Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.CO.C[N:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+]([O-])=O)[C:6]1=O.[C:18]([O:22][C:23]([N:25]1[CH2:30]CC(=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][C:6]2[N:5]=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:7]=2[CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2M solution of NH3 in MeOH (225 mL, 452.25 mmol) was added to a reaction vessel containing 1-methyl-3,5-dinitro-1H-pyridin-2-one (6 g, 30.15 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, 33.15 mmol). The vessel was then sealed and the reaction was stirred for 24 h at 70° C. After the resulting mixture was cooled to RT, the solvent was removed to give crude product as yellow solid. After recrystallization in MeOH, the desired title compound was obtained as tan solid. MS (ES+): 280.1 (M+H)+. Calc'd for C13H17N3O4—279.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12](O)([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C(=O)O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)=C(C(=O)O)c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
A solution of 96.5 g of 2-(p-fluorophenyl)-3-hydroxy-3-methylbutyric acid in 200 ml of CH2Cl2 was cooled in an ice bath and then treated dropwise with 240 g of conc. sulphuric acid within 30 minutes, with the temperature being held at ≤20°. The CH2Cl2 was then removed to 20° on a rotary evaporator. The yellowish solution was stirred at 20° for a further 45 minutes and then poured into 1 kg of ice/water mixture while stirring well. The white precipitate was filtered off under suction, washed 3 times with 100 ml of water each time and twice with 100 ml of hexane each time and finally dried in a drying oven at 40° for 16 hours and at 100° for 2 hours. There were obtained 87.5 g of 2-(p-fluorophenyl)-3-methylcrotonic acid as a white powder of m.p. 124-126°; GC purity 99.9%; yield 95.6% based on p-fluorophenylacetic acid.
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:20][N:2]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Hydroxylamine hydrochloride (0.65 g, 9.42 mmol) was added to a suspension of ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (2.0 g, 7.85 mmol) in absolute ethanol (40 mL) and the reaction was heated to reflux for 4 hours. After cooling to room temperature, the resulting white solid was filtered, washed with water and cold ethanol and dried in vacuo to obtain ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (1.19 g, 4.73 mmol).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:37][CH2:36][C@H:35]1[C:38]([OH:40])=[O:39]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:37][CH2:36][C@H:35]4[C:38]([OH:40])=[O:39])=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC[C@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-2-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [C:1]1(=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:15])[CH:3]=[CH:2]1.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29](Br)Br.[I-].[Na+]>CN(C)C=O>[CH:27]1[C:28]2=[C:19]3[C:20](=[CH:21][CH:22]=[C:23]2[CH:24]=[CH:25][CH:26]=1)[CH:29]=[C:2]1[C:3]([C:4](=[O:15])[C:5]2[C:14]([C:1]1=[O:16])=[CH:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2)=[CH:18]3
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Reactant: BrCc1c(C(Br)Br)ccc2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc3ccccc3cc2C(=O)c2cc3c(ccc4ccccc43)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In an atmosphere of argon, 6.9 g (33 mmole) of 1,4-anthraquinone, 9.8 g (25 mmole) of 1-(bromomethyl)-2-(dibromomethyl)naphthalene and 25 g (660 mmole) of sodium iodide were dissolved into 85 ml of dry dimethylformamide. After the exothermic reaction was completed, the reaction solution was heated to 70° C. and stirred for 8 hours. After the reaction was completed, the formed crystals were separated by filtration and washed with methanol and water and light yellow needle crystals of 8,15-benzo[a]pentacenequinone were obtained in the quantitative amount.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[CH:3][N:4]([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cnnc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnnc1)c1csc(N)n1)C(=O)O
Yield: 9.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((4H-1,2,4-triazol-4-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (77 mg, 0.117 mmol), DCM (3 mL) and TFA (1 mL, 13.0 mmol) for 2 h. The crude residue purified by reverse phase prep HPLC (XBridge, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 ml/min), affording the title compound (5.6 mg, 10%) as a white powder. LCMS: m/z=500.8 (M−1); 1H NMR (400 MHz, D2O): δ 8.52 (s, 2H), 6.90 (s, 1H), 5.30 (d, J=5.6 Hz, 1H), 4.56 (m, 2H), 4.42 (q, 1H), 1.30 (s, 6H).
Reaction SMILES: C(O[CH:5]([C:24]1(Br)[C:30](=[O:31])[N:29]2[C@@H:25]1[S:26][CH:27]=[C:28]2[C:32]([O:34]CC1C=CC([N+]([O-])=O)=CC=1)=[O:33])[C:6]1[N:23]=[C:9]2[N:10]=[CH:11][C:12]3[CH2:17][N:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:14][C:13]=3[N:8]2[N:7]=1)(=O)C.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[CH2:21]([O:20][C:18]([N:16]1[CH2:15][CH2:14][C:13]2[N:8]3[N:7]=[C:6](/[CH:5]=[C:24]4\[C@@H:25]5[N:29]([C:30]\4=[O:31])[C:28]([C:32]([OH:34])=[O:33])=[CH:27][S:26]5)[N:23]=[C:9]3[N:10]=[CH:11][C:12]=2[CH2:17]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2c(cnc3nc(C(OC(C)=O)C4(Br)C(=O)N5C(C(=O)OCc6ccc([N+](=O)[O-])cc6)=CS[C@@H]54)nn23)C1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)N1CCc2c(cnc3nc(/C=C4/C(=O)N5C(C(=O)O)=CS[C@H]45)nn23)C1
Temperature: 3 °C

Procedure:
ethyl 2-[(acetyloxy)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-8,9-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-7(6H)-carboxylate (220 mg, 0.28 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phosphate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 2%; Yellow crystals; mp>250° C. (Dec); (M+H+Na) 449. 1H NMR (DMSO-d6) δ 8.61 (s, 1H), 7.01 (s, 1H), 6.90 (s, 1H), 6.44 (s, 1H), 4.74 (m, 2H, CH2), 4.13 (q, 2H, J=5.4 Hz), 3.84 (s, m, 2H, CH2), 1.22 (t, 3H, CH3, J=5.7 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: COc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Yield: 25.8 %

Procedure:
The title compound (0.095 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 3-methoxy-benzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15; found, m/z 368.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.32 (d, J=7.9 Hz, 1H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.84 (s, 1H), 6.80 (d, J=8.2 Hz, 1H), 5.57 (s, 2H), 3.79 (s, 3H), 3.48-3.46 (br m, 2H), 3.44-3.42 (br m, 2H), 3.33-3.31 (br m, 2H), 3.16-3.14 (br m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][C:32]([CH2:35][O:36][CH:37]([CH3:39])[CH3:38])=[CH:33][CH:34]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:30]=[N:31][C:32]([CH2:35][O:36][CH:37]([CH3:39])[CH3:38])=[CH:33][CH:34]=1
Reactant: CC(C)OCc1ccc(CN)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)OCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (408 mg, 0.96 mmol) with 3-aminomethyl-6-(iso-propoxy)methyl-pyridine (190 mg, 1.05 mmol) in toluene (8 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient) to obtain 7-chloro-6-[(6-iso-propoxymethyl-pyridin-3-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. MS (ES+) m/z: 456 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([C:15]([CH3:17])=[CH2:16])[CH:5]=1)([O-])=O.O>C1(C)C=CC=CC=1.Cl.[Fe]>[CH2:16]=[C:15]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][C:11]([F:12])([F:14])[F:13])[NH2:1])[CH3:17]
Reactant: C=C(C)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1cc(N)ccc1OC(F)(F)F
Yield: 95.4 %

Procedure:
To a solution of 4-nitro-2-(prop-1-en-2-yl)-1-(trifluoromethoxy)benzene (275 mg, 1.11 mmol) in toluene (9.85 mL) was added iron (1.24 g, 22.25 mmol) and concentrated HCl (3.38 μL, 0.11 mmol) (3 drops). The mixture was stirred vigorously under reflux and water (0.20 mL, 11.13 mmol) was added and the r×n was stirred at reflux for 2 hr. The crude mixture was filtered through celite and concentrated under reduced pressure. The crude was diluted with EtOAc and dried with Na2SO4, filtered and concentrated under reduced pressure to give 3-(prop-1-en-2-yl)-4-(trifluoromethoxy)aniline (230 mg). LCMS retention time=1.46 minutes (LC method 5); MS (m+1)=218.2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)cc1
Yield: 56.5 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (98 mg), 120 mg 6-(4-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 118 mg (57%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][OH:15]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=[O:15]
Reactant: Cc1cccc(-c2nc(CO)c(C)[nH]2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C=O)c(C)[nH]2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-methyl-2-m-tolyl-4-imidazolemethanol (13.0 gm., 0.064 mole), activated manganese dioxide (65 gm.) and methylene chloride (200 ml.) is stirred at room temperature for 20 hours. The reaction mixture is then filtered, the solvent removed in vacuo to afford 9.1 gm. (0.045 mole) of peach-colored solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:22]([CH3:36])[CH:21]=2)[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>CO>[CH3:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:8])=[CH:13][CH:12]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)=[C:22]([CH3:36])[CH:21]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2ccc(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)(C)C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(c2ccc(C(=O)NCCC(=O)O)s2)C(C)(C)C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A solution of 3-({5-[2,2-dimethyl-1-(2-methyl-4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (chiral Isomer 1) (36 mg, 0.067 mmol) in methanol (1.0 mL) is treated with 5N NaOH (0.067 mL) and shaken at rt overnight. The reaction is neutralized with 1N HCl (0.068 mL), and extracted into ethyl acetate (2×). The combined organic layers are dried and concentrated, giving the title compound (21.6 mg). MS (ES): 520.3 [M+H]+.
Reaction SMILES: C(Cl)Cl.[CH:4]12[CH2:9][CH:8]1[CH2:7][N:6]([C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[C:13]([C:27]([OH:29])=O)=[CH:12][N:11]=1)[CH2:5]2.[OH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:4]12[CH2:9][CH:8]1[CH2:7][N:6]([C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[C:13]([C:27]([NH:37][C@H:34]3[CH2:35][CH2:36][C@H:31]([OH:30])[CH2:32][CH2:33]3)=[O:29])=[CH:12][N:11]=1)[CH2:5]2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1F
Reaction time: 17 h

Procedure:
In the mixture of DCM (20 mL) and THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (580 mg, 1.62 mmol), trans-4-hydroxycyclohexylamine (187 mg, 1.62 mmol), TEA (485 mg, 4.79 mmol) and HATU (2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (743 mg, 1.95 mmol). The reaction was conducted at ambient temperature for 17 h. The solvent was removed by evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and concentrated to give a solid, which was purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-formamide as a faint yellow solid (200 mg, 27.1% yield).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:46][N:45]([CH3:47])[C:43](=[O:44])[CH2:42][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)CCl
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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]chrysen-9-yl)benzoate (50 mg, 0.092 mmol), 2-chloro-N,N-dimethylacetamide (33.5 mg, 0.276 mmol), potassium phosphate (78 mg, 0.368 mmol) and potassium iodide (36.6 mg, 0.221 mmol) in acetonitrile (1 mL) was heated at 120° C. for 33 h in a sealed tube. The reaction mixture was quenched with distilled water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a pale yellow solid (30 mg, 52%). LCMS: m/e 629.51 (M+H)+, 3.03 min (method 10). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:16]=2)=[C:5]([CH:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20]C)=[O:19])[N:4]([CH3:27])[N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:71]2[CH:75]=[C:74]([CH2:76][CH2:77][CH3:78])[S:73][CH:72]=2)O1.[OH-].[Li+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([O:22][CH:17]([C:5]1[N:4]([CH3:27])[N:3]=[C:2]([C:71]2[CH:75]=[C:74]([CH2:76][CH2:77][CH3:78])[S:73][CH:72]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:16]=1)[C:18]([OH:20])=[O:19])([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Reactant: CCCc1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc(-c2nn(C)c(C(OC(C)(C)C)C(=O)O)c2-c2ccc3c(c2)CCCO3)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a degassed solution of methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-(tert-butoxy)acetate (11i) (50 mg, 0.114 mmol) in dioxane (1 mL) was added Palladium (II) acetate (1.3 mg, 0.006 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.7 mg, 0.011 mmol). After stirring for 30 minutes at room temperature, potassium carbonate (47 mg, 0.343 mmol) in solution in water (0.25 mL) and 4,4,5,5-tetramethyl-2-(5-propylthiophen-3-yl)-1,3,2-dioxaborolane (11c) (40 mg, 0.160 mmol) were added and the reaction mixture was heated at 110° C. until consumption of the starting materials. Then lithium hydroxide (11 mg, 0.46 mmol) was added. The heating was maintained until completion of the reaction. The mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with ethyl acetate (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(3,4-dihyd ro-2H-1-benzopyran-6-yl)-1-methyl-3-(5-propylthiophen-3-yl)-1H-pyrazol-5-yl]acetic acid (example 11) (40 mg, 0.09 mmol, 75%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:1]1([O:7][C:17]2[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=2[C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(OC2CCCCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of cyclohexanol (46.8 grams, 0.467 mol) in anhydrous THF (1 L) was added sodium hydride (20.3 grams, 0.508 mol) at −40° C. under nitrogen. The reaction mixture was allowed to warm slowly to room temperature and stir for another 1 hour. It was then cooled down to −55° C. and 2,6-dinitrobenzonitrile (78.4 g, 0.406 mol) was added. The reaction was stirred at room temperature overnight, then cooled down to −20° C., and citric acid (23.4 grams, 0.122 mol) was added. The mixture was then poured into ice water (5 L) which contained citric acid (7.8 g, 0.041 mol), stirred for 15 minutes, and the precipitated product was collected by filtration. The crude product was recrystallized from isopropanol (750 mL, heated to boiling, then cooled down to 0° C.), filtered, washed with isopropanol (300 mL), then air dried to give 84.4 g yellow solid. The solid was dissolved in dichloromethane (169 mL) and filtered through a plug of alumina to give the title compound as a pale yellow solid (83.2 g, 83.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.4 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 4.75 (m, 1H), 7.79 (dd, J=2.0, 8.0 Hz, 1H), 7.84-7.91 (m, 2H).