Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.B(O[O-])=[O:18].[Na+]>Cl>[ClH:3].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:18])=[CH:8][CH:9]=1
Reactant: O=BO[O-]
Reactant: Clc1ccc(SC2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(c1ccc(Cl)cc1)C1CCNCC1

Procedure:
A solution of 5.78 g (0.020 mole) of 4-[(p-chlorophenyl)thio]piperidine hydrochloride hydrate and 4.61 g (0.030 mole) of sodium perborate in 200 ml of dilute hydrochloride acid was stirred at room temperature overnight. The reaction mixture was quenched in dilute sodium hydroxide and the resulting basic solution was extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a white solid, the free base of the title compound. The free base was reacted with ethereal hydrogen chloride and the salt was recrystallized from methanol-diethyl ether to give the product as a white crystalline solid, m.p. 22°-221° C.
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)C1C=CC=CC=1)C.[C:46]([CH2:48][CH2:49][C:50](Cl)=[S:51])#[N:47]>O1CCCC1>[C:46]([CH2:48][CH2:49][C:50]([NH:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[S:51])#[N:47]
Reactant: N#CCCC(=S)Cl
Reactant: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1

Procedure:
To 244 mg of benzhydryl 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate in 20 ml of anhydrous tetrahydrofuran were added dropwise at -7° C. with stirring 115 mg of N,N-diethylaniline and, subsequently, 115 mg of cyanomethylthioacetyl chloride in 5 ml of anhydrous tetrahydrofuran. After completion of the reaction, the reaction mixture was then treated in the same manner as in Example 1--(a) to give a crude product. The crude product was purified by developing it with ethyl acetate by the use of silica gel thin layer chromatography (20×20×0.2 cm) to yield 50 mg of benzhydryl 7-cyanomethylthioacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21].[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:18][CH:19]=[C:20]([CH3:21])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Reactant: COC(CC(C)=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 75.5 %

Procedure:
A solution of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.7 g) in ethanol (50 ml) and toluene (150 m) was combined with acetyl acetoaldehyde dimethyl acetal (4.0 g) and 85% potassium hydroxide (0.67 g), and the mixture was heated under reflux. 85% Potassium hydroxide (0.14 g) was added three times at an interval of 30 minutes, and then heated under reflux further for 1 hour. The solvent was distilled off under reduced pressure, and the residue was combined with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was subjected to a column chromatography on a silica gel (EtOAc-hexane) to obtain 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.5 g) as a crystal. Melting point and NMR data were in agreement with those of the compound obtained in Reference Example 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](=[O:35])[NH:31][CH:32]4[CH2:34][CH2:33]4)[C:23]=3[CH:22]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[N:6][CH:7]=1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](=[O:35])[NH:31][CH:32]4[CH2:34][CH2:33]4)[C:23]=3[CH:22]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:38])[CH2:19][CH2:20]2)=[O:14])=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCNC(=O)C4CCNCC4)ncc3Cl)cc12
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CN1CCC(C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 16.9 %

Procedure:
A stirred suspension of piperidine-4-carboxylic acid {3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-amide (231 mg, 0.450 mmol) in 1,2-dichloroethane (3 mL) and methanol (3 mL) is treated at room temperature with aqueous 37% formaldehyde (0.200 mL, 3.02 mmol) in the presence of sodium triacetoxyborohydride (165 mg, 0.779 mmol) for 24 hours. The mixture is then concentrated under reduced pressure, and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 8-15%, to provide the title compound (40 mg, 17% yield). ES+(m/z) 527 (35Cl) and 529 (37Cl) [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:15][CH:16]1[CH2:18][CH2:17]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CC1CC1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from cyclopropylmethyl-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (85%). MS (ESI): m/z=359.152 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)benzamide (0.02 g, 20%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14]C1C=CC(S)=CC=1.ICCC>>[Cl:14][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCS(=O)(=O)c1ccc(F)cc1
Solvent: CCCI
Product: CCCS(=O)(=O)c1ccc(Cl)cc1
Yield: 82 %

Procedure:
Following the general method as outlined in Intermediate 105, starting from 4-chlorothiophenol (Aldrich) and 1-iodopropane, the title compound was obtained as an oil which solidified upon standing in 82% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: BrCc1ccccc1Br
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2Br)oc1C
Yield: 41.3 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (1.00 g, 10.4 mmol), commercial 2-bromobenzylbromide (2.60 g, 10.4 mmol) and 1.6M n-BuLi/hexanes (4.16 mL, 10.4 mmol) in THF. Purification on Biotage KP-Sil eluting with 100% pet. ether gave 1.14 g (41%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.84 (s, 3 H), 2.11 (s, 3 H), 3.96 (s, 2 H), 5.81 (s, 1 H), 7.19 (dt, 1 H), 7.26-7.37 (m, 2 H), 7.60 (dd, 1 H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([C:11]2[N:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: CCCC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(=O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A mixture of 4-(trifluoromethyl)pyrazole (116 mg, 0.85 mmol), 1-(6-chloropyridin-3-yl)butan-1-one (130 mg, 0.71 mmol), and potassium carbonate (294 mg, 2.12 mmol) was stirred 4 h at 50° C. The mixture was cooled to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (200 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.97-8.99 (m. 1H), 8.90-8.91 (m, 1H), 8.39 (dd, J=8.5, 2.4 Hz, 1H), 8.08 (dd, J=8.58, 0.78 Hz, 1H), 7.93 (s, 1H), 2.94 (t, J=7.4 Hz, 2H), 1.74-1.85 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)[CH3:24].Cl.ClCC1C=NC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:29]=[N:28][CH:27]=[CH:23][CH:24]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Agent: ClCc1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccnc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)pyridine hydrochloride and isolated as light-yellow gum (2.5 mg, 16%). MS (m/e): 374.4 (MH+).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:12]C(=O)OC(C)(C)C)[CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([OH:11])[CH3:10]
Reactant: CC(O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)[C@H](N)Cc1ccccc1

Procedure:
A solution of 19.3 g of tert-butyl (1R)-1-benzyl-2-hydroxypropylcarbamate in 160 cm3 of dioxane and 67 cm3 of 6.5N hydrochloric dioxane is stirred at room temperature for 5 hours and is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A yellow oil is obtained, and is taken up in 50 cm3 of water and basified to a pH in the region of 10 with potassium carbonate. This mixture is extracted with 3 times l1o cm3 of ethyl acetate and the combined organic phases are then dried over sodium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 12.9 g of a 75%/25% mixture of the two diastereoisomers A and B of (3R)-3-amino-4-phenyl-2-butanol are obtained in the form of an orange-colored oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm). A mixture of diastereoisomers is observed: from 0.70 to 1.50 (broad unres. mult.: 2H); 1.08 (d, J=6Hz: 3H); from 2.25 to 2.45 (mt: 1H); from 2.70 to 2.85 (mt: 2H); 3.44 (mt: 1H); from 4.25 to 4.75 (unres. mult.: 1H); from 7.10 to 7.35 (mt: 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH:7]([O:9][C:10](=[O:30])[C@H:11]([CH3:29])[N:12](C12C(C)(C)C1CCC(C)C2=O)OC(C)(C)C)[CH3:8])=[O:5])[CH3:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:1]([O:3][C:4]([O:6][CH:7]([O:9][C:10](=[O:30])[C@H:11]([CH3:29])[NH2:12])[CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)OC(C)OC(=O)[C@H](C)N(OC(C)(C)C)C12C(=O)C(C)CCC1C2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)OC(C)OC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound from step 1 (12.9 g) is solubilised in 25 ml of CH2Cl2 and 25 ml of trifluoroacetic acid is added at 0° C. The mixture is stirred at ambient temperature for 3 hours. When the reaction is complete, the reaction mixture is evaporated to dryness. The residue is taken up 3 times with cyclohexane and the mixture is re-evaporated to remove the excess TFA. Slightly brown oil, 13.4 g (99%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCCCC2)cc1
Reaction time: 27 h

Procedure:
A solution of 4-bromobenzaldehyde (5 g), piperidine (2.9 mL), and acetic acid (1.5 mL) in DCE (65 mL) was treated with sodium triacetoxyborohydride (6.9 g). After 27 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (50 mL), and extracted with DCM (2×50 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Kugelrohr distillation of the residue (160° C., 5 mm Hg) gave the title compound as a pale yellow oil (5.9 g).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1.[H][H].C>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: Cc1cc(Nc2ccccc2[N+](=O)[O-])cc2c1NC(=O)CC2C
Reactant: [H][H]
Product: Cc1cc(Nc2ccccc2N)cc2c1NC(=O)CC2C

Procedure:
This compound, m.p. 195°-199°, was prepared similarly to Preparation 17 using 3,4-dihydro-4,8-dimethyl-6-[(N-2-nitrophenyl)-amino]-2-(1H)-quinolone, hydrogen and palladised charcoal as starting materials. The product was characterised spectroscopically and used directly in Examples 13, 15 and 16 without further purification.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:31][O:32][CH2:33][CH2:34]Cl>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:34][CH2:33][O:32][CH3:31])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COCCCl
Reactant: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cccc2c(Nc3ccccc3C)c(C(=O)C(C)C)cnc12
Yield: 11.3 %

Procedure:
A mixture of 3-isobutyryl-4-(2-methylphenylamino) 8-hydroxyquinoline (5.0 g, 15.6 mmol), potassium t-butoxide (2.63 g, 23.4 mmol) and 2-chloroethyl methyl ether (2.85 ml, 31.2 mmol) in tetrahydrofuran (250 ml) was heated at reflux for 3 days, then the solvent evaporated. Water was added, the product extracted into dichloromethane, and the organic extracts dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0%-5% methanol) removed unchanged starting material, then further chromatography (silica gel, 1%-1.5% methanol in dichloromethane) and crystallization from petroleum ether (40-60) gave 3-isobutyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (0.67 g), m.p. 68°-70°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(=O)=O.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[CH2:19][C:20]([OH:22])=[O:21]>CO>[N+:1]([C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][CH:10]([CH2:19][C:20]([OH:22])=[O:21])[C:9]2=[O:8])=[CH:14][CH:15]=1)([O-:4])=[O:2]
Reactant: O=C(O)CC1CCc2ccccc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=C=O
Solvent: CO
Product: O=C(O)CC1CCc2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 0.67 h

Procedure:
To nitric acid (density=1.50) cooled with dry ice and methanol is added 1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid at -10 to -15° C. The resulting mixture is stirred below 0° C. for 40 minutes and poured into ice. The precipitated crystals are collected by filtration to give 7-nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccnc4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccc[n+]([O-])c4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (E)-N-[4-(3-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (250 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol-tetrahydrofuran-acetone to give (E)-N-[4-(1-oxidopyridin-3-yl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 193) (208 mg) as pale yellow crystals. 1H-NMR (200 MHz, DMSO-d6) δ 2.38 (3H, s), 6.95 (1H, d, J=15.7 Hz), 7.31 (2H, d, J=8.1 Hz), 7.45-7.57 (2H, m), 7.59-7.94 (12H, m), 8.19 (1H, d, J=6.5 Hz), 8.58 (1H, s). IR (KBr) 3423, 1672, 1597, 1531, 1477, 1340, 1201, 901, 835, 793 cm-1 ;
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[CH3:19][O:20][C:21]([C@:23]1([CH2:29]O)[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH3:19][O:20][C:21]([C@:23]1([CH2:29][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])=[O:22]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)[C@]1(CO)CCCN1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@]1(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (11.7 g, 38.1 mmol) was added to a solution of Intermediate 85e (2.20 g, 12.7 mmol) and Et3N (12.8 g, 127 mmol) in DCM (100 mL) at 0° C., then the mixture stirred at RT for 30 min. The mixture was diluted with DCM and washed with 10% aq. K2CO3 solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow solid (2.51 g, 65%). 1H NMR (400 MHz, CDCl3): 0.97-1.15 (21H, m), 1.72-1.96 (2H, m), 2.23-2.35 (2H, m), 2.46 (3H, s), 2.89-2.99 (2H, m), 3.69 (3H, m), 4.12-4.22 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2
Reactant: COc1ccc2cc(F)cnc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2cc(F)cnc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Fluoro-7-methoxyquinoline (130 mg, 0.74 mmol) was taken up in dichloromethane (2 ml) under nitrogen and treated with boron tribromide (4 ml of a 1.0M solution of in dichloromethane). The reaction mixture was stirred for 24 hours at ambient temperature followed by quenching the reaction by the slow addition of excess methanol. The solution was stirred for a further 2 hours and evaporated to dryness to give 3-fluoro-7-hydroxyquinoline which was used without further purification.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][C@H:9]([OH:21])[CH:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:22]>C(Cl)Cl.CC(C)=O.O=[Mn]=O>[OH:20][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[CH:10]([C:9](=[O:21])[CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C@@H:3]2[OH:22])[CH2:11]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Mn]=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 45 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of androstane-3β,6α,17β-triol (3.00 g) in CH2Cl2/acetone/—H2O (300/150/6 mL), activated MnO2 (30.0 g, 345 mmol) was added in three portions over 8 h. The mixture was stirred at 45° C. overnight. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was evaporated and the residue was purified by flash chromatography (SiO2, CH2Cl2/n-n-hexane/i-PrOH 10/5/1) to give 3β,17β-dihydroxyandrostan-6-one (0.89 g, 30%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.54 (d, 1H), 4.48 (d, 1H), 3.45 (m, 1H), 3.30 (m, 1H), 2.27 (dd, 1H), 2.08-0.90 (m, 19H), 0.62 (s, 3H), 0.61 (s, 3H).