Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:41]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:54]1([CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:48]2[CH2:49][CH2:50][N:51]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:52][CH2:53]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a methylene chloride solution (100 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (9.96 g) and N-hydroxy succinimide (4.6 g) was added dropwise a methylene chloride solution (50 ml) of N,N'-dicyclohexylcarbodiimide (8.24 g) with a length of time for 1 hour under cooling with ice. After being stirred at room temperature for 4 hours, the reaction mixture was again cooled with ice, and a methylene chloride solution (50 ml) of 1-(diphenylmethyl)piperazine (10.08 g) was added dropwise in 20 minutes. The mixture was stirred overnight at room temperature. Following the removal of the precipitate by filtration, the solvent was removed by distillation under reduced pressure, and ethyl acetate was added. After any insoluble matters were again removed by filtration, the filtrate was washed first with an aqueous sodium bicarbonate solution and then with a saturated sodium chloride solution, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained. This reaction mixture was purified by silica gel column chromatography (developing solvent: chloroform followed by chloroform:methanol=50:1) to yield 16.5 g of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][C:24]([NH:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])([CH3:26])[CH3:25])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C(#N)C>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][C:24]([NH:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])([CH3:26])[CH3:25])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)NC(=O)NC(C)(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)NC(=O)NC(C)(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Yield: 92.7 %

Procedure:
A mixture of N-(2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea (4.24 g, 9.39 mmol) and 5% platinum on carbon (1.0 g) in acetonitrile (700 mL) was hydrogenated at 30 psi (2.1×105 Pa) overnight on a Parr apparatus. The mixture was filtered through CELITE filter agent, which was subsequently rinsed with acetonitrile and dichloromethane. The filtrate was concentrated under reduced pressure to yield 3.67 g of N-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea as a pale yellow foam that was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:23]([O-])=O)[CH3:2]>C(O)C.O.C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[NH2:23])[CH3:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCC)c([N+](=O)[O-])cc23)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C#Cc1cccc(Nc2ncnc3cc(OCC)c(N)cc23)c1
Temperature: 70 °C
Yield: 73.9 %

Procedure:
7-ethoxy-N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine (8 g, 0.024 mol) was dissolved in a mixture of 80 ml ethanol, 80 ml H2O and 10 ml acetic acid. The reaction was heated to 70° C., then Fe (5.4 g, 0.096 mol) was added. The reaction mixture was heated to reflux for 4 hours. The resulting clear reaction solution was concentrated under reduced pressure to remove solvent. The pH of the residue was adjusted to 9 with 4N aqueous NaOH, and was washed with 200 ml EA/MeOH (50/1) until TLC show no product can be detected in the organic layer. The combined organic layers were concentrated, grey solid was precipitated and filtered to afford 7-ethoxy-N4-(3-ethynylphenyl)quinazoline-4,6-diamine as grey solid 5.4 g (74.2% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])O.[Na+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: COC(=O)CBr
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2ccc(N)cc21
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A suspension of 6-nitroindoline (1.0 g, 6.1 mmol) and sodium hydrogen carbonate (0.6 g, 7.1 mmol) in DMF (60 ml) was stirred at room temperature. Methyl bromoacetate (0.68 mL, 1.09 g, 7.1 mmol) was added slowly and the mixture was heated at 90° C. for 1 hour. The mixture was cooled, the solvents evaporated under reduced pressure, and the residue partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was dried over MgSO4 and then evaporated to give an orange solid. The solid was dissolved in methanol (100 ml), 5% Pd/C (50 mg, cat.) was added and the suspension was stirred under an atmosphere of hydrogen for 2 hours, during which time the yellow colour disappeared. The catalyst was removed by filtration through celite and the solvent was evaporated to give the amine as a brown oil (0.95 g, 75%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:36])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:35])[CH2:22][CH2:23][C@H:24]([O:26]C(NCCN(C)C)=O)[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].Cl.IC>>[CH3:8][CH:6]([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:36])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:35])[C:20]([CH2:25][C@H:24]([CH2:23][CH2:22]2)[OH:26])=[CH:19][CH2:18]3)[CH2:11][CH2:10]1)[CH3:1])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CI
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3-β-[N(N′,N′,N′-trimethylethane)carbamoyl]cholesterol (TC-Chol), a quaternary ammonium derivative of Chol, was synthesized by methylation of DC-Chol with iodomethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[Si]([CH:14]=[N+:15]=[N-:16])(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.O1CCCC1.ClCCl>[NH:16]1[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[CH2:8][CH:14]=[N:15]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C1CC=NN1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 60.3 %

Procedure:
A 1 L rb flask was charged with t-butylacrylate (11.33 mL, 78 mmol) in toluene (100 mL) and tetrahydrofuran (THF) (100 mL). To this was added via addition funnel TMS-diazomethane (50.5 mL, 101 mmol) dropwise over 25 minutes under N2. The reaction mixture was stirred at 25° C. for 4.5 h. The solvent was evaporated under reduced pressure. The crude product was dissolved in dichloromethane (70 mL) and cooled in an ice bath. To this solution was added TFA (7.21 mL, 94 mmol.) dissolved in 30 mL of dichloromethane via addition funnel. After addition was complete the mixture was stirred at 25° C. for 0.5 h. The solvent was evaporated and the residue was neutralized by the addition of sat. NaHCO3 and extracted into DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by automated silica gel column chromatography (column: 120 g, 0-38% ethyl acetate in hexane, 34 min). The solvent was removed under reduced pressure to afford 8 g (47 mmol, 60%) of 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate as pale yellow oil. LC-MS (ES) m/e 171.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:71])[CH2:36][C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:71])[CH2:36][C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 94 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform, 52 mg (72%) of the desired compound (Rf 0.18, 10% methanol in chloroform) as a white solid, m.p. 110°-114° C. Mass spectrum: (M+1)+ =821.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=[O:12].O.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cccc(N2CCCCC2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(N2CCCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of methyl 3-(2-oxopiperidin-1-yl)benzoate (114 mg) described in a document (J. Med. Chem. 1997, 40, 331.) in THF (3.0 mL)-water (0.5 mL) was added lithium hydroxide monohydrate (61.5 mg). The mixture was stirred at room temperature overnight, and 10% citric acid solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (34.7 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])=[CH:4][CH:3]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1.O>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>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]([C:13]1[C:12]([CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:42]=[N:41][C:40]([O:39][CH3:38])=[CH:45][CH:44]=3)=[CH:3][CH:4]=2)[N:19]2[C:14]=1[CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]2)=[O:28]
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccc(-c2ccc(OC)nc2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
A solution of ethyl 3-{3-[(4-bromophenyl)carbamoyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (55 mg, 0.097 mmol), 2-(methoxy)pyridine-5-boronic acid (15 mg, 0.097 mmol) and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.007 mmol) in 1,4-dioxane (4 mL) is heated in the microwave at 120° C. for 20 minutes then 100° C. for 16 h. The mixture is cooled to 23° C., poured into water and extracted with EtOAc. The combined organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 50% EtOAc in hexanes) gives ethyl 3-[1-(2,2-dimethylpropanoyl)-3-{[4-(6-methoxypyridin-3-yl)phenyl]carbamoyl}-7-(propan-2-yl)indolizin-2-yl]-2,2-dimethylpropanoate (22 mg, 38%) that is dissolved in 1,4-dioxane (3 mL) and water (0.5 mL). To this mixture is added 10M aqueous NaOH (5 drops) and solution is stirred at 23° C. until reaction is complete. The mixture is acidified with HOAc and resulting solid is filtered, washed with water, collected, and dried to give the title compound (14 mg, 67%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:19]#[N:20])[N:14]=[CH:15][C:8]=12>>[Cl:3][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:19]#[N:20])[N:14]=[CH:15][C:8]=12
Reactant: Cc1ccc(C#N)cc1-n1ncc2c(O)ncnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C#N)cc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Phosphorus oxychloride (8.90 mL, 95.52 mmol) was added to 3-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-methylbenzonitrile (Intermediate AM3) (1.2 g, 4.78 mmol). The resulting solution was stirred at 100° C. for 4 hours. The reaction mixture was evaporated and then azetroped with toluene to remove any residual POCl3. Ice/water was added and the formed precipitate was filtered washing well with water and dried overnight in vacuo over P2O5 to afford 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-methylbenzonitrile (1.16 g, 90%). 1H NMR (400 MHz, DMSO) 2.21 (3H, s), 7.73 (1H, d), 7.97-8.00 (1H, m), 8.06 (1H, d), 8.81 (1H, s), 8.91 (1H, s); HPLC tR=2.05 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH:22](Br)[C:21]2=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH:22]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:21]2=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Br
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1cccnc1
Reaction time: 0.5 h
Yield: 0.8 %

Procedure:
To a solution of 3-hydroxypyridine (8.56 g, 0.090 mol) in 300 ml of dimethylformamide was added NaH (60% in oil, 3.6 g, 0.090 mol). After stirring 0.5 hour, 6-benzyloxy-3-bromo-4-chromanone (30.0 g., 0.090 mol) was added in one portion. After stirring for 1 hour, the reaction mixture was poured into 1 liter of water and extracted 3×250 ml of ethyl acetate. The organic layers were combined, washed 1×100 ml H2O, 1×100 ml 10% LiCl and 1×100 ml brine, dried (Na2SO4) and stripped to yield 40 g of crude title product, which was chromatographed on silica gel using 1:4 ethyl acetate:CH2Cl2 as eluant to yield 1.13 g of purified title product as an off-white powder; mp 133°-134° C. A portion (290 mg) was recrystallized from isopropyl ether to yield 240 mg of white powder.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1>COCCOC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords ethyl 2-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}acetoacetate as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB(/[CH:9]=[CH:10]/[CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)O1.I[C:27]1[C:35]2[O:34][CH2:33][C:32](=[O:36])[C:31]=2[CH:30]=[CH:29][C:28]=1[O:37][CH3:38].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>[CH3:38][O:37][C:28]1[CH:29]=[CH:30][C:31]2[C:32](=[O:36])[CH2:33][O:34][C:35]=2[C:27]=1/[CH:9]=[CH:10]/[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2c(c1I)OCC2=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: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of tert-butyl (E)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidine-1-carboxylate (0.176 g, 0.501 mmol) in 1,4-dioxane (5 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.145 g, 0.501 mmol) synthesized in Example B46, Step 2, 2 M aqueous sodium carbonate (0.750 mL, 1.50 mmol) and tetrakis(triphenylphosphine)palladium (0.0579 g, 0.0501 mmol), and the mixture was refluxed for 12 hours by heating. The reaction mixture was cooled to room temperature, concentrated, and added with water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0313 g, 16%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.[OH-].[Na+:19].[O:20]1CCOCC1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:19]
Reactant: O=C1Cc2cc(Oc3ccccc3)ccc2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccccc2)cc1CC(=O)[O-]
Reaction time: 24 h

Procedure:
A mixture of 2-oxo-5-phenoxyindoline (3.5 g.), sodium hydroxide (1.24 g), dioxane (20 ml.) and water (20 ml.) was refluxed under heating for a week with stirring. The reaction mixture was concentrated to dryness and the residue was dissolved in water (50 ml.) under heating and filtered. The filtrate was washed with diethyl ether and evaporated. The residue was dissolved in ethanol (100 ml.) under heating and filtered. The filtrate was concentrated at ordinal pressure to a volume of 30 ml. The concentrate was allowed to stand for one day at ambient temperature, and the precipitates were collected by filtration to give crystals of the captioned compound (2.5 g.). mp 239° to 242° C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[C:13]1=[O:16])[CH:18]=[CH:19][CH3:20]
Reactant: O=C1CCc2ccc(-c3ccccc3)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Yield: 72 %

Procedure:
A solution of 13.2 g of 6-phenyl-1-indanone, 11 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110ml of 2,2-dimethoxy-propane was boiled under reflux for 48 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 12.0 g (72%) of (RS)-2-(2-buten-1-yl)-6-phenyl-1-indanone was obtained as a light yellow solid which was used without further purification in the next reaction.
Reaction SMILES: C([O-])([O-])=O.[Ca+2].[C:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)(=[O:8])[CH3:7].[I:16]Cl>O.CO.CCOCC>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([C:6](=[O:8])[CH3:7])=[CH:10][C:11]=1[I:16]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.4 %

Procedure:
To a stirred suspension of CaCO3 (4.5 g, 45.27 mmol) in H2O (15 mL) was added a solution of 4-acetylaniline (4.1 g, 30.18 mmol) in MeOH (25 mL), followed by a solution of iodine monochloride (5.2 g, 31.88 mmol) in MeOH (20 mL) dropwise. The reaction was stirred at r.t. for 45 minutes, then diluted with Et2O (150 mL). The organic fraction was separated, washed with water (100 mL), then brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (3.5 g, 44%) as a brown oil that was used without further purification. δH (DMSO-d6) 8.14 (1H, d, J 1.8 Hz), 7.70 (1H, dd, J 8.3 and 1.8 Hz), 6.75 (1H, d, J 8.3 Hz), 6.10 (2H, s), 2.41 (3H, s). LCMS (ES+) 261 (M)+, 283 (M+Na)+, RT 3.026 minutes (Method 4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and 2,5-dimethoxyaniline (59 mg, 0.385 mmol) similar to Example 13 and isolated as a greenish-yellow solid (24 mg, 17%). 1H NMR (CDCl3): 9.67–9.66 (m, 1H), 8.74–8.70 (m, 2H), 8.02 (s, 1H), 7.44–7.39 (m, 1H), 6.91 (s, 1H), 7.67 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.65 (dd, J=3.0, 9.0 Hz, 1H), 3.86 (d, J=7.2 Hz, 6H).