Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].FC(F)(F)C(O)=O>>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
30 mg (0.1 mole) Z-Phe-OH and 13 mg (0.1 mmole) Leu-NH2 are placed into an unsealed glass container having a 12 mm inner diameter and stirred with a spatula. Then, a mixture of 161 mg (0.5 mole) Na2 SO4.10H2O and 5 mg thermolysine is added, the glass container is closed and subjected to ultrasonic waves in an ultrasound bath at 40° C. After 20 minutes the reaction is stopped with 0.4 ml 5% (v/v) aqueous trifluoroacetic acid. The analytical evaluation is carried out by means of HPLC and comparison with an authentic specimen.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:28]=[C:15]2[C:16](=O)[N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH2:19][N:14]2[N:13]=1)=O)C>C1COCC1>[C:21]1([CH2:20][N:17]2[CH2:18][CH2:19][N:14]3[N:13]=[C:12]([CH2:10][OH:9])[CH:28]=[C:15]3[CH2:16]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cc2n(n1)CCN(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2n(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A 1M solution of lithium aluminum hydride in THF (6.5 mL, 6.5 mmol) was added dropwise to a stirred solution of 4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.81 g, 2.7 mmol) in THF (16 mL) under N2 at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, quenched with MeOH and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in methanol in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-methanol (0.67 g, 100% yield) as a colorless oil. C14H17N3O LCMS: Rt 1.25, m/z 244 [M+H]+ (see LCMS Method 1).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O)(C)(C)C.Cl.[CH3:33]O>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:33])=[O:30])[CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1/C=C\CCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (2.90 g) in methanol (50 ml) saturated with hydrogen chloride was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was dissolved in chloroform (50 ml) and the solution was washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (2.28 g) as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[Cl:26])=[O:19])([CH3:4])([CH3:3])[CH3:2].[C:28]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:40][CH2:39][C:37]2[N:38]=[C:34]([C:31]3[CH:32]=[CH:33][C:28]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:29][CH:30]=3)[O:35][C:36]=2[CH3:52])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[Cl:26])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1cc(Cl)sc1Cl
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)c2cc(Cl)sc2Cl)c1
Yield: 81.5 %

Procedure:
A mixture of 3-(2-{[(2,5-dichloro-thiophene-3-carbonyl)-amino]-methyl}-4-hydroxy-phenyl)-propionic acid tert-butyl ester (280 mg, 0.651 mmol) and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (498 mg, 1.15 mmol), were reacted according to Standard procedure A to give, after radial chromatography (hexanes/EtOAc 98:2 to 90:10), the title compound as a white solid (367 mg, 82%). 1H NMR (400 MHz, CDCl3): 1.36 (s, 9H), 2.37 (s, 3H), 2.55 (t, 2H, J=7.3 Hz), 2.87 (t, 2H, J=7.3 Hz), 2.96 (t, 2H, J=6.6 Hz), 4.22 (t, 2H, J=6.8 Hz), 4.58 (d, 2H, J=5.4 Hz), 6.80 (dd, 1H, J=8.3 Hz, J=2.4 Hz), 6.88 (d, 1H, J=2.9 Hz), 6.97 (t, 1H, J=5.9 Hz), 7.10 (d, 1H, J=8.8 Hz), 7.13 (s, 1H), 7.36 (t, 1H, J=7.3 Hz), 7.45 (t, 2H, J=7.8 Hz), 7.63 (d, 2H, J=8.3 Hz), 7.65 (d, 2H, J=6.3 Hz), 8.02 (d, 2H, J=7.8 Hz). MS (ES) m/e 691.2 [M+1].
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17]
Reactant: O=C1COCCN1CCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1COCCN1CCO
Yield: 66.7 %

Procedure:
Dissolve 4-(2-benzyloxy-ethyl)-morpholin-3-one (1.7 g, 7.23 mmol) in ethanol (25 mL) and add 5% Pd/C (0.30 g). Hydrogenate at 60 psi overnight, filter the black mixture through Celite®, and wash the Celite® with additional ethanol (approximately 10 mL). Concentrate the filtrate to give the title compound as an oil (0.7 g, 70%). MS (ES+) 146.3 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 4.11 (s, 2H), 3.83 (t, 2H, J=5.1 Hz), 3.73 (t, 2H, J=5.3 Hz), 3.49 (t, 2H, J=5.3 Hz), 3.43 (t, 2H, J=5.1 Hz), 3.12 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: NCc1ccccc1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCc3ccccc3)c2)c1
Yield: 85 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.24 g, 0.0044 mol) and benzylamine (40 mL) was heated at 180° C. for 20 hours The excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 1.33 g (85% yield) of the titled compound as a clear oil, which solidified upon standing: mp: 73-75° C. Anal. Calc'd. for C23H22N40.2H2O: C, 76.83; H, 6.39; N, 15.06. Found: C, 76.88; H, 6.37; N, 14.92.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:9]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[C:10](O)=[O:11])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:9]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Temperature: -80 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
The crude acid from Step A was suspended in 12 mL of dry benzene and the mixture was treated with 350 mL of oxalyl chloride. To this suspension was added one drop of pyridine and a very vigorous reaction was apparent. The clear homogenous solution was warmed to reflux temperature for 10 minutes then kept at about 70° C. for 2 days under an argon atmosphere. Most of the solvents were evaporated under high vacuum and the semi-solid was dissolved in 6 mL of tetrahydrofuran. To this chilled (-80° C., dry ice-acetone) solution under argon was added dropwise 0.5 mL (0.5 mmole, 1.0M in tetrahydrofuran) of lithium aluminum hydride and the reduction was complete in one hour. The crude reaction mixture was quenched with 2.0M HCl and the organic residue was extracted with ethyl acetate, dried and evaporated to give 0.21 g (88.7%) of the title compound which was pure enough to be used in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1ccc2ccccc2n1

Procedure:
2-Chloroquinoline (2.45 g, 15.0 mmol), o-methoxyphenylboronic acid (2.73 g, 18.0 mmol,) and potassium carbonate (5.59 g, 40.4 mmol) were dissolved in 40 mL ethylene glycol dimethyl ether and 20 mL of water. To the stirred solution was added tetrakis(triphenylphosphine)palladium(O) (1.04 g, 0.89 mmol) and the entire mixture was allowed to reflux under a N2 atmosphere for 20 hours. The cooled reaction mixture was then removed of water. Additional ethyl acetate (150 mL) was added and the solvent was washed three times using 100 mL portions of brine. The organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent concentrated. The residue purified via column chromatography using 50% ethyl acetate/hexanes as the eluents to give 2-(o-methoxyphenyl)quinoline.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:17][OH:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:17]=[O:18])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CO)c(-c2ccccc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C=O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methanol (1 g, 3.8 mmol) in CH2Cl2 (50 mL) was added Dess-Martin periodinane (2.4 g, 5.71 mmol). The reaction was stirred for 2 h at RT, then concentrated in vacuo and purified directly on normal phase silica gel to provide 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carbaldehyde as a white solid.
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:12]([O:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Reactant: OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=CC1=C[C@H]2CC(OCc3ccccc3)O[C@H]2C1
Temperature: 25 °C

Procedure:
Purified lactol 7 (591.5 mg, 3.84 mmol, 1 eq.), was dissolved in CH2Cl2 (7 ml) and stirred at r.t. Benzyl alcohol (794.1 μL, 7.68 mmol, 2 eq.) was added via syringe and amberlyst 15 (56.5 mg) and MgSO4 (1.16 g) were added as solids. The reaction mixture was stirred at r.t. for 36 h. The reaction mixture was filtered through a sinter funnel and the solids washed with CH2Cl2 (2×10 ml). The filtrate was concentrated under reduced pressure to give the crude material which was purified by column chromatography eluting with petrol/EtOAc (9:1) to give the benzyl acetal 56 (as an approximately 1.5:1 mixture of diasteroisomers, 657.8 mg, 70%) as pale yellow oil.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][C:5]#[N:6].N[NH:9][C:10]([NH2:12])=[S:11].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:2]([C:1]1[S:11][C:10]([NH2:12])=[N:9][N:7]=1)[CH2:3][CH2:4][C:5]1[S:11][C:10]([NH2:12])=[N:9][N:6]=1
Reactant: NNC(N)=S
Reactant: N#CCCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(CCCc2nnc(N)s2)s1
Temperature: 85 °C
Yield: 106.6 %

Procedure:
A mixture of glutaronitrile (5.00 g, 53.13 mmol) and thiosemicarbazide (9.68 g, 106.26 mmol) in TFA (50 mL) was heated at 85° C. for 4 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(propane-1,3-diyl)-bis(1,3,4-thiadiazol-2-amine) (1004, 13.72 g). 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.03 (s, 4H), 2.87 (t, J=7.5 Hz, 4H), 2.02-1.95 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl>>[CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[N:5]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1nn(CCN2CCOCC2)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (prepared as in WO 98/49166) (20.0 g, 0.11 mol), potassium carbonate (29.9 g, 0.22 mmol) and cesium carbonate (7.08 g, 21.7 mmol) were stirred together at room temperature. After 15 minutes 4(2-chloroethyl)morpholine.HCl (22.2 g, 0.12 mol) was added and the reaction mixture was heated at 55° C. for 16 h. The reaction mixture was concentrated in vacuo, and then partitioned between water (500 mL) and ethyl acetate (350 mL). Solid sodium carbonate was added until the pH reached 10, and then the organic layer was separated. The aqueous layer was extracted with further ethyl acetate (150 mL). The combined organic layers were concentrated in vacuo, combined with 1.6 g of a previous identical batch and purified by flash column chromatography (eluting with methanol:ethyl acetate:NH3 0:100:0 to 20:80:1). Two products were separated. The first product was triturated from diethyl ether to yield 3-ethyl-1-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrazole-5-carboxamide as cream coloured crystals (16.2 g, 54.5 mmol).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](Cl)=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[O:29][CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN1CCCC1=O>[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[O:29][CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Sodium hydride (400 mg of an 80% suspension in paraffin oil, 13.3 mmol) was added to a solution of phenol (1.26 g, 13.3 mmol) in dry 1-methyl-2-pyrrolidinone (20 ml) and the mixture stirred for 10 minutes. 7-Benzyloxy-4-chloro-6-methoxyquinazoline (1.6 g, 5.3 mmol), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy4-phenoxyquinazoline (1.6 g, 84%) as a yellowish solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.C([O:12][C:13](=O)[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=O)C>CC(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[NH:9][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])=[CH:14][C:13](=[O:12])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2F)[nH]c2cc(C3CC3)nn12
Temperature: 25 °C

Procedure:
5-Cyclopropyl-2H-pyrazol-3-ylamine (2.9 g, 0.0235 mol) was suspended in AcOH (18 ml), 3-(2-fluorophenyl)-3-oxopropionic acid ethyl ester (4.67 ml, 1.1 eq) was added and the mixture heated at reflux for 3 h. The mixture was cooled to rt and concentrated underreduced pressure. The residue was stirred with EtOAc and the solid collected by filtration to give 2 g of 2-cyclopropyl-5-(2-fluorophenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one. Step B: The compound from step A (1 g, 0.00371 mol) was dissolved in POCl3 (12 ml) and cooled to 0° C. N,N-dimethylaniline (1.4 ml, 3 eq) was added and the mixture heated at 80° C. for 16 h. The mixture was cooled to rt and the volatiles removed. The resulting residue was dissolved in CH2Cl2, poured onto ice, and taken to pH 8 with NaHCO3 (s). The CH2Cl2 layer was removed, washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, hexane-EtOAc/hexane 1:9) to give 0.85 g of the title compound. LCMS: MH+=288.1.
Reaction SMILES: [O:1]=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:9][C:8]=2[CH:27]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11]([OH:1])([C:15]([O:17][CH3:18])=[O:16])[CH:10]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:9][C:8]=2[CH:27]=1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reactant: O=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
Oxygen was bubbled through a solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (7.0 g, 19.46 mmole) in 100 ml of dry tetrahydrofuran at 0° C. while a 0.67M solution of potassium hexamethyldisilazide in toluene (87.64 ml, 58.76 mmole) was added dropwise over 15 minutes. The reaction was continued for 1 hour with the continued bubbling of oxygen at 0° C. The reaction was quenched with 75 ml of a 5% solution of potassium bisulfate, followed by the addition of solid sodium sulfite and 10 ml of methanol. The reaction was stirred for 30 minutes and extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated sodium bicarbonate, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was recrystallized from isopropyl alcohol to yield 4.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[C:28]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCCC1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCN(C1CCCC1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 83.3 %

Procedure:
The title compound was prepared as described in Example 14. C, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.5 g, 1.39 mmol) and cyclopentanone (0.951 g, 11.3 mmol) to provide the title compound (0.495 g, 83% yield): ES-MS (m/z) 428 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].[C:37]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46](O)=O)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN(C(C)C)C(C)C>CN(C)C=O.C(O)(=O)C>[C:40]([O:39][C:37]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]1[NH:25][C:26]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=[CH:34][C:35]=2[N:36]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)c1cccc(N)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
HATU (10.66 g, 28.0 mmol) was added in one portion to a stirred solution of methyl 2,3-diaminobenzoate (4.1 g, 24.7 mmol), N-Boc-L-proline (5.49 g, 25.5 mmol), and Hunig's base (4.9 mL, 28.0 mmol) in dimethylformamide (50 mL). The reaction mixture was stirred 3 h and solvent removed in vacuo, and the residue was diluted with ethyl acetate, washed with 0.1N HCl, sat'd NaHCO3, brine, and dried (Na2SO4). Concentration gave a reddish brown viscous oil which was taken up in glacial acetic acid (60 mL) and heated at 60° C. for 16 h. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate, washed with sat'd NaHCO3 soln., brine, and dried (Na2SO4). Concentration gave a residue that was divided into two lots, and each lot pre-adsorbed onto SiO2 (dichloromethane), applied to a 40 M Biotage SiO2 column, and eluted by gradient 10%-100% B (1440 mL); A=hexanes; B=ethyl acetate to give J.33 (S)-methyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole-7-carboxylate 7.05 g (83%) as a reddish oil. 1H NMR (500 MHz, DMSO-d6) δ: 7.86 (d, J=7.9 Hz, 1H), 7.78 (t, J=5 Hz, 1H), 7.28-7.24 (m, 1H), 5.20-5.11 (m, 1H), 3.95 (s, 3H), 3.60-3.52 (m, 1H), 3.43-3.38 (m, 1H), 2.33-2.22 (m, 1H), 2.15-2.0 (m, 2H), 1.91-1.86 (m, 1H), 1.40/1.05 (s, 9H). LC (Cond.-D2): RT=1.86 min; LC/MS: Anal. Calcd. for [M+H]+ C18H24N3O4: 346.18; found 346.26; HRMS: Anal. Calcd. for [M+H]+ C18H24N3O4: 346.1767; found: 346.1776.