Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:32][CH2:33][S:34][CH3:35])[NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28].[Li+].[OH-].O>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:32][CH2:33][S:34][CH3:35])=[O:31])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
The product of Example 304F (291 mg, 0.56 mmol) was dissolved in THF(4 mL) and saturated aqueous LiOH (1 mL). Water (1 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was thoroughly evaporated and formic acid was added to pH3 The reaction was evaporated to dryness and ethyl acetate (10 mL) was added followed by a minimum quantity of H2O (−1 mL) to completely solubilize the free acid and the water soluble salts, respectively. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The ethyl acetate layers were combined and dried over Na2SO4, filtered, and evaporated and then lyophilized to give the title compound (242 mg, 86%) as an amorphous white solid. 1H NMR (300 MHz, CD3OD) δ 8.30 (bs, 1H), 8.14 (m, 1H), 7.76-7.33 (m, 9H), 5.28 (s, 2H), 4.87-4.40 (m, 1H), 2.40-2.06 (m, 2H), 2.04-1.94 (m, 4H contains methionine SMe), 1.92-1.80 (m, 1H). MS (CI) 505 (M+H)+ 505. Anal calcd for C25H23O4N2SF3: 0.65H2O solvate: C, 58.17; H, 4.74; N, 5.43. Found: C, 58.17; H, 4.80; N, 5.31. HRMS FAB Calcd m/z MH+ for C25H23O4N2SF3 505.1409, found 505.1408.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=O)=[C:7]([Cl:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:7]([Cl:23])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2ccc(F)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)c(Cl)c1
Yield: 74.7 %

Procedure:
1.78 ml (1.78 mmol) of a 1M borane-THF complex solution in THF were added under nitrogen at rt to 198 mg (0.59 mmol) of 4-tert-butyl-2-chloro-N-[2-(4-fluoro-phenyl)-ethyl]-benzamide dissolved in 3 ml THF. The reaction mixture was heated to reflux over night. At rt 5 ml 2N aqueous HCl solution were added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was basified with 7 ml 2N aqueous NaOH solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (5 g silica gel; DCM/methanol 19:1) to yield 141 mg (67%) of (4-tert-butyl-2-chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine as a yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.40-7.22 (m, 5H), 7.09 (t, 2H), 3.74 (s, 2H), 2.73 (s, 4H), 1.26 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2].CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]2[N:20]=1)=O>>[CH2:1]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:19]3[N:24]=[CH:23][C:22]4=[CH:25][CH:26]=[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]4[N:20]=3)=[CH:11][CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCOC(c2ccc(N)cc2)C1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Product: CCN1CCOC(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)C1
Yield: 0.3 %

Procedure:
Following a procedure analogous to 251c, 4-(4-Ethyl-morpholin-2-yl)-phenylamine (0.16 g, 78 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (94 mg, 26 mmol) were converted to the title compound (35 mgs, 22%) isolated as a TFA salt. H-NMR (DMSO-d6) δ 9.89 (broad s, 1H), 9.56 (s, 1H), 9.00 (s, 1H), 7.79 (d, J=3.3 Hz, 1H), 7.69-7.66 (m, 3H), 7.59-7.58 (m, 2H), 7.20 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.8 Hz, 2H), 4.63 (d, J=11.1 Hz, 1H), 4.18 (d, J=12.9 Hz, 1H), 3.85 (t, J=8.3 Hz, 1H), 3.59-3.32 (m, 2H), 3.12-2.98 (m, 4H), 2.86 (s, 3H), 1.25 (t, J=7.8 Hz, 3H); LC/MS (ESI+): 507.1 (M+H).
Reaction SMILES: [C:1]([CH:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)CCC>[C:2]1([C:1]2[C:9]3[S:13][C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[C:10]=3[NH:20][N:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C1Sc2ccccc2C1=O
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: c1ccc(-c2n[nH]c3c2sc2ccccc23)cc1

Procedure:
A mixture of 2-benzoylbenzo[b]thiophen-3(2H)-one (1.50 g, supplied by the Maybridge Chemical Company, Tintagel, England) hydrazine hydrate (0.3 ml) and butan-1-ol (50 ml) was boiled under reflux under nitrogen for 7.5 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica using toluene/ethyl acetate (7.5:1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether, and filtered to give 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 236-238° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1.[H-].[Na+].[CH2:35](Br)[CH:36]=[CH2:37]>C1COCC1>[Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:37]([O:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)[CH:36]=[CH2:35]
Reactant: O=C(c1ccccc1)c1ccc(CO)cc1
Reactant: C=CCBr
Agent: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 92 %

Procedure:
4-Bromomethyl benzophenone (2) was prepared as described in Reference Example 1. 4-Bromomethyl benzophenone (2) was converted into 4-Hydroxylmethyl benzophenone (3) as described in Reference Example 2. To a solution of 3 (0.5 g, 3.4 mmol) in dry THF (10 ml) was added sodium hydride (0.3 g, 60% dispersion in mineral oil, 6.7 mmol). The mixture was stirred for 5 min, then allyl bromide (0.8 g, 6.7 mmol) was added. The mixture as stirred for 18 h. the quenched with water and concentrated in vacuo. The residue was portioned between DCM and water, the organic layer collected, dried over MgSO4 and concentrated. A mineral oil impurity was removed using a silica plug eluting with petrol then ethyl acetate to yield 9 (0.6 g, 92%) as a yellow oil; δH (CDCl3) 4.08 (dt, 2H, J=1.4, 5.5 Hz, OCH2CH═CH2), 4.60 (s, 2H, ArCH2O), 5.24 (ddt 1H, J=1.4, 3.2, 10.3 Hz, OCH2CH═CHH), 5.34 (ddt 1H, J=1.4, 3.2, 17.3 Hz, OCH2CH═CHH), 5.88-6.08 (m, 1H, OCH2CH═CHH), 7.42-7.50 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.54-7.62 (m, 1H, 4′-H), 7.78-7.82 (m, 4H, 2-, 2′-, 6-, 6′-H) ppm; δC (CDCl3) 61.4, 71.3 (ArCH2O, OCH2CH═CH2), 117.3 (OCH2CH═CH2), 127.0, 128.1 (3-, 3′-, 5-, 5′-C), 129.8, 130.1 (2-, 2′-, 6-, 6′-C), 132.2 (4′-C), 134.3 (OCH2CH═CH2), 136.6, 137.5 (1-, 1′-C), 143.1 (4-C), 196.2 (C═O) ppm; νmax (thin film) 3061, 2855, 1658, 1609, 1447, 1412, 1278, 1089, 924 cm−1; m/z (Er) 252 ([M+], 85%), 222 (100%); found 252.1158, C17H16O2 requires 252.1150.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCc1nc(Cl)cc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1nc(Nc2ccc(CCO)cc2)cc(-c2cccc(Cl)c2)n1
Yield: 19.6 %

Procedure:
A solution of 4-chloro-6-(3-chlorophenyl)-2-ethylpyrimidine (0.100 g, 0.39 mmol), 4-aminophenethyl alcohol (0.081 g, 0.59 mmol) and HCl in dioxane (4.0 M, 0.023 mL, 0.59 mmol) in ethanol (2 mL) was heated to 85° C. for 3 h. After this time, the reaction was cooled, neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.027 g, 27%) as a light yellow solid. MW=353.85. 1H NMR (DMSO-d6, 500 MHz) δ 8.01 (t, J=1.8 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.69-7.57 (m, 4H), 7.25 (d, J=8.3 Hz, 2H), 7.04 (s, 1H), 3.61 (t, J=7.0 Hz, 2H), 2.87 (q, J=7.6 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H); APCI MS m/z 354 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCCC1.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2cc(Br)cnc21
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Temperature: 65 °C
Yield: 70.1 %

Procedure:
Into a 50 ml round bottom pressure tube were added 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (2.36 g, 5.2 mmol), 2-methoxyphenyl boronic acid (792 mg, 5.2 mmol), [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-complex with dichlormethane (1:1) (43 mg, 0.052 mmol), acetonitrile (20 mL), tetrahydrofuran (5 ml) and of sodium carbonate (aq. 2 M, 9 ml, 18.0 mmol). The flask was sealed and heated at 65° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (20% ethyl acetate in hexanes) to give 1.58 g (70%) of 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine. 1H-NMR (250 MHz, CDCl3) δ 8.355 (d, J=2.0 Hz, 1H), 8.155 (d, J=2 Hz, 1H), 7.64 (s, 1H), 7.50 (dd, J=7.5, 1.5 Hz, 1H), 7.23-7.35 (m, 1H), 6.98-7.10 (m, 2H), 5.68 (s, 2H), 3.86 (s, 3H), 3.58 (t, J=8.4 Hz, 2H), 0.94 (t, J=8.4 Hz, 3H), −0.06 (s, 9H); MS: m/z 432.1+434.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH:8]=2)[NH:3]1.C1C(=O)N(Br)C(=O)C1.[CH2:27]([SH:30])[CH:28]=[CH2:29]>>[CH2:27]([S:30][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH:8]=2)[NH:3][C:2]([CH3:18])([CH3:1])[CH:11]=1)[CH:28]=[CH2:29]
Reactant: C=CCS
Reactant: CC1=CC(C)(C)Nc2ccc(-c3ccsc3)cc21
Agent: O=C1CCC(=O)N1Br
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccsc3)cc21

Procedure:
2,2,4-Trimethyl-6-thiophen-3-yl-1,2-dihydroquinoline was brominated with NBS using the procedure described in Example 1 and then coupled with allyl mercaptan using the procedure described in Example 2 to provide 22 mg of the title compound as a oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH2:29][CH3:30])[CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[CH2:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH2:29][CH3:30]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCCC1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 131 was coupled with tyramine following procedure F. The product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 432. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.35 (s, 1H) 8.29 (d, 2H) 8. 7.81 (d, 1H) 7.68 (t, 1H) 7.49 (d, 1H) 7.2-7.2 (m, 3H) 6.68 (d, 2H) 4.8 (d, 1H) 4.17 (d, 1H) 3.85 (br s, 2H) 3.68 (d, 1H) 3.1-3.6 (m, 6H) 2.9 (t, 2H) 2.2 (m, 1H) 1.9 (m, 1H) 1.38-1.65 (m, 1H) 1.05 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[F:11][C:12]([F:16])([F:15])[CH2:13]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH2:13][C:12]([F:16])([F:15])[F:11])=[CH:5][C:3]=1[NH2:4]
Reactant: FC(F)(F)CI
Reactant: Cc1cc(Cl)c(N)cc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
A mixture of 9.4 g of 2-chloro-4-methyl-5-mercaptoaniline, 20 g of 2,2,2-trifluoroethyl iodide, 13 g of potassium carbonate and 200 ml of N,N-dimethylformamide was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 13.5 g of 2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)aniline.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:21])[NH:8][C:9]1([C:12](=[O:20])[NH:13][C:14]2([C:17](=[NH:19])[NH2:18])[CH2:16][CH2:15]2)[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN(C)[CH:24]=[C:25]([I:28])[CH:26]=O.CNC.C1COCC1>CCO.CCOCC>[C:2]([O:6][C:7](=[O:21])[NH:8][C:9]1([C:12](=[O:20])[NH:13][C:14]2([C:17]3[N:18]=[CH:26][C:25]([I:28])=[CH:24][N:19]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN(C)C=C(I)C=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 18.4 %

Procedure:
To a solution of [1-(1-carbamimidoyl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester hydrochloride (1.65 g, 5.2 mmol) in anhydrous EtOH (21 mL), was added 3-dimethylamino-2-iodo-propenal (1.3 g, 5.63 mmol) and 2M dimethylamine in THF (3.36 mL, 6.7 mmol). The vessel was capped and heated at 70° C. overnight. After 18 h, EtOH was removed in-vacuo and the dark orange residue was triturated with 5% iPrOH in EtOAc. A yellow solid was filtered off. The filtrate was concentrated in vacuo and purified by normal phase flash chromatography on silica gel (0→5% MeOH/CH2Cl2) to yield a black oil. This oil was treated with Et2O to precipitate a white solid. The solid was filtered off and the filtrate was reprocessed to give another crop of slightly darker solids. A total of 426 mg of {1-[1-(5-iodo-pyrimidin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester was isolated, m/z 445.5 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([C:23](O)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([N:3]1[CH:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])=[O:24]
Reactant: CC1CCCC(CCOc2ccccc2)N1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: CC1CCCC(CCOc2ccccc2)N1C(=O)c1ccccc1-c1ccccc1

Procedure:
The title compound was prepared according to general procedure A using 2-methyl-6-(2-phenoxyethyl)piperidine and biphenyl-2-carboxylic acid. MS (ESI) 400 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:25]=[CH:24][C:18]3[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38]([C:30]1[CH:31]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=4[CH:16]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:27])[CH:3]=2)[CH:33]=[CH:34][C:29]=1[F:28])=[O:39])[CH3:42]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 133, step 3) by Suzuki coupling with 4-fluoro-3-ethoxycarbonylphenylboronic acid [CAS Reg. No. 874219-36-0]. The title compound was used without further analysis.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:25])[CH2:14][C@:15]4([CH3:24])[C@@H:19]([C:20](CO)=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:24][C@:15]12[CH2:14][C:13](=[O:25])[C@H:12]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:2]3([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=4)[C@@H:16]1[CH2:17][CH2:18][C@@H:19]2[C:20]([OH:28])=[O:21]
Reactant: CC(C)=O
Reactant: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O

Procedure:
Alternatively, corticosterone, in an appropriate solvent such as acetone, may be treated directly with Jones reagent to yield androst-4-ene-3,11-dione-17β-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:16]2[O:17][CH2:18][CH:19]([OH:20])[CH:15]2[O:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:20][CH:19]1[CH2:18][O:17][CH:16]2[CH:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][O:14][CH:15]12)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OC1COC2C(OCCOCc3ccccc3)COC12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1COC2C(OCCOCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a suspension of 6-(2-(benzyloxy)ethoxy)hexahydrofuro[3,2-b]furan-3-ol (1.50 g, 5.36 mmol) in anhydrous DCM (20 mL) was added N,N-diethylethanamine (1.20 mL, 8.60 mmol) and N,N-dimethylpyridin-4-amine (0.13 g, 1.07 mmol) under the nitrogen atmosphere, and the mixture was cooled down to 0° C. To the mixture was added methanesulfonyl chloride (0.50 mL, 6.50 mmol) at 0° C., and then the mixture was moved to room temperature and stirred overnight. The mixture was diluted with DCM (50 mL), washed with brine (50 mL) and dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as yellow liquid (1.81 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(Cl)Cl.B(Br)(Br)Br>CO>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=Cc1ccc(O)c(O)c1Cl

Procedure:
To a stirred solution of 25 g. (0.134 m.) of 2-chloroisovanillin in 80 ml. of methylene chloride at 0°C. is added dropwise 19 ml. (0.2 m.) of boron tribromide and the mixture is stirred at 25°C. for 3 hours. Methanol (100 ml.) is added and the solution is concentrated to give 2-chloroprotocatechualdehyde, m.p. 193°-195°C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[C:34]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>O1CCOCC1>[F:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)=[CH:33][C:34]=1[C:35]1[N:36]=[CH:37][CH:38]=[CH:39][N:40]=1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Reactant: CC1(C)OB(c2cnc(F)c(-c3ncccn3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(F)c(-c4ncccn4)c3)cc2)[C@H]1c1ccccc1
Temperature: 110 °C

Procedure:
(S)-3-(4-Iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(2.61 g, 6.64 mmol), sodium carbonate (6.64 mL, 13.28 mmol), 2-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)pyrimidine (Intermediate H) (2 g, 6.64 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.542 g, 0.664 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (16.60 mL) and stirred at 110° C. overngight. LC-MS indicated that there was complete conversion to the desired product. The final reaction material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide (S)-3-(4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as yellow solid. m/z (ESI) 441.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([C:20](=[O:22])[NH2:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N:11]1([C:14]2[CH:19]=[N:18][C:17]([C:20]([NH2:21])=[O:22])=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(C(N)=O)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cnc(N2CCNCC2)cn1

Procedure:
0.25 mmol of 5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was stirred for 1 hour in 1 ml of dioxane saturated with gaseous HCl. Concentration of the reaction mixture led to the title compound, as a colorless solid. MS (m/e): 208.3 (MH+, 100%)