Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.Cl[C:9]([O:11][CH3:12])=[O:10]>>[CH3:12][O:11][C:9]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10]
Reactant: COP(OC)OC
Reactant: COC(=O)Cl
Product: COC(=O)P(=O)(OC)OC

Procedure:
One hundred and thirty parts of trimethyl phosphite are heated to 125° C. and treated with 100 parts of methyl chloroformate at a rate sufficient to maintain a reaction temperature of at least 100° C. After gas evolution stops, the residue is distilled to obtain 131 parts of dimethyl methoxycarbonylphosphonate, b.p. 83°-85° C./1.2 mm., nD25 = 1.4210.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([C:22]([N:24]1[CH2:47][CH2:46][CH2:45][C@H:25]1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[N:40]1[CH:44]=[N:43][N:42]=[N:41]1)=[O:27])=[O:23])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O)(C)(C)C>C(Cl)Cl>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][C@H:16]([C:22]([N:24]1[CH2:47][CH2:46][CH2:45][C@H:25]1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=1[N:40]1[CH:44]=[N:43][N:42]=[N:41]1)=[O:27])=[O:23])[NH2:15]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (1 mL) was added to a solution of N-(tert-butoxycarbonyl)-4-methyl-D-leucyl-N-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)benzyl]-L-prolinamide (32 mg, 0.06 mmol) in dry CH2Cl2 (3 mL). The solution was stirred at room temperature for 30 min and was then concentrated in vacuo. The title compound was isolated by reverse phase HPLC as a white foam. 1H NMR (400 MHz, CD3OD)): δ 9.62 (s, 1H), 8.03 (s, 1H), 7.89 (dd, J=1.5, 8.2 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 4.42 (d, J=15.6 Hz, 1H), 4.35 (d, J=15.6 Hz, 1H), 4.30 (dd, J=3.7, 8.6 Hz, 1H), 4.17 (apparent t, J=6.4 Hz, 1H), 3.83–3.78 (m, 1H), 3.62–3.56 (m, 1H), 2.25–2.18 (m, 1H), 2.15–1.85 (m, 4H), 1.64 (dd, J=6.8, 14.8 Hz, 1H), 1.01 (s, 9H). HRMS (ESI, M+H): 468.2324 (found); 468.2335 (calculated).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([C:17](Br)(CC)[C:18]([O-:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:18]([CH2:17][CH2:15][CH2:16][O:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)([OH:20])=[O:19]
Reactant: CCC(Br)(CC)C(=O)[O-]
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)CCCOc1ccc2oc3ccccc3c2c1

Procedure:
2-Hydroxydibenzofuran (0.5 gm, 2.7 mmol), ethylbromobutyrate (0.78 mL, 5.4 mmol), potassium carbonate (1.1 gm, 8.1 mmol), and sodium iodide (10 mg) were combined in 2-butanone (15 mL). The reaction was refluxed until complete, then the reaction filtered and the solvent removed under reduced pressure. The residue was taken up in 6M aqueous KOH/methanol, 1:1. After the hydrolysis was complete the reaction was acidified to pH 3 and the product extracted with ethyl acetate. The residue was purified by column chromatography (silica gel, ethyl acetate/hexanes/acetic acid, 10:30:60:0.5). The yield was 0.52 gm of product. Mass spectrum: DCI/NH3, (m+H)+ @ m/z 271, (m+NH4)+ @ m/z 288, (m+NH4 ·NH3)+ @ m/z 305.
Reaction SMILES: [CH:1]([O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6])([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO.O>[CH:1]([O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1)[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)OC(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)OC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
To the solution of methyl 4-(1-isopropoxyethyl)benzoate (161 mg, 0.73 mol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (50 mg, 2.1 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (50 mL*3), evaporated the solvent to give 4-(1-isopropoxyethyl)benzoic acid (137 mg, 90%)
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]CCCCCCC.C(C=O)=O.[C:36]([OH:55])(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C1(C)C=CC=CC=1.C(O)C>[C:48]1([CH3:47])[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=1[NH:31][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:12][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[C:36]([OH:55])(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: Cc1ccccc1-c1c[nH]nn1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=CC=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1NCCCCCCCC/C=C\CCCCCCCCc1c[nH]nn1
Yield: 343.6 %

Procedure:
Approximately 53 grams (0.4 mole) tolyltriazole, 111 grams (0.4 mole) oleyl amine, 100 ml ethanol, and 100 ml toluene were charged to a 1 liter flask equipped with an agitator, Dean-Stark apparatus, and dropping funnel. This mixture was stirred to a homogeneous mixture. Glyoxal (29 grams, 0.2 mole, 40% in water) was added dropwise and then stirred at room temperature for 12 hours. Water was then azeotropically removed by heating to reflux temperatures of approximately 100°-120° C. While maintaining a temperature of less than or equal to 60° C., 56 grams (0.2 mole) oleic acid was added slowly. The reaction mixture was stirred at 60° C. for 1 hour. The orange product (243 grams) was isolated by filtration and removal of solvent under reduced pressure.
Reaction SMILES: [CH:1]([O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])[CH3:2]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH2:15][C:11]1[CH:10]=[C:9]([S:6]([NH:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)ONS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: CC(C)ONS(=O)(=O)c1cccc(N)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a Parr H2 vessel containing 5% Pd/BaSO4 (0.350 g) was added a methanolic solution (125 mL) of N1-isopropoxy-3-nitro-1-benzenesulfonamide (3.50 g, 0.0135 mol) at rt under Ar atm. The solution was hydrogenated at 45 psi for approx. 1.0 h. The reaction mixtire was filtered (½″ celite pad) and evaporated to give the product as yellow crystalline solid 2.90 g (96%). 1H NMR (CDCl3) 1.20(d,25H); 4.27(m, 1H); 7.05(s,1H); 7.75(1,1H); 8.22(d, 1H); 8.48 (dd,1H); 8.74(t, 1H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[N:13]([CH3:24])[C:12]=2[CH:11]=[CH:10][C:9]=1[O:25][CH3:26])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:34](N1CCCCC1)=[O:35].COC1C(C(C)(C)O[SiH2]C(C)(C)C)(C=O)C2SC3C(=CC=C(OC)C=3)N(C)C=2C=C1.[BH4-].[Li+]>C(OCC)C.O1CCCC1.O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[C:9]([O:25][CH3:26])=[CH:10][CH:11]=[C:12]2[C:21]=1[S:20][C:19]1[C:18]([CH2:34][OH:35])=[C:17]([O:22][CH3:23])[CH:16]=[CH:15][C:14]=1[N:13]2[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2C
Reactant: O=CN1CCCCC1
Agent: COc1ccc2c(c1)SC1=C(C=CC(OC)C1(C=O)C(C)(C)O[SiH2]C(C)(C)C)N2C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1CO)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2C
Temperature: 0 °C
Yield: 67.6 %

Procedure:
A solution of 4.56 g (10.9 mmol) of 4-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-10-methyl-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 7.5 ml of n-butyllithium solution (1.6M in hexane) and 1.89 g (16.84 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1c. The resulting 3,7-dimethoxy-4-(tert.butyldimethyl-silanyloxymethyl)-10-methyl-phenothiazine-4-carbaldehyde was dissolved in 50 ml of tetrahydrofuran and reduced with 12.0 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.8.b. The reaction mixture was poured into ice/1M sodium dihydrogen phosphate solution, whereupon the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:1), whereupon, after recrystallization from ethyl acetate/hexane and drying, 3.30 g (67.6%) of [6-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-10-methyl-phenothiazine-4-yl]methanol were obtained as a white solid of m.p. 46°-47°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C@@H:48]([N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[C:49](=[O:52])[NH:50][CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([C@@H:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[F:40])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.19 g; 0.78 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.12 g; 0.86 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.90 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.33 g; 0.78 mmol) and diisopropylethylamine (0.17 mL; 0.86 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 50 mL), water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.47 g of (2-((((1R)-1-(((1R)-2-(2-fluorophenyl)-1-methylcarbamoyl-ethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)methyl-carbamoyl)methoxy)-1,1-dimethylethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C(F)(F)F)c2)CCCC1=O
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 3-(trifluoromethyl)benzyl chloride (1.53 g, 6.0 mM) and sodium iodide (900 mg, 6.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.02 g (63%) of the 9-[(3-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.6 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 7.0 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1727 and 1652. MS (ES) m/e 400, 402.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C.O>[CH2:10]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([Cl:9])=[C:2]([Br:1])[N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)c(Br)n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(NCc2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 11A (500 mg, 2.410 mmol) in 1,2-dichloroethane (10 mL) and acetic acid (5 mL) was treated with benzaldehyde (281 mg, 2.65 mmol) and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (2.043 g, 9.64 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (25 mL), treated with saturated sodium bicarbonate solution, extracted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude title compound. Purification by column chromatography (silica gel, 15% ethyl acetate in hexane) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](OCC)(OCC)OCC>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 110 °C

Procedure:
A suspension of 2-amino-4-methylbenzamide (1.2 g, 8.0 mmol) in CH(OEt)3 (10 mL) was heated in a sealed tube at 110° C. for 4 h. Then the reaction was quenched with aq. NaHCO3 solution at rt and the precipitate obtained was filtered and dried. The solid mass was purified by column chromatography to afford 1.1 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.05 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[CH3:44][NH:45][S:46]([C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1)(=[O:48])=[O:47].B(O)O>>[CH3:40][C@:18]12[C@@:17]3([CH3:41])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:42])([CH3:43])[C:12]([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([S:46](=[O:48])(=[O:47])[NH:45][CH3:44])[CH:50]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24][C@@H:23]1[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(S(=O)(=O)NC)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 3-(N-methylsulfamoyl)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (32.47 mg, 62%). LCMS: m/e 606.58 (M−H)−, 4.47 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.94 (s, 3H), 0.95 (s., 3H), 1.00 (br. s., 6H), 1.03 (s, 3H), 1.04-1.78 (m, 17H), 1.71 (s, 3H), 1.88 (t, J=7.03 Hz, 2H), 2.14 (dd, J=17.28, 6.15 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.31-2.39 (m, 1H), 2.46 (d, J=4.69 Hz, 3H), 2.99-3.08 (m, 1H), 4.61 (s., 1H), 4.74 (s, 1H), 5.34 (d, J=5.86 Hz, 1H), 7.39 (d, J=8.20 Hz, 1H), 7.46 (q, J=5.27 Hz, 1H), 7.51-7.58 (m, 2H), 7.71 (d, J=7.62 Hz, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.[ClH:22].O1CCOCC1>O1CCOCC1>[ClH:22].[NH2:8][CH2:9][CH2:10][S:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCSc1noc2ccc(F)cc12
Agent: Cl
Solvent: C1COCCO1
Product: NCCSc1noc2ccc(F)cc12
Temperature: 5 °C

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethylthio)-5-fluoro-1,2-benzisoxazole (0.20 g) in dioxane (2 ml) was added 4N-hydrochloric acid/dioxane solution (0.8 ml) with stirring at 5° C., and the mixture was then stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol and ethyl acetate, to give the title compound (0.14 g) as a colorless needle.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]1(B(O)O)[C:29]2[C:30]3=[C:31]4[C:26](=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]4[CH:21]=[CH:20][C:19]3=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2[C:22]3[C:31]4=[C:30]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:29]5[CH:28]=[CH:27][C:26]4=[CH:25][CH:24]=2)=[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: COc1ccc(Br)c(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)c(-c2ccccc2)c1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 11.1 g (42.4 mmol) of 2-bromo-5-methoxybiphenyl, 10.43 g (42.4 mmol) of pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 12.4 g (76%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=[O:3])[CH3:2].[OH-:22].[K+].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]([NH2:19])=[O:22])[C:9]=1[C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cc(F)cc(F)c1
Yield: 29 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (0.20 g, 0.65 mmol) and potassium hydroxide (0.074 g, 1.3 mmol) in ethanol (0.9 mL) was refluxed for 2 hours. After cooled, the mixture was acidified with 1 N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 80% ethyl acetate in hexane, to yield the desired product (61 mg, 29%). LCMS calculated for C16H13ClF2NO2 (M+H)+: m/z=324.1. found: 324.0.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[CH:22]=[CH:23][C:24](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COCOc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Yield: 66.7 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.0 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil and 4.63 g (19.4 mmol) of 3-methoxy-4-methoxymethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 5.06 g (yield 67%) of Compound 194 as pale yellow flocculent precipitates.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[C:8]=1[CH:9]=[O:10])[CH3:6].[Br:17]Br>ClCCl>[Br:17][C:14]1[C:7]([CH2:5][CH3:6])=[C:8]([C:11]([CH2:15][CH3:16])=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: BrBr
Reactant: CCc1cccc(CC)c1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(Br)c(CC)c1C=O
Temperature: 40 °C

Procedure:
To a solution of 8.01 g (60 mmol) aluminum trichloride in 10 ml dichloromethane were added at ambient temperature drop-wise 5.52 g (34 mmol) 2,6-diethyl-benzaldehyde (Example 1 c)); exothermic reaction. To the resulting dark red solution was added slowly drop-wise a solution of 5.5 g (34 mmol) bromine in 7 ml dichloromethane; strong exothermic reaction. Then the mixture was heated to 40° C. for 3 hours. The reaction mixture was cooled to ambient temperature and poured onto ice. The organic phase was separated and the aqueous solution extracted with dichloromethane, the combined extracts washed with 2N HCl solution, saturated sodium bicarbonate solution and brine, dried over MgSO4, filtered and evaporated: 7.0 g 3-bromo-2,6-diethyl-benzaldehyde of 90% purity (HPLC) that did not require further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH3:16].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH3:16]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)[nH]c2ccc(F)cc12

Procedure:
Ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate (8.3 g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture of ethanol (20 mL) and water (15 mL) was heated at reflux for 1 hour. The volume was reduced to 10 mL under reduced pressure and the solution brought to an acidic pH with a 3N aqueous solution of hydrochloric acid. The resulting precipitate was filtered, washed with water (100 mL) and dried in vacuo at 80° C. overnight to afford 5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ES) m/z 192.0