaction SMILES: C[O-].[Na+:3].[Na].O.[CH3:6][O:7][Si:8]([O:13]C)([O:11][CH3:12])[O:9][CH3:10]>CO>[CH3:6][O:7][Si:8]([O:11][CH3:12])([O:9][CH3:10])[O-:13].[Na+:3]
Reactant: CO[Si](OC)(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CO[Si]([O-])(OC)OC
Yield: 96.4 %

Procedure:
A solution of 81 gm (1.5 mol) of sodium methylate in methanol, prepared by reacting 34.0 gm (1.5 mol) of sodium with 500 ml methanol, was mixed with 27.0 gm (1.5 mol) of water and subsequently with 1000 gm (6.6 mols) of tetramethoxy-silane. The mixture was heated for about 15 minutes under reflux. Then methanol and excess tetramethoxy-silane were distilled off under water jet-vacuum. 231.5 gm of sodium trimethoxy-silanolate were obtained. Theoretically 240.3 gm (1.5 mol) of this compound should have been formed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C@@H:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CN(C1C=CC=CN=1)C>C1COCC1.C(N=C=NC(C)C)(C)C>[CH3:22][C@H:23]([O:20][C:19]([CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH2:15]1)=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC[C@@H](C)O
Reactant: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCC[C@H](C)OC(=O)C1CCc2cc(OCc3ccccc3)ccc2C1
Reaction time: 24 h
Yield: 53 %

Procedure:
To a solution of 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (31) (1 equi.), (R)-1-methylheptyl-1-ol (13) (1 equi.), and DMAP (dimethylaminopyridine) (0.1 equi.) in THF (25 mL/mmole), DIC (diisopropyl carbodiimide) (1.2 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (3% EtOAc/hexanes) gave 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (1S)-1-methylheptyl ester (36) as a colorless oil (53%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].[OH-].[Li+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][O:9][C:7]([NH:6][CH2:5][CH:4]([CH3:19])[C:3]([OH:20])=[O:2])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C)CNC(=O)OCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(COC(=O)NCC(C)C(=O)O)cc1
Yield: 97.3 %

Procedure:
A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methyl ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treated with lithium hydroxide (1.3 equivalents) at room temperature for a period of 2 h. The solution was concentrated in vacuo and the residue taken up in a mixture of water and ether and the phases separated and the organic phase discarded. The aqueous phase was acidified with aqueous potassium hydrogen sulfate to pH=1.5 and then extracted three times with ether. The combined ethereal phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.60 g, 97% of N-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which was purified by recrystallization from a mixture of ethyl acetate and hexane to give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. 1H NMR (D6-acetone/300 MHz) 1.16 (3H, d, J=7.2 Hz), 2.70 (1H, m), 3.31 (2H, m), 3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH2:16]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.O>O1CCCC1>[CH2:16]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 40.9 %

Procedure:
Analogously to the preparation of Example 1, 14.4 g (0.07 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted at room temperature with 26.56 g (0.077 mol) of 4-dodecylbenzenesulfonyl chloride in 100 ml of tetrahydrofuran in the presence of 10.6 g (0.105 mol) of triethylamine. For working-up, the reaction mixture is poured into water and extracted several times with methylene chloride. After drying over magnesium sulfate, the solvent is distilled off in a rotary evaporator. The brown oil that remains is then purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:1). 14.75 g (41%) of α-(4-dodecylphenylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of a viscous yellow oil. The 1H-NMR spectrum shows that it is the (syn) isomer. The UV/Vis spectrum (acetonitrile) shows an absorption band at 350 nm (ε=10700) that extends to 435 nm. Elemental analysis: C28H38N2O5S
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=1)=[O:5].[CH3:20][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:18][Si:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH3:20])[CH:7]=[N:8]1
Reactant: CON(C)C(=O)c1cnn(COCC[Si](C)(C)C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
N-Methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (325.8 mg, 1.14 mmol) in tetrahydrofuran (2 mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 4.32 mL, 4.23 mmol) under cooling with ice and the reaction mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1, to ethyl acetate/MeOH=20/1) to give the desired product (89.9 mg, 33% yield).