Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH3:18][N:19]=[C:20]=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:12])[S:10][N:19]([CH3:18])[C:20]2=[O:21])=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Agent: [K+]
Product: Cn1sc(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
Reagents: 4-Fluorophenyl isothiocyanate (1.1 g, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), methyl isocyanate (0.38 ml, 6.5 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][F:21]>CN(C=O)C>[F:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCF
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (100 g, 66.0 mmol, 1.0 equiv; commercially available) in anhydrous DMF (40 mL) was added K2CO3 (13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2 mg, 72.0 mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. The K2CO3 was removed by filtration and the organic phase concentrated under reduced pressure. To the residue was added a sat. solution of NaCl (100 mL) and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product crystallized from a mixture of isopropanol/diethyl ether to yield 12.69 g (97%) of the title compound. 1H NMR (300 MHz, DMSO): δ 3.89 (s, 3H), 4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 9.84 (s, 1H). MS (ISP): 198.6 [M+H]+.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[CH3:9][C:10]([Si:13]([CH3:34])([CH3:33])[O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]1[CH2:27]OS(C)(=O)=O)([CH3:12])[CH3:11]>C1COCC1>[CH3:11][C:10]([Si:13]([CH3:34])([CH3:33])[O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]1[CH3:27])([CH3:9])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
Superhydride (45.8 mL, 1M, 45.8 mmol) was added dropwise to an ice cold solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate (4.69 g, 11.47 mmol) in THF. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was quenched with i-propanol until gas evolution ceased. The reaction was diluted with saturated NaHCO3 then extracted with ethyl acetate, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to yield the title compound (2.69 g, 8.5 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.0 (s, 6H), 0.8 (s, 9H), 1.0 (m, 3H), 1.4 (s, 9H), 1.6 (m, 1H), 2.0 (m, 1H), 3.3 (m, 2H), 3.5 (m, 1H), 4.0 (m, 1H). ES+=316.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9](SC)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:21](CC)C(C)C)(C)C.N.O>CN1CCCC1=O.ClC1C=CC=C(C(OO)=O)C=1>[NH2:21][C:9]1[N:8]=[C:7]([NH:14][CH2:15][CH2:16][CH3:17])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNc1nc(N)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 11.7 g) in N-methylpyrrolidone (90 mL), meta-chloroperbenzoic acid (70 to 75% wt, 20.8 g) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, N,N-diisopropylethylamine (23.9 mL) and 10% aqueous ammonia (60.0 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water (400 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 8.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Li])CCC.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 1-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran was cooled to -65° and 61.5 ml of 2.1M solution of n-butyllithium in hexane was added dropwise over a period of 15 minutes. The mixture was stirred for 15 minutes and a solution of 16.44 ml of chlorotrimethylsilane in 68 ml of tetrahydrofuran was added dropwise over a period of 15 minutes. The mixture was then allowed to warm up to room temperature overnight and evaporated to dryness. Ethyl ether was added, the solids were filtered off, the filtrate was evaporated to dryness and the residue was distilled to give 1-ethoxycarbonyl-4-trimethylsilylpiperazine, b.p. 102°-107°/0.1 mm/Hg.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:24]=[N:23][C:11]2[O:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[CH:24]=[N:23][C:11]2[O:12][CH2:13][CH2:14][NH:15][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cnc2c(c1)NCCO2
Temperature: 40 °C
Reaction time: 24 h
Yield: 20.3 %

Procedure:
To a suspension of tert-butyl 7-(tert-butylcarbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (1.425 g, 4.25 mmol) in DCM (5 mL) and DMF (5 mL) was added TFA (3 mL, 38.9 mmol). The reaction was stirred at 40° C. for 24 h. Additional TFA (2.2 mL, 28.5 mmol) was added to consume unreacted starting material. The reaction was allowed to stir at room temperature for 2 h. A further addition of TFA (4.4 mL, 57.0 mmol) was performed and the reaction was allowed to stir for 2 h. Upon consumption of the starting material the reaction mixture was concentrated in vacuo and purified by flash column chromatography using a gradient elution of DCM and 2-8% MeOH spiked with 1% TEA. The eluant was evaporated to yield an orange oil. The oil was treated with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to provide N-tert-butyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (203 mg, 0.864 mmol, 20% yield 3 steps) as a white solid. LCMS (+ESI) m/z=236.1 [M+H]+;
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[CH2:31]([O:36][C:37](Cl)=[O:38])[CH2:32][CH2:33][CH2:34][CH3:35]>O1CCOCC1>[CH2:31]([O:36][C:37](=[O:38])[NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:22]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cn1cncc1C(=NOCc1nccc(N)n1)c1ccccc1
Reactant: CCCCCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)Nc1ccnc(CON=C(c2ccccc2)c2cncn2C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 9.5 %

Procedure:
To a solution of 2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.65 mmol) in 1,4-dioxane (10 mL) were sequentially added triethylamine (0.18 mL, 1.30 mmol) and chloroformic acid pentyl ester (0.38 mL, 2.60 mmol). After stirring at room temperature for 19 h, the mixture was concentrated in vacuo, diluted in ethyl acetate (50 mL), washed with water (20 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification on silica gel afforded pentyl{2-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}carbamate [26 mg, yield 9%; HPLC/MS: m/z=423 (M+H); log P(HCOOH)=2.66].
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Br:10][CH2:11][C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=O>>[BrH:10].[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:8][CH:11]=[C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[N:9]=2)[CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1cccnc1
Product: Br
Product: CCOC(=O)c1ccc(-c2csc(-c3cccnc3)n2)cc1
Yield: 67 %

Procedure:
In the same manner as in Example 28, thionicotinamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(3-pyridyl)-4-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 67%. Pale yellow prisms. Melting point: 234 to 236° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1.C(NC(=O)C(F)(F)F)CC1C=CC=CC=1.C(O)(C(F)(F)F)=O>O1CCCC1.[Ru]>[F:14][C:2]([F:1])([F:13])[CH:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][NH:4]1
Reactant: FC(F)(F)C1=NCCc2ccccc21
Agent: [Ru]
Agent: O=C(NCCc1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1NCCC2CCCCC21

Procedure:
20 g (0,101 mol) of 1-(Trifluoromethyl)-3,4-dihydroisoquinoline [prepared from N-(phenethyl)trifluoroacetamide analogously to U.S. Pat. No. 3,956,333 (11.5.76; Sterling Drug Inc.)] were hydrogenated in 100 ml of tetrahydrofuran on 5 g of ruthenium on alumina (about 10% Ru content) at 150° C. for 8 h at an H 2 pressure of 100 bar in a 0.3 1 V4A autoclave. After filtration, the THF was stripped off and the crude product was fractionareal in a water pump vacuum by means of a microdistillation apparatus. B.p.16 (main fraction): 94°-96° C. Yield: 19 g (0.092 mol) (91% of theory) The product was obtained as a diastereomer mixture. 19F--NMR: δ=+5.9 ppm(d, JH-F =8.5 Hz)(according to integral about 99%) 19F--NMR: δ=+14.2 ppm(d, JH-F =8.5 Hz) (according to integral <1%) (against external CF3COOH).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=1)(=[O:26])=[O:27])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
2-Aminobenzophenone (20 mg) was dissolved in 1 mL of methylene chloride and 4-nitrobenzenesulfonyl chloride (34 mg, 1.5 equiv) was added thereto followed by pyridine (16 mL, 2 equiv). After 10 minutes the reaction mixture was oncentrated in vacuo, subjected to flash chromatography (eluting with 0% to 25% EtOAc/hexane) to provide N-(2-benzoylphenyl)-4-nitrobenzenesulfonamide. ESMS, M+H+ found: 383.1.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6](=[O:8])[CH3:7])[CH2:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:40][N:41]1[CH2:46][CH2:45][C:44]2([CH2:55][C:54]3[C:49](=[N:50][CH:51]=[C:52](/[CH:56]=[CH:57]/[C:58](O)=[O:59])[CH:53]=3)[NH:48][C:47]2=[O:61])[CH2:43][CH2:42]1>CN(C)C=O>[C:6]([CH:4]1[CH2:5][N:2]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:52]2[CH:53]=[C:54]3[C:49](=[N:50][CH:51]=2)[NH:48][C:47](=[O:61])[C:44]2([CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]2)[CH2:55]3)[CH2:3]1)(=[O:8])[CH3:7]
Reactant: CC(=O)C1CNC1
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Azetidin-3-yl)ethanone hydrochloride (110 mg, 0.8 mmol), EDCI (153 mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol) and diisopropylethylamine (700 μL, 4.0 mmol) were successively added to a solution of (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (136 mg, 0.4 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (9:1:0.1) as eluent. Precipitation in a mixture DCM/pentane allowed isolation of the title product as a yellow solid (44.6 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[Cl-:18].[CH3:19][N+:20](=[CH2:22])[CH3:21]>C(#N)C>[ClH:18].[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][CH:8]([CH2:19][N:20]([CH3:22])[CH3:21])[C:7]1=[O:11]
Reactant: [Cl-]
Reactant: C=[N+](C)C
Reactant: COc1ccc(C=C2CCCC2=O)c(OC)c1
Solvent: CC#N
Product: COc1ccc(C=C2CCC(CN(C)C)C2=O)c(OC)c1
Product: Cl
Yield: 73.3 %

Procedure:
0.03 mol of 2-(2,4-dimethoxybenzylidene)cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was then suction filtered, dried and recrystallized in acetonitrile/chloroform to give 2-(2,4-dimethoxybenzylidene)-5-dimethylaminomethyl-cyclopentanone hydrochloride with a yield of 73.3%.
Reaction SMILES: C([Li])CCC.[S:6]1[CH2:10][CH2:9][S:8][CH:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>C1COCC1.C(OCC)C>[C:20]([CH2:19][CH2:18][CH2:17][C:7]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:8][CH2:9][CH2:10][S:6]1)#[N:21]
Reactant: N#CCCCBr
Reactant: CCOC(=O)C1SCCS1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCC#N)SCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (6.5 mL, 1.6 M in hexane) was added to a solution of ethyl 1,3-dithiolane-2-carboxylate (1925 mg, 10 mmol) in THF (10 mL) at −78° C. under N2. The reaction mixture was stirred for 30 min at −78° C. and then 4-bromobutanenitrile (1469 mg, 10 mmol) in THE (10 mL) was added. The mixture was warmed to room temperature and stirred for 30 min. It was diluted with diethyl ether and washed with 1 N HCl and H2O, and dried. Evaporation and purification by column chromatography afforded ethyl 2-(3-cyanopropyl)-1,3-dithiolane-2-carboxylate: LCMS tR=1.86 Min (5 min run, UV254nm), Mass calculated for, M+259.0, observed LC/MS m/z 260.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=1[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
Ethyl 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoate (704 mg) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and lithium hydroxide monohydrate (333 mg) was added to the solution, and then the mixture was stirred at 60° C. for 3 hours. After the organic solvent was distilled off, the mixture was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (606 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:39]2[CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35][C:34]=2[N:33]=[C:32]([CH2:42][N:43]([CH3:56])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[N:31]=1>>[CH3:41][C:37]1([CH3:40])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:42][NH:43][CH3:56])[N:31]=[C:30]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:39]=2[CH2:38]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CN(Cc1nc(Cl)c2c(n1)CCC(C)(C)C2)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CNCc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and N-((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)-N-methyl-2-nitrobenzenesulfonamide (reagent preparation 17) in step 3 followed by 2-nitrobenzenesulfonyl-group deprotection. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (br s, 1H), 8.06 (br s, 1H), 7.75 (d, 1H), 7.53 (dd, 1H), 7.01 (d, 1H), 4.68 (s, 2H), 4.33-4.27 (m, 2H), 3.91-3.85 (m, 2H), 3.48 (s, 2H), 2.68 (t, 2H), 2.54 (s, 3H), 2.45 (s, 2H), 2.12 (s, 3H), 1.59 (t, 2H), 0.87 (s, 6H); MS (EI) for C28H33N7O: 484 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)=[CH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[CH:16][N:15]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)=[CH:21][C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])=[CH:16][N:15]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)nc2)cc1OC
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Oc3ccc(Cl)cc3)nc2)cc1OC

Procedure:
In dimethylformamide (20 ml) was dissolved 4-chlorophenol (330 mg). To the solution was added, while stirring, 60% sodium hydride (dispersion in paraffin) (103 mg). When exothermic reaction and evolution of hydrogen gas ceased, 4-[3-(2-chloro-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (500 mg) and cuprous iodide (24 mg) were added to the reaction mixture, followed by stirring for 5 hours at 150° C. The reaction mixture was poured into water, which was subjected to extraction with dichloromethane. The extract solution was dried over anhydrous magnesium sulfate, which was then concentrated. The concentrate was purified by means of a silica gel column chromatography (eluted with ethyl acetate) to obtain 4-[3-(2-(4-chlorophenoxy)-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No. 3 ) (420 mg) as a resinous solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].[Al+3].[Cl-:7].[Cl-].[Cl-].[C:10]([SiH:14]([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].COC1C=CC=CC=1OC>>[CH3:1][SiH:2]([CH3:5])[Cl:3].[C:10]([Si:14]([CH3:16])([CH3:15])[Cl:7])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Cl-]
Reactant: C[SiH](C)C(C)(C)C
Agent: [Al+3]
Solvent: COc1ccccc1OC
Product: CC(C)(C)[Si](C)(C)Cl
Product: C[SiH](C)Cl
Reaction time: 1 h

Procedure:
A four-necked flask equipped with a condenser, thermometer, dropping funnel, and stirrer was charged with 129.1 g (1.0 mol ) of dimethyldichlorosilane and 1.3 g (0.01 mol) of AlCl3, which were agitated with the stirrer. To the flask at room temperature, 58.2 g (0.5 mol) of t-butyldimethylsilane was added dropwise over one hour. Thereafter, agitation was continued for one hour while the flask was kept at 30° C. 2.8 g (0.02 mol) of o-dimethoxybenzene was added to the reaction solution which was agitated for a further one hour. Dimethylchlorosilane and t-butyldimethylchlorosilane were isolated from the reaction solution by distillation. There were obtained 42.8 g of dimethylchlorosilane and 69.0 g of t-butyldimethylchlorosilane in a yield of 91% and 92%, respectively.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][S:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[CH:21]([C:26](Cl)=[O:27])[CH2:20][CH2:19][C:18]2=[O:29]>C(N(CC)CC)C>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Cl:25])[CH:21]([C:26]([N:9]1[CH2:10][CH2:11][S:12][CH2:13][CH:8]1[CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:27])[CH2:20][CH2:19][C:18]2=[O:29]
Reactant: O=C1CCC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: C1CCN(CC2CSCCN2)CC1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CCC(C(=O)N2CCSCC2CN2CCCCC2)c2cc(Cl)c(Cl)cc21
Yield: 121.1 %

Procedure:
The procedure described in Example 24 was repeated, but using 2.0 g of 3-(piperidinomethyl)thiomorpholine, 2.2 ml of triethylamine and 3.52 g of 6,7-dichloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 3.67 g of the title compound, melting at 245°-254° C. (dec.).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].N[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1.C1([N:30]=C=NC2CCCCC2)CCCCC1>O.CN(C)C=O>[CH3:2][N:3]([CH2:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[C:12]([NH2:30])[CH:11]=1)=[O:6])[CH3:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CN(C)CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(C(=O)CN(C)C)cc1N
Reaction time: 2 h
Yield: 67 %

Procedure:
In 1 ml of water was dissolved 0.7 g of N,N-dimethylglycin hydrochloride. This solution was mixed with a solution of 1.0 g of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone in 20 ml of dimethylformamide. To this mixture was added under ice-cooling 1.2 g of dicyclohexylcarbodiimide, and the reaction was effected for 2 hours. The reaction mixture was allowed to stand for 2 days in a cool place and concentrated under reduced pressure. Water was added to the residue and any insoluble matter was eliminated by filtration. Sodium hydrogen carbonate was added to the filtrate to make it alkaline whereby crystals were precipitated which were then recrystallized from methanol-water to obtain 950 mg of the end product. M.P. 195°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17]O)([O-:3])=[O:2].C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:17][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl

Procedure:
To a round bottom flask equipped with a nitrogen inlet and a water cooled condenser, 2-nitro-5-phenoxy-phenyl-methanol (2.7 g, 11.1 mmol) and triethylamine (4.7 mL, 33.9 mmol) were dissolved in dichloromethane (100 mL). Methane sulfonyl chloride (2.6 mL, 33.3 mmol) was added to the reaction mixture which was subsequently heated to reflux for 16 h. The next day the reaction was removed from the heating source, allowed to cool and poured into a separatory funnel which contained a water solution of 1N HCl. The organic phase washed 2 times with 1N HCl and one time with saturated brine solution. The phases were separated and the ethyl acetate layer was dried with sodium sulfate, filtered and the solvent removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes:ethyl acetate as the mobile phase (9:1) to yield a residue.