Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:14][C:15](=[N:17][OH:18])[CH3:16].O>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:18][N:17]=[C:15]([CH3:16])[CH3:14])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)=NO
Solvent: c1ccncc1
Solvent: O
Product: CC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 16 h

Procedure:
To a solution of mesitylenesulfonyl chloride (2.0 g, 9.05 mmol) in pyridine (30 mL) was added acetone oxime (0.67 g, 9.05 mmol), and the solution was stirred under N2 for 16 hours. It was poured into 500 ml of water and stirred for 1 hour. The precipitate was filtered and dried. Acetone O-(2,4,6-trimethylphenylsulfonyl)oxime was obtained as white powder (57.6%) yield.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([C:8](=[O:33])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[O:31][CH3:32])=[CH:19][CH:18]=2)[CH:10]=1)[CH3:7])C.[Li+].[OH-].Cl>O1CCOCC1.O>[F:30][C:26]1[C:27]([F:29])=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[C:8]([N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH3:7])=[O:33])=[CH:18][CH:19]=2)=[C:24]([O:31][CH3:32])[CH:25]=1
Reactant: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)N(C)CC(=O)O)c2)cc1

Procedure:
A solution of {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester (17 g, 36 mmol) in dioxane (400 mL) was treated with a solution of LiOH (4.4 g, 180 mmol) in water (400 mL) at room temperature for 12 h, followed by acidification with dilute HCl to pH-2-4. The mixture was extracted with ethyl acetate (3 times). The combined layer was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid as an off-white solid, 13.5 g (85%), after drying in high vacuum at 60° C. for 48 h. LC-MS (ES) calculated for C26H25F2NO5, 441; found m/z 442 [M+H]+.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16](I)=[C:15]3[C:10]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[N:13]([CH3:19])[C:14]3=[O:18])=[N:9]2)=[CH:3][CH:2]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[K])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]([NH:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[C:15]3[C:10]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[N:13]([CH3:19])[C:14]3=[O:18])=[N:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3ccc(-c4ccccc4)cc3)nc21
Reactant: Nc1ccncc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccncc3)n(Cc3ccc(-c4ccccc4)cc3)nc21
Temperature: 150 °C

Procedure:
2-(biphenyl-4-ylmethyl)-3-iodo-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (13.6 mg, 0.026 mmol) is dissolved in anhydrous and degassed THF, and then 4-pyridyl amine (13 mg, 0.132 mmol), Pd2(dba)3 (12 mg, 0.013 mmol) and Xantphos (9 mg, 0.016 mmol) are added, followed by tBuOK (7.5 mg, 0.065 mmol). The reaction mixture is heated in microwave at 150° C. for 40 minutes. After cooling and filtration, the filtrate is purified by a semi-preparative HPLC to give product. MS (ESI) m/z 481.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])[CH:5]=[CH:4][N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c2ccc(Nc3ccnc(Cl)n3)cc2nn1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (2.21 g; 8 mmol, 1 equiv) was dissolved in DMF (11 ml) and cesium carbonate (7.9 g; 24.2 mmol, 3 equiv) was added. The reaction mixture was stirred for 30 min under nitrogen. Iodomethane (0.8 ml, 13 mmol, 1.6 equiv) was added and the reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured in ice cold water and stirred for 30 minutes. The resulting precipitate was collected by filtration to yield the desired compound (0.84 g, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H].[ClH:18]>O.[Pd]>[ClH:18].[ClH:18].[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: NC(=O)c1cc(N)cc(N)c1

Procedure:
3,5-dinitrobenzamide (18) (412.0 g, 2.00 moles, Aldrich) was added to a suspension of 10% Pd/C (10.4 g) in concentrated HCl (360 ml) and water (3.64 L). The mixture was hydrogenated at 60psi in a Parr hydrogenation apparatus until hydrogen was no longer being consumed. The solution was filtered through a Celite pack and washed with 500 ml water. The filtrate and washings of 3,5-diaminobenzamide bis-hydrochloride (19), were combined and used for the subsequent iodination.
Reaction SMILES: F[H-]F.[NH4+].[C:5]1(=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[CH:6]1.C([Si](CC)(CC)[C:20]([F:23])([F:22])[F:21])C.C1C2C(=CC=CC=2)C=CC=1>CN(C)C=O>[OH:16][C:5]1([C:20]([F:23])([F:22])[F:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[CH:6]1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: F[H-]F
Agent: [NH4+]
Solvent: c1ccc2ccccc2c1
Solvent: CN(C)C=O
Product: O=C1C=CC(O)(C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 74 mg (1.3 mmol) of ground ammonium bifluoride, 174 mg (1.1 mmol) of 1,4-naphthoquinone, and 1 mL of N,N-dimethylformamide was treated with 239 mg (1.3 mmol) of triethyltrifluoromethylsilane and stirred vigorously at room temperature for one hour. Gas chromatographic analysis of the reaction mixture showed that the major naphthalene-desired product was 1,4-dihydro-4-hydroxy-1-oxo-4-trifluoromethylnaphthalene.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH:27][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:25])[CH3:26])=[CH:18][CH:17]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(C)(N)CCc1ccc(OCCO)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(CCc1ccc(OCCO)cc1)NCC(O)c1ccccc1
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A solution of phenyl glyoxal monohydrate (3.6 g) and 3-[4-(2-hydroxyethoxy)phenyl]-1,1-dimethylpropylamine (5 g) in benzene (100 ml) was heated under reflux with removal of water by a Dean and Stark trap. When water removal was complete, the benzene was evaporated under reduced pressure, the residue dissolved in methanol and sodium borohydride (2 g) added. The solution was stirred at ice-water temperature for 15 minutes, the methanol evaporated and the residue portioned between ethyl acetate and water. The organic layer was dried MgSO4 and evaporated to give a solid (6 g) which was purified on a silica gel column eluting with 4% methanol in chloroform. The product (2.8 g) was crystallised from dichloromethane, mp 118°-120° C.
Reaction SMILES: C([NH:4][C:5]([N:7]1[CH2:11][CH2:10][S:9][CH:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:23][CH2:22]1)=[S:6])(=O)C.[OH-].[Na+]>C(O)C>[F:33][C:29]1[CH:28]=[C:27]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:8]3[N:7]([C:5](=[S:6])[NH2:4])[CH2:11][CH2:10][S:9]3)[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)NC(=S)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=S)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Yield: 90 %

Procedure:
A mixture of 2.87 g of N-acetyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide, 7.3 ml of 10% aqueous sodium hydroxide solution and 60 ml of ethanol is refluxed for 20 hours and then concentrated under reduced pressure to remove solvent. The residue is extracted with ethyl acetate, and the extract is washed with a saturated sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethyl acetate=2:1). 2.36 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide are obtained. Yield: 90%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH:6]([C:14](=[O:16])[CH3:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].C([N:21](CC)CC)C.Cl.NO.Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:14]([CH3:15])[O:16][N:21]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1noc(C)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 77.8 %

Procedure:
The 1,3-diketone obtained in Step 1 (34.7 mmol, 8.9 g) was dissolved in chloroform (50 ml). 4.91 g of triethylamine (1.4 eq, 48.6 mmol) and hydroxylamine-HCl salt (1.3 eq, 45.1 mmol, 3.13 g) were added and the mixture was refluxed for 3 h. The reaction was cooled to room temperature and 1N aq. HCl (100 ml) was added followed by extraction with DCM (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Column purification by silica gel yielded (6.89 g, 77% yield) of tert-butyl 3-(ethoxycarbonyl)-5-methylisoxazole-4-carboxylate. 1H NMR (300 MHz, CDCl3), δ 4.42 (q, 2H), 2.66 (s, 3H), 1.53 (s, 15H), 1.39 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C@@H:20]2[O:46][C@H:45]([CH2:47][O:48]C(=O)C(C)(C)C)[C@@H:37]([O:38]C(=O)C(C)(C)C)[C@H:29]([O:30]C(=O)C(C)(C)C)[C@H:21]2[O:22]C(=O)C(C)(C)C)=[CH:5][C:6]2[C:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][O:8][C:7]=2[CH:19]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([C@@H:20]2[O:46][C@H:45]([CH2:47][OH:48])[C@@H:37]([OH:38])[C@H:29]([OH:30])[C@H:21]2[OH:22])=[CH:5][C:6]2[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][O:8][C:7]=2[CH:19]=1
Reactant: COc1cc2occ(CCc3ccccc3)c2cc1[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2occ(CCc3ccccc3)c2cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a suspension of 1-[6-methoxy-3-(2-phenylethyl)-benzo[b]furan-5-yl]-1-deoxy-2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranose (0.03 g) in methanol (4 mL) was added sodium methoxide (28% methanol solution, 0.038 mL), and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was purified directly by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (0.015 g).
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[C:11]([F:29])=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31].[Cl-].[Li+]>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>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([NH2:9])=[C:3]([C:10]2[C:11]([F:29])=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH:15]=2)[C:2]=1[CH:30]=[CH2:31]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cnc(Cl)c(Br)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1c(Cl)ncc(N)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (93 mg, 0.19 mmol), vinyltributyl tin (63 μL, 0.21 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol %) and lithium chloride (25 mg, 0.59 mmol) in 1,4-dioxane (1.0 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, diluted with water (10 mL) and extracted with DCM (3×20 mL). The combined organic layer was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 4 g column, ISCO, 0-10% MeOH in DCM) to afford the title compound as a beige powder (77 mg, 82%). 1H NMR (CDCl3, 400 MHz): 8.50 (dd, J=2.5, 1.0 Hz, 1H), 7.94 (s, 1H), 7.88 (dd, J=8.5, 2.5 Hz, 1H), 7.54-7.47 (m, 4H), 6.53 (dd, J=18.0, 11.5 Hz, 1H), 5.37 (dd, J=11.5, 1.0 Hz, 1H), 5.11 (dd, J=18.0, 1.0 Hz, 1H), 3.60 (s, 2H), 3.55-3.50 (m, 2H), 2.48-2.35 (m, 4H), 1.68-1.58 (m, 4H), 1.50-1.44 (m, 2H). LCMS (Method B): RT=2.32 min, M+H+=423/425.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[NH2:2].Cl[C:14]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=3[CH:43]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=3[CH:43]=2)=[CH:22][CH:23]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccccc1B(O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(Cl)c(C(=O)OC)c3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4C(N)=O)c(C(=O)OC)c3)cc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a microwave vial was added dioxane (9 mL), water (0.900 mL), 2-carbamoylphenylboronic acid (148 mg, 0.900 mmol), methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (131 mg, 0.3 mmol), tribasic potassium phosphate (255 mg, 1.200 mmol), dicyclohexyl (2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos, 24.63 mg, 0.060 mmol), and palladium(II) acetate (13.47 mg, 0.060 mmol). The vial was capped, degassed, flushed with N2 and heated in the microwave for 13 minutes at 130° C. The reaction mixture was filtered and solvent removed under a stream of nitrogen. The crude product was then taken up in 4 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5 μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25 mL/min. over 20 minutes with a 10 minute hold. The solvent was removed giving 58.3 mgs (36% yield) of methyl 2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 2.93 (d, J=4.52 Hz, 3H), 3.62 (s, 3H), 6.35 (br. s., 2H), 7.09-7.15 (m, 1H), 7.22 (t, J=8.91 Hz, 2H), 7.31-7.43 (m, 3H), 7.52 (d, J=4.27 Hz, 1H), 7.58-7.71 (m, 3H), 7.81 (dd, J=8.03, 2.01 Hz, 1H), 8.01 (d, J=1.25 Hz, 1H), 8.09-8.20 (m, 3H). LCMS m/z 523.3 (M+H), Rt=3.051 min., 96% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:6]4[CH2:5][CH2:4][NH:3][C:2]([CH3:8])([CH3:1])[CH2:7]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CC1(C)CNCCN1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCNC(C)(C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
2,2-Dimethylpiperazine (343 mg, 3.00 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (217 mg, 47%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)=[O:8].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)ccc1OC(=O)N1CCOCC1
Yield: 83.2 %

Procedure:
Using 5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]1([NH:20][C@@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C:39]([O:41][CH3:42])=[O:40])[C@H:31]3[C@H:22]2[C@:23]2([CH3:44])[C@@H:28]([CH2:29][CH2:30]3)[CH2:27][C@@H:26]([OH:43])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O.N>CC(C)=O.CCOCC>[CH:14]1([NH:20][C@@H:21]2[CH2:38][C@@:36]3([CH3:37])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C:39]([O:41][CH3:42])=[O:40])[C@H:31]3[C@H:22]2[C@:23]2([CH3:44])[C@@H:28]([CH2:29][CH2:30]3)[CH2:27][C:26](=[O:43])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Agent: O=[Cr](=O)=O
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Yield: 96.8 %

Procedure:
Jones reagent was added dropwise to a stirred solution of methyl 11α-cyclohexylamino-3β-hydroxy-5α-androstane-17β-carboxylate (300 mg) in acetone (40 ml) until the reagent colour was not discharged. Water (200 ml) was added and the mixture was brought to pH 10 with 0.88 NH3 solution. Ether (50 ml) was added and the mixture was filtered. The aqueous phase was separated, extracted with ether (50 ml) and the organic phase was washed with water, dried and evaporated to leave an oil (289 mg) which crystallised from petrol to give the title compound m.p. 93°-94° C., [α]D -12°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>CCO>[CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 3-oxo-butyric acid ethyl ester (7 mL, 53.7 mmol), aniline (5 g, 53.7 mmol), acetic acid (0.060 mL) and 4 Å molecular sieves (5 g) in EtOH (20 mL) was refluxed for 5 h. After cooling to r.t., the mixture was filtered. EtOAc was added to rinse the solids, and the filtrate was concentrated to give a reddish oil, which was purified by silica gel chromatography (0-10% EtOAc/hexanes) to give 7 g of the title compound as a pale yellow oil. 1H NMR (CDCl3, 200 MHz): δ=10.38 (br s, 1H), 7.00-7.40 (m, 5H), 4.69 (s, 1H), 4.15 (q, 2H, J=7.0 Hz), 2.00 (s, 3H), 1.29 (t, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].[C:42](O)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[N:45][CH:44]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:42]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2cccnc2)c1
Temperature: 75 °C
Yield: 74.5 %

Procedure:
A stirred solution containing 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.508 g, 0.863 mmol), nicotinic acid (0.108 g, 0.863 mmol), 2-chloro-1-methylpyridinium iodide (0.272 g, 1.04 mmol) and triethylamine (0.288 mL, 2.07 mmol) in CH2Cl2 (8.63 mL) was heated at 75° C. in a sealed tube for 3 days. The reaction was cooled to ambient temperature and concentrated. The crude product was purified on Biotage KP-Sil eluting with a 10 & 15% acetone/hexane step gradient to give 0.446 g (74%) of the title compound. 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 1.58 (s, 3 H), 2.18 (s, 6 H), 2.35 (s, 3 H), 7.18 (s, 2 H), 7.36-7.46 (m, 3 H), 7.68-7.72 (m, 1 H), 7.98 (d, 1 H), 8.15 (dd, 1 H), 8.22-8.26 (m, 2 H), 8.50-8.53 (m, 2 H), 8.95 (dd, 1 H), 9.30 (d, 1 H).