Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.CCCCCC>C1COCC1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH:5]([CH2:3][OH:2])[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and crystallization from diethyl ether/hexane yielded the title compound, white solid, m.p. 82° C. and MS: m/e=350 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:16]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)c1
Reactant: O=[Se]=O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
Meta-phenoxytoluene is oxidized by selenium dioxide in the presence of a dehydration agent to yield meta-phenoxy-benzaldehyde containing less than 250 ppm dissolved selenium at a selectivity based on the toluene of about 90% or better.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1
Reactant: COc1cccc([C@@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 35 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-methoxyphenyl)piperidin-1-yl]-methanone (21 mg, 0.059 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 7.0 mg of the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C:15]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[CH2:16][N:17]=2)=[CH:9][C:8]=1[Br:30])(=O)=O.[NH3:31].CO.COC(C)(C)C>C1COCC1>[Br:30][C:8]1[CH:9]=[C:10]([C:13]2[CH2:14][C:15]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:20])([F:19])[F:21])[CH2:16][N:17]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][NH2:31]
Reactant: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl methanesulfonate (1.0 g) in THF (5 ml) was added dropwise to a mixed solution of aqueous ammonia (30%, 30 ml), methanol (30 ml) and THF (30 ml), and the reaction mixture was stirred for 20 hours at room temperature. The mixture was concentrated under reduced pressure to give residual material. The residue was dissolved with t-butyl methyl ether and washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After separating the drying agent by filtration, the reaction liquor was distilled off under reduced pressure, to obtain 1-{2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]phenyl}methanamine (0.8 g).
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[OH-].[Na+]>O>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:19][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
A mixture of N-(3-hydroxypyridin-4-yl)-4-nitrobenzamide (260 mg, 1 mmol) and polyphosphoric acid (1.5 mL) was stirred at 150° C. for 6 hrs. The reaction mixture was poured into water and sodium hydroxide was added until pH=5. The precipitate was collected by filtration, washed with water until neutral and dried to give 2-(4-nitrophenyl)oxazolo[5,4-c]pyridine as brown solid (177 mg, yield: 73%). 1HNMR (400 MHz, DMSO-d6) δ: 9.21 (1H, s), 8.62 (1H, d, J=4.8 Hz), 8.51 (4H, d, J=18, 8.8 Hz), 7.95 (1H, d, J=5.2 Hz).
Reaction SMILES: I[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[N:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].O.ClCCl>CN(C)C=O>[N:14]([CH:2]1[C:8](=[O:9])[NH:7][C:6]2[N:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ncccc2CCC1I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NC1CCc2cccnc2NC1=O
Temperature: 20 °C
Yield: 94.9 %

Procedure:
To 333 mg of the intermediate obtained in Step G in 6 mL of dimethylformamide (DMF) was added 600 mg of sodium azide. The mixture was stirred at 20° C. 20 h before addition of water and extraction with dichloromethane. The extracts were combined and dried over sodium sulfate. Evaporation of the solvent gave 223 mg of the product characterized by its NMR and mass spectra.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7]([Cl:16])=[O:8]
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(C)cc(OCC(=O)Cl)c1

Procedure:
To a solution of 3,5-dimethylphenoxyacetic acid (9.0 g, 50 mmole) in benzene (100 mL) was added thionyl chloride (10.89 mL). The resulting mixture was refluxed for 2 hr, then the benzene was removed by distillation. The residual material was dried in vacuo to give 3,5-dimethylphenoxyacetyl chloride, which was dissolved in 20 ml of acetonitrile and used in situ. L-Glutamic acid (8.8 g, 60 mmole) was dissolved in a solution of sodium carbonate (12.72 g, 150 mL, 120 mmole) and the 3,5-dimethylphenoxyacetyl chloride in the acetonitrile solution was slowly added while the pH 8 was adjusted from time-to-time by adding sodium carbonate solution. The reaction mixture was stirred at room temperature for 2 hr, and acidified to pH 2 to give a solid precipitate. The solid precipitate was collected by filtration, treated with hot benzene, filtered, again and washed again with benzene to give Intermediate 31 (9.2 g).
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[NH2:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH2:23]C)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22]>C(O)C>[C:1]([NH:3][CH:4]=[N:8][C:9]1[N:13]2[CH:14]=[CH:15][C:16]3[C:21]([C:12]2=[N:11][C:10]=1[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])#[N:2]
Reactant: CCOC=NC#N
Reactant: CCc1nc2c3cccc(Cl)c3ccn2c1N
Solvent: CCO
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=CNC#N
Temperature: 25 °C
Reaction time: 45 h
Yield: 37.7 %

Procedure:
Ethyl N-cyanoformimidate (3.2 g) was added to a suspension of 3-amino-7-chloro-2-ethylimidazo[2,1-a]isoquinoline (2.3 g) in ethanol (60 ml) and the mixture was stirred at room temperature for 45 hours. The mixture was evaporated in vacuo and the residual solid was washed successively with diethyl ether and ethyl acetate to give N-cyano-N'-(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)formamidine (1.0 g).
Reaction SMILES: CO[C:3](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[NH:14][C:13]1=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[N:25]1([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:3](=[C:12]3\[C:13](=[O:24])[NH:14][C:15]4[C:20]\3=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=4)/[C:4]3[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: COC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccc(OC)cc1
Product: COc1ccc(/C(Nc2ccc(CN3CCCCC3)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 39d from 3-[1-methoxy-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone and 4-piperidinomethyl-aniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:18]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[N:12][N:13]([CH3:18])[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 0.25 h

Procedure:
3-Nitro-(1H-tetrazol-5-yl)benzene (0.99 g) was added at 0° C. to a magnetically stirred suspension of sodium hydride (243 mg, 60% oil dispersion) in 50 ml of dry tetrahydrofuran. The reaction mixture was stirred for 15 minutes and then iodomethane was added in 6 increments of 0.5 ml over a 3 hour period. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (50 ml) and ethyl acetate. The aqueous layer was extracted (2×15 ml) with ethyl acetate and the combined organic extracts were washed with brine, dried, and concentrated. The title compound was obtained as a solid after flash chromatography on silica gel (chloroform-methanol, 95:5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[NH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:22]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][C:13](=[O:15])[CH3:14])=[CH:18][CH:19]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Product: COc1ccc(C=Cc2ccc(OC(C)=O)cc2)c(N)c1

Procedure:
Synthesized from 4-bromo-3-nitroanisole (2.3 g) and 4-acetoxystyrene (1.7 ml) according to an analogous synthetic method to Example 107, the title compound (1.2 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH:91]1[CH2:96][CH2:95][O:94][CH2:93][CH2:92]1>CCOC(C)=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O1CCOCC1>[O:94]1[CH2:95][CH2:96][N:91]([C:2]2[CH:3]=[C:4]3[C:15]4([CH2:19][S:18][C:17]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:92][CH2:93]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(N3CCOCC3)cc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A vial was charged with 3-bromo-7-(pyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.080 g, 0.117 mmol), palladium diacetate (2.62 mg, 0.012 mmol), sodium tert-butoxide (0.071 ml, 0.583 mmol), and xantphos (0.013 g, 0.023 mmol). Dioxane (1.166 ml) and morpholine (0.030 ml, 0.350 mmol) were added sequentially and the reaction was stirred at 100° C. for 24 hours. The mixture was cooled to RT and was diluted with EtOAc (20 mL) and washed with water. The aqueous layer was extracted with EtOAc (3×15 mL), and the combined organic layers were, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 12 g, gradient elution 0-100% EtOAc:Hex) to afford 3-morpholino-7-(pyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as an off-white solid.
Reaction SMILES: [OH-].[K+].C(O)C.[NH2:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>O>[N:21]1[CH:22]=[CH:23][C:18]([O:16][C:9]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:7]([CH:8]=2)[NH2:6])=[CH:19][CH:20]=1
Reactant: Clc1ccncc1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Oc2ccncc2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A solution of 0.1 m. of potassium hydroxide in water is added to an ethanol (100 ml.)-water (175 ml.) mixture containing 15.4 g. (0.1 m.) of 3-amino-4-nitrophenol. The mixture is then heated to 50°C. at which point a solution of 0.1 m. of 4-chloropyridine in 75 ml. of ethanol is added dropwise over a 45 minute period. Then the mixture is heated at reflux for 18 hours, cooled and worked up to give a crystalline yellow solid, m.p. 170°-175°C. of 5-(4-pyridyloxy)-2-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[P:11](OCC)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(Cc1c(Cl)cccc1Cl)OCC

Procedure:
2,6-Dichlorobenzyl chloride (1200 grams) and triethyl phosphate (1115 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated for a period of 60 minutes until the temperature reached 195° C. After this time the mixture was cooled and thereafter distilled under reduced pressure to yield the desired product O,O-diethyl 2,6-dichlorobenzylphosphonate having a boiling point of 158° to 168° C. at 0.4-0.6 mm of Hg pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[CH:20]([OH:25])[C:21]([CH3:24])([OH:23])[CH3:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[C:20](=[O:25])[C:21]([OH:23])([CH3:22])[CH3:24]
Reactant: CC(C)(O)C(O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(O)C(=O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Reaction time: 2 h
Yield: 20.1 %

Procedure:
0.15 g of 1-[2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl]-2-methyl-propane-1,2-diol was dissolved in 10 ml of dichloromethane, and 0.20 g of Dess-Martin reagent was added thereto at 0° C. After 2 hours of stirring, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 0.03 g of 1-[2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl]-2-hydroxy-2-methyl-propan-1-one (Compound Number 398).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[C:34]([O:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:27])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
iv)—A solution of the aldehyde (12.3 g) mentioned above in dry pyridine (150 ml) was cooled to 4° C. Benzoyl chloride (8 ml) was added in 5 min. and the reaction mixture was stirred for 1.5 h at room temperature. Then it was poured into water (2 l) and the resulting mixture was stirred overnight. The product was extracted into dichloromethane and the combined organic phases were concentrated under reduced pressure to give (3β,5α,20R)-3-(benzoyloxy)-4,4,20-trimethylpregna-8,14-diene-21-carboxaldehyde (16.1 g). The product was used in the following step without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7].[C:9](OC(=O)C)(=[O:11])[CH3:10]>O>[C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)CCCCBr
Solvent: O
Product: CC(=O)NC(=O)CCCCBr
Temperature: 25 °C
Yield: 53 %

Procedure:
A stirred solution of 100 g. (0.55 mole) of 5-bromovaleramide, 62.4 g. (0.61 mole) of acetic anhydride, and 5.4 g. (0.055 mole) of concentrated sulfuric was heated on a steam bath under nitrogen for 1.5 hours (internal temperature 93°). The mixture was then cooled to room temperature diluted with 250 ml. of water. The resultant tan granular precipitate was collected by filtration and dissolved in 600 ml. of methylene chloride. The solution was washed with saturated sodium bicarbonate (100 ml.) and saturated brine (100 ml.), was dried (anhydrous magnesium sulfate), treated with Darco, and filtered. Hexane was added to effect crystallization which afforded 64.8 g. (53.0% yield) of N-acetyl-5-bromovaleramide melting at 88°-90° .
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:15][CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCC1CCOC1
Product: N#Cc1c(OCC2CCOC2)cccc1[N+](=O)[O-]
Yield: 48 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and 3-hydroxymethyltetrahydrofuran in 48% yield as an orange-red solid. 1H NMR (400 MHz, DMSO-d6) δ 1.68 (m, 1H), 2.00 (m, 1H), 2.70 (m, 1H), 3.54 (m, 1H), 3.66 (m, 1H), 3.76 (m, 2H), 4.03 (m, 1H), 4.19 (m, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.90-7.95 (m, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26]>C(Cl)(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][S:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCNS(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(N-Boc-4-piperidinyl)ethyl-amine (1-6) (0.45 g, 2.0 mmoles) in CHCl3 (20 ml) was treated with added triethylamine (0.405 g, 4.0 mmoles) followed by 3-chlorosulfonylbenzoyl chloride (3-1) (0.44 g, 2.0 mmoles) and the resulting solution was stirred at room temperature for 16 hours. The solvent was then removed and the residue was taken up in EtOAc and washed with H2O, 10% KHSO4 solution, brine and dried (Na2SO4). Solvent removal provided a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (95)/MeOH(5) to give pure 4-1.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1cccc(CN)c1
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1cccc(CNc2cccn3nc(Cl)nc23)c1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol), and 3-methoxy-benzylamine (1.26 mL, 9.72 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white solid, (1.90 g. 77%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.08 (d, J=6.4 Hz, 1H), 7.24 (m, 2H), 6.96 (s, 3H), 6.79 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 4.44 (d, J=5.9 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:3]([NH2:4])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Agent: II
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1F
Temperature: 120 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a stirred suspension of compound 2 (0.100 g, 0.570 mmol, 1.00 equiv) in dry DMSO (4.6 mL) were added 4-fluorobenzylamine (0.210 g, 1.72 mmol, 3.00 equiv) followed by Et3N (69.6 mg, 0.690 mmol, 1.20 equiv) and I2 (catalytic, 1.00 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 24 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.100 g, 62.5%) as yellow solid. TLC: 20% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J=1.60, 9.60 Hz, 1H), 7.31-7.28 (m, 2H), 7.08-7.03 (m, 2H), 6.11-6.03 (m, 3H, 2Exc), 4.82 (br s, 1H, Exc), 4.44 (d, J=5.2 Hz, 2H); LC-MS: m/z=278 (M+-1) at RT 3.64 (91.7% purity)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: C1=COCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
to a vigorously stirred solution of N-hydroxyphthalimide (10.0 g, 61.4 mmol) in CH2Cl2 (70 mL) and dioxane (80 mL) was added dihydropyran (6.16 mL, 67.6 mmol) and p-toluenesulfonic acid (200 mg). The resulting solution was stirred overnight at room temperature. The reaction was quenched by slow addition of saturated NaHCO3 (100 mL). After separation, the organic layer was washed with brine and dried over Na2SO4. Solvent removal under vacuum yielded 13.4 g (88%) of 2-(tetrahydro-2H-pyran-2-yloxy)isoindoline-1,3-dione as a white solid.