Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([F:7])[F:6])C.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]([F:6])([F:7])[C:4]([OH:16])=[O:3])=[CH:13][CH:12]=1)#[N:15]
Reactant: CCOC(=O)C(F)(F)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the above-described scheme, 2-(4-cyanophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2a; 202.7 mg, 0.9 mmol), 1N K2CO3 solution (2.7 mL) and DMF (2.7 mL) were put into an eggplant flask, and the mixture was stirred at 25° C. for 18 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-cyanophenyl)-2,2-difluoroacetic acid (Compound 4a) was obtained with a yield of 79%.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[CH2:12][CH2:11][C:10](=O)[CH:9]=1)([CH3:7])([CH3:6])[CH3:5].Cl>C(OCC)C>[CH3:1][C:11]1[CH2:10][CH:9]=[C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH:12]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)C1=CC(=O)CC1
Agent: Cl
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1
Temperature: 0 °C

Procedure:
To a 500 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 100 ml of dehydrated diethyl ether and 57 ml (170 mmol) of diethyl ether solution of 3.0 M methyl magnesium bromide were charged under a nitrogen atmosphere. In the ice bath, 19.6 g (142 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour. The resultant solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The obtained organic layers were combined, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, twice with water, and twice with saturated brine and dried over magnesium sulfate and the solvent was distilled off. Thereafter, the purification was conducted by distillation under reduced pressure to obtain 13.5 g of a pale yellowy transparent liquid. The yield constant was 70%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][N:51]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][N:51]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: Cc1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)nc1
Yield: 93.3 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-amino-5-methylpyridine (143 mg; 1.32 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) provided after flash chromatography (Biotage 40S; eluent: 30% ethyl acetate/hexanes) 352 mg of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-5-methyl-pyridin-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C23H27N3O2 (M+) 377.2103, found 377.2107.
Reaction SMILES: C(OC([O:8][C:9]1[C:18]2[NH:17][C:16](=[O:19])[CH2:15][O:14][C:13]=2[C:12]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][N:32]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[C:33](=[O:51])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH3:50])[CH:49]=3)[CH:40]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)=O)(C)(C)C.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>C(Cl)Cl>[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59].[CH:52]1([N:32]([CH2:31][CH2:30][NH:22][CH2:21][CH2:20][C:12]2[C:13]3[O:14][CH2:15][C:16](=[O:19])[NH:17][C:18]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[C:33](=[O:51])[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[N:46]=[N:47][N:48]([CH3:50])[CH:49]=3)[CH:40]=2)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CCNCCc3ccc(O)c4c3OCC(=O)N4)C3CCCCC3)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl(2-(N-cyclohexyl-3-(3-(1-methyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanamido)ethyl)carbamate [Example 5, Step iv)] (290 mg), DCM (5 mL) and TFA (2.5 mL) was stirred at 25° C. for 30 min. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (94 mg). MS [M+H]+=591.3 (calc=591.3295) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.69 (s, 1H), 7.57 (dt, J=1.6 and 8.0 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 4.12 (s, 3H), 3.75-3.64 (m, 5H), 3.52-3.44 (m, 2H), 3.12 (t, J=7.3 Hz, 2H), 3.02 (t, J=5.6 Hz, 2H), 2.88 (t, J=6.7 Hz, 2H), 2.86 (t, J=7.0 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.80-1.72 (m, 2H), 1.69-1.58 (m, 2H), 1.46-1.24 (m, 5H), 1.15-1.03 (m, 1H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][OH:18].O>CO>[OH:18][CH2:17][CH2:16][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2
Reactant: OCCBr
Reactant: O=C1CCc2c(O)cccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CCc2c(cccc2OCCO)N1
Yield: 16.5 %

Procedure:
4.2 Grams of potassium hydroxide were dissolved in 200 ml of methanol, then 10 g of 5-hydroxy-3,4-dihydrocarbostyril were added thereto. Next, 10 g of 2-bromoethanol were added dropwise thereto under refluxing conditions. The reaction mixture was further refluxed for 4 hours, then was concentrated. To the residue thus obtained was added water, and the insoluble matter was collected by filtration, and was washed with water, then recrystallized from methanol to yield 2.1 g of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 176°-178° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(OCC)C.[OH:10][CH2:11][C:12]1[N:24]2[C:15]([C:16]3[CH:17]=[C:18]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]([C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=4)=[N:20][C:21]=3[CH:22]=[CH:23]2)=[N:14][N:13]=1.B(F)(F)F.CCOCC>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:30][C:29]1([C:28]2[CH:31]=[CH:32][C:25]([C:19]3[C:18]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:17][C:16]4[C:15]5=[N:14][N:13]=[C:12]([CH2:11][OH:10])[N:24]5[CH:23]=[CH:22][C:21]=4[N:20]=3)=[CH:26][CH:27]=2)[CH2:2][CH2:1]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2ccc(-c3nc4ccn5c(CO)nnc5c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethylmagnesium bromide in diethyl ether (0.4 mL, 1.2 mMol, 3M) was added at −70° C. to a solution of 15-1 (0.1 g, 0.3 mmol) and titanium (IV) isopropoxide (0.17 g, 0.6 mMol) in anhydrous THF (7 mL). After 10 min, the cold bath was removed and the reaction was warmed to room temperature. After stirring for 1 hour, more ethylmagnesium bromide in diethyl ether (0.18 mL, 0.5 mMol, 3M) was added and the reaction was cooled to 0° C. in an ice bath and was treated with boron trifluoride etherate (0.18 g, 1.2 mMol). The reaction was stirred at 0° C. for 30 minutes then warmed to room temperature for 1 hour. The reaction was quenched with 1N HCl followed by stirring for 3 hours. The solution was basified with 1M NaOH, extracted with chloroform, dried with Na2SO4, filtered and concentrated in vacuo. Crude residue was taken up in methanol and purified using a C18 reverse phase HPLC to give 15-2 as a solid. LC/MS (M+1) calculated: 408.4; observed: 408.0
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[N:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]3=[N:22][CH:21]=2)=[N:4][C:5]([N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:78][N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1.C(=O)([O-])O.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.O1CCOCC1.C1(C)C=CC=CC=1>[CH3:29][C:28]1[C:23]2[N:24]([C:20]([C:3]3[C:2]([N:82]4[CH2:83][CH2:84][N:79]([CH3:78])[CH2:80][CH2:81]4)=[CH:7][N:6]=[C:5]([N:8]([C@H:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:13])[C:9](=[O:11])[CH3:10])[N:4]=3)=[CH:21][N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)N(c1ncc(Br)c(-c2cnc3c(C)cccn23)n1)[C@@H](C)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N(c1ncc(N2CCN(C)CC2)c(-c2cnc3c(C)cccn23)n1)[C@@H](C)c1ccccc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
The mixture of 17 mg of N-[5-bromo-4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-pyrimidinyl]-N-[(1S)-1-phenylethyl]acetamide [16-1], 2.17 mg of bis(dibenzylideneacetone)palladium, 19 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 17.2 mg of cesium carbonate, 5.0 μL of 1-methylpiperazine, 0.25 mL of toluene, and 0.5 mL of 1,4-dioxane, was stirred at 80° C. for 3 days. After cooling the reaction mixture back to room temperature, a saturated aqueous solution of sodium hydrogen carbonate and water were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative reversed phase liquid chromatography, to obtain 0.6 mg of N-[4-(8-methylimidazo[1,2-a]pyridin-3-yl)-5-(4-methyl-1-piperazinyl)-2-pyrimidinyl]-N-[(1S)-1-phenylethyl]acetamide [16-2].
Reaction SMILES: C[O:2][C:3](=[O:34])/[C:4](=[N:31]\[O:32][CH3:33])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][CH3:27])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:28][C:25]([CH3:29])([CH2:26][CH3:27])[C:24](=[O:30])[O:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5](/[C:4](=[N:31]/[O:32][CH3:33])/[C:3]([OH:34])=[O:2])=[CH:10][CH:9]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc(/C(=N/OC)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc(/C(=N/OC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As in Example 19, (Z)-4-[2-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenyloxy]ethoxy]-alpha-methoxyiminobenzeneacetic acid methyl ester (0.231 g) in methanol (5 mL) was treated with 1N sodium hydroxide (0.54 mL) and the mixture was stirred overnight at room temperature. The usual work up gave 0.188 g of an oil which was purified by flash chromatography over silica gel (formic acid-diethyl ether 1:49) to yield 0.07 g of recovered starting ester along with 0.055 g of (Z)-4-[2-[2-[(2,2-dimethyl-1 -oxobutoxy)methyl]-6-methylphenyloxy]ethoxy]-alpha-methoxyiminobenzene acetic acid as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](=[O:24])[CH3:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[CH3:29][N:30]([CH3:32])/[CH:31]=[CH:23]/[C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:26])[N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24]
Reactant: CC(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Reactant: COC(OC)N(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/C=C/N(C)C)cc2OCC3)n(C(C)C)n1
Reaction time: 8 h

Procedure:
1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)ethanone (2.6 g, 0.0074 mol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (0.98 mL, 0.0074 mol) was mixed in Xylenes (30 mL, 0.07 mol) and was heated to reflux and stirred overnight. LCMS showed complete conversion to desired product. The solvent was removed and (E)-3-(dimethylamino)-1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)prop-2-en-1-one was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[CH2:3]1.[BH4-].[Na+].II>C1COCC1>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:10]=2[CH2:11][OH:12])[CH2:5]1
Reactant: C[C@@H]1CN(c2c(C(=O)O)ccc(F)c2F)C[C@H](C)O1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO)ccc(F)c2F)C[C@H](C)O1

Procedure:
To a stirred and ice-bath cooled solution of 2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid (Intermediate 1, 27.0 g, 99.6 mmol) in THF (250 mL) was added sodium borohydride (12.56 g, 358.6 mmol) in small portions, followed by iodine (32.5 g, 139.4 mmol) in THF (250 mL). The addition was carried out such that the temperature maintained below 10° C. The mixture brought to room temperature and refluxed for 12 hours. It was cooled and then quenched with methanol (250 mL). Solvents were evaporated and the residue treated with 2M NaOH (500 mL) for 2 hours. The aqueous layer extracted with ethyl acetate (3×150 mL), and the combined organic phases were washed with water and brine before being dried (Na2SO4) and concentrated to give the title compound as a gummy solid. MS (ES) MH+: 257.2 for C13H17F2NO2
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:33][CH:32]=1)([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), (4-isopropoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate (2.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.88 g, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1COCC1.[Li+].[OH-]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1csc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2ccc([N+](=O)[O-])cc2)n1
Reaction time: 2.5 h

Procedure:
To a solution of Ethyl 2-(4-nitrophenyl)thiazole-4-carboxylate in THF, 1N LiOH was added at RT and stirred for 2-3 hr. After completion of reaction THF was removed under reduced pressure. Obtained material was dissolved in water acidified with 1N HCl and white solid precipitated out. It was filtered and dried. Yield 4.4 gm (97%). MS (ESI) m/z: 249(M−H)−; 1HNMR (DMSO-d6, 300 MHz): δ 13.233 (s, 1H), 8.658 (s, 1H), 8.358 (d, 2H), 8.269 (d, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:25]=[C:24]2[O:26][CH2:27][O:28][C:23]2=[CH:22][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CN(C=O)C>[Cl:3][C:4]1[CH:25]=[C:24]2[O:26][CH2:27][O:28][C:23]2=[CH:22][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=3)=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a stirring suspension of sodium hydride (0.016 g, (60% in mineral oil), 0.402 mmol) in DMF (2 mL) was added ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-5-hydroxyindole-2-carboxylate (0.100 g, 0.268 mmol). After 15 minutes, 4-trifluoromethylbenzyl bromide (0.096 g, 0.402 mmol) was added. After 1.5 hours, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), filtered and concentrated to a residue that was purified by column chromatography (ethyl acetate/hexane) to give the title compound as a white solid (0.124 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2ccccc2n1
Yield: 60.5 %

Procedure:
To a mixture of 2-methylquinazolin-4(3H)-one (9.2 g, 0.0574 mol) and phosphorous oxychloride (5.8 g, 0.037 mol) in dry toluene (250 ml) was added N,N-dimethyl aniline (13.9 g, 0.14 mol) and the mixture was refluxed for 3 h. The reaction mixture was cooled and washed with water, brine and dried. The solvent was removed under vacuum and the residue was purified by chromatography (silica gel, 60-120 mesh) eluting with pet ether/ethyl acetate (9/1) to afford 4 g (39%) of the titled compound as a solid.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]CC)=[O:17])=[CH:15][C:11]=3[CH2:10][CH:9]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(Cc1ccc(-c3ccccc3)cc1)=CC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)C(Cc1ccc(-c3ccccc3)cc1)CC2
Yield: 49.5 %

Procedure:
The title compound was synthesized from ethyl 6-(biphenyl-4-ylmethyl)-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate (0.0343 g, 0.1 mmol, 1 equiv) and sodium hydroxide (0.36 mL, 3.6 mmol, 10 M, 35 equiv), according to General Procedure 7. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 70% methanol and increasing to 100% over 7 minutes) afforded the title compound (15.7 mg, 50%) with purity by HPLC of 93.3% (UV). LCMS m/e 316.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.20 (m, 1H) 2.41-2.50 (m, 2H) 2.75 (dd, J=13.62, 8.54 Hz, 1H) 3.06-3.12 (m, 1H) 6.55 (s, 1H) 7.24 (d, J=8.10 Hz, 2H) 7.28-7.33 (m, 1H) 7.41 (t, J=7.61 Hz, 2H) 7.53 (d, J=8.13 Hz, 2H) 7.60 (d, J=7.20 Hz, 2H) 8.50 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]2=[O:15].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]2=[O:15])=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.08 g (20 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Pharm. Sci., 11, 1051 (1963)] 2.37 ml (30 mmol) of ethyl isocyanate, 2.8 ml (20 mmol) of triethylamine and 50 ml of dimethylformamide is stirred at room temperature overnight. The solution is evaporated to dryness and the residue is treated with 1 N hydrochloric acid. The solid is filtered to give 4.56 g of 6-[[(ethylamino)carbonyl]-amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp>320° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1C1NC(C2C=CC(C3C4C(=C(B5OC(C)(C)C(C)(C)O5)C=CC=4)C=CC=3)=CC=2)=CN=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCCC1C1NC(Br)=CN=1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>COCCOC.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]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3cccc4c(B5OC(C)(C)C(C)(C)O5)cccc34)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)[nH]1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 85 °C
Yield: 87.3 %

Procedure:
2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (159 mg, 0.281 mmol), 2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (178 mg (0.562 mmol), Pd(PPh3)4 (65 mg, 0.0562 mmol) and K2CO3 (0.281 mL of a 2 M aqueous solution, 0.562 mmol) were combined in 1,2-dimethoxyethane (3 mL) and degassed with bubbling N2 for 12 min. The mixture was then heated to 85° C. for 22 hours then cooled to RT, diluted with ethyl acetate (50 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (80% to 100% EtOAc/hexanes) to afford 2-(5-{4-[5-(1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester)-naphthalen-1-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (42 mg, 22%).