Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:10][C:11]([F:25])([F:26])[C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 2,4-bis(trifluoromethyl)phenylboronic acid (1.38 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled to room temperature and concentrated and the residue then partitioned between water and CH2Cl2. The organic layer concentrated and purified by chromatography (20% ethyl acetate:hexanes) to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([OH:28])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])([CH3:7])[CH3:6].[BH4-].[Na+]>CO.C1COCC1>[OH:28][C:3]([C:2]([F:30])([F:1])[F:29])([CH2:4][C:5]([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][OH:12])[CH:9]=1)([CH3:7])[CH3:6])[CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(CO)c1
Reaction time: 0.75 h
Yield: 31.5 %

Procedure:
To a solution of the 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde (20.0 mg, 0.05 mmol) in methanol (0.50 mL) and THF (0.50 mL) was added NaBH4 (20.0 mg, 0.48 mmol). The reaction vessel was sealed and stirred for 45 minutes. The solvent was evaporated in vacuo and the off-white solid was re-dissolved in EtOAc and water and transferred to a separatory funnel. The aqueous layer was extracted with two 10 mL portions of EtOAc and the combined organic layers were washed with one 10 mL portion of brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give a white foam. The material was chromatographed (6% MeOH/CH2Cl2, 0.5% NH4OH) to give the desired compound, 1-[2-hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one as a white foam (6.6 mg, 36%).
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[C:13]1([C@@H:19]2[CH2:21][C@H:20]2[C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:22]([C@@H:20]3[CH2:21][C@H:19]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:23])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CC(N2CCNCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
To a stirring slurry of 4A (130 mg, 0.610 mmol) in anhydrous DCM (3.5 mL) under an argon (g) atmosphere was added TEA (0.162 mL, 1. 16 mmol). After 1 min. trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.096 mL, 0.55 mmol) was added in one portion to the now clear solution. The reaction was left to stir for ca. 1.5 h at ambient temperature before being washed with H2O (2×2 mL), dilute aq. K2CO3 (1×2 mL), H2O (1×2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting gum was subjected to flash chromatography (basic alumina—8 g; gradient elution: 5% EtOAc/Hexane for 1 min. then 5-55% EtOAc/Hexane over 7 min. at 18 mL/min) to afford 90 mg 4B as a white solid (57% yield). m/z (ES+) M+1=285.2; HPLC tR=1.54 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.80-3.46 (m, 4H), 2.72 (quintet, J=7.9 Hz, 1H), 2.47 (ddd, J=9.0, 6.3, 4.0 Hz, 1H), 2.39-2.25 (m, 4H), 2.08-1.98 (m, 2H), 1.95 (td, J=4.4, 3.7 Hz, 1H), 1.92-1.81 (m, 2H), 1.78-1.59 (m, 3H), 1.27-1.24 (m, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C@@:10]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@@H:14]1[CH2:20][CH:21]=[C:22]3[CH2:27][C@@H:26]([OH:28])[CH2:25][CH2:24][C@:23]3([CH3:29])[C@H:13]1[CH2:12][CH2:11]2.O.C(OCC)(=[O:33])C>N1C=CC=CC=1>[Si:1]([O:28][C@H:26]1[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@@H:22]([C@@H:21]([OH:33])[CH2:20][C@@H:14]3[C@@H:13]2[CH2:12][CH2:11][C@@:10]2([CH3:9])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[OH:19])[CH2:27]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](C1)[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
tert-Butyldimethylsilylchloride (9.72 g) was added, at room temperature, to a solution of prasterone (V, 15 g) in pyridine (60 mL). After 24 hrs, the reaction mixture was poured into iced water (600 mL). Ethyl acetate was added, the two layers were separated, the organic layer washed with sodium bicarbonate (5%), sodium dihydrogenphosphate (5%) and brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude residue, [3β-tert-butyldimethylsilyloxy-androst-5-en-17-one, g 23.9; 1H-NMR (300 MHz. CDCl3, ppm from TMS): 5.32 (1H, d), 3.48 (1H, hept), 2.49 (1H, dd), 2.35-0.8 (33H, m), 0.03 (6H, s)] was dissolved in diethyl ether/ethanol (335 mL/250 mL), cooled to 0° C. and treated with sodium borohydride (4 g). The reaction mixture was stirred at room temperature for 1 hr. then quenched with 1N hydrochloric acid to pH=7, diluted with brine (300 mL) and extracted with diethyl ether. The organic layer was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude residue, [3β-tert-butyldimethylsilyloxy-androst-5-en-17β-ol, g 21; 1H-NMR (300 MHz, CDCl3, ppm from TMS): 5.32 (1H, m), 3.62 (1H, m), 3.48 (1H, hept), 2.35-0.8 (34H, m), 0.03 (6H, s)] was dissolved in tetrahydrofurane (850 mL), cooled to 0° C. and treated with borane-dimethylsulfide complex (THF, 1M, 155 mL). The reaction mixture was stirred at room temperature for 2 hrs, then it was cooled to 0° C. and quenched with water (300 mL), and sodium perborate tetrahydrate (43 g). The mixture was stirred overnight at room temperature, ammonium chloride (30%, 300 mL) was added, the two layers were separated, the organic one dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by flash-chromatography (SiO2 ; n-hexane/ethyl acetate 75/25) to give to give 18 g of the title compound (II-a) as a foam. 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.68 (1H, t), 3.52 (1H, hept), 3.42 (1H, dd), 2.20-0.6 (35H, m), 0.03 (6H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(NCc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(NCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 13.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-benzylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 68-1-4 and 3-ethynyl-pyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (190 μL, 1.37 mmol). The mixture was stirred for 6.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (17 mg, 8.4%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][NH:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][N:12]([C:23](=[O:24])[C:22]4[CH:21]=[C:20]([O:19][CH3:18])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc3c(c2)OCO3)CCNC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-(3-benzo[1,3]dioxol-5-yl-pyrrolidin-3-yl)-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][CH:33]3OC(C)(C)[O:36][CH:35]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]3[CH2:34][C@@H:35]([OH:36])[CH2:41][C:42](=[O:43])[O:44]3)[C:10]([CH:28]([CH3:29])[CH3:30])=[C:11]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 15 h

Procedure:
(4R-cis))1,1-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol), is dissolved in 200 mL of tetrahydrofuran and 15 mL of 10% hydrochloric acid solution is added, and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (3.01 g) is isolated in two crops.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(#N)C.O.FC(C(O)=O)(F)F>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:20]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 0.28 mmol) was taken up in a mixture of acetonitrile-H2O-TFA. The solvent was removed under reduced pressure and the residue obtained was dissolved in CDCl3. After a brief exposition to daylight (5-10 min), the solution turned purple. The mixture was stirred open to the atmosphere at room temperature until complete disappearance of the starting material (8 h). Solvent was removed under reduced pressure and the residue was purified by reverse phrase HPLC to give 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-yl)butanoic acid. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=1.9 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.16 (s, 1H), 7.03 (dd, J=9.4, 1.9 Hz, 1H), 7.00-6.98 (m, 2H), 6.85 (d, J=7.9 Hz, 1H), 6.16 (s, 1H), 6.02 (s, 2H), 4.29-4.24 (m, 2H), 2.48 (dd, J=6.9, 6.9 Hz, 2H), 2.12-2.04 (m, 2H), 1.69 (dd, J=6.8, 3.7 Hz, 2H), 1.43 (s, 9H), 1.09 (dd, J=6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 463.0.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH2:9]Cl)=[C:7]([CH3:14])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([O-:29])(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH2:9][O:29][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:7]([CH3:14])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)OCc1c(C)cc(C(C)(C)C)c(O)c1C
Temperature: 0 °C

Procedure:
A mixture of 30 g. (0.13 mole) of 4-tert.-butyl 3-hydroxy-2,6-dimethylbenzyl chloride and 29.4 g. (0.13 mole) of sodium laurate in 35 ml. of dimethylformamide was heated at 94°-102° C. for a period of 7 hours. The hot melt was added to 300 g. of ice water slurry. The oil was taken up in 250 ml. of benzene, washed with water and dried over anhydrous sodium sulfate. The salt was filtered and the filtrate concentrated in vacuo to give 44 g. of an oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO[C:6]([C:8]1[N:9]=[N:10][N:11]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][C:34]=2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:12]=1[N:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[O:7]>CO>[C:29]([O:28][C:26](=[O:27])[N:13]([C:12]1[N:11]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[C:36]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:35][C:34]=2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:10]=[N:9][C:8]=1[C:6](=[O:7])[NH:3][CH2:1][CH3:2])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:16][CH:15]=1)([CH3:31])([CH3:30])[CH3:32]
Reactant: CCN
Reactant: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Solvent: CO
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: 80 °C

Procedure:
EtNH2 (1.5 ml of a solution 2 M in MeOH) was added to 1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-[tert-butoxycarbonyl-(4-morpholin-4-yl-phenyl)-amino]-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (110 mg, 0.15 mmol) and the mixture was heated to 80° C. for 24 hours in a sealed tube. The solvent and the excess of amine were removed under reduced pressure and the residue was used in the next reaction without any purification.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][C:39]([C:42](=[N:44][O:45][CH2:46][CH3:47])[CH3:43])=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:48][O:49]C(=O)C)[CH2:7][O:8]2)(=O)C.CO.O.O.[OH-].[Li+]>C1COCC1>[CH2:46]([O:45][N:44]=[C:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C:23]3[CH:22]=[C:21]([C@@:9]45[O:20][C@@:6]([CH2:48][OH:49])([CH2:7][O:8]4)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]5[OH:16])[CH:26]=[CH:25][C:24]=3[Cl:27])=[CH:34][CH:33]=2)=[CH:41][CH:40]=1)[CH3:43])[CH3:47]
Reactant: CCON=C(C)c1ccc(Oc2ccc(Cc3cc([C@]45OC[C@](COC(C)=O)(O4)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)ccc3Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCON=C(C)c1ccc(Oc2ccc(Cc3cc([C@]45OC[C@](CO)(O4)[C@@H](O)[C@H](O)[C@H]5O)ccc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(4-(1-(ethoxyimino)ethyl)phenoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (210.0 mg, 0.28 mmol), in THF (1.6 mL), methanol (2.4 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (14.0 mg, 0.34 mmol) at 0° C. The reaction mixture was stirred at r.t. for 1 h. After the completion of reaction as confirmed by TLC, volatiles were evaporated in vacuo and the compound was diluted with ethyl acetate (50 mL). The organic layer was washed with water (2×10 mL), dried over Na2SO4 and concentrated to afford title compound (160.0 mg, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][N:28]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:33]=1[CH3:47])[C:27]2=[O:48].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:18][O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:2]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N:28]5[C:27](=[O:48])[C:26]6[C:31](=[C:22]([F:21])[CH:23]=[CH:24][CH:25]=6)[N:30]=[CH:29]5)[C:33]=4[CH3:47])=[N:3][CH:4]=[C:5]([C:19]#[N:20])[C:6]=3[NH:7][C:8]=2[CH:9]=1)=[O:16]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(Cl)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2c(F)cccc2c1=O
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: C1COCCO1
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5c(F)cccc5c4=O)c3C)c12
Temperature: 110 °C
Yield: 34 %

Procedure:
A stirred mixture of methyl 1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate (0.285 g, 0.998 mmol), 8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one (0.379 g, 0.998 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol) and Sodium carbonate[2M aqueous] (0.499 mL, 0.998 mmol) in Dioxane (2 mL) was heated at 110° C. for 16 hours overnight. LC-MS showed complete conversion to the desired product mass plus residual starting material[boronic ester] and a byproduct. The reaction mixture was concentrated. The residue was taken up in 10 ml DMF, stirred and filtered. The filtrate was concentrated; the residue triturated with methanol and filtered. The solid residue labeled 89040-079-04 was dried overnight. LC-MS showed the solid residue to be the desired product Methyl-4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid [0.172 g, 0.342 mmol, 34% yield]. The product had an HPLC Retention Time=3.510 min [mixture of rotamers][4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 504.3.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37])([OH:3])=[O:2]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1CCC(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of (1RS, 2SR, 3SR)-3-[2-[(E)-2-carboxy-ethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (43 mg, 0.08 mmol) in ethanol (5 mL) was added 10% palladium on activated carbon (40 mg). The resulting suspension was stirred overnight under an atmosphere of hydrogen then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound (35 mg, 82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O-].[Na+].IC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])[CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOc1ccc(N(C)C(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 6-chloro-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide (50 mg, 0.155 mmol) in DMF (2 ml) was added sodium methoxide (12 mg, 0.222 mmol) in DMF (1 ml) and the reaction mixture was stirred for 10 min. To the mixture was added iodomethane (22 mg, 0.155 mmol) slowly and the mixture was stirred for at room temperature for 3 h. It was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography to yield the titled compound as a light brown liquid. 1H NMR (CDCl3): 8.17 (d, J=2.1, 1H), 7.68-7.65 (m, 1H), 7.35 (d, J=2.7, 1H), 7.21 (t, J=7.8, 2H), 7.10-7.06 (m, 1H), 4.08-4.01 (m, 2H), 3.40 (s, 3H), 1.44 (t, J=6.9, 3H).
Reaction SMILES: C[O-].[Na+].[Na].[OH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CO>[O:21]1[CH2:20][CH:19]1[CH2:17][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16]
Reactant: ClCC1CO1
Reactant: O=C1NCCc2c(O)cccc21
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C1NCCc2c(OCC3CO3)cccc21
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of sodium methoxide (made from 2.4 g (106 mmol) of sodium) in 360 ml of methanol was added 14.5 g (106 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone. Then 22.2 g of epichlorohydrin in 250 ml of methanol was added dropwise at 55°. After 18 hours an additional 5 g of epichlorohydrin was added and the mixture was stirred for two hours more. The reaction was cooled and concentrated. The residue was chromatographed (SiO2, chloroform/methanol 8:1) to provide 7.9 g (34%) of the desired product. An analytical sample was obtained by recrystallization from chloroform; mp 165°-166°.