Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:55])([CH3:54])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:53])([C@@:17]4([CH3:52])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([NH:38][CH2:39][CH2:40][C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH:44]2[C:48]([O:50]C)=[O:49])=[O:42])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.Cl>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:55])([CH3:54])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:53])([C@@:17]4([CH3:52])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([NH:38][CH2:39][CH2:40][C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH:44]2[C:48]([OH:50])=[O:49])=[O:42])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)N3CCCC3C(=O)OC)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: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)N3CCCC3C(=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: 85 °C
Yield: 45.8 %

Procedure:
To a solution of methyl 1-(3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)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-carboxamido)propanoyl)pyrrolidine-2-carboxylate (63 mg, 0.083 mmol) in Dioxane (2 mL) was added NaOH (1N) (0.417 mL, 0.417 mmol). The mixture was heated to 85° C. for 15 h, then cooled to rt and was diluted with 5 mL of 1N HCl and was extracted with dichloromethane (4×5 mL). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-10% MeOH in DCM gradient with 0.1% HOAc then by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 1-(3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-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-carboxamido)propanoyl)pyrrolidine-2-carboxylic acid (27.3 mg, 0.038 mmol, 45.0% yield) as a white solid. LCMS: m/e 726.4 (M−H)−, 2.36 min (method 4). 1H NMR (500 MHz, Acetic) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.78 (s, 1H), 4.64 (s, 1H), 4.57 (dd, J=8.70, 3.51 Hz, 1H), 3.52-3.75 (m, 4H), 3.09-3.20 (m, J=18.43, 11.08, 11.08, 4.27 Hz, 1H), 2.68-2.82 (m, 2H), 2.58 (td, J=12.36, 3.05 Hz, 1H), 1.73 (s, 3H), 1.07 (s, 6H), 1.05 (s, 3H), 1.03-2.53 (m, 25H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25]/[CH:26]=[CH:27]\[CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:21])([CH3:20])[CH:14]=[C:13]4[CH3:22].[I-].[CH:30]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25][CH:26]=[C:27]([CH3:30])[CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:20])([CH3:21])[CH:14]=[C:13]4[CH3:22]
Reactant: C/C=C\CC1Oc2ccc(O)c(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: COc1c(O)ccc2c1-c1ccc3c(c1C(CC=C(C)C)O2)C(C)=CC(C)(C)N3

Procedure:
The intermediate aldehyde from Example 282 and isopropyltriphenylphosphonium iodide were processed according to Example 282 to give the desired compound. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.91 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 6.46 (d, J=9 Hz, 1H), 6.14 (s, 1H), 5.60 (dd, J=9, 3 Hz, 1H), 5.43 (s, 1H), 5.15 (m, 1H), 3.64 (s, 3H), 2.45-2.18 (m, 2H), 2.15 (s, 3H), 1.63 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); MS (APCI) m/e (M+H)+ 392, (M−H)− 390.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].Br[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[OH:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cc(OC)cc(OC)c2)c1
Yield: 85.6 %

Procedure:
3,5-Dimethoxybenzaldehyde (0.84 g, 5.03 mmol), 1-bromo-3,5-dimethoxybenzene (1.20 g, 5.53 mmol), and n-butyl lithium (2.20 ml, 5.53 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 60% EtOAc in hexane in about 40 min.) to give Bis-(3,5-dimethoxy-phenyl)-methanol as an off-white solid (1.31 g, 86%): 1HNMR (CDCl3) 6.55 (d, J=2 Hz, 4H, Ar), 6.36 (t, J=2 Hz, 2H, Ar), 5.67 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 12H, 4OCH3), 2.24 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH:18]([CH3:21])[CH2:19][OH:20])[CH:16]=O)[CH:8]=[CH:9][C:2]1=2.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH3:16])[CH:18]([CH3:21])[CH2:19][OH:20])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(CO)N(C=O)CCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)N(C)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
In 4.3 mL of tetrahydrofuran is dissolved 0.43 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-hydroxy-1-methylethyl)-formamide. To the solution thus obtained is dropwise added at an ice-cooled temperature 5.60 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran. The resulting mixture is stirred at ambient temperature for 1.5 hours. The reaction mixture is acidified with 1.9 mL of 6 mol/L hydrochloric acid and heated under reflux for one hour. After cooling the reaction mixture to ambient temperature, water and ethyl acetate are added, pH is adjusted to 9.5 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the oily product thus obtained is purified by column chromatography (eluent: chloroform:methanol=30:1) to obtain 0.20 g of 2-[[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl](methyl)amino]-1-propanol as a light yellow-colored oily product.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13]C=1C(O)=O>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([NH:15]C(=O)C)=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH3:3].Cl.[OH-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH3:3]
Reactant: CCCOc1cc2ccccc2cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cc2ccccc2cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
N-(3-Propoxynaphthalen-2-yl)acetamide (2.5 g, 10.2 mmol) was dissolved in ethanol (10 ml). Concentrated hydrochloric acid (5.2 ml) was added thereto, and the resulting mixture was stirred for 4 hours while heating under reflux. The reaction mixture was cooled to room temperature, and a 5N aqueous sodium hydroxide solution (12.5 ml) was added thereto to adjust its pH to 11, followed by extraction using dichloromethane. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (dichloromethane). The purified product was concentrated to dryness under reduced pressure, giving a white powder of 3-propoxynaphthalen-2-ylamine (2.05 g, yield: 100%).
Reaction SMILES: C([C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[C:7](=[O:8])[CH2:6][S:5][CH2:4]1)#N.S(=O)(=O)(O)O>O1CCOCC1>[O:8]=[C:7]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1
Reactant: CC(C(=O)O)c1ccc(CC2(C#N)CSCC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(CC2CSCC2=O)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
2-[4-(3-Cyano-4-oxothiolan-3-ylmethyl)phenyl]propionic acid (1.27 g) obtained in Example 7 was dissolved in 1,4-dioxane (10.0 ml), 30% aqueous sulfuric acid (10.0 ml) was added to the solution and stirred overnight at 110° C. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (550 mg, 50%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][C:11]=1[OH:33])C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:17]2[CH2:22][C:21]([CH3:23])([CH3:24])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][C:11]=1[O:33][CH2:6][C:5]([O:4][CH2:3][CH3:2])=[O:7]
Reactant: CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)ccc1C
Temperature: 100 °C
Yield: 99 %

Procedure:
Bromoethylacetate (187 mg, 1.12 mmol), compound 41 (150 mg, 0.449 mmol), and K2CO3 (185 mg, 1.34 mmol) were combined with dry acetone (5 mL) in a sealed microwave vessel. The mixture was heated at 100° C. for 20 minutes in a Personal Chemistry Emrys Optimizer microwave. The reaction was allowed to cool to room temperature and the solids filtered. The solids were rinsed twice with acetone and the solvent was removed in vacuuo to give 187 mg (99%) of compound 42. The crude material was used without additional purification. 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.20-1.25 (m, 5H), 1.75 (s, 2H), 1.90 (s, 2H), 2.23 (s, 3H), 4.22 (m, 3H), 4.46 (s, 2H), 6.73 (d, J=8.3 Hz, 1H), 6.75-7.05 (m, 2H), 7.09-7.46 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3[S:22][C:21](=O)[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1.[S:25]1CC(=O)NC1=S>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3[S:22][C:21](=[S:25])[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)S1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1cnn2ccc(-c3ccccc3F)nc12

Procedure:
5-((5-(2-Fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2-thioxothiazolidin-4-one was prepared using the same procedure as for the synthesis of 5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione using Rhodanine instead of thiazolidine-2,4-dione.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:32]=[CH:31][C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[N:21][N:22]5C(OC)=O)=[O:16])=[CH:11][C:10]=3[C:33]([F:36])([F:35])[F:34])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[OH-].[Na+]>CO>[CH:5]12[N:8]([C:9]3[CH:32]=[CH:31][C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[N:21][NH:22]5)=[O:16])=[CH:11][C:10]=3[C:33]([F:34])([F:36])[F:35])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: COC(=O)n1ncc2c(NC(=O)NCc3ccc(N4C5CCCC4CC5)c(C(F)(F)F)c3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(N2C3CCCC2CC3)c(C(F)(F)F)c1)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h

Procedure:
A suspension of methyl 4-[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-1-carboxylate (1.65 g, 3.29 mmol) in methanol (30 mL) was treated with 1.2 N NaOH in MeOH (10 mL). The mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The separated aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (7% to 10% MeOH/CH2Cl2) to provide the title compound as a solid. The obtained solid was treated with ethanolic HCl followed by precipitation with diethyl ether to provide the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.19 (s, 1H), 7.62 (d, 1H, J=7.5 Hz), 7.57 (d, 1H, J=2.0 Hz), 7.46 (dd, 1H, J=8.5, 2.0 Hz), 7.19 (t, 1H, J=8.1 Hz), 7.10 (m, 3H), 4.31 (m, 2H), 3.72 (m, 2H), 1.93 (m, 2H), 1.87-1.56 (m, 5H), 1.48 (m, 3H); MS (ESI) 444 (M+H)+; Anal. Calcd for C23H24F3N5O.1.6HCl: C, 55.05; H, 5.14; N, 13.96. Found: C, 54.95; H, 4.66; N, 13.53.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[C:11]([CH2:24][NH:25][C:26]([C@@H:28]2[CH2:33][N:32]([CH3:34])[CH2:31][CH2:30][N:29]2[C:35](=[O:42])[C@H:36]([OH:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:27])[CH:10]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH2:13][C:12]1[CH:22]=[CH:23][C:9]([Cl:8])=[CH:10][C:11]=1[CH2:24][NH:25][C:26]([C@@H:28]1[CH2:33][N:32]([CH3:34])[CH2:31][CH2:30][N:29]1[C:35](=[O:42])[C@H:36]([OH:41])[C:37]([CH3:39])([CH3:40])[CH3:38])=[O:27]
Reactant: CN1CCN(C(=O)[C@H](O)C(C)(C)C)[C@H](C(=O)NCc2cc(Cl)ccc2CNC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)[C@H](O)C(C)(C)C)[C@H](C(=O)NCc2cc(Cl)ccc2CN)C1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL, 50% solution in CH2Cl2) was added to a solution of tert-Butyl 4-chloro-2-[{(S)-1-{(R)-2-hydroxy-3,3-dimethylbutanoyl}-4-methylpiperazine-2-carboxamido}methyl]benzylcarbamate (0.022 g, 0.0043 mmol) in CH2Cl2 (1 mL) and the reaction mixture was stirred under nitrogen for 1 h. The solvent was removed at reduced pressure and the residue was azeotroped with toluene (5 mL). The solid was washed with ether (2×4 mL) and dried under high vacuum to afford the title compound as a white hygroscopic solid. 1H NMR (MeOD-d4, 300 MHZ) (δ) ppm: 7.36-7.55 (m, 3H), 5.21-5.38 (m, 1H), 4.37-4.53 (m, 3H), 4.26-4.28 (m, 3H), 3.95-3.68 (m, 2H), 3.16-3.22 (m, 1H), 2.55-2.73 (m, 5H), 0.97 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[CH:6]=[CH:7][N:8](C)C)[CH3:2].Cl.Cl.[NH2:15]N>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[CH:7][NH:8][N:15]=1)=[O:12])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C=CN(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
4-Dimethylamino-2-oxo-but-3-enoic acid ethyl ester (195 g, 1.14 mol) and hydrazine dihydrochloride (119.7 g, 1 eq) were dissolved in EtOH (1 L) and stirred at room temperature overnight. The mixture was then heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with water three times and dried. The filtrate was concentrated to a thick oil and added dropwise into a flask with stirred EtOAc (200 mL). The resulting solid was filtered and rinsed with a small amount of EtOAc. The filtered solids were combined to give the product (62 g, 39% yield). MS (ES) m/z 141.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:5]2[CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[C:26]1[C:30]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[C:29]([CH:48]([CH3:50])[CH3:49])[O:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[Cl:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[C:26]1[C:30]([CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:5]4[CH3:17])=[CH:37][CH:38]=2)=[C:29]([CH:48]([CH3:50])[CH3:49])[O:28][N:27]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)c1cc(C)c2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 60 °C
Yield: 52.1 %

Procedure:
Palladium(II)acetate (1.2 mg, 5.4 μmol) was added to ethyl 6-bromo-4-methyl-2-quinolinecarboxylate (31.5 mg, 107.1 μmol), 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}methyl)isoxazole (52.3 mg, 107.1 μmol), triphenylphosphine (2.8 mg, 10.7 μmol), and potassium phosphate (79.6 mg, 374.8 μmol). Then, dioxane (2.1 mL) was added to the mixture, followed by water (10.7 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 17 hours, then allowed to cool to room temperature. Water was added, followed by ethyl acetate, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate:hexanes to give 32.1 mg (52%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.25 (d, J=2 Hz, 1H), 8.17 (d, J=9 Hz, 1H), 8.10 (dd, J=9, 2 Hz, 1H), 7.98 (s, 1H), 7.78 (d, J=9 Hz, 2H), 7.65-7.62 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.94 (d, J=9 Hz, 2H), 4.89 (s, 2H), 4.41 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 2.82 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([NH:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: NC1CCc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(NC3CCc4ccccc43)c2cc1OC
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.066 g, 0.25 mmol), 1-aminoindan (0.66 mg, 0.50 mmol), 2-butanole (2 ml), DMF (2 ml) was heated for 48 h at 100° C. After cooling, the solution was reduced by evaporation. The residue was dissolved in water (3 ml) and treated with aqueous ammonia. The solid product was fitered off washed with water air dried for 0.5 h, washed again with heptane and dried. The residue was purified by chromatography on silica (CH2Cl2/MeOH) to give 63 mg, (70%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[C:28]([O:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC1(CCN2C(=O)CSC2CCCc2ccc(C(=O)O)cc2)CCCCC1
Temperature: 0 °C

Procedure:
A solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazoldinyl]propyl}benzoic acid (3.9 g., 0.01 mole) and acetic anhydride (1.2 g., 0.012 mole) in pyridine (15 ml.) is kept at 25° C. for 5 days. It is then poured into 50 ml. of ice water and the mixture brought to pH 5.0 by the addition of 2 N hydrochloric acid. The oily product is extracted into chloroform and purified by column chromatography on silica gel with elution by 2% methanol in chloroform.
Reaction SMILES: [C@@H:1]1([N:12]2[C:16]3[C:17]4[NH:18][C:19]5[C:24]([C:25]=4[C:26]4[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[C:27]=4[C:15]=3[C:14]3[CH:34]=[CH:35][CH:36]=[N:37][C:13]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=5)[O:9][C@H:8]([CH2:10]O)[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:58].O>N1C=CC=CC=1>[Cl:58][CH2:10][C@H:8]1[O:9][C@@H:1]([N:12]2[C:16]3[C:17]4[NH:18][C:19]5[C:24]([C:25]=4[C:26]4[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[C:27]=4[C:15]=3[C:14]3[CH:34]=[CH:35][CH:36]=[N:37][C:13]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=5)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CN1C(=O)c2c(c3c4cccnc4n([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c3c3[nH]c4ccccc4c23)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CN1C(=O)c2c(c3c4cccnc4n([C@@H]4O[C@H](CCl)[C@@H](O)[C@H](O)[C@H]4O)c3c3[nH]c4ccccc4c23)C1=O
Temperature: 25 °C
Reaction time: 2.3 h

Procedure:
To a solution of the compound of Example 17 (0.353 mmol) dissolved in 2.5 ml of pyridine there is added a solution of triphenylphosphine (1.415 mmol) and then carbon tetrachloride (0.707 mmol). The mixture is stirred at ambient temperature for 2.30 hours and is then poured into water. The mixture is extracted with ethyl acetate and the organic phase is washed successively with a 1N aqueous solution of hydrochloric acid, water and a saturated solution of NaHCO3. After evaporating off the solvent and then purifying by chromatography over silica gel (ethyl acetate), the expected product is isolated.