Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[OH:9])[CH:17]=2)[N:22]=[C:21]([C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)[C:20]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(-c3cncnc3)c(-c3ccccc3)c(Cl)c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of (4-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol (75 mg, 0.15 mmol, Example 17), pyrimidin-5-ylboronic acid (23 mg, 0.18 mmol), PdCl2(dppf) (11 mg, 0.015 mmol) and K2CO3 (42 mg, 0.30 mmol) in 10 mL dioxane was combined with 2 mL of water and heated to 70° C. After 3 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified on an ISCO using 0-10% methanol in ethyl acetate and lyophilized to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ=9.06 (s, 1H), 8.64 (s, 2H), 8.60 (d, J=2.0 Hz, 1H), 8.57 (d, J=3.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.69-7.78 (m, 2H), 7.27-7.42 (m, 8H), 7.19 (dd, J=6.3, 2.8 Hz, 2H); MS m/e 535.8 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:30][CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OC4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 48.1 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 206f (108 mg, 0.30 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (115 mg, 0.30 mmol), Pd(dppf)Cl2 (15 mg, 0.015 mmol), K3PO4 (135 mg, 0.60 mmol), sodium acetate trihydrate (90 mg, 0.60 mmol) in acetonitrile (10 mL) and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 206g (90 mg, 52%) as a yellow brown solid. MS-ESI: [M+H]+ 624.2.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:25]CC)(=O)[CH2:18][C:19]([O:21]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:19]([OH:21])=[CH:18][C:17](=[O:25])[N:15]([CH3:16])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNc1cc(=O)n(Cc2ccccc2)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(=O)cc(O)c2c(=O)n(Cc3ccccc3)cnc21
Yield: 56.9 %

Procedure:
3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (2 g, 9.3 mmol, 1 eq) and diethyl malonate (2 mL, 14.5 mmol, 1.55 eq) were heated in phenyl ether (3 mL, 19 mmol, 2 eq) at 240° C. in a microwave reactor for 6 hours. Upon cooling a precipitate formed which was filtered and washed with ether to give 1.5 g of the title compound as a tan solid (57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.51 (s, 3 H) 5.20 (s, 2 H) 5.72 (s, 1 H) 7.31 (br. s., 1 H) 7.38 (d, J=3.03 Hz, 4 H) 8.93 (s, 1 H) 11.61 (s, 1 H). [M+H] calc'd for C15H13N3O3, 284; found, 284.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].B(Br)(Br)Br.B(F)(F)F.[CH3:19][CH2:20][O:21]CC.C(O)(=O)C>O.ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([C:20](=[O:21])[CH3:19])[CH:5]=[CH:4][C:3]=1[OH:10]
Reactant: COc1cccc(O)c1F
Reactant: CCOCC
Agent: BrB(Br)Br
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(F)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
A solution of 2-fluoro-3-methoxy-phenol (0.5 g, 3.53 mmol) and dichloromethane is stirred at −78° C. A 1M solution of boron tribromide in dichloromethane (3.9 mL, 3.9 mmol) is added slowly and the mixture is stirred 10 min cold, then warmed to 0° C. and stirred 1 hr. The reaction is quenched with ice and stirred at room temperature overnight. The product is extracted with ethyl acetate (2×50 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting residue is combined with boron trifluoride diethyl etherate (1.3 mL, 10.3 mmol) and acetic acid (0.2 mL, 3.28 mmol) and heated to reflux 8 hr. The mixture is cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is diluted with hexanes (50 mL), cooled to 0° C., and filtered to give the title compound (310 mg, 58%) as a tan solid. MS ES 171 m+1.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:17]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a suspension of 1-(4-chlorophenyl)piperazine dihydrochloride (539 mg) and 3-(chlorosulfonyl)benzoic acid (441 mg) in dichloromethane (50 ml) was added diisopropylethylamine (0.8 ml). After stirring overnight at room temperature the reaction mixture was washed with 2N HCl (3×25 ml) and brine (25 ml), dried over MgSO4, filtered and evaporated to give the title compound as white solid (290 mg, 38%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][CH2:8][CH2:9][Cl:10].[OH-].[Na+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Cl:10][CH2:9][CH2:8][CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCCCBr
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ClCCCn1ccnc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Imidazole (680 mg), 1-bromo-3-chloropropane (0.79 ml), tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium hydroxide solution (1 ml) were dissolved in acetone (10 ml), and the solution was stirred at 50° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography by development with chloroform to give an intermediate (1-(3-chloropropyl)-1H-imidazole, 525 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6](Br)[CH:5]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([Cl:19])[CH:21]=2)[C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[CH:8][CH:9]=1)=[O:18]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c(-c2ccc(OC)c(Cl)c2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
150 mg of 3-Bromo-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester, 113 mg of 3-chloro-4-methoxyphenylboronic acid, 129 mg K2CO3, 10 mg of palladium(II)acetate, and 25 mg of triphenylphosphine were dissolved using 10 ml of DMF and 0.5 ml of water. The reaction mixture was stirred at 120° C. for 2 h, then cooled to room temperature, 50 ml of water added and extracted three times using 30 ml of EA each. The organic layer was dried using MgSO4 and volatiles were evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded 90 mg of the title compound, viscous oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[C:5](=[O:23])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]CC2C=CC=CC=2)[O:10]1)[CH2:2][CH3:3]>C(O)(=O)C.[Pd].C(O)C>[CH2:24]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:23])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[O:10]1)[CH2:25][CH3:26]
Reactant: CCCN(CCC)C(=O)COCC1CCC(COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)COCC1CCC(CO)O1
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 10.9 g of N,N-dipropyl-2-[[tetrahydro-5-[(phenylmethoxy)methyl]-2-furanyl]methoxy]acetamide (0.03 mole) in 125 ml of glacial acetic acid is added 2.5 g of 10% palladium on carbon. The mixture is hydrogenated at 55 psi over a period of 18 hours (debenzylation reaction taking up 98% of the calculated theory). The mixture is removed and the Pd/C filtered through a pad of "celite" filter aid. The acetic acid is then removed in vacuo yielding a pale yellow oil. The resulting oil is dissolved in 100 ml of ethanol and evaporated. The oil is then redissolved in ethanol and again evaporated in vacuo. The oil is then taken up in 200 ml of chloroform and washed with 100 ml of saturated NaHCO3 solution, 150 ml of water and finally with 200 ml of saturated NaCl solution. The CHCl3 layer is separated, dried over anhydrous Na2SO4 and then the CHCl3 is removed in vacuo yielding 7.6 g of crude product whih is vacuum distilled and the fraction distilling at 180°-183° @ 0.4 mm is collected yielding 7.1 g (87%) of the above compound.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[OH:24][CH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][N:32]2[CH3:35])=[CH:28][CH:27]=1>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:30]3[C:29]4[C:33](=[CH:34][C:26]([CH2:25][OH:24])=[CH:27][CH:28]=4)[N:32]([CH3:35])[CH:31]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1ccc2ccc(CO)cc21
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Temperature: 80 °C

Procedure:
2,6-Dimethylpyridine (0.12 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from step (c), 273 mg, 1 mmol) and 6-(hydroxymethyl)-1-methylindole (from step (a), 161 mg, 1 mmol) in anhydrous dimethylformamide (2 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 3 hours. The reaction mixture was cooled, and partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using diethyl ether as eluant) to live the subtitle compound as a colourless foam (273 mg).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:21]1[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][CH2:25]2>C(COC)OC.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>[C:1]1([C:21]2[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][CH2:25]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2c(c1Br)C=CC2
Reactant: OB(O)c1cccc2ccccc12
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: [Cs+]
Solvent: COCCOC
Product: Cc1ccc2c(c1-c1cccc3ccccc13)C=CC2
Yield: 86 %

Procedure:
1-Naphthylboronic acid (10 g, 58.1 mmol) was dissolved in dimethoxyethane (150 mL), and aqueous solution (100 mL) of cesium carbonate (25.3 g, 78 mmol), 4-bromo-5-methylindene (8.1 g, 39 mmol), tetrakis(triphenylphosphine)palladium (1.8 g) were sequentially added. Solution was reacted for 21 hours while heating under reflux, then, reaction solution was poured into 1N hydrochloric acid-ice water, and after stirring, reaction solution was extracted with diethyl ether. Organic layer was washed with magnesium sulfate, then, solvent was distilled off under reduced pressure to obtain the crude product. This was purified by silica-gel column chromatography to obtain the desired 4-(1-naphthyl)-5-methylindene (8.6 g, yield: 87%).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:23][C:24]1([CH3:50])[CH2:49][O:48][C:27]2([CH2:32][C:31]3(NN[C:34]4([CH2:39][CH2:38][CH:37]([CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)[CH2:36][CH2:35]4)[S:33]3)[CH2:30][CH2:29][CH2:28]2)[O:26][CH2:25]1.[NH2:51][NH2:52].C(=O)(O)[O-].[Na+]>CCCCCC>[CH3:23][C:24]1([CH3:50])[CH2:25][O:26][C:27]2([CH2:32][C:31]3([N:52]=[N:51][C:34]4([CH2:39][CH2:38][CH:37]([CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)[CH2:36][CH2:35]4)[S:33]3)[CH2:30][CH2:29][CH2:28]2)[O:48][CH2:49]1
Reactant: NN
Reactant: CC1(C)COC2(CCCC3(C2)NNC2(CCC(C4CCCCC4)CC2)S3)OC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: CC1(C)COC2(CCCC3(C2)N=NC2(CCC(C4CCCCC4)CC2)S3)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Powdered calcium carbonate (102 g) was suspended in hexane (1.5 1), lead tetraacetate (99.8 g) was added, and the mixture was stirred at 0° C. for 30 minutes. The hydrazine 11-cyclohexyl-14,15-diaza-7-thiadispiro (5.1.5.2) pentadecan-4-one (2',2'-dimethyltrimethylene)ketal (0.15 mol) in hexane (2.51) (not completely soluble so the insoluble solids were added as a suspension) was added over a period of one hour at 0° C. The reaction mixture was stirred and allowed to warm to 20° C. over a two-hour period. A TLC at this time showed the reaction to be complete. Saturated aqueous sodium bicarbonate was added, the mixture was filtered, and the filtrate was washed with saturated NaHCO3 and with water and then dried over Na2SO4. The dry solution was filtered and concentrated under reduced pressure, giving 45.5 g of solid. This solid was chromatographed over silica gel (1.9 kg, 5% ethyl acetate-hexane) and the desired product was eluted after increasing the solvent polarity to 40% ethyl acetate-hexane. A sample was recrystallized twice from pentane, giving white crystals: IR 1586, 1448, 1446, 1439, 1367, 1363, 1290, 1258, 1152, 1136, 1124, 1110, 1058, 1045, 1018, 980, 972, 967, 955, 910, 904 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:72]([CH3:98])=[C:73]([C:80]([C:82]3[CH:91]=[C:90]4[C:85]([C:86](=[O:97])[N:87]([CH2:93][C:94]([O-:96])=[O:95])[C:88](=[O:92])[NH:89]4)=[CH:84][CH:83]=3)=[O:81])[N:74]3[C:79]=2[CH:78]=[CH:77][CH:76]=[CH:75]3)=[CH:67][CH:66]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([CH3:58])=[C:29]([C:36]([C:38]3[CH:47]=[C:46]4[C:41]([C:42](=[O:57])[N:43]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:44](=[O:48])[NH:45]4)=[CH:40][CH:39]=3)=[O:37])[N:30]3[C:35]=2[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:23][CH:22]=1.O>C(Cl)Cl.CO>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:72]([CH3:98])=[C:73]([C:80]([C:82]3[CH:91]=[C:90]4[C:85]([C:86](=[O:97])[N:87]([CH2:93][C:94]([OH:96])=[O:95])[C:88](=[O:92])[NH:89]4)=[CH:84][CH:83]=3)=[O:81])[N:74]3[C:79]=2[CH:78]=[CH:77][CH:76]=[CH:75]3)=[CH:67][CH:66]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([CH3:58])=[C:29]([C:36]([C:38]3[CH:47]=[C:46]4[C:41]([C:42](=[O:57])[N:43]([CH2:49][C:50]([OH:52])=[O:51])[C:44](=[O:48])[NH:45]4)=[CH:40][CH:39]=3)=[O:37])[N:30]3[C:35]=2[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:23][CH:22]=1
Reactant: Cc1c(-c2ccc(OCCCCCN(CCCCCOc3ccc(-c4c(C)c(C(=O)c5ccc6c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c6c5)n5ccccc45)cc3)CCOCCO)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)[O-])c(=O)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2ccc(OCCCCCN(CCCCCOc3ccc(-c4c(C)c(C(=O)c5ccc6c(=O)n(CC(=O)O)c(=O)[nH]c6c5)n5ccccc45)cc3)CCOCCO)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
Trifluoroacetic acid (0.44 g, 3.89 mmol) is added to the tert-butyl 2,2′-({[2-(2-hydroxyethoxy)ethyl]imino}bis[pentane-5,1-diyloxybenzene-4,1-diyl(2-methylindolizine-1,3-diyl)carbonyl(2,4-dioxo-1,4-dihydroquinazoline-7,3(2H)-diyl)])diacetate (0.50 g, 0.39 mmol) in suspension in 4 mL of a DCM/MeOH mixture (1/1). The solution is stirred for 8 h at ambient temperature. The reaction mixture is run into water. The precipitate formed is filtered off, washed with water then with ethanol, and dried under vacuum. Purification by preparative HPLC on Kromasil C18 10 μm reverse phase [A=H2O/(CH3COONH4 0.1 M) 90/10; B=CH3CN/(CH3COONH4 0.1 M) 90/10, gradient A/B: 70/30 to 56/44] gives 25 mg (5%) of a yellow powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([CH:48]([CH3:50])[CH3:49])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH2:4][CH2:3]1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].O.[OH-].[Li+]>C1COCC1.O>[O:51]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([CH:48]([CH3:49])[CH3:50])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH2:4][CH2:3]1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NC(=O)CN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)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: 75 °C
Reaction time: 5.5 h

Procedure:
To a solution of methyl 4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate, TFA (33 mg, 0.040 mmol) in THF (Volume: 3 mL) was added a 0.753 molar solution of lithium hydroxide monohydrate (0.316 mL, 0.158 mmol) in H2O. The reaction mixture was heated to 75° C. After 5.5 h, the reaction was concentrated to dryness. The crude residue was dissolved in THF (1.2 mL), MeOH (0.3 mL) and 1N HCl (0.2 mL). The solution was filtered and injected into reverse phase HPLC for purification using HPLC method 3 to give 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-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, TFA (17.9 mg, 0.021 mmol, 54.1% yield) as a white solid. LCMS: m/z 707.6 (M+H+), retention time 2.030 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.93 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.13 (s, 1H), 5.31 (dd, J=1.5, 6.1 Hz, 1H), 3.26-3.22 (m, 5H), 3.21-3.15 (m, 4H), 2.66-2.59 (m, 1H), 2.37 (dd, J=6.7, 12.5 Hz, 1H), 2.17 (dd, J=6.4, 17.1 Hz, 1H), 1.99-1.91 (m, 1H), 1.80-1.70 (m, 4H), 1.67-1.57 (m, 2H), 1.57-1.45 (m, 9H), 1.44-1.39 (m, 1H), 1.39-1.26 (m, 3H), 1.18-1.11 (m, 2H), 1.09 (s, 3H), 1.04 (s, 6H), 0.96 (s, 3H), 0.95 (s, 3H), 0.91 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccnc2cc(O)ccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 87.2 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 9), was reacted with 7-hydroxy-4-methylquinoline (80 mg, 0.5 mol), (Chem. Berich. 1967, 100, 2077), to give 6-methoxy-4-(4-methylquinolin-7yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (155 mg, 87%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:22]1)=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-{(S)-3-[2-((S)-2-tert-butoxycarbonylaminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (2.054 g, 4.04 mmol) in DCM (40 mL) was added TFA (14 mL) and the mixture stirred at RT for 1.5 h. Toluene was added and the volatiles removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording the title compound as a purple oil (1.443 g, 87%). LCMS (Method B): RT 1.60 min [M+H]+ 409.