Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:26][C:27]1[N:28]=[C:29]2[N:33]([C:34]=1[S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:31][S:30]2>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:35]([C:34]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[Cl:26])(=[O:36])=[O:37])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1c(Cl)nc2sccn12
Yield: 64.1 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92) (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 149 mg, 0.58 mmol) in THF. 172 mg (65%) of 98 was obtained as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH:29]([OH:33])[CH2:28]2)=[O:25])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl.O1CCCC1.O>[Cl:11][C:12]1[C:13]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]2)=[O:25])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1
Reactant: O=C(NC1CCCC(O)C1)c1noc(-c2ccc(F)cc2)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCC(NC(=O)c2noc(-c3ccc(F)cc3)c2Cl)C1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 18.9 %

Procedure:
A solution of oxalyl chloride (30 μL, 0.34 mmol) in dichloromethane (1 mL) was cooled to −78° C. A solution of dimethylsulfoxide (48 μL, 0.675 mmol) in dichloromethane (0.5 mL) was added drop wise and the mixture was stirred for 5 minutes at −78° C. A solution of 4-chloro-5-(4-fluorophenyl)-N-(3-hydroxycyclohexyl)isoxazole-3-carboxamide (104 mg, 0.307 mmol) in tetrahydrofuran (3 mL) and (0.5 mL) dichloromethane was added over 5 minutes and the reaction mixture was to stirred for 15 minutes at −78° C. Triethylamine (0.215 mL, 1.53 mmol) was added and the reaction was stirred for 10 minutes at −78° C., then allowed to warm to room temperature and stir for an additional 20 minutes. Water was added and the mixture was extracted three times with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, concentrated in vacuo, and purified by silica gel chromatography, eluting with 2% methanol in dichloromethane to give the title compound (19.7 mg, 0.058 mmol). MS (ESI) m/z (M+H+): 337.2/339.2
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[OH:32][C:33]1([C:40]2[S:41][CH:42]=[CH:43][N:44]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:36]3[CH2:35][CH2:34][C:33]([OH:32])([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)[CH2:38][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:10]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)C(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyl 3-(3-cyanophenyl)-3-oxopropionate (0.91 g, 4.48 mmol) in 20 mL of carbon tetrachloride at 0° C. was added N-bromosuccinimide (0.80 g, 4.48 mmol). The resulting solution was allowed warm to 25° C. and was stirred for 2 h. The insoluble succinimide was filtered off and the solution was concentrated in vacuo to afford an oil (1.2 g, 95%) which was sufficiently pure to be used without purification. MS(H2O GC-MS) 282/284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[K].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([SH:27])[CH:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Reactant: Sc1cccnc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1C
Reaction time: 0.5 h

Procedure:
To a solution in DMF (2 mL) of 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (275 mg, 1.0 mmol) was added 3-pyridinethiol potassium salt (224 mg, 1.5 mmol). The reaction mixture was stirred for 30 minutes and then was poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (40% ethyl acetate-hexanes) gave 4-(3-pyridylthiomethyl)-2-(2-methylphenyl)benzoic acid methyl ester which was converted to the title compound by saponification of the methyl ester, coupling with methionine methyl ester hydrochloride, and saponification as described in Examples 319I-J. 1H NMR (300 MHz, DMSO-d6) δ 12.53 (bs, 1H), 8.49 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.79 (dt, 1H), 7.43 (s, 2H), 7.31 (dd, 1H), 7.19 (m, 2H), 7.11 (m, 2H), 7.05 (m, 1H), 4.36 (s, 2H), 4.20 (m, 1H), 1.92-2.23 (m, 8H), 1.66-1.90 (m, 2H). MS (CI, NH3) m/e 467, 449. Anal calcd for C25H26N2O3S2: C, 64.35; H, 5.62; N, 6.00. Found: C, 64.00; H, 5.62; N, 5.89.
Reaction SMILES: [Si:1]([C:8]1[C:13]([Cl:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[CH:22][CH:23]=2)=O)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].O.[NH2:32][NH2:33]>O1CCOCC1>[Si:1]([C:8]1[C:13]([Cl:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:33][N:32]=2)[C:9]=1[F:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(C(=O)c2cccnc2F)nc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)c1c(F)c(-c2n[nH]c3ncccc23)nc(F)c1Cl
Yield: 89.7 %

Procedure:
[4-[tert-butyl(dimethyl)silyl]-5-chloro-3,6-difluoro-2-pyridyl]-(2-fluoro-3-pyridyl)methanone (294.86 g, 762.2 mmol) was dissolved in dioxane (2.212 L) and calcium carbonate (152.5 g, 1.524 mol) was added. The reaction was cooled in an ice bath and hydrazine hydrate (190.8 g, 185.4 mL, 3.811 mol) was added dropwise over 15 minutes via cannula to the yellow suspension keeping the internal temperature below 10° C. During addition, the internal temperature dropped to 7.1° C. and the colour changed from light yellow to mango orange. The resulting mixture was allowed to warm to ambient overnight. Lc/Ms after this time indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite, washing copiously with dichloromethane (ca 2.5 L). Water (400 ml) was added to the filtrate followed by a saturated solution of sodium bicarbonate (400 mL). The organic phase separated and washed again with a saturated aqueous sodium bicarbonate (350 mL). The combined aqueous layers were back-extracted with dichloromethane (2×400 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was slurried in petroleum ether, filtered and dried (81 g). The Celite was further washed with dichloromethane/methanol 7:1 (3×800 ml) and with 4 L of dichloromethane/methanol 4:1 until no remaining compound was observed on TLC. The filtrate was concentrated in vacuo. The residual solid was triturated with Petroleum ether as described above (185 g). The solids were combined and dried at 40° C. under vacuum. This gave the title compound as an off-white solid (260.5 g, 89%); 1H NMR (CDCl3) 0.63 (6H, d), 1.07 (9H, s), 7.44 (1H, m), 8.76 (1H, m), 9.07 (1H, m), 13.31 (1H, brs); 19F NMR (decoupled) −104.7, −73.8; MS ES (+) 381.1 (M+1).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][NH:18][C:17](=O)[CH:16]=[C:11]23)=[CH:4][CH:3]=[N:2]1.O=P(Cl)(Cl)Cl.[CH:28]1([C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[CH2:30][CH2:29]1.N1C=CC=CC=1>ClCCCl>[CH:28]1([C:31]2[N:32]=[CH:33][N:34]([C:17]3[CH:16]=[C:11]4[C:12]5[C:7]([CH2:8][CH2:9][N:10]4[C:20](=[O:21])[CH2:19][N:18]=3)=[C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)[CH:15]=[CH:14][CH:13]=5)[CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C1C=C2c3cccc(-c4ccno4)c3CCN2C(=O)CN1
Reactant: c1nc(C2CC2)c[nH]1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4ccno4)c3CCN12
Temperature: 100 °C
Yield: 35.2 %

Procedure:
Example 100. A solution of 9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCl3 (57 μL, 0.61 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and 4-cyclopropyl-1H-imidazole (50 mg, 0.46 mmol) and pyridine (74 μL, 0.91 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 0:100 and DCm/MeOH 99:1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.67-0.79 (m, 2 H); 0.80-0.91 (m, 2 H); 1.80-1.91 (m, 1 H); 3.17 (t, J=6.06 Hz, 2 H); 3.90 (t, J=6.19 Hz, 2 H); 4.37 (s, 2 H); 6.47 (s, 1 H); 6.63 (s, 1 H); 7.18 (s, 1 H); 7.50 (t, J=7.83 Hz, 1 H); 7.70-7.83 (m, 2 H); 7.88 (s, 1 H); 8.38 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]([CH3:37])[C@@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=O)[CH2:4][OH:5].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:35][O:34][CH2:33][C@H:32]([CH3:36])[O:31][C:16]1[CH:15]=[C:14]([C:11]2[NH:10][C:9]([C:7]3[O:5][CH2:4][C@@H:3]([C@@H:2]([OH:1])[CH3:37])[N:6]=3)=[CH:13][CH:12]=2)[CH:19]=[C:18]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
N-[(1S,2S)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.24 g, 2.32 mmol) synthesized in Example (93a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.63 g, 3.49 mmol) and triethylamine (0.97 mL, 6.97 mmol) were added at 0° C., followed by stirring for 1 hour under nitrogen atmosphere. The temperature was raised naturally, and stirring was carried out at room temperature for 2 hours, followed by stirring at 50° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired compound (800 mg, yield 67%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC(=O)[NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:45].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:45].[ClH:45].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:30]3[CH2:31][CH2:32][CH:28]([NH2:27])[CH2:29]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: O
Product: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)C1
Temperature: 60 °C
Yield: 52.8 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (800 mg, 2.66 mmol) obtained in Step 6 of Example 1, (pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.00 g, 5.32 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (720 mg, 3.72 mmol) and N-methylmorpholine (0.58 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (5.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (2.00 mL), followed by heating under reflux at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 122 (398 mg, 38%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[CH3:21])[C:14]([C:4]1[C:3](=[O:24])[C:12]2[C:7](=[N:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:23]
Reactant: COC(=O)C(=CNc1cccc(C)n1)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2n1
Yield: 62 %

Procedure:
Experimental conditions analogous to those described for Step 2 of Example 1 were used with 0.59 g (1.82 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(6-methyl-pyridin-2-ylamino)-acrylic acid methyl ester in 30 mL of diphenyl ether to yield 0.33 g of 3-(3,4-Dimethyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one as a brown solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])=[CH:3][C:4]=1[CH3:11])([O-:10])=[O:9]
Reactant: NCCNCCO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCNCCO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 42.1 %

Procedure:
2 g of 4-fluoro-2-methyl-nitrobenzene, 1.61 g of 2-(2-aminoethylamino)ethanol and 2.14 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 1.3 g of 2-[2-(4-nitro-3-methylphenylamino)ethylamino]ethanol (7) were obtained.
Reaction SMILES: [CH:1](/[C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH3:6]>C(O)(C(F)(F)F)=O>[CH:1](/[C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC/C=C/c1cnc2ccc(NCCCNC(=O)OC(C)(C)C)nn12
Solvent: O=C(O)C(F)(F)F
Product: CCCC/C=C/c1cnc2ccc(NCCCN)nn12
Yield: 29 %

Procedure:
The product from step B was stirred in TFA (3 mL) for 3 h. The reaction mixture was concentrated and partitioned between ethyl acetate and saturated sodium carbonate solution and the organic layer removed and concentrated. Purification by column chromatography (12 g ISCO column eluting with methylene chloride and methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 70% methylene chloride over 30 min at 25 mL/min) provided the title compound (26 mg, 29%) as a yellow solid; 1H NMR (500 MHz, CD3OD) δ 7.56 (d, J=9.6 Hz, 1H), 7.45 (s, 1H), 6.69-6.61 (m, 3H), 3.51 (t, J=6.4 Hz, 2H), 3.07 (t, J=7.4 Hz, 2H), 2.29-2.27 (m, 2H), 2.06 (m, 2H), 1.50-1.43 (m, 4H), 0.96 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.3, 133.2, 128.8, 128.6, 125.7, 116.7, 113.6, 39.5, 39.0, 34.4, 32.9, 27.9, 23.4, 14.3 (one aromatic carbon overlapping); HPLC tR=10.9 min (Luna), 94.7%; ES-MS: (M+H)=274 m/z.
Reaction SMILES: C[O:2][C:3]([C@:5]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[CH:10]([C@:11]3([CH3:36])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)=[O:4].[Br-].[Li+]>CN(C=O)C>[C:30]([C:29]1[CH:28]=[C:27]([C:14]2[C:15]([CH3:26])([CH3:25])[C@H:16]3[C@:11]([CH3:36])([CH2:12][CH:13]=2)[CH:10]2[C@:19]([CH3:24])([C@@:20]4([CH3:23])[C@H:7]([CH2:8][CH2:9]2)[C@H:6]2[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:5]2([C:3]([OH:4])=[O:2])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)[CH:35]=[CH:34][CH:33]=1)([OH:32])=[O:31]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OC)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6cccc(C(=O)O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(c6cccc(C(=O)O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 18.3 %

Procedure:
A mixture of 3-((1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-3a-(methoxycarbonyl)-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)benzoic acid (140 mg, 0.244 mmol) and lithium bromide (425 mg, 4.89 mmol) in DMF (2 mL) was heated to 100° C. for 2 days. TLC indicated starting material was consumed and desired product was observed. The reaction mixture was filtered and the clear solution was purified by HPLC to provide the desired product (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-9-(3-carboxyphenyl)-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 as a white solid (25 mg, 17%). LCMS: m/e 557.48 (M−H)−, 5.67 min (method 6). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (s, 3H), 0.91 (s, 3H), 0.96 (s, 3H), 0.98 (s, 3H), 1.00 (s, 3H), 1.01-1.76 (m, 17H), 1.68 (s, 3H), 1.79-1.89 (m, 2H), 2.04-2.19 (m, 2H), 2.27-2.32 (m, 1H), 2.93-3.05 (m, 1H), 4.59 (s, 1H), 4.73 (d, J=2.01 Hz, 1H), 5.26 (d, J=4.77 Hz, 1H), 7.29-7.35 (m, 1H), 7.40 (t, J=7.65 Hz, 1H), 7.66 (s, 1H), 7.83 (d, J=7.53 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
4-(Benzyloxy)phenol (2.89 g, 0.01443 mol) in dimethylformamide (15 ml) and 2-(dimethylamino)ethyl chloride hydrochloride (2.32 g, 0.01611 mol) were added simultaneously in small portions to a 55-65% sodium hydride dispersion in mineral oil (0.033 mol) in dimethylformamide (5 ml) at 0° C. Then the mixture was allowed to warm to 90° C., and stirring was continued for 1.5 h. The cooled mixture was poured into water. The resultant mixture was extracted with toluene. The combined extracts were washed with 2.5 M NaOH and water and dried over Na2SO4. Toluene was evaporated and the residual product was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][CH:13]=[C:14]([CH3:16])[N:15]=1)[C:5]([OH:7])=[O:6].C(O)(=O)C.[Br:21]Br.S(=O)(O)[O-].[Na+]>>[Br:21][C:13]1[S:12][C:11]([C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH3:1])=[N:15][C:14]=1[CH3:16]
Reactant: Cc1csc(-c2ccc(C(=O)O)cc2C)n1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)ccc1-c1nc(C)c(Br)s1
Yield: 87 %

Procedure:
3-Methyl-4-(4-methylthiazol-2-yl)benzoic acid (all recovered product from step A above) was dissolved in acetic acid (20 mL, 349 mmol), and bromine (1.774 mL, 34.4 mmol) was added. After sonicating for 5 minutes, LCMS showed complete conversion. Excess sodium bisulfite was added to the reaction solution until the red color disappeared. The suspension was filtered, and the filtrate was concentrated. The crude was purified on a silica gel column, eluting with 30% ethyl acetate, to give title compound as a white solid (6.2 g, 87% yield). LCMS (M+H)+: 313.9. 1H NMR (DMSO, 500 MHz): δ 7.90 (s, 1H), 7.85 (s, 2H), 2.56 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:23])[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([CH3:21])[CH2:14][CH:13]([CH3:22])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:23])[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH3:21])[CH2:14][CH:13]([CH3:22])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)C1=C(C)CC(C)CC1(C)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: CC1=C(C(=O)O)C(C)(c2ccc(Cl)c(Cl)c2)CC(C)C1

Procedure:
Following the procedure of Step 7, Example 1-3, (except that potassium hydroxide was used in place of sodium hydroxide), methyl (4RS,6RS)-6-(3,4-dichlorophenyl)-2,4,6-trimethylcyclohex-1-enecarboxylate was converted to Example 6. Mass spectrum m/z 313.14 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[CH3:5].[OH-].[K+].Cl>C(O)C.O>[Cl:24][C:8]1[CH:9]=[C:10]([F:23])[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)=[CH:12][C:7]=1[O:6][CH:4]([CH3:5])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2cc(OC(C)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture of 1.3 g (0.0034 mole) of methyl-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate and 1.0 g (0.018 mole) of potassium hydroxide in 15 mL of ethanol and 15 mL of water was heated at reflux for three hours. The mixture was allowed to cool to room temperature and stand for two days. The solvent was evaporated from the mixture leaving a solid. This solid was dissolved in water, and the solution was made acidic with concentrated hydrochloric acid. This solution was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent from the filtrate left 0.85 g of 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionic acid as a solid (mp 50°-55° C.), Compound A2.