Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH2:13][C:14](OC)=[O:15])[CH:10]=[CH:11][CH:12]=1.[BH4-].[Li+].O>ClCCl>[OH:15][CH2:14][CH2:13][C:9]1[CH:8]=[C:7]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1cccc(N2CCNC2=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Product: O=C1NCCN1c1cccc(CCO)c1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
Methyl [3-(2-oxo-1-imidazolidinyl)phenyl]acetate was dissolved in dry dichloromethane (10 vol). Lithium borohydride (2M solution in THF, 4.3 vol) was added dropwise over 1 hour at 20° C. The resulting suspension was stirred at 20° C. for 2.5 hours. Water (2 vol) is added dropwise at 20° C. over 60 minutes. The resulting suspension was concentrated to 2 vol and aqueous ammonium chloride solution (7%, acidity corrected with 10% hydrochloric acid to pH 3, 3 vol) was added. The suspension was stirred at 20° C. for 2 hours then filtered. The filter-cake was washed thoroughly with aqueous ammonium chloride solution (7%, acidity corrected with 10% hydrochloric acid to pH 3, 2 vol) and water (2 vol) until the filtrate had an acidity of pH 7. The filter-cake was dried at 80° C. to give the title compound (75% th.).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH2:7]1.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:26][N:25]=[C:16]([C:13]1[S:12][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2]([F:23])([F:1])[F:22])[CH2:7]2)=[N:15][CH:14]=1)[NH2:17]
Reactant: NO
Reactant: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carbonitrile (370 mg, 1.1 mmol), hydroxylamine hydrochloride (303 mg, 4.4 mmol) and sodium carbonate (231 mg, 2.2 mmol) in EtOH—H2O (4:1, 20 mL) was heated at 80° C. for 2 h. Solvent was evaporated in vacuo. The residue was diluted with H2O, extracted three times with EtOAc, dried (Na2SO4) and concentrated. Trituration with hexanes:Et2O (1:1) gave the title compound as white powder. 1H NMR (400 MHz, acetone-d6): δ 8.73 (s, 1 H), 7.66 (m, 2 H), 7.52 (s, 1 H), 7.38 (d, 1 H), 7.16 (t, 1 H), 5.46 (m, 3 H), 3.94-3.88 (m, 1 H), 3.75-3.59 (m, 3 H), 2.56-2.30 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]=O)=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:22][CH:23]=1)[S:6]([C:9]1[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])(=[O:7])=[O:8]
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCC=O)cc2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCCN3CCCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.1 %

Procedure:
To a solution of N-(2-chloro-4-hydroxy-benzyl)-2,4,6-trimethyl-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.040 g, 0.08 mmol) in 0.5 mL methylene chloride was added piperidine (0.009 g, 0.11 mmol) and NaB(OAc)3H (0.034 g, 0.16 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% methanol/methylene chloride) afforded 0.052 g of the title compound. MS 541.1 (M+1)+
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12](=[O:19])[C:13](=[CH:17][CH:18]=2)[C:14](O)=O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].S(Cl)([Cl:24])=O.[ClH:26]>ClCCl>[ClH:24].[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12](=[O:19])[C:13](=[CH:17][CH:18]=2)[CH2:14][Cl:26])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CC)c1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)c1cccc(-c2ccc(CCl)c(=O)[nH]2)c1
Reaction time: 8 h

Procedure:
A suspension of 3.0 g. (10.48 mmoles) of 6-[m-(diethylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid in 50 ml. dichloromethane under nitrogen is treated with 0.85 ml. (11.54 mmoles) of thionyl chloride. Solution occurred at once and in about 15 minutes a solid started to appear. The suspension is allowed to stire at room temperature overnight. The solid 6-[m-(diethylamino)-phenyl]-1,2-dihydro-2-oxonicotinyl chloride, hydrochloride is collected and washed with dichloromethane. There is obtained 3.28 g. of the acid chloride, hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH:8]=[N:7][C:6]=12.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CN1CCCC1=O>[CH2:26]([NH:33][C:10]1[N:5]2[N:4]=[CH:3][C:2]([Br:1])=[C:6]2[N:7]=[CH:8][C:9]=1[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(c1cnc2c(Br)cnn2c1Cl)N1CCC(c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
3-Bromo-7-chloro-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (3.0 g, 7.2 mmol) obtained in step 3 was dissolved in N-methylpyrrolidinone (30 mL), benzylamine (2.0 mL, 17.9 mmol) was added, and the mixture was stirred at 70° C. for 2 hr. 10% Aqueous citric acid solution (10 mL) and water (100 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed with water (50 mL) to give the title compound (3.2 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].O>C(#N)C>[C:24]1(=[O:33])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(OCCCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Methyl 3-hydroxybenzoate (3.0 g, 19.7 mmol) was dissolved in 50 mL of acetonitrile and K2CO3 (3.27 g, 23.7 mmol) was added. The resulting mixture was reacted with N-(4-bromobutyl)phthalimide (6.68 g, 23.7 mmol) and KI (3.93 g, 23.7 mmol) and stirred overnight at 70° C. Following the addition of water, the resulting mixture was extracted with chloroform. The organic layer was washed with brine. The organic layer was dried with sodium sulfate and then concentrated under reduced pressure, followed by recrystallization with n-hexane/ethyl acetate to give a white crystal (6.60 g, 94.8%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([CH2:16][CH2:17][CH2:18][OH:19])[CH:7]=1)=[O:4].NC1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]([F:20])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([CH2:16][CH2:17][CH:18]=[O:19])[CH:7]=1)=[O:4]
Reactant: O=C(Nc1cc(CCCO)cc(C(F)(F)F)c1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: O=CCCc1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 42 %

Procedure:
2,2,2-Trifluoro-N-[3-(3-hydroxypropyl)-5-(trifluoromethyl)phenyl]acetamide (240 mg, 0.76 mmol) prepared by a method similar to that in the above “intermediate aniline: Synthesis 6” was dissolved in dichloromethane (5 mL), and Dess-Martin periodinane (355 mg, 0.84 mmol) was added thereto under ice-cooling. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 14 hours. The reaction solution was partitioned between a saturated sodium bicarbonate solution (30 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated brine and then concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=1:1) to give 2,2,2-trifluoro-N-[3-(3-oxopropyl)-5-(trifluoromethyl)phenyl]acetamide (100 mg, 42%) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.CN([C:15](=[CH2:18])[C:16]#[N:17])C>CO>[NH2:17][C:16]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[N:10]=[CH:18][CH:15]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C=C(C#N)N(C)C
Agent: Cl
Solvent: CO
Product: Nc1ccnn1-c1ccc(Cl)cc1

Procedure:
21.5 g (0.12 mol) of 4-chlorophenylhydrazine hydrochloride was suspended in 150 mL of methanol, 5 mL of concentrated hydrochloric acid was added, and the mixture was heated at reflux, which gave a clear, yellow-brown solution. To this solution was added dropwise 11.5 g (0.12 mol) of dimethylaminoacrylonitrile over a period of 30 minutes. After 1.5 h at reflux, most of the solvent was removed under vacuum. The remaining residue was taken up in 40 mL of dimethylformamide, and 9 mL of concentrated ammonia solution was added at room temperature. The resulting white precipitate was filtered off and discarded. The clear filtrate was used in Step 10.2 without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:14])[CH2:12][CH3:13])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+].C(O)(=O)C>O>[CH3:13][CH:12]([C:11]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)=[O:14])[C:15]([O:16][CH3:17])=[O:18]
Reactant: CCC(=O)c1c(C)nn2ccccc12
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)C(=O)c1c(C)nn2ccccc12

Procedure:
2-Methyl-3-propionylpyrazolo[1,5-a]pyridine (5.28 g) was dissolved into dimethyl carbonate (100 ml), and, after adding sodium hydride (3.37 g), the mixture was refluxed for 8 hours under heat. Under cooling in water bath, acetic acid was added, then, following dilution with water, the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate:n-hexane=1:3˜1:1) to obtain aimed product (5.13 g) as a yellow oily product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>C(Cl)Cl>[CH3:5][O:6][C:7]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1O
Solvent: ClCCl
Product: COc1c(O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 29562.2 %

Procedure:
Fuming HNO3 (0.34 mL, 0.008 mmol) was carefully added to a mixture of 2-methoxyphenol (0.886 mL, 0.008 mmol) in anhydrous DCM (10 mL) at −20° C. After stirring for 2 h at RT, the mixture was concentrated under vacuum. Chromatography (10-30% EtOAc/hexanes) provided 9A12 (400 mg, 29%) and 2-methoxy-3-nitrophenol (400 mg, 29%).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([O:7][CH2:6][CH2:5][CH2:4][NH2:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCCOCc1ccccc1
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A 60% sodium hydride dispersion in mineral oil (4 g, 0.1 mol) in a small portion at room temperature was added to a stirred solution of 3-amino-1-propanol (7.51 g, 0.1 mol) in THF (150 mL). The mixture was stirred for 30 min under nitrogen, and benzyl bromide (11.9 mL, 0.1 mol) was added. The mixture was stirred for 10 h at room temperature, and concentrated in vacuo. The residue was partitioned between 1 N aqueous HCl solution and CH2Cl2. The aqueous layer was adjusted to pH 10 with 10% aqueous NaOH solution, and extracted with CH2Cl2 (3×100 mL). The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1 to 2:1, v/v) to give 3-(benzyloxy)propylamine (1.37 g, 8.3%) as a yellow oil. 1,3-Dicyclohexylcarbodiimide (14.4 mg, 0.07 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise to a mixture of 5 (32 mg, 0.07 mmol) and 3-(benzyloxy)propylamine (11.6 mg, 0.07 mmol), and 1-hydroxybenzotriazole hydrate (9.5 mg, 0.07 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 18 h at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (30:1, v/v) to afford 8 (36 mg, 85%) as a pale yellow liquid. 1H NMR (CDCl3) δ 8.05 (s, 1H, H4), 7.44 (d, 1H, H5, J=8.7 Hz), 7.19-7.28 (m, 11H, H6+2×OCH2Ph), 6.78-6.82 (m, 3H, H2′+H5′+H6′), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=6.9 Hz, J=1.5 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.2 Hz, J=1.5 Hz), 4.45 (s, 4H, 2×OCH2Pb), 4.38 (s, 2H, 2-CH2OBn), 3.55 (m, 4H, 3-CONHCH2CH2CH2OBn), 1.87 (quintet, 2H, 3-CONHCH2CH2CH2OBn. J=6.3 Hz); MS (FAB, positive) m/z 604 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
4.00 g of methyl 3-(hydroxymethyl)benzoate was dissolved in 80 mL of methylene chloride, to which 9.47 g of triphenylphosphine was added in small portions in an ice bath followed by addition of 12.00 g of carbon tetrabromide in small portions, and this solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to yield 5.02 g of methyl 3-(bromomethyl)benzoate as colorless oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:22][CH3:23])[CH2:12][C:13](=[O:21])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=1.O>C(O)(=O)C>[Cl:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:22][CH2:23][N:1]=[O:3])[CH2:12][C:13](=[O:21])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:7]=1
Reactant: O=N[O-]
Reactant: CNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite, 21.26 g (0.308 m) was added over a period of 20 min to a stirred solution of 71 g (0.237 m) of 7-chloro-3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one in 500 ml of acetic acid. Following the addition, the mixture was stirred for 1 hr at room temperature and was then diluted with 1.5 l. of water. The precipitated product was collected, washed with water and dissolved in methylene chloride. The solution was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was crystallized from ether to yield yellow crystals with mp 121°-124°. A second crop was obtained from the mother liquor.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>FC(F)(F)S(O)(=O)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[I:1]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
N-Iodosuccinimide (1.71 g, 7.60 mmol) was added to a solution of 1-chloro-4-nitrobenzene (1.17 g, 7.42 mmol) in trifluoromethanesulfonic acid (10 ml) at 0° C., then stirred 1 hour at room temperature. The reaction was quenched with ice-water and extracted with MeCl2 (3×50 ml). Organics were combined washed with 10% sodium bisulfite (20 ml) then dried over Na2SO4, filtered and evaporated solvent yielding the title compound as a white solid (1.3 g, 62%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[O:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[CH2:39][S:40]([CH2:42][CH2:43][N:44]1[CH:48]=[CH:47][N:46]=[N:45]1)=[O:41]>C(OCC)(=O)C.ClCCl>[CH3:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=3)[O:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[CH2:39][S:40]([CH2:42][CH2:43][N:44]1[CH:48]=[CH:47][N:46]=[N:45]1)(=[O:6])=[O:41]
Reactant: Cc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1CS(=O)CCn1ccnn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1CS(=O)(=O)CCn1ccnn1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
35 mg (0.15 mmol) 75% 3-chloroperoxybenzoic acid dissolved in 5 ml ethyl acetate were given at −30° C. to solution of 52 mg (0.10 mmol) 1-[2-(2-methyl-4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl-methanesulfinyl)-ethyl]-1H[1,2,3]triazole in 25 ml dichloromethane. The mixture was stirred for 48 h and slowly allowed to reach room temperature. Additional 20 ml dichloromethane were added, washed with conc. sodium carbonate solution, water, dried and evaporated to give 29 mg (53%) of the title compound.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:11]=[C:12]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:13]=1)=[O:7]>O.C1COCC1>[CH2:19]([N:18]1[C:14]([C:12]2[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH:11]=2)=[N:15][N:16]=[N:17]1)[CH3:20]
Reactant: CCn1nnnc1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCn1nnnc1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of LiOH.H2O (39.1 mg, 0.931 mmol) in H2O (8 mL) was added dropwise to a suspension of 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (200 mg, 0.621 mmol) in THF (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the mixture turned clear. THF was removed under vacuum and the aqueous solution was acidified by 10% HCl to pH=3. The precipitate was collected and dried to afford 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid as white solid (162 mg, 84%). MS (M+H)=309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:39](S(C(F)(F)F)(=O)=O)[S:40]([C:43]([F:46])([F:45])[F:44])(=O)=[O:41]>C(Cl)Cl.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][NH:30][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:41])=[O:39])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.3 %

Procedure:
A solution of 2-[10a-(4-chloro-benzene sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethylamine (71 mg, 0.168 mmol) in CH2Cl2 (5 mL) at −78° C. was treated with 2,6-lutidine (33 μL, 0.284 mmol), Tf2O (45 μL, 0.948 mmol) and warmed slowly to ambient temperature. After 17 h, the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative-chromatography over silica gel (eluted in hexanes/EtOAc 1:1) to afford the title compound (29 mg, 30%): 1H NMR (CDCl3 400 MHz) δ 7.61 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.08 (m, 1H), 6.44 (m, 1H), 5.22 (dd, J=11.7, 2.9 Hz, 1H), 4.12 (d, J=11.7 Hz, 1H), 3.57 (m, 3H), 3.01 (m, 1H), 2.56 (m, 1H), 2.33 (m, 1H), 1.91 (m, 2H), 1.56 (m, 1H), 1.15 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7]>>[C@@H:2]([O:5][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[C:11]#[N:12])([CH2:3][CH3:4])[CH3:1]
Reactant: CC[C@H](C)O
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC[C@H](C)Oc1cccc([N+](=O)[O-])c1C#N
Yield: 85.2 %

Procedure:
Prepared as in Example 111c from (S)-butan-2-ol and 2,6-dinitrobenzonitrile in 85.2% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (t, J=7.6 Hz, 3H), 1.29 (d, J=6.4 Hz, 1H), 1.69 (m, 2H), 4.72 (m, 1H), 7.74 (dd, J=6.8, 2.4 Hz, 1H), 7.86 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([N:15]([CH2:18]C)[CH2:16][CH3:17])C>>[CH3:18][N:15]([CH3:13])[C@@H:16]1[CH2:17][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:1][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
This titled amide was prepared from the trans-diamine and 4-nitrobenzoylchloride according to general procedure B using p-nitrobenzoylchloride (1.86 g.; 0.01 mole), the diamine (1.42 g.; 0.01 mole) and triethylamine (1.01 g.; 0.01 mole). The crude oil was crystallized from ether-petroleum ether (30°-60°); 2.232 g. (77% yield) of yellow needles, m.p. 103°-104°. The analytical sample melted at 102°-103°. uv sh 215 nm (ε 2,000); λmax 266 (11,800). ir NH 3380, 3320; N-alkyl 2780; C=O 1645; C=C 1605, 1595; amide II/NO2 /C=C 1535, 1525, 1485, 1350; aromatic 870, 845, 720, nmr in CDCl3 and 100 MHz was in accord. Mass spectrum M+ 291.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[N:8][C:6]=2[N:7]=1.[BrH:15]>CC(O)=O>[Br:15][CH2:12][C:10]1[CH:9]=[N:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:14])[C:5]=2[CH:11]=1
Reactant: Nc1nc(N)c2cc(CO)cnc2n1
Reactant: Br
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(CBr)cnc2n1

Procedure:
The intermediate III-2 was prepared from 2,4-diaminopyrido [2,3-d]pyrimidine-6-methanol (III-1) by the procedure described in J. Med. Chem., 35:332 (1992). This particular preparation analyzed for a 1.75 HBr° 0.25 CH3COOH salt (formula wt. 406.7). The material was suitable for conversions to compound 33.