Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C@H:23]1[CH2:28][C@H:27]([CH3:29])[CH2:26][NH:25][CH2:24]1.[I-].[K+]>CN(C)C=O>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][C@@H:27]([CH3:29])[CH2:28][C@H:23]([CH3:22])[CH2:24]2)=[CH:7][CH:8]=1)=[O:11]
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Reactant: C[C@@H]1CNC[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCN2C[C@@H](C)C[C@H](C)C2)cc1

Procedure:
A mixture of methyl 4-(3-chloropropoxy)benzoate (4.57 g), potassium carbonate (8.29 g), cis and trans-3,5-dimethylpiperidine (5.31 mL) and a catalytic amount of potassium iodide in N,N-dimethylformamide (100 mL) is stirred overnight at 100° C. The suspension is filtrated and the precipitate washed with ethanol. The filtrate is concentrated under reduced pressure and purified by chromatography over silica gel with a gradient of dichloromethane/methanol from 98/2 to 90/10. Fraction containing the expected products are pooled and concentrated under reduced pressure yielding 5.33 g of cis and trans-1-{3-[4-(methoxycarbonyl)phenoxy]propyl}-3,5-dimethylpiperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH:13]2[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]2)[CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([F:8])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:8][C:6]1[CH:5]=[C:4]([C@@H:9]([CH:13]2[CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18]2)[CH2:10][CH:11]=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=S1(=O)CCC([C@@H](CCO)c2cc(F)cc(F)c2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC[C@@H](c1cc(F)cc(F)c1)C1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-3-(3,5-difluorophenyl)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propan-1-ol (1.26 g) in dichloromethane (10 ml) was added Dess-Martin periodinane (588 mg) in one portion. The resulting mixture was stirred at room temperature for 2 hours. The mixture was partitioned between 1N NaOH solution and dichloromethane. The organics were dried and evaporated to give the title compound as an oil, which was subsequently used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH2:19][CH:20](O)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:21]([CH:20]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:18][CH2:19]1)[CH2:22][CH3:23]
Reactant: CCCC(O)CN
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCC1CN=C2C=CC(c3cccc(C(F)(F)F)c3)=NN21
Temperature: 130 °C

Procedure:
A mixture of 3.0 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 5.0 g of 1-amino-2-pentanol is heated at 130° C. for 18 hours, cooled, diluted with water and extracted with dichloromethane. As for Example 3, the obtained product is reacted with thionyl chloride and the ring is closed with potassium carbonate in ethanol to give 2,3-dihydro-3-propyl-6-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to give the product of the Example.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 8 h

Procedure:
To 3,4-diamino-benzoic acid ethyl ester (4.0 g, 22.2 mmol) in 100 mL dichloromethane was added 1,3-dichloro-2-isothiocyanato-benzene (4.5 g, 22 mmol) in 50 mL dichloromethane. After stirring overnight and refluxing for another 6 hrs, the solvent was evaporated. After adding 200 mL dichloromethane, triethylamine (7 mL, 50 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) have been added, methanesulfonyl chloride (1.7 mL, 22 mmol) in 50 mL dichloromethane was added to the reaction mixture. After stirring for 2 h, another portion of methanesulfonyl chloride (1.7 mL, 22 mmol) was added. After stirring at room temperature overnight, the solvent was evaporated. The residue was mixed with 150 mL methanol and 40 mL 4N NaOH (aq), stirred over night, another 20 mL 4N NaOH (aq) added and refluxed for 2 h. The solvent was removed, the residue mixed with water and methanol and the mixture neutralized with 4 N HCl (aq). The mixture was filtered, washed with water and dried.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
(R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (11 grams), powdered potassium hydroxide (20 grams) and hexadecyl bromide (27.96 grams) in toluene (150 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature; water was added (100 ml) and the resulting mixture was extracted with dichloromethane (3×75 ml). The combined organic phase was washed with water (50 ml) and the solvent removed under reduced pressure. The residue was dissolved in 200 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid (v/v) and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of water (100 ml). The product was extracted with dichloromethane (3×100 ml), and the organic phase was washed consecutively with water (100 ml). saturated aqueous solution of sodxium carbonate (100 ml) and again with water (100 ml). The solvent was removed under reduced pressure and the product was crystallized from hexane (200 ml) to give 21.69 grams (yield 82%) of pure 1-hexadecyl-glycerol. upon drying in a desiccator under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][NH:13][CH2:14]2)[CH2:10][CH2:9]1)=[O:6].C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>ClCCl>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:5]([NH:7][C@H:8]1[C@H:15]2[C@H:11]([CH2:12][N:13]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:42])[F:43])[CH:33]=3)(=[O:40])=[O:39])[CH2:14]2)[CH2:10][CH2:9]1)=[O:6]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-4-Methyl-2-morpholino-N-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)pentanamide (191 mg, 0.617 mmol), triethylamine (0.129 mL, 0.926 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.109 mL, 0.679 mmol) were combined in dichloromethane (0.5 mL). The reaction was stirred at room temperature for 3 hours. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=6.2, 1H), 8.38 (s, 1H), 8.19 (d, J=7.9, 1H), 7.92 (d, J=7.8, 1H), 7.72 (t, J=7.9, 1H), 4.27-4.20 (m, 1H), 3.90 (dd, J=2.3, 10.0, 1H), 3.76-3.67 (m, 4H), 3.20 (ddd, J=3.9, 9.4, 10.9, 3H), 2.97 (dd, J=7.1, 9.6, 1H), 2.78-2.72 (m, 2H), 2.72-2.67 (m, 2H), 2.62-2.53 (m, 2H), 1.94 (dt, J=6.2, 12.1, 1H), 1.89-1.77 (m, 3H), 1.64-1.54 (m, 2H), 1.30 (ddt, J=6.5, 9.3, 12.8, 1H), 0.92 (d, J=4.4, 3H), 0.91 (d, J=4.4, 3H); MS (ESI+) m/z 518(M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[CH3:51][O:52][N:53]=[C:54]1[CH2:59][CH2:58][N:57]([C:60](=[NH:63])[CH2:61][SH:62])[CH2:56][CH2:55]1>C(#N)C.CS(C)=O.O1CCCC1.O.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[CH3:51][O:52][N:53]=[C:54]1[CH2:59][CH2:58][N:57]([C:60](=[NH:63])[CH2:61][S:62][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:56][CH2:55]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CON=C1CCN(C(=N)CS)CC1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CON=C1CCN(C(=N)CSC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
0.22 ml of diisopropylethylamine and 0.21 ml of diphenylphosphoryl chloride was added dropwise to an ice-cooled solution of 363 mg of p-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 5 ml of anhydrous acetonitrile, and the mixture was stirred for one hour with ice-cooling. A solution of 0.18 ml of diisopropylethylamine and 394 mg of 2-(4-methoxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride in 3 ml of dimethylsulfoxide was then added dropwise to the mixture, which was stirred for a further 20 minutes with ice-cooling. The reaction mixture was poured into 100 ml of anhydrous ether, and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 20 ml of tetrahydrofuran, 7 ml of water and 23 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to catalytic hydrogenation at room temperature for 3 hours in the presence of 0.3 g of 10% palladium-carbon. The product was worked up and purified in the same manner as in Example 2, giving 18 mg of the title compound.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C@:14]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=O)[C:15]3=[O:33])[CH2:13]2)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[C@:14]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:29])[C:15]3=[O:33])[CH2:13]2)=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Product: CC(C)NC(=O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from isopropyl amine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C27H25ClN2O2: 444, observed (M+H)+: 445.2 1H NMR (400 MHz, MeOD-d4) δppm 1.23 (d, J=6.82 Hz, 6 H) 2.21 (d, J=8.59 Hz, 2 H) 3.21-3.28 (m, 1 H) 4.07-4.25 (m, 1 H) 5.10 (s, 2 H) 6.05 (d, J=7.58 Hz, 1 H) 6.69 (t, J=7.58 Hz, 1 H) 6.88 (d, J=7.83 Hz, 1 H) 7.05 (t, J=7.83 Hz, 1 H) 7.16-7.25 (m, 2 H) 7.25-7.34 (m, 2 H) 7.37-7.52 (m, 2 H) 7.69 (d, J=7.58 Hz, 1 H) 7.78 (s, 1 H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O)(=[O:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[CH2:1])(=[O:9])[CH3:8]
Reactant: CC(=O)OCC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(COC(C)=O)c1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (8.48 g, 23.7 mmol) in THF (75 ml) was added potassium tert-butoxide (2.66 g, 23.7 mmol) at room temperature. The mixture was stirred at 40° C. for 1 hour. After cooling to room temperature, a solution of 2-[4-tert-butylphenyl]-2-oxoethyl acetate (U.S. Pat. No. 3,526,634, 2.78 g, 11.9 mmol) in THF (25 ml) was added to the mixture. The mixture was heated at reflux for 3 hours. The mixture was concentrated, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with hexane/EtOAc (9:1), to afford the title compound (2.13 g, 77%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Li+].[OH-]>C1COCC1.CO>[CH3:16][O:15][C:13]([NH:12][CH:4]([CH2:5][CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:17])=[O:2])=[O:14]
Reactant: COC(=O)NC(CC1CCOCC1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)NC(CC1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (0.11 g, 1.1 mmol) in THF (3.3 mL) and MeOH (1.1 mL) at 0° C. (external, ice bath) was added aqueous LiOH (1 M, 0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 18 h and concentrated to provide 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid which was used crude in the next step. LCMS-ESI+: calc'd for C10H17NO5: 231.11 (M+); Found: 231.99 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH3:17])[C:7]2=[O:18].[CH3:19][C@@H:20]1[C:24]2[NH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:23]=2[C:22](=[O:37])[NH:21]1>>[CH3:17][N:8]1[C:7](=[O:18])[C:6]2[C:11](=[C:2]([C:26]3[NH:25][C:24]4[C@@H:20]([CH3:19])[NH:21][C:22](=[O:37])[C:23]=4[CH:27]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1
Reactant: Cn1c(NC2(C)CC2)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC5(C)CC5)nc34)[nH]c21
Yield: 52 %

Procedure:
This compound (85 mg, 52% yield) as a brown solid was prepared according to the procedure described for Example 448, using 8-iodo-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (713) (160 mg, 0.45 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (130 mg, 0.50 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (1H, br.), 8.13 (1H, dd, J=7.6, 1.4 Hz), 7.83 (1H, dd, J=7.8, 1.4 Hz), 7.69 (2H, d, J=3.1 Hz), 7.18 (1H, t, J=7.7 Hz), 6.96 (1H, s), 4.64 (1H, q, J=6.6 Hz), 3.40 (3H, s), 1.56 (3H, s), 1.37 (3H, d, J=6.7 Hz), 1.01 (2H, m), 0.86 (2H, m). MS (ESI, pos. ion) m/z: 364.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[NH:8][C:7](=[O:23])[CH2:6][CH2:5]2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[O:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[NH:8][C:7](=[O:23])[CH2:6][CH2:5]3)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1CCc2cc(Br)c(OCc3ccc(C(=O)O)cc3)cc2N1
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: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(-c3ccc(Cl)cc3)c(OCc3ccc(C(=O)O)cc3)cc2N1
Reaction time: 0.08 h
Yield: 66.7 %

Procedure:
To a solution of 4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (100 mg, 0.27 mmol) and 4-chlorophenyl boronic acid (62 mg, 0.40 mmol) in N,N-dimethylformamide (2.0 mL) in a Biotage microwave vial was added sodium bicarbonate (200 mg, 2.38 mmol) and water (0.50 mL). The reaction mixture was stirred for 5 minutes under an atmosphere of dry N2. Pd(PPh3)4 (10 mg, 0.009 mmol) was added, and the resulting mixture was sealed and subjected to microwave irradiation at 130° C. for 8 minutes. The mixture was cooled, diluted with ethyl acetate (5 mL), filtered through celite, washed with 10% N,N-dimethylformamide in ethyl acetate (40 mL), transferred to a separation funnel, and the organic phase was washed with 1N sodium carbonate (20 mL), 30% ammonium chloride (20 mL) and brine (30 mL), dried and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC with a gradient acetonitrile/water (5-98%) to afford 4-((6-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (72 mg, 0.18 mmol, 66%). LCMS mz 408.0 (M+H), 430.0 (M+Na), anal HPLC>96% in purity, 1H NMR (400 MHz; dmso-D6) δ10.1 (σ, 1H), 7.95 (d, J=8.2 Hz, 2H); 7.55 (d, J=9.0 Hz, 2H); 7.48 (m, 4H); 7.18 (s, 1H); 6.69 (s, 1H); 5.15 (s, 2H); 2.87 (m, 2H); 2.47 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of 2-indanone (13.47 g, 102 mmol) in anhydrous benzene (100 mL) was added to phenylmagnesium bromide (3.0 M in diethyl ether, 50.9 mL, 153 mmol) at 5° C. over 2.5 hours. The reaction was allowed to warm to room temperature over 30 minutes. The solution was cooled to 0° C. and 150 mL of water are added. The resultant mixture was diluted with 200 mL of hexanes, neutralized with 5 M HCl, and washed with brine (2×100 mL). The aqueous layer was extracted with hexanes (2×50 mL), and the combined organic layers were dried (MgSO4), filtered, and the solvent removed in vacuo from the filtrate to yield a brown oil. This oil and p-toluenesulfonic acid (0.50 g) were dissolved in benzene (250 mL) in a round-bottom flask below a Soxhlet extractor containing 4 Å molecular sieves. After refluxing for 2.5 hours, the solution was filtered and cooled to 5° C. overnight. The product, a white flaky solid, was collected by filtration, and was washed with 50 mL of cold benzene. Additional product is obtained by concentrating the filtrate, cooling, and filtering the crystals (12.60 g, 64.3% yield). 1H NMR (400 MHz, 20 C, CDCl3) 7.62 (d, J=7.3 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 7.39 (M, 3H), 7.27 (m, 2H), 7.22 (s, 1H), 7.18 (t, J=7.4 Hz, 1H), 3.78 (S<2H). 13C{1H} NMR (100 MHz, 20 C, CDCl3): 146.3, 145.3, 143.1, 135.9, 128.6, 127.5, 126.5, 126.4, 125.6, 124.7, 123.6, 120.9, 38.9.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:21][OH:22].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:19][C@@H:20]([C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: Clc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: COc1ccc([C@H](N)CO)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (55 mg, 0.20 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (33 mg, 0.20 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (68 μL, 0.39 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC (100×20.2 mm, C18 column; 25-50% CH3CN-water [10 mM Et2NH]) to give an off-white solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:53])[CH2:11][CH2:12][NH:13][CH2:14][C@:15]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:16]1[C@@H:17]1[C@@:30]([CH3:33])([CH2:31][CH2:32]2)[C@@:29]2([CH3:34])[C@@H:20]([C@:21]3([CH3:46])[C@@H:26]([CH2:27][CH2:28]2)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)=[O:4].[OH-].[Na+].O.Cl>O1CCOCC1.CO>[C:41]([C:40]1[CH:44]=[CH:45][C:37]([C:24]2[C:25]([CH3:36])([CH3:35])[C@H:26]3[C@:21]([CH3:46])([CH2:22][CH:23]=2)[C@@H:20]2[C@:29]([CH3:34])([C@@:30]4([CH3:33])[C@H:17]([CH2:18][CH2:19]2)[C@H:16]2[C@H:47]([C:50]([CH3:52])=[CH2:51])[CH2:48][CH2:49][C@:15]2([CH2:14][NH:13][CH2:12][CH2:11][C:10]([N:6]2[CH2:7][CH2:8][CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[O:53])[CH2:32][CH2:31]4)[CH2:28][CH2:27]3)=[CH:38][CH:39]=1)([OH:43])=[O:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC[C@H]3C(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC[C@H]3C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 45 h
Yield: 85.2 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-3-oxopropylamino)methyl)-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 (10 mg, 0.014 mmol) in dioxane (1 ml) and methanol (2 ml) was added 1N sodium hydroxide (0.08 ml, 0.08 mmol) and H2O (0.5 ml). The resulting mixture was stirred at rt for 45 h. The reaction mixture was neutralized with 1N HCl and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (8.5 mg, 85%). MS: m/e 713.5 (MH+), 1.68 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.95 (s, 3H) 0.97 (s, 3H) 1.04 (s, 3H) 1.08 (s, 3H) 1.18 (s, 3H) 1.73 (s, 3H) 0.87-1.86 (m, 20H) 1.99-2.10 (m, 4H) 2.15 (dd, J=17.32, 6.53 Hz, 1H) 2.24-2.33 (m, 1H) 2.52 (td, J=9.60, 4.14 Hz, 1H) 2.83-2.92 (m, 3H) 3.24-3.28 (m, 1H) 3.38 (t, J=6.15 Hz, 2H) 3.52-3.68 (m, 2H) 4.48 (dd, J=8.41, 3.39 Hz, 1H) 4.64 (s, 1H) 4.76 (d, J=1.76 Hz, 1H) 5.30 (dd, J=6.15, 1.63 Hz, 1H) 7.21 (d, J=8.53 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H).