Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([Cl:10])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Br)cc1Cl
Reaction time: 0.33 h

Procedure:
To a stirring solution of (4-bromo-2-chlorophenyl)methanol (4.5 g, 20 mmol) in DCM (50 mL) was added Dess-Martin periodinane (9.3 g) at 23° C. Reaction refluxed after addition. After 20 min, TLC (1:4 EtOAc/Hex) suggests full conversion of alcohol. Suspension then washed with 5% NaHCO3 (100 mL plus 15 g dry NaHCO3). Organic dried over MgSO4, concentrated onto dry silica (15 g), then purified on silica (120 g) eluting with 0>10% EtOAc/hex. 4-bromo-2-chlorobenzaldehyde isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure BB and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 81-83° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH2:1]([C:5]1([CH2:33][CH2:34][CH2:35][CH3:36])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][O:26]COC)[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>Cl.O1CCOCC1>[CH2:1]([C:5]1([CH2:33][CH2:34][CH2:35][CH3:36])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][OH:26])[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3c(COCOC)csc3N2)=C(O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
A solution of the product of Example 10F (27 mg, 0.051 mmol) in 4.0 N HCl in dioxane (4 mL) was stirred at 25° C. for 18 hours and concentrated in vacuo. A suspension of the residue in acetonitrile (2 mL) was treated with 1.0 N sodium hydroxide solution (51 μL, 0.051 mmol) and stirred at 25° C. for 1 h. The solution was lyophilized to afford the title compound (28 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 16.82 (m, 1 H), 8.04 (d, J=7.35 Hz, 1 H), 7.47 (m, 2 H), 7.32 (t, J=7.35 Hz, 1 H), 6.95 (s, 1 H), 5.32 (t, J=5.70 Hz, 1H), 4.61 (m, 2 H), 2.09 (m, 2 H), 1.70 (m, 2 H), 1.02 (m, 4 H), 0.84 (m, 2 H), 0.67 (m, 6 H), 0.49 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC(=N)c2ccccn2)cc1

Procedure:
The title compound was prepared from 2-cyanopyridine (9.7 g, 93 mmol) and 4-methylaniline (10 g, 93 mmol) by following the procedure described in preparation 10 (8.2 g, yield 41.6%). MS m/z:212.1(M+).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[C@@H:12]([C:31]([O:33][CH3:34])=[O:32])[C@@:11]([OH:36])([CH3:35])[CH2:10]2)[CH2:5][C@H:4]([N:37]([CH3:39])[CH3:38])[C@@H:3]1[O:40][C@@H]1O[C@@H](C)[C@@H](O[C@@H]2O[C@@H](C)C(=O)CC2)[C@@H](O)C1.Cl.CO.[OH-].[Na+].O>CC(C)=O.CO>[CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:31]([O:33][CH3:34])=[O:32])[C:11]([OH:36])([CH3:35])[CH2:10]2)[CH2:5][CH:4]([N:37]([CH3:39])[CH3:38])[CH:3]1[OH:40]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@H](O)[C@H](O[C@H]5CCC(=O)[C@H](C)O5)[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Yield: 61.8 %

Procedure:
To a solution of 100 mg of auramycin A in 20 ml of acetone and 1 ml of methanol was added 1 ml of 0.2 N hydrochloric acid-methanol with stirring and reacted at room temperature for 40 minutes. The reaction mixture was neutralised by dilute sodium hydroxide solution and 20 ml of water was added and extracted with 20 ml of chloroform twice. The extracts were combined and concentrated to a small volume in vacuo. The concentrate was chromatographed by a column packed with silica gel (chloroform:methanol, 95:5). The fractions containing auramycin D were concentrated in vacuo to give 43 mg of auramycin D.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:32]
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)Cc1ccccc1Br
Product: O=C(Cc1ccccc1Br)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 484,486 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and o-bromphenylacetyl chloride.
Reaction SMILES: O=[C:2]([C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=O.[C:20]1([C:26](=[NH:28])[NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:20]1([C:26]2[NH:28][C:4](=[O:6])[CH:3]=[C:2]([C:9]3[N:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:12]=[CH:11][CH:10]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccnn1-c1ccccc1
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccnn2-c2ccccc2)nc(-c2ccccc2)[nH]1
Yield: 27.5 %

Procedure:
To a solution of ethyl 3-oxo-3-(1-phenyl-1H-pyrazol-5-yl)propanoate (300 mg) in DMF (10.0 mL) was added benzenecarboximidamide (139 mg) at room temperature. The reaction mixture was heated using a microwave reactor at 140° C. for 30 min. The reaction mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (100 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH:7]=[CH2:8])[CH2:5][OH:6].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:6][CH2:5][CH:4]([CH3:3])[CH:7]=[CH2:8]
Reactant: COC(CBr)OC
Reactant: C=CC(C)CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(C)COCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt %, 928 mg) was added to a solution of 2-methyl-3-buten-1-ol (2 g) in DMF (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Bromoacetaldehyde dimethyl acetal (5.45 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred for 16 hours with gradual heating to room temperature. Ethyl acetate and aqueous sodium chloride were added to the reaction solution, and the organic layer was separated. The same operation was performed on the same scale. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (4.92 g).
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[C:23]1([CH2:22][C:21]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:9]4[C:4]5[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:32]6[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=6)[C:3]=5[S:11][CH:10]=4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cccnc2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 120 °C
Yield: 51.6 %

Procedure:
To a 25 mL pressure tube was charged 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (182 mg, 0.356 mmol), 3-pyridinylboronic acid (43.7 mg, 0.356 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14.53 mg, 0.018 mmol), and sodium carbonate (75 mg, 0.712 mmol) followed by dioxane (5 mL), and water (1 mL). The reaction was heated at 120° C. for 30 min in microwave reactor. Water (20 mL) and ethyl acetate (20 mL) were added and the layers were separated. The organic layer was washed with brine, concentrated, and the residue purified by silica gel chromatography (0%-100% EtOAc in hexanes) to afford the tittle compound 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(3-pyridinyl)thieno[3,2-c]pyridin-4-amine (85 mg) as a gray solid. LC-MS (ES) m/z=463.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (d, J=1.8 Hz, 1H) 8.62 (dd, J=4.8, 1.5 Hz, 1H) 8.18 (d, J=8.1 Hz, 1H) 8.10 (dt, J=8.1, 1.9 Hz, 1H) 7.96 (s, 1H) 7.56 (dd, J=8.1, 4.8 Hz, 1H) 7.50 (s, 1H) 7.23-7.40 (m, 7H) 5.63 (br. s., 2H) 4.26 (t, J=8.5 Hz, 2H) 3.90 (s, 2H) 3.24 (t, 2H)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][CH:11]([CH3:14])[CH2:12][CH3:13]>>[CH3:10][CH:11]([CH2:12][CH3:13])[CH2:14][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: CCC(C)CCl
Reactant: Oc1ccccc1S
Product: CCC(C)CSc1ccccc1O
Yield: 57 %

Procedure:
This compound was prepared in 57% yield from 2-mercaptophenol and 1-chloro-2-methylbutane according to the procedure for 1p in Example VIII. 1H NMR (CDCl3): δ 0.86 (t, J=4.85 Hz, 3H), 1.00 (d, J=6.60 Hz, 3H), 1.18-1.27 (m, 1H), 1.46-1.58 (m, 2H), 2.55 (dd, J=7.15, J=12.35, 1H), 2.70 (dd, J=5.75, 12.65, 1H), 6.75 (d, J=1.1 Hz), 6.86 (dt, J=1.1 Hz, J=4.93 Hz, 1H), 6.98 (dd, J=1.4 Hz, J=8.25 Hz, 1H), 7.24 (dt, J=1.65 Hz, J=7.40 Hz, 1H, 7.45 (dd, J=1.65 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 11.26, 18.74, 28.56, 34.80, 44.36, 114.77, 119.98, 120.81, 130.89, 135.80, 156.80; HRMS (FAB): 196.09219 calcd for C11H16OS [M]+. found 196.09293 (3.6 ppm, 0.7 mmu).
Reaction SMILES: [CH2:1]([C@H:5]([N:9]1[C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][O:23][C:22]2=[O:32])[C:10]1=[O:33])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ClC(O[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O.C(O)C1C=CC=CC=1>ClCCl>[CH2:1]([C@H:5]([N:9]1[C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([N:21]2[C@@H:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][O:23][C:22]2=[O:32])[C:10]1=[O:33])[C:6]([O:8][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H](C(=O)O)N1C(=O)[C@@H](N2C(=O)OC[C@@H]2c2ccccc2)[C@H]1CCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)N1C(=O)[C@@H](N2C(=O)OC[C@@H]2c2ccccc2)[C@H]1CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.79 gm (1.76 mMol) 2-(S)-isobutyl-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-(phenyl)ethyl)azetidin-2-on-1-yl]acetic acid in 20 mL dichloromethane was cooled to −4° C. To this solution were added 0.26 mL (1.85 mMol) triethylamine followed by 0.26 mL (1.85 mMol) benzyl chloroformate. After 5 minutes 0.20 mL (1.93 mMol) benzyl alcohol were added and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was then washed sequentially with two portions each of 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane: ethyl acetate to provide the title compound as a colorless, crystalline solid.
Reaction SMILES: C(C1C=CC(C2C=C(C)SC=2CO)=CC=1)C.OC1C(F)=CC(CCC(OCC)=O)=CC=1F.[CH2:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:45]=[C:44]([CH3:46])[S:43][C:42]=2[CH2:47][O:48][C:49]2[C:54]([F:55])=[CH:53][C:52]([CH2:56][CH2:57][C:58]([O:60]CC)=[O:59])=[CH:51][C:50]=2[F:63])=[CH:37][CH:36]=1)[CH3:34]>>[CH2:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:45]=[C:44]([CH3:46])[S:43][C:42]=2[CH2:47][O:48][C:49]2[C:50]([F:63])=[CH:51][C:52]([CH2:56][CH2:57][C:58]([OH:60])=[O:59])=[CH:53][C:54]=2[F:55])=[CH:37][CH:36]=1)[CH3:34]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(C)cc2-c2ccc(CC)cc2)c(F)c1
Agent: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCc1ccc(-c2cc(C)sc2CO)cc1
Product: CCc1ccc(-c2cc(C)sc2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 196 step 7 by coupling of (3-(4-ethylphenyl)-5-methylthiophen-2-yl)methanol and ethyl 3-(4-hydroxy-3,5-difluoro phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-methylthiophen-2-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.0 Hz, 2H), 7.21 (d, J=7.1 Hz, 2H), 6.88 (s, 1H), 6.75 (d, J=7.8 Hz, 2H), 5.10 (s, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.45 (s, 3H), 2.01 (m, J=7.8 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]=[N+:5]=[N-:6])([CH3:3])[CH3:2].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)N=[N+]=[N-]
Product: CC(C)n1cc(-c2ccc(F)cc2)nn1

Procedure:
A mixture of isopropylazide [G. A. Olah, D. J. Donovan, J. Org. Chem., 43, 860, (1978)] (54.5 g; 640.3 mmol) and 4-fluorophenylacetylene [J. B. Lambert et al., J. Am. Chem. Soc., 107, 5443, (1985)] (39 g; 325.1 mmol) was heated at 70° C. for 41 hours. The excess of isopropylazide was distilled off an the resultant crude compound was purified by chromatography on silica gel (230-400 mesh), eluent methylene chloride:acetone=39:1, giving the title compound (m.p. 54°-55° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:18].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:23][NH:22][CH2:21]1)=[O:18]
Reactant: COCCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl(3S, 5R)-3-[{[1-(5-methoxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (123 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The m reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (76 mg).
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:22](=[O:24])[CH3:23])[C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C1C(=O)N(C(=O)NC(=O)c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a stirred slurry of 841 mg (3.0 mmole) of N-benzoyl-2-oxindole-1-carboxamide in 5 ml of N,N-dimethylformamide was added 806 mg (6.6 mmole) of 4-(N,N-dimethylamino)pyridine. Stirring was continued for a few minutes, and then the slurry was cooled in an ice-bath and a solution of 337 mg (3.3 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 65-70 ml. of ice-water and 2.2 ml of 3N hydrochloric acid. The solid which precipitated was recovered by filtration. It was recrystallized from ethanol to give 385 mg of the title compound as tan crystals, mp 198° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:28])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:29]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:29])[C:11]=4[N:12]=[C:13]3[CH3:28])[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: N
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 16 h

Procedure:
4-Chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c]quinoline (2.307 g, 5.873 mmol) was treated according to the method described in Part B of Example 27 using 60 mL of 7 N ammonia in methanol. Following the purification steps, the solid product was stirred for 16 hours in 25% potassium hydroxide in ethanol, isolated by filtration, washed with water and isopropyl alcohol, and dried. The resulting white solid was stirred for one hour with 6 N hydrogen chloride in ethanol, and the mixture was then adjusted to pH 14 with the addition of 6 N potassium hydroxide. The solid was isolated by filtration, washed with water and diethyl ether, and dried under high vacuum at 100° C. for 18 hours to provide 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 294.0-296.0° C.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:6][CH:5](O)[C:4]=2[CH:3]=1.C1C=CC(OC(Cl)=S)=CC=1>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: COc1ccc(N2CC(O)c3cc(Cl)sc3S2(=O)=O)cc1
Agent: CN(C)c1ccncc1
Agent: S=C(Cl)Oc1ccccc1
Solvent: ClCCCl
Product: COc1ccc(N2C=Cc3cc(Cl)sc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A solution of the product from Step C (1.4 g, 4.05 mmol) and 4-dimethylaminopyridine (0.74 g, 6.08 mmol) in 1,2-dichloroethane (10 mL) were cooled in an ice bath. Phenyl chlorothionoformate (0.67 mL, 4.86 mM) was added slowly. The cooling bath was removed and the mixture was stirred at room temperature for 18 hr, mixed with 3:1 hexane/ethyl acetate (25 mL) and filtered through silica gel. The filtrate was concentrated and heated under vacuum (200° C./0.5 mm Hg) approximately 5 min followed by cooling the mixture to room temperature. The residue was purified by column chromatography (silica gel, 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) which gave 0.91 g (65%) of the desired product as an oil which was not purified further.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][CH:16]([OH:24])[CH2:17][CH2:18]1)[C@H:13]([OH:26])[CH2:12]3)([O:3][CH3:4])=[O:2].BrN1C(=O)CCC1=O>O1CCOCC1.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=[O:26])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](O)[C@@]4(O)CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 17β-Carbomethoxy-3,β,5α,6β-trihydroxy-androstane (43.5 g, 0.24 mol), as prepared in example 16, in 450 mL of dioxane is diluted with 50 mL of water, and maintained at 25° C. by means of an external cooling bath. To this suspension is added N-bromosuccinimide (22.5 g, 0.25 mol). The mixture is stirred for 8 h. The mixture is cooled in an ice bath and the solid collected by filtration, washed with 50% methanol/water, and air dried to afford 17β-carbomethoxy-6-oxo-3β,5α-dihydroxy-androstane as a white solid, mp 258°-260° C. Anal. Calcd. for C21H32O5 : C, 69.20; H, 8.85. Found: C, 69.38; H, 8.92.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[N:6]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:6]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:3]1
Reactant: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)cc1=O
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of methyl 6-oxo-3,4-diphenyl-1(6H)-pyridazinenonanoate (6 g, 14 mmol), 5N NaOH solution (8.6 mL, 43 mmol) and methanol (100 mL) was heated to reflux on a steam bath. After 30 minutes, the mixture was concentrated, diluted with water and acidified to pH=1 with 2N HCl solution. The mixture was extracted with CH2Cl2, the combined extracts dried over sodium sulfate and concentrated to leave an oil that crystallized on standing. Recrystallization from a mixture of CH2Cl2 and hexanes gave 6-oxo-3,4-diphenyl-1(6H)-pyridazinenonanoic acid (3.92 g, 67%) mp 100°-103° C.