Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCCCN1CCN(CCO)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN3CCN(CCO)CC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(6-amino-hexyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.0 minutes. 1H NMR (400 MHz, CD3OD) δ 7.17 (d, 1H, J=6.4, 9.6 Hz), 7.01 (m, 1H), 5.44 (s, 2H), 3.64 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.8 Hz), 2.7-2.4 (bm, 8H), 2.50 (t, 2H, J=6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H), 1.35 (m, 4H) ppm; MS (APCl, m/z): 555 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CS(C)=O.[F:28][C:29]([F:35])([F:34])[S:30]([NH2:33])(=[O:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:28][C:29]([F:35])([F:34])[S:30]([NH:33][C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:32])=[O:31]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 13.7 %

Procedure:
According to Example 132, by use of 2-chloro-3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxaline (Compound BJ) (70 mg, 0.21 mmol), dimethyl sulfoxide (2 mL), trifluoromethanesulfonamide (31 mg, 0.21 mmol) and potassium carbonate (28 mg, 0.21 mmol), the mixture was stirred and reacted at 150° C. for 1.5 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution was added thereto, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 20/1). Further, slurry purification was performed using isopropyl ether, to give 1,1,1-trifluoro-N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)-ethoxy]quinoxalin-2-yl}methanesulfonamide (Compound 149) (13 mg, 14%).
Reaction SMILES: [CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8]2=[O:24])=[C:5]([CH3:25])[C:4](=[O:26])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:24])=[C:5]([CH3:25])[C:4](=[O:26])[O:3]1
Reactant: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)C(C)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(N2CCC3(CCNCC3)C2=O)C(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (195 mg, 0.535 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (2.06 mL, 26.8 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles the residue was dissolved in methylene chloride (1 mL) and treated with hydrogen chloride (4 mL, 1N in diethyl ether) and concentrated to give 2-(2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+1)+: 265.19.
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3](N)=[NH:4].[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[NH2:7][C:1]1[N:2]=[C:3]([NH2:4])[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15](=[S:16])[N:6]=1
Reactant: N=C(N)N=C(N)N
Reactant: S=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(N)n(-c2ccccc2)c(=S)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To 25 ml of dry dimethylformamide were dissolved 2.0 g of diguanide and 2.7 g of phenyl isothiocyanate and the solution was placed at 40°~50° C. for 30 minutes. The solution was added to 200 ml of ice water to produce white precipitates, which subsequently was filtered and dried to obtain 4.05 g of the title compound having the characteristics of:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([OH:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH2:2][C:3]3[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of 300 mg (0.91 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine and 199 mg (0.91 mmol) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester in 5 ml DMF was added 443 mg (136 mmol) cesium carbonate. The reaction mixture was stirred at RT for 3 h and then taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography with AcOEt/heptane 1:4 to provide 152 mg of pure {5-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18](OC)=[O:19])[CH:12]=[C:11]2[CH3:22]>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][OH:19])[CH:12]=[C:11]2[CH3:22]
Reactant: COC(=O)c1cc(C)c2cc(Br)ccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(CO)nc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere at 0C, 1.50 mL (1.50 mmol) of a lithium aluminum hydride solution (1M in THF) was slowly added to a solution of 0.65 g (2.32 mmol) of methyl 6-bromo-4-methylquinoline-2-carboxylate in 30 mL of THF and the mixture was stirred for 30 minutes at 0° C. A further 0.25 mL of lithium aluminum hydride solution (1M in THF) was added and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was combined with a few drops of EtOAc, worked up using the Fieser-Fieser method, and the precipitate was filtered off and washed with EtOAc. The filtrate was evaporated down in vacuo. Yield: 0.25 g (43% of theoretical); C11H10BrNO (M=252.107); calc.: molpeak (M+H)+: 252/254 (Br); found: molpeak (M+H)+: 252/254 (Br); Rf value: 0.25 (silica gel, PE/EtOAc 3:2).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]=[C:9]=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:17])=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCCCC2)c1N=C=S
Reactant: N
Solvent: CCO
Product: Cc1cccc(N2CCCCC2)c1NC(N)=S

Procedure:
Reaction of 6-methyl-2-piperidinophenyl isothiocyanate (6.8 g) with 25% aqueous ammonia solution (65 ml) in ethanol (20 ml) for 8 hours at room temperature gave 1-(6-methyl-2-piperidinophenyl) thiourea as a pale yellow solid (m.p. 197°-198° C.).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@@:11]2([F:20])[C:16]([O:18][CH3:19])=[O:17])(C(C)(C)C)(C)C.Cl>C(#N)C.CCOC(C)=O>[F:20][C@@:11]1([C:16]([O:18][CH3:19])=[O:17])[C@@H:12]2[C@H:10]1[C:9](=[O:8])[CH2:14][C@H:13]2[OH:15]
Reactant: COC(=O)[C@]1(F)[C@@H]2[C@H]1C(=O)C[C@H]2O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@]1(F)[C@H]2[C@H](O)CC(=O)[C@H]21

Procedure:
TBS-ether 6′ (150 mg, 0.528 mmol) was treated with 1 M HCl (0.106 mL) in acetonitrile (0.8 mL) at rt for 2 h. The reaction was diluted with EtOAc, quenched by addition of a small amount of saturated aq. NaHCO3, washed with H2O and brine (twice), and dried over Na2SO4. The solvents were removed under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to afford hydroxy ketone 7′ as colorless solid: 1H NMR (CDCl3, 400 MHz) δ 4.60 (d, J=5.2 Hz, 1H), 3.72 (s, 3H), 2.67 (dd, J=5.2, 3.6 Hz, 1H), 2.42 (dd, J=5.2, 2.4 Hz, 1H), 2.34 (dd, J=18.9, 5.2 Hz, 1H), 2.22 (br-s, 1H), 2.08 (d, J=18.9 Hz, 1H), 1.93 (dd, J=3.6, 2.4 Hz, 1H); 13C NMR (CDCl3, 101 MHz) δ 208.8, 169.8, 68.3, 52.5, 42.7, 36.2, 34.2, 25.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:6]=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:22]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]([NH:1][C:2]2[N:3]=[N:4][N:5]([CH2:7][C:8]([F:9])([F:11])[F:10])[N:6]=2)=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1nnn(CC(F)(F)F)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnn(CC(F)(F)F)n1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 146-148 and MS: (neg. ions): m/e=360.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8](/[CH:11]=[CH:12]/[C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:27]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O.O>[CH3:24][O:23][C:14]1[CH:15]=[C:16]([O:21][CH3:22])[CH:17]=[C:18]([O:19][CH3:20])[C:13]=1/[CH:12]=[CH:11]/[S:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([NH2:27])[CH:5]=1)(=[O:10])=[O:9]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-((E)-2-(4-methoxy-3-nitrobenzylsulfonyl)vinyl)-1,3,5-trimethoxybenzene (1.3 mmol) in acetone-water (10:5, 25 mL) was heated to 50° C. After 30 min, sodium hydrosulfite (Na2S2O4, 26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C.) for 1 h. The heated mixture was then cooled to room temperature (25° C.) and water (25 mL) was added. A solid precipitate formed and was separated by filtration. The filtered product was washed with aqueous sodium bicarbonate. The product was distributed between water and ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The ethyl acetate was removed under reduced pressure and the crude product obtained thereby was recrystallized from 2-propanol to yield the desired (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzenamine product. m.p. 148-150° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][C:20]=1[C:27]([F:30])([F:29])[F:28])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][C:20]=1[C:27]([F:29])([F:30])[F:28])[CH3:18]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1C(F)(F)F

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.26 g, 1.13 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained in Example (39e) (117.5 mg, 0.56 mmol), WSC hydrochloride (0.38 g, 1.98 mmol) and HOBT (76 mg, 0.56 mmol), to obtain 0.19 g of the title compound as a white foamy substance (79%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(Br)ccc2C12OCCO2
Yield: 85.7 %

Procedure:
Into the solution of 6-bromoindoline-2,3-dione (3.3 g) in Toluene (90 mL), was added Ethylene Glycol (9 g) and p-TsOH (555 mg). The reaction was heated to reflux and water was removed. After completion of the reaction, Toluene was removed, the residue was purified by silica gel column chromatography to provide 3.38 g of 6′-bromospiro[[1,3]dioxolane-2,3′-indolin]-2′-one. 1H NMR (400 MHz, Chloroform-d) δ 7.59 (br., 1H), 7.21 (d, J=1.1 Hz, 2H), 7.00 (s, 1H), 4.60-4.51 (m, 2H), 4.35-4.27 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][N:33]=[N+]=[N-])[CH:26]=1)[CH3:21].O>O1CCCC1>[CH2:20]([O:22][C:23](=[O:36])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:26]=1)[CH3:21]
Reactant: CCOC(=O)Cc1cccc(CCN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(CCN)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
Triphenylphosphine (3.88 g, 23.3 mmol) was added in one portion to a stirred solution of ethyl[3-(2-azidoethyl)phenyl]acetate (Preparation 57) (3.88 g, 16.6 mmol) in tetrahydrofuran (100 ml) at room temperature under nitrogen. The reaction was stirred for 18 hours and water (5 ml) added and the reaction heated at 50° C. for 4 hours, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in saturated aqueous sodium hydrogen carbonate (40 ml) and the aqueous extracted with dichloromethane (3×50 ml). The combined organics were dried (sodium sulfate), the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichlromethane:methanol (95:5, by volume) to give the title compound as a colourless oil (3.11 g). 1H NMR (400 MHz, CDCl3): δ 7.26-7.22 (1H, t), 7.13-7.08 (3H, t), 4.16-4.11 (2H, m), 3.58 (2H, s), 2.96-2.93 (2H, t), 2.74-2.71 (2H, t), 1.25-1.22 (3H, t) ppm. LRMS (electrospray): M/Z [M+H]+ 208, [M+NA]+ 230, [M−H]− 206.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[NH2:8]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(N)cc1F
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A mixture of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (12.0 g , 55.7 mmol), iron powder (10.3 g, 180 mmol) and ammonium chloride (14.5 g , 270 mmol) in 170 mL of ethanol and 50 mL of water is heated at reflux for 1.5 hours then filtered hot through a pad of Diatomaceous earth, washing with ethanol. The filtrate is cooled to room temperature and the precipitated solids are removed by filtration. The filtrate is concentrated to a small volume and partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to provide 9.45 g of 3-fluoro-4-(2-methoxyethoxy)aniline as a brown liquid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[N+:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([CH:5]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[CH3:2])[CH:18]=1
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: [Cl-]
Product: Cc1ccccc1C(c1cc(Cl)c2ccccc2c1O)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-methyl-benzylidene)-piperidinium chloride and 4-chloro-1-naphthol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].Cl[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].O>CN(C=O)C>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cccc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (14.27 g) in DMF (143 mL) was added sodium hydride (60% dispersion in mineral oil, 6.6 g) at 0° C., and the mixture was stirred under argon atmosphere at 0° C. for 2 hr. To the reaction mixture was added a solution of (2-(chloromethoxy)ethyl)(trimethyl)silane (27.5 g) in DMF (20 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:24][OH:25]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(Cl)cc1Cl
Yield: 79.3 %

Procedure:
To 0.32 g of N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]phthalimide in 15 ml of ethanol, 0.66 g of hydroxylamine hydrochloride was added and refluxed with heating for 4 hours with stirring. After completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was mixed with 30 ml of water and 50 ml of ethyl acetate, and the resulting organic layer was collected. The organic layer was washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was washed with 10 ml of hexane to obtain 265 mg of the desired product as yellow crystals.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([CH3:27])[C:14]([C:20]1[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=1)([OH:19])[C:15]([F:18])([F:17])[F:16]>CCCCCCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C@@H:13]([CH3:27])[C@:14]([C:20]1[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=1)([OH:19])[C:15]([F:18])([F:16])[F:17]
Reactant: Cc1cncc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)n1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1cncc([C@](O)([C@H](C)c2ccc(Cl)cc2Cl)C(F)(F)F)n1

Procedure:
These compounds were obtained by preparative HPLC (Column: Chiralpack AD; solvent: 1% isopropanol in heptane) from racemic 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-(6-methyl-pyrazin-2-yl)-butan-2-ol (Example 39).
Reaction SMILES: [CH2:1](O)C.C[O-].[Na+].[N:7]1[CH:8]=[CH:9][N:10]2[C:16]=1[CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[NH:12][C:11]2=[S:21].CI>O>[CH3:1][S:21][C:11]1[N:10]2[CH:9]=[CH:8][N:7]=[C:16]2[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1
Reactant: S=C1Nc2ccccc2Cc2nccn21
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSC1=Nc2ccccc2Cc2nccn21

Procedure:
Absolute ethanol (20,000 ml) is charged into a 20 gallon flask and stirred under nitrogen atmosphere; 517.62 g (9.58 moles) of sodium methoxide are added. After stirring for 30 minutes there is complete solution and 2,063 g (9.58 moles) of 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione are added. There is complete solution after stirring at room temperature for 1 hour. The solution is then cooled to 1°, and 1,360 g (9.58 moles) of methyl iodide are added over 30 minutes. The reaction mixture is stirred at 5° for 4 hours and at ambient temperature overnight. The turbid solution is then cooled to 5° and diluted with 50,000 ml of water. The resulting suspension is stirred for 4 hours at 5°. The solid is collected, and dried (5 mm Hg/60°) to give 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine, m.p. 87°-8°.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH2:13]([OH:16])[C:14]#[CH:15]>C1C=CC=CC=1>[OH:16][CH2:13][C:14]1[CH:15]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Yield: 23 %

Procedure:
4.8 g (0.03 mole) of 3-diazooxindole is suspended in 500 ml of benzene and 1.96 g (0.033 mole) of propargyl alcohol added. The reaction mixture is refluxed overnight under nitrogen, after which 19.6 g (0.33 mole) of propargyl alcohol is added and the reaction continued under reflux for a total of 48 hours. The tan solid which precipitates is filtered off (1.5 g, 23% yield), m.p. 272°-275° (sl. dec.). Recrystallization from methanol gives crystals of the title compound, m.p. 286°-288° (sl. dec.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1.[N+](C1C=CC([CH:36]2[S:40]/[C:39](=[N:41]\[C:42](=[O:44])[O-])/[N:38]([C:45]3[CH:50]=[C:49]([CH3:51])[CH:48]=[CH:47][C:46]=3[CH:52]([CH3:54])[CH3:53])[C:37]2=[O:55])=CC=1)([O-])=O>>[CH:52]([C:46]1[CH:47]=[CH:48][C:49]([CH3:51])=[CH:50][C:45]=1[N:38]1[C:37](=[O:55])[CH2:36][S:40]/[C:39]/1=[N:41]\[C:42](=[O:44])[N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:53])[CH3:54]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: CNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)N(C)CCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using N-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB24) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a pale orange foam (0.160 g, 63%).