Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=2[CH3:22])=[N:5][N:6]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=3[CH3:22])[S:3][CH2:2]2)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1-c1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C1=NN(c2ccc(F)c(C#N)c2)CS1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
tert-Butyl 3-(4-(2-Bromo-1,3,4-thiadiazol-5-yl)-3-methylphenyl)propenoate (0.15 g, 0.39 mmol, from Step A), 3-cyano-4-fluorophenyl boronic acid (0.097 g, 0.59 mmol, from Step B) and sodium carbonate (0.21 g, 1.95 mmol) were dissolved in DMF (6 mL) and water (0.2 mL). The reaction mixture was degassed for 5 min with a balloon of argon after which tetrakis(triphenylphosphine) palladium (0.1 g) was added. The reaction was heated at 80° C. for 3 h. The reaction was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% ethyl acetate/hexane afforded 0.05 g of product: ESI-MS (m/z) 422.2; HPLC A: 4.21 min.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(N(C(C)C)CC)(C)C.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:27][C@H:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:26])[N:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)nc(Cl)n1)c1ccccc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of cyanuric chloride (25.0 g, 0.135 mol), diisopropylethylamine (17.5 g, 0.135 mol) in THF (500 mL) at 0° C. was added dropwise a solution of (1S)-1-phenylethylamine (16.4 g, 0.135 mol) in THF (100 mL) while maintaining the reaction temperature at or near 0° C. The reaction mixture was allowed to warm to ambient temperature then was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL) and extracted with 1 N HCl (250 mL), H2O (250 mL) and brine (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a white solid (35 g, 96%) MP 146-147° 1H NMR (CDCl3) δ 7.39 (m, 5H), 6.40 (b d, 1H), 5.25 (m, 1H), 1.59 (d, 3H); MS (ESI+) (M+) 269.1 obs.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:32])=[CH:4][CH:3]=1
Reactant: Clc1ccc(SCC(Cn2ccnc2)OCc2ccc(Cl)cc2Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CC(Cn1ccnc1)OCc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To 6.1 g (0.0143 mole) 3-(4-chlorophenylthio)-2-(2,4-dichlorobenzyloxy)-1-(1-imidazolyl)propane in methylene chloride (25 ml) at 0° C., 2.8 g (0.0143 mole) 85% meta-chloroperoxybenzoic acid in methylene chloride (50 ml) were added dropwise over about 30 minutes. The reaction mixture was maintained at about 0° C. during the addition and for about 11/2 to 2 hours after the addition. The reaction mixture was washed with a sodium bicarbonate solution (5%), with a bisulfite solution, dried, filtered, and concentrated to give 6.1 g of the above-identified product as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([NH:18]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:26].CO>CO>[ClH:26].[NH2:18][C:16]1[N:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])=[CH:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)n2)cc1
Agent: Cl
Solvent: CO
Product: CNS(=O)(=O)c1ccc(-c2cccc(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyridin-2-ylcarbamate (8.5 g, 23.4 mmol) in MeOH (10 mL) was added HCl/MeOH (2M, 50 mL) at room temperature. The suspension was stirred at room temperature overnight. The solid product was collected by filtration, washed with MeOH, and dried to give 4-(6-aminopyridin-2-yl)-N-methylbenzenesulfonamide hydrochloride (5.0 g, 71%). 1H NMR (300 Hz, DMSO-d6) δ 8.12 (d, J=8.4 Hz, 2H), 7.91-7.96 (m, 3H), 7.58-7.66 (m, 1H), 7.31-7.53 (m, 1H), 7.27 (d, J=6.6, 1H), 6.97 (d, J=9.0, 1H), 2.43 (d, J=4.8 Hz, 3H). MS (ESI) m/z (M+H)+264.0.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:25])=O>C1C=CC=CC=1>[Cl:25][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CCCc1ccc(C(O)Cc2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)CCCc1ccc(C(Cl)Cc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 3.49 g of methyl 4-[4-(1-hydroxy-2-Phenylethyl)phenyl]butyrate in 17 ml of benzene, 1.10 ml of thionyl chloride was added dropwise under ice-cooling, and then stirring was continued at room temperature for 1.5 hours. The reaction solvent was removed under reduced pressure, and the residue was dissolved in ether. The ether layer was washed with water and dried, and then the solvent was removed under reduced pressure to yield 3.30 g of pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.FC(F)(F)C(O)=O.[CH3:22][O:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:22][O:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:25]1
Reactant: CO[C@H]1CCC[C@@H](N)C1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](OC)C1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To a stirring solution of ethyl 4-chloro-2-(methylthio)-pyrimidine-5-carboxylate (1.084 g, 4.66 mmol) and (1R,3S)-3-methoxycyclohexanamine trifluoroacetate (1.133 g, 4.66 mmol) in ethanol (18.63 mL) was added DIEA (2.434 mL, 13.97 mmol). The reaction mixture was heated to 60° C. for 17 h. The reaction was removed from heat, cooled to room temperature and concentrated. The crude material was purified by silica gel chromatography (0-25% ethyl acetate in hexanes) to afford ethyl 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.4284 g, 4.39 mmol, 94% yield) as a clear oil. MS (ESI) m/z 326.2 [M+1]+.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])C=C.I[C:36]1[CH:41]=[CH:40][N:39]=[C:38]2[NH:42][C:43](=[O:45])[O:44][C:37]=12>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[C:11]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[NH:42][C:43](=[O:45])[O:44][C:37]=23)[S:10][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]c2nccc(I)c2o1
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Product: O=c1[nH]c2nccc(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)c2o1

Procedure:
The title compound was prepared from 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole and 7-iodo[1,3]oxazolo[4,5-b]pyridin-2(3H)-one using procedures analogous to those described in Example 8-A, Steps 2 and 3. LC/MS (AA) ES+ 429, 431. 1H NMR (400 MHz, d6 DMSO) δ: 8.03 (d, J=5.77 Hz, 1H), 7.83 (s, 1H), 7.59 (d, J=2.01 Hz, 1H), 7.43-7.39 (m, 2H), 7.36 (d, J=8.29 Hz, 1H), 7.06 (s, 2H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)(Cl)Cl>[C:5]1([NH:11][N:12]=[CH:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC=O
Reactant: NNc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC=NNc1ccccc1

Procedure:
Following the same procedure described in Example 1, Part A, but using 100 ml. carbon tetrachloride as the solvent for 5.8 g. (0.1 mole) propionaldehyde, adding a solution of 10.8 g. (0.1 mole) phenylhydrazine in 25 ml. carbon tetrachloride, and removing the water formed by the reaction as its carbon tetrachloride azeotrope (volume of about 50 ml.), there was obtained a carbon tetrachloride solution of propionaldehyde phenylhydrazone.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Indole-4-carbaldehyde (580 mg) was dissolved in 8 ml of dimethylformamide, then 176 mg of sodium hydride (content 60%) was added to the resulting solution with ice-cooling, followed by stirring for one hour, addition of 777 mg of benzenesulfonyl chloride and stirring for one hour. To the reaction solution, there were added 50 ml of ethyl acetate and 50 ml of a saturated sodium hydrogen carbonate aqueous solution followed by stirring for 30 minutes. After separation of phases, the aqueous phase was further extracted with 50 ml of ethyl acetate. The combined organic phase was washed with 50 ml of saturated common salt solution, dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to give a crude product. The crude product was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=9/1) to give 842 mg of 1-benzenesulfonylindole-4-carbaldehyde as pale brown crystals. The yield thereof was found to be 74%.
Reaction SMILES: [CH3:1][Mg]Cl.[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15](=[O:17])[CH3:16].[NH4+].[Cl-]>CCCCCCC.C1COCC1>[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])([CH3:1])[CH3:16]
Reactant: C[Mg]Cl
Reactant: COc1ccc(C(C)=O)c(F)c1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methylmagnesium chloride (3M in THF, 1.74 mL, 5.22 mmol) was added dropwise to a stirred solution of 1-(2-fluoro-3,4-dimethoxyphenyl)ethanone (J. Chem. Soc. Perkin Trans. 2 1994, 547-555) (646 mg, 3.26 mmol) in heptane (3.1 mL) and THF (1.4 mL) at −20° C. under N2. The reaction was allowed to warm to room temperature and was stirred for 4 h. 50% Saturated NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil. LCMS calc.=197.1; found=197.1 (M-OH)+. 1H NMR (600 MHz, CDCl3) δ 7.14 (t, J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 1.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.56-2.25 (br s, 1H), 1.58 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[H-].[Na+].Br[CH2:13][C:14]1[S:22][C:21]2[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:19][C:18]([Cl:29])=[N:17][C:16]=2[CH:15]=1>O1CCCC1>[Cl:29][C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:21]2[S:22][C:14]([CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6]([CH3:9])(=[O:8])=[O:7])=[CH:15][C:16]=2[N:17]=1
Reactant: COCCNS(C)(=O)=O
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of N-(2-Methoxy-ethyl)-methanesulfonamide (61 mg) in tetrahydrofuran (1.5 ml) under nitrogen was added sodium hydride, 60% dipersion in mineral oil, (18 mg). The reaction mixture was stirred at room temperature for 30 minutes. 6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (140 mg) was added. The reaction mixture was stirred at room temperature for 2 hours and then 50° C. for 5 hours. The solvents were removed in vacuo to give a crude product. This was purified by flash chromatography to give N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-methoxy-ethyl)-methanesulfonamide (124 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:17])[CH:7]([N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C(=O)OC(C)(C)C)n1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)OC(C)(C)C)n1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution containing (3-nitro-pyrazol-1-yl)-propionic acid tert-butyl ester (2.30 g, 9.53 mmol) in methanol (100 mL), palladium, 10 wt. % on activated carbon, wet (˜300 mg) was added to the solution. The vial was charged with hydrogen gas (via balloon) and the mixture was stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo to afford (3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (1.87 g, 93%) as a yellow oil which was used in the following step with no further purification.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:46])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:45])[CH3:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:44][C:33]1([CH3:45])[C@H:34]([C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:37])[CH2:35][C@@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:47])([CH2:12][CH2:13]2)[C@@:10]2([CH3:48])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:46]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 10, 0.340 g, 0.492 mmol) in MeOH:THF (2:1) (6 ml) NaOH (2N, 2 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.190 g: Yield: 59%; 1H NMR (300 MHz, CDCl3): δ 5.94 (d, 1H, J=7.8 Hz), 4.73 (s, 1H), 4.58 (s, 1H), 4.17-4.13 (m, 1H), 3.73-3.59 (m, 1H), 3.54-3.41 (m, 1H), 3.40-3.30 (m, 2H), 3.22-3.04 (m, 2H), 2.93-2.83 (m, 1H), 2.52-2.23 (m, 3H), 2.00-1.82 (m, 2H), 1.79-1.42 (m, 15H), 1.41-1.11 (m, 17H), 0.96, 0.93 (s, 10H), 0.82, 0.80 (s, 6H), 0.75 (s, 3H). 0.71-0.62 (m, 1H); Mass: [M+1]+ 649 (100%), [M+Na]+ 671 (60%); IR (KBr, cm−1): 3450, 2937, 2862, 2587, 2126, 1622, 1459, 1373, 1251, 1192, 1049, 1024, 882, 853; M.R: 110.0° C.-116.3° C.; HPLC: 97.2%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:44])=[C:20]([CH:43]=2)[C:21]([NH:23][C:24]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][C:25]=2[C:26]([O:28]C(C)(C)C)=[O:27])=[O:22])[CH2:12][CH2:11]1)[CH3:9]>>[CH2:8]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:44])=[C:20]([CH:43]=2)[C:21]([NH:23][C:24]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])[CH2:14][CH2:15]1)[CH3:9]
Reactant: CCN1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to the obtained tert-butyl 2-(5-(1-ethylpiperidin-4-yl)-2-hydroxybenzamido)-4-phenylbenzoate (0.040 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and methanol and water were added to the residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 5.0 mg of 2-(5-(1-ethylpiperidin-4-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 10 g.) was added to dry tetrahydrofuran (100 ml.) at 30° C. To the solution was added acetic anhydride (10 ml.) and stirred at the same temperature for 30 minutes. Sodium acetate (3 g.) was added to the solution and stirred at 30° C. for 4 hours. 6 N Hydrochloric acid (10 ml) was dropwise added to the reaction mixture under ice-cooling and the solvent was evaporated in vacuo below 30° C. After adding water into the residue, the mixture was stirred at 20° to 25° C. for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-(2-methoxyimino-3-oxo-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 7 g.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].CN(C=O)C.S(Cl)([Cl:25])=O>>[Cl:25][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]([O:16][CH3:17])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCl
Temperature: 80 °C
Yield: 59 %

Procedure:
7-(2-Chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (5 g, 19 mmol) was suspended in thionyl chloride (28 mL) and DMF (0.7 mL) was added. The mixture was heated at 80° C. for 1.5 hours under anhydrous conditions. The excess thionyl chloride was evaporated off and toluene was added to remove the last traces by azeotropic distillation (repeated twice). The solid was suspended in ice-water and the pH adjusted to 7.5 with sodium hydroxide 2N first then with a saturated sodium hydrogen carbonate solution. The solid was collected by filtration, washed with water, ether and dried over P2O5 under vacuum. The crude product was purified by flash chromatography using dichloromethane/acetonitrile (95/5 up to 90/10). Evaporation of the solvent gave 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (3.06 g, 59%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1[F:17])=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:17][C:9]1[C:10]2[S:14][N:13]=[CH:12][C:11]=2[CH:15]=[CH:16][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc2cnsc2c1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2cnsc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid tert-butyl ester (1.0 g, 4.0 mmol) in DCM (10 mL) was added water (0.2 mL) and TFA (10 mL). There reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was azeotroped with toluene to give the title compound as a yellow solid (788 mg, 100%). LCMS (method B): RT=2.86 min, [M−H]−=196.
Reaction SMILES: [C:1](O)(=O)C.C=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:38][C:17]3[C:18](=[O:37])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([CH:30]5[CH2:34][CH2:33][NH:32][CH2:31]5)=[O:29])=[C:24]([O:35][CH3:36])[CH:23]=4)[CH:20]=[CH:21][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CCOCC>CO.C(Cl)Cl>[ClH:7].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:38][C:17]3[C:18](=[O:37])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([CH:30]5[CH2:34][CH2:33][N:32]([CH3:1])[CH2:31]5)=[O:29])=[C:24]([O:35][CH3:36])[CH:23]=4)[CH:20]=[CH:21][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1C(=O)C1CCNC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1C(=O)C1CCN(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
Add acetic acid (1.50 g, 2.48 mmol) and formaldehyde (0.20 g, 2.48 mmol, 37% aqueous solution) to a solution of 2-(4-chloro-phenyl)-6-[3-methoxy-4-(pyrrolidine-3-carbonyl)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, trifluoro-acetic acid (0.36 g, 0.62 mmol) in methanol (31 mL). Stir the mixture at RT for 15 min, then add sodium triacetoxyborohydride (0.55 g, 2.48 mmol), and continue to stir the mixture at RT for 2 h. Dilute the mixture with CH2Cl2 (200 mL), wash with saturated NaHCO3, and back extract the aqueous with CH2Cl2 (100 mL). Wash the combined organic phases with water (100 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by filtering with Et2O (100 mL) and water (50 mL). To prepare the HCl salt dissolve the solid in CH2Cl2, and add 1 eq 1M HCl/ether. Allow the solution to stir for 15 min, and concentrate to give 0.16 g (50%) of the title compound. LC-MS/ES m/z (35Cl) 479.0 [M+H]+.