Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1.[P:13]([O-:20])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:11][C:9]1[CH:10]=[C:5]([PH:13](=[O:20])[C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=2)[CH:6]=[C:7]([CH3:12])[CH:8]=1
Reactant: CCOP([O-])OCC
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc([PH](=O)c2cc(C)cc(C)c2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Under an argon atmosphere, a solution of magnesium (25 g, 0.95 equivalent) and a small amount of iodine in THF (250 mL) was stirred at room temperature for 1 hr. 5-Bromo-m-xylene (200 g, 1.08 moL) was added at 48° C., and the mixture was stirred at 5° C. for 1 hr. Diethyl phosphite (78.3 g, 0.52 equivalent) was added at 5° C., and the mixture was stirred at 5° C. for 2 hrs. Water (200 mL) was added at 3° C., and toluene (200 mL) and 6M-HCl (160 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (100 mL), 5% aqueous NaHCO3 solution (100 mL) and 5% aqueous NaCl solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered by gravity. The filtrate was concentrated under reduced pressure and the residue was recrystallized from diisopropyl ether-heptane to give the title compound (43.3 g, white crystals). yield 33.3%.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].[OH-].[K+]>CO>[F:11][C:12]1[C:17]([CH:18]([OH:19])[C:10]2[C:3]3[C:2]([CH3:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: Cc1ncnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(C)c23)c1F
Temperature: 25 °C
Reaction time: 30 h
Yield: 37.7 %

Procedure:
To 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (42, 0.192 g, 1.44 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (9, 0.456 g, 1.73 mmol), potassium hydroxide (0.263 g, 4.69 mmol) and 1.0 mL of methanol were added to provide a solution. The reaction was allowed to stir at room temperature for 30 hours, then quenched with water and adjusted to pH ˜5 with acetic acid and sodium bicarbonate and extracted with ethyl acetate and saturated sodium chloride. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane with 4% acetic acid. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (P-0055, 215 mg). 1H-NMR(dmso-d6) showed it contains about >80% of the desired compound, used in the next step without further purification. MS(ESI) [M+H−]+=397.1.
Reaction SMILES: [O:1]([C:8](Cl)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1.CN1CCOCC1>C(Cl)Cl>[C:2]1([O:1][C:8]([O:11][CH2:12][C:13]2([CH3:17])[CH2:16][O:15][CH2:14]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC1(CO)COC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1(COC(=O)Oc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A 0.552 mL (4.42 mmol) sample of phenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 376 mg (3.68 mmol) of 3-hydroxymethyl-3-methyloxetane and 60.7 mL (5.52 mmol) of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The mixture was stirred at 0° C. for 3.5 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.582 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)cc1N
Yield: 94 %

Procedure:
To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([O:10][C:11](=[O:18])[CH:12]=[C:13]([NH2:17])[O:14][CH2:15][CH3:16])[CH3:9]>C(O)(C)C>[CH2:8]([O:10][C:11]([C:12]1[CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:12]([C:11]([O:10][CH2:8][CH3:9])=[O:18])[C:13]([O:14][CH2:15][CH3:16])=[N:17][C:13]=1[NH2:17])=[O:18])[CH3:9]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1ccco1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccco1

Procedure:
Upon heating a solution of 4.8 g of furan-2-aldehyde and 15.9 g of 3-amino-3-ethoxy-acrylic acid ethyl ester in 50 ml of alcohol for 8 hours, 2-amino-4-(2-furyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 110°C (isopropanol) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)C)cc12)C(=O)OCC
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A mixture of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (2.5 g), pyridine (1.2 g) and dichloromethane (55 ml) was stirred under ice-cooling. To the reaction mixture was added dropwise isobutyryl chloride (1.06 g). The reaction mixture was stirred under ice-cooling for 30 minutes and at ambient temperature for 20 minutes. After ice-water was added to the reaction mixture, the resultant mixture was stirred and extracted with chloroform. Insoluble materials were removed by filtration from the extracts. The extracts were washed three times with water and with aqueous solution saturated with sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by a column chromatography using silica gel (developing solvent: chloroform) and crystallized from a mixture of chloroform and hexane to give crystalline diethyl [(6-isobutyramido-4-quinazolinylamino)methylene]propanedioate (1.28 g). Crystals (0.67 g) of the same compound were recovered from the mother liquor by substantially the same crystallization as mentioned above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([CH3:27])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([CH3:27])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: COC(=O)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and methyl 2-chloro-6-methyl-pyrimidine-4-carboxylate. The reaction was heated to reflux for 16 h. The title compound was obtained as a pale-brown solid in 18% yield.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S].[CH2:21](N)[CH2:22][NH2:23]>>[CH2:13]([O:12][C:8]1[C:9]([O:10][CH3:11])=[C:2]([C:3]([C:4]2[NH:23][CH2:22][CH2:21][N:5]=2)=[CH:6][CH:7]=1)[NH2:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCN
Reactant: COc1c(OCc2ccccc2)ccc(C#N)c1N
Agent: [S]
Product: COc1c(OCc2ccccc2)ccc(C2=NCCN2)c1N
Temperature: 100 °C
Yield: 86 %

Procedure:
A mixture of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile (Step 5, 144 g, 566 mmol) and sulfur (55 g, 1.7 mol) in ethylenediamine (800 mL) was degassed for 30 minutes then heated to 100° C. After 16 h the reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, diluted with a saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting solids were recrystallized from EtOAc and hexanes to afford the title compound (145 g, 86%): 1H NMR (DMSO-d6) δ: 7.27-7.48 (5H, m), 7.14 (1H, d), 6.92 (2H, m), 6.64 (1H, m), 6.32 (1H, d), 5.11 (2H, s), 3.67 (3H, s), 3.33 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)#[CH:2].Br[C:18]1[N:22]([CH2:23][CH2:24][F:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1>>[F:25][CH2:24][CH2:23][N:22]1[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=[C:18]1[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][CH:8]=1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: FCCn1c(Br)nc2ccccc21
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nc3ccccc3n2CCF)cn1
Yield: 31.5 %

Procedure:
tert-Butyl (5-ethynylpyridin-2-yl)carbamate (22 mg, 0.1 mmol) and 2-bromo-1-(2-fluoroethyl)-1H-benzo[d]imidazole (24.3 mg, 0.1 mmol) was reacted using general procedure B to afford tert-butyl (5-((1-(2-fluoroethyl)-1H-benzo[d]imidazol-2-yl)ethynyl)pyridin-2-yl)carbamate (12 mg, 31%). 1H NMR (300 MHz, CDCl3): 8.51 (d, J=1.6 Hz, 1H), 8.47 (m, 1H), 7.88 (dd, J=8.8, 2.4 Hz, 7.40-7.34 (m, 3H), 7.31 (d, J=12.8 Hz, 6.22 (s, 1H), 4.80 (t, J=4.8 Hz, 1H), 4.68 (t, J=4.8 Hz, 1H), 4.53 (m, 1H), 4.47 (m, 1H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1Cl)=[O:4].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][C:18]=1[F:23])=[O:4]
Reactant: COC(=O)c1ccn2cncc2c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A suspension of 8-chloro-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (500 mg, 2.38 mmol), 4-bromo-2-fluoroaniline (543 mg, 2.86 mmol), Pd2dba3 (110 mg, 0.12 mmol), 2-dicyclohexylFphosphino-2′,6′-diisopropoxybiphenyl (224 mg, 0.48 mmol) and K3PO4 (710 mg, 3.33 mmol) in toluene (10 mL) was degassed and then heated at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with water and brine, then loaded onto a 10 g Isolute® SCX-2 cartridge which was eluted with methanol and then a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, ethyl actetate in DCM) to afford the title compound as a yellow oil (240 mg, 28%). LCMS (method B): RT=3.40 min, [M+H]+=364/366.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][O:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.CS(C)=O>C(#N)C>[CH3:15][O:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[S:22]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:24])=[O:23]
Reactant: COc1cnc(OC)n2nc(N)nc12
Reactant: COc1ccsc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1ccsc1S(=O)(=O)Nc1nc2c(OC)cnc(OC)n2n1
Reaction time: 96 h
Yield: 50.9 %

Procedure:
To a slurry of 0.8 g (4.5 mmol) of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine in 7 mL of acetonitrile was added 1.3 g (6.1 mmol) of 3-methoxythiophene-2-sulfonylchloride, 0.6 mL of dry pyridine and 0.003 mL of dry DMSO. After 96 hr, the reaction mixture was partitioned with CH2Cl2 and water. The organic phase was separated, washed with dilute aqueous HCl, dried over MgSO4, filtered and concentrated. The residue was taken into a small amount of CH2Cl2 before ether was added slowly with stirring to precipitate a fine tan solid. The solid was collected by filtration and dried under vacuum to give 0.85 g (50%) of the desired product. mp 227-228° C. 1H NMR (300 MHz, DMSO-d6): δ 12.1 (s, 1H); 7.8 (d, 1H, J=5.6); 7.6 (s, 1H); 7.0 (d, 1H, J=5.6); 4.1 (s, 3H); 3.9 (s, 3H); 3.8 (s, 3H). Calc'd for C12H13N5O5S2: C, 38.81; H, 3.53; N, 18.86; S, 17.27. Found: C, 38.32; H, 3.49; N, 18.91; S, 17.34.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(F)c3n2)nc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(F)cccc23)n[nH]1
Temperature: 100 °C
Yield: 4 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline (295 mg, 0.90 mmol) in DMA (2.2 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate and acetic acid (0.12 mL), and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC using an ammonium acetate modifier. A later eluting fraction was treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM, whereupon a precipitate formed, which was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (13 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.86 (br s, 1H), 8.67 (s, 1H), 8.52 (d, J=9 Hz, 1H), 8.00-8.02 (m, 2H), 7.77 (m, 1H), 7.63 (m, 1H), 5.97 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 389 (M+H)+.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[Li+].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C.Br[C:22]1[CH:53]=[CH:52][C:25]([CH2:26][N:27]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:28](=[O:43])[C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.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:48]([O:47][C:45](=[O:46])[CH2:44][N:27]([CH2:26][C:25]1[CH:52]=[CH:53][C:22]([C:1]([OH:3])=[O:2])=[CH:23][CH:24]=1)[C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][CH:30]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN(Cc1ccc(C(=O)O)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
Prepared using General Procedure 21. To a stirred suspension of lithium formate (1.19 g, 22.9 mmol) in DMF (10 mL) was added DIEA (2.67 mL, 15.3 mmol) and acetic anhydride (1.44 mL, 15.3 mmol) at room temperature. After 30 min the reaction mixture was purged with N2 and a solution of tert-butyl 2-(N-(4-bromobenzyl)-4-((tert-butoxycarbonyl)amino)benzamido)acetate INT-61 (3.97 g, 7.64 mmol) and PdCl2(dppf) (0.559 g, 0.764 mmol) in DMF (5 mL) was added. The reaction mixture was heated for 1 h at 120° C. The reaction mixture was poured onto 1 M citric acid (200 mL) and extracted with EA (200 mL). The organics were washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (1% AcOH in EA/hexanes) to afford 2.92 g (79%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-((tert-butoxycarbonyl)amino)benzamido)methyl)benzoic acid INT-62 as a red-tinged foam. LCMS-ESI (m/z) calculated for C26H32N2O7: 484; found 430 [M-t-Bu+H]+, tR=2.23 min (Method 10).
Reaction SMILES: Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.CC1C(CN2C(=O)N3C=CC(C4C=CC(C#N)=CC=4)=C(C4C=CC=CC=4)C3=N2)=CC=C(C(F)(F)F)N=1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:3]2[C:2]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[C:7]([CH3:8])[N:6]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=4)[N:11]=[C:5]3[CH:4]=2)=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Agent: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccccc3)c(-c3ccc(C#N)cc3)ccn2c1=O
Product: Cc1c(-c2ccncc2)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Yield: 64.5 %

Procedure:
The title compound (16 mg, 64%) as a light yellow powder was prepared from 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.05 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42.5 mg, 0.2 mmol) by procedures analogous to those used for the preparation of 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-8-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile. HPLC/MS: retention time=2.87 min, [M+H]+=496.4.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.C([Li])CCC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1>[C:20]([C:10]1[N:9]([CH3:12])[N:8]=[C:7]([C:6]2[CH:5]=[C:4]([CH3:13])[NH:3][C:2]=2[CH3:1])[CH:11]=1)([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1cc(-c2ccn(C)n2)c(C)[nH]1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cc(C)[nH]c2C)nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of 3-(2,5-dimethylpyrrolyl)-1-methyl-pyrazole (5.0 g, 28.6 mmol) in dry tetrahydrofuran (250 mL) was cooled to -78° C. Then, n-butyllithium (19.5 mL, 1.6M, 31.2 mmol) was added dropwise over 15 min followed by stirring for 2 h at -78° to -60° C. Ethyl chloroformate (3.58 mL, 37.5 mmol) was added and the solution was warmed to room temperature and stirred 1 h. The solvent was removed at reduced pressure and the residue was partitioned between ether and water. Phases were separated and the organic layer was washed with brine, filtered through a cone of sodium sulfate, and concentrated to leave an oil. This residue was chromatographed on Silica Woelm®TSC (600 g, 15% ether-hexane) to give after an 850 mL forerun, 0.18 of an impurity in 500 mL and 4.69 g of oil in 700 mL. The oil was kugelrohr distilled, 100° to 110° C., (0.15 mm) to give 4.24 g, 60% of 5-carboethoxy-3-(2,5-dimethylpyrrolyl)-1-methylpyrazole as a clear oil; IR (neat) 1728, 1546, 1494, 1273, 1252 cm-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH2:24]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN1C(=O)CCC1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:26]5[CH2:27][CH2:28][CH2:29][CH:25]5[CH2:24][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: C1CNC(CN2CCCC2)C1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3CN3CCCC3)cc1OCC2
Temperature: 150 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene from Example 135 (150 mg, 0.454 mmol), TEA (0.500 mL), and 1,2′-methylenedipyrrolidine (420 mg, 2.73 mmol) in NMP (0.500 mL) was stirred at 150° C. for 24 hr under nitrogen atmosphere. The resultant mixture was purified by reverse phase combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to afford 105 (81 mg, 40% yield) as white solid. LCMS (ESI): RT=4.54 min, m/z: 449.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 5.98-5.93 (m, 2H), 4.52-4.47 (m, 4H), 4.14 (s, 1H), 3.47 (s, 1H), 3.27 (s, 1H), 2.58-2.56 (m, 2H), 2.50-2.46 (m, 4H), 2.06-1.93 (m, 2H), 1.92-1.87 (m, 2H), 1.70-1.67 (m, 4H), 1.48 (s, 6H)
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:22])([CH3:21])[CH2:18][CH2:19]O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C1(S([O-])(=O)=O)C=CC=CC=1>CN(C=O)C>[C:1]([CH2:19][CH2:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)([OH:22])[CH3:21])#[N:2]
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: [C-]#N
Agent: O=S(=O)([O-])c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(O)(CCC#N)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
9.7 g. of KCN are dissolved in 150 ml. of DMF and a solution of 40 g. of 3-(4'-fluoro-4-biphenylyl)-butane-1,3-diol-1-benzenesulfonate in 150 ml. of DMF is added dropwise at 20°, while stirring. The mixture is heated to 80° for 6 hours, poured onto ice water and worked up in the customary manner to give 1-cyano-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 118° - 120°.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:16])[N:8]=[CH:7][N:6]=1.C(N(CC)CC)C>COCCOC.O>[Cl:16][C:9]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=[CH:7][N:8]=1
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(Cl)ncnc1N(C)C
Reaction time: 1 h

Procedure:
Dimethylamine (50 ml of a 40% aqueous solution) is added dropwise to a solution of methyl 4,6-dichloropyrimidin-5-yl-acetate (80 g, 0.36 mol) in 1,2-dimethoxyethane (300 ml) and triethylamine (56 ml, 0.4 mol) at room temperature with cooling. After stirring for 1 hour the mixture is diluted with water and the product extracted with diethyl ether. Drying (MgSO4), evaporation of the solvent and distillation gives the methyl 4-chloro-6-dimethylamino-pyrimidin-5-yl-acetate as a colorless solid (74 g), b.p. 135°-138° C./1.5 torr, m.p. 30°-32° C.