Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-cyanobenzaldehyde (5-1) (20.0 g, 152.5 mmol) and ethylene glycol (25.5 mL, 457.5 mmol) in toluene (250 mL) was added p-toluenesulfonic acid (300 mg). The flask was equipped with a Dean-Stark trap and the mixture heated to reflux. After 5 hours, the mixture was concentrated. The residue was taken up in ethyl acetate and washed with saturated NaHCO3, H2O (2×), and brine. The organic layer was dried (Mg504), filtered, and concentrated to give 4-(1,3-dioxolan-2-yl)benzonitrile as a clear oil which solidified under vacuum: 1H-NMR (500 MHz, CDCl3) δ 7.67 (d, J=8.06 Hz, 2H), 7.59 (d, J=8.30 Hz, 2H), 5.85 (s, 1H), 4.13-4.05 (m, 4H).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2cc(C)c(C)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cc(C)c(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (636 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (78) as white solid (817 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]1=[O:17])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:1]([O:5][C:6](=[O:18])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:26](=[O:28])[CH3:27])[C:11]1=[O:17])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(N)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(3-Amino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (500 mg, 1.98 mmol) in dichloromethane (5 mL) was added triethylamine (220 mg, 2.18 mmol) followed by acetic anhydride (202 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 12 hours and then partitioned between EtOAc and aqueous 1M HCl. The organic layer was washed with saturated aqueous NaHCO3, brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (40% ethyl acetate/hexane) to afford the title compound as a colourless oil (569 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 0.87 (3H, t), 1.40 (9H, s), 1.91 (1H, m), 2.13 (3H, s), 2.19 (1H, m), 5.38 (1H, dd), 6.26 (1H, t), 6.99 (1H, d), 8.33 (1H, d), 8.43 (1H, br s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=1)(=O)C>O1CCCC1>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:36]=[CH:37][C:13]([OH:12])=[CH:14][CH:15]=3)[CH:28]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(-c3cccc(Cl)c3)ccc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2cccc(Cl)c2)ccc1C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.6 mg of potassium carbonate was added to a mixed solution of 0.5 mL of methanol and 0.5 mL of tetrahydrofuran containing 15 mg of 2-(4-acetoxybenzamido)-4-(3-chlorophenyl)benzoic acid and stirred at room temperature for 2 hours. After insoluble were removed by filtration, 10% citric acid aqueous solution was added and a solid substance was separated by filtration to obtain 10 mg of 4-(3-chlorophenyl)-2-(4-hydroxybenzamido)benzoic acid as white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][NH:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][N:20]([C:24]5[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: c1nc2c(c(Nc3ccc4c(c3)OCCO4)n1)CNCC2
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc5c(c4)OCCO5)c3C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4 A molecular seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:10]1=2.O.NN>CO.[Ni]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]1=2
Reactant: CN1CCCC1CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN1CCCC1CCN1CCSc2cc(N)ccc21
Reaction time: 3 h

Procedure:
A solution of 4-(2-(1-methylpyrrolidin-2-yl)ethyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.82 g, 2.67 mmol) in methanol (10 mL) under an argon atmosphere was treated with hydrazine hydrate (1.29 mL, 26.7 mmol) and a small amount of Raney Nickel (˜0.15 g, 2.67 mmol). The reaction was transferred to a pre-heated oil bath at 65° C. After 3 hours, the reaction was poured over a pad of Celite, rinsing with methanol. The filtrate was concentrated, and the residue was poured over a pad of silica gel. The silica gel pad was rinsed with 1:9 (2M NH3 in methanol):dichloromethane (200 mL). The filtrate was concentrated, dried under reduced pressure, and carried on to the next step. 1H-NMR (DMSO-d6) δ 6.48 (brd, J=9.3 Hz, 1H), 6.27-6.24 (m, 2H), 4.42 (brs, 2H), 3.33-3.29 (m, 2H), 3.13-3.06 (m, 2H), 2.99-2.96 (m, 2H), 2.96-2.90 (m, 1H), 2.19 (s, 3H), 2.06-1.97 (m, 2H), 1.96-1.78 (m, 2H), 1.63-1.60 (m, 2H), 1.56-1.40 (m, 2H); ESI-MS (m/z, %): 278 (MH+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=[O:7])([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([C:16]([F:19])([F:17])[F:18])[CH:10]=1)=[O:7]
Reactant: O=C(Nc1ccc(Br)c(C(F)(F)F)c1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1C(=O)Nc1ccc(Br)c(C(F)(F)F)c1

Procedure:
A solution of 2-nitro-N-(4-bromo-3-trifluoromethylphenyl)benzamide (intermediate 1a; 32 g, 82 mmol) in methanol (1000 mL) is hydrogenated at atmospheric pressure over Raney nickel (6 g) at 21° C. The calculated amount of hydrogen is taken up after 7 hours. The mixture is filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by recrystallisation from diethylether-hexane to give the title compound as a colourless crystalline solid, m.p. 142–144° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][OH:4].[C:6]([C:10]1[CH:11]=[C:12](CCCCCCO)[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:11]=[C:12]([CH2:1][CH2:2][CH2:3][OH:4])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:18])[CH3:19])[C:15]=1[OH:16])([CH3:7])([CH3:9])[CH3:8]
Reactant: OCCCO
Reactant: CC(C)(C)c1cc(CCCCCCO)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(CCCO)cc(C(C)(C)C)c1O
Yield: 35.5 %

Procedure:
Substitution of 38 grams (0.5 moles) of 1,3-propanediol for the 1,6-hexanediol of Example 3 and heating the mixture for 5 hours yielded after workup 9.4 grams (35.5% yield) of 3-(3,5-di-tert.-butyl-4-hydroxyphenyl) propanol. The product is a pale yellow oil of a boiling point 135°-140° C. at 0.15 mm. of mercury which crystallized on standing to give a solid with a melting point of 67.5 to 69° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[CH2:15][O:16][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (600 mg, 2.53 mmol), methyl 4-hydroxybenzoate (462 mg, 3.03 mmol), Ph3P (795 mg, 3.03 mmol) in THF (10 ml) was added DIAD (597 ul, 3.03 mmol) at room temperature. The mixture was heated at reflux for 3 h with stirring. After cooling to room temperature, the mixture was concntrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (831 mg, 88%) as a colorless oil. 1H-NMR (CDCl3) δ1.48 (s, 9 H), 2.53-2.61 (m, 2 H), 3.63-4.41 (series of m, total 8 H), 6.94 (d, J=8.8 Hz, 2 H), 7.99 (d, J=8.8 Hz, 2 H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[NH:26][C:25]=2[CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:25]=2[CH:30]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4ccc(Cl)cc43)CC2)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-chloro-3H-benzooxazol-2-one (105 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (16): HPLC retention time, 2.50 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 436.3, found, 436.4.
Reaction SMILES: [C:1](=[O:40])([O:36][CH:37](I)[CH3:38])[O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CC(OC[C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50](NC(/C(/C3N=C(N)SC=3)=N\OC)=O)[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O-:70])=[O:69])=O.[Na+]>CN(C=O)C>[S:66]1[C@@H:49]2[CH2:50][C:51](=[O:52])[N:48]2[C:47]([C:68]([O:70][CH:37]([O:36][C:1]([O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:40])[CH3:38])=[O:69])=[CH:46][CH2:67]1
Reactant: CC(I)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)C1=CCS[C@@H]2CC(=O)N12

Procedure:
A solution of 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl carbonate (0.156 mmol) and cefotaxime sodium (67.8 mg, 0.142 mmol) in 3.2 mL dry N,N′-dimethylformamide was stirred under argon for 22 h. The reaction mixture was concentrated and subjected to column chromatography (silica, 2/1 petroleum ether-ethyl acetate, and then 20/1 CH2Cl2-methanol) to yield an oil enriched in the desired product. The oil was dissolved in 10 mL ethyl acetate, washed with water, dried, and concentrated. A second chromatography (silica, 40/1 CH2Cl2-methanol) gave the title compound (59.7 mg) as cream-colored solids.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH2:20][CH2:21][OH:22])=[C:14]([CH3:23])[CH:13]=1)[NH:6][C:5]2=[O:24].[C:25](OC(=O)C)(=[O:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[OH:22][CH2:21][CH2:20][O:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:7]2[NH:6][C:5](=[O:24])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:25](=[O:27])[CH3:26])[CH:3]=3)[N:8]=2)=[CH:13][C:14]=1[CH3:23]
Reactant: Cc1cc(-c2nc3ccc(N)cc3c(=O)[nH]2)cc(C)c1OCCO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-5-nitro-benzamide (680 mg, 3.75 mmol) and 4-[2-(tert-butyldimethylsilanoxy) ethoxy]-3,5-dimethylbenzaldehyde (1.16 g, 3.75 mmol) in N,N-dimethyl acetamide (35 mL), NaHSO3 (736 mg, 4.14 mmol) and p-TSA (71 mg, 0.375 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with water and the solids were filtered off to give crude product (590 mg, 44%). To a solution of above crude product (490 mg, 1.38 mmol) in DMF (20 mL) and MeOH (20 mL), Pd—C (100 mg, 10%) was added and the reaction mixture was hydrogenated for 4 h at room temperature at 30 psi H2. The reaction mixture was filtered and the solvent was evaporated to give crude product. The crude was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in CH2Cl2 as eluent) to give 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one (190 mg, 42% yield). To a solution of 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one (95 mg, 0.29 mmol) in pyridine (5 mL), acetic anhydride (108 mg, 0.73 mmol) was added and the mixture was stirred for 16 h at room temperature. The solvent was removed and the solids were dissolved in a mixture of MeOH (10 mL) and THF (10 mL) (compound was partially soluble). Then K2CO3 (100 mg, 0.73 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was removed and the crude was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:27][O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>C1COCC1.O>[OH:24][CH:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)[CH:29]([O:28][CH3:27])[C:30]([O:32][CH3:33])=[O:31]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COCC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
Sodium bis-(trimethylsilyl)amide (440 mL 0.44 mol 1.0 M in THF) was cooled to −70° C. under a nitrogen atmosphere. A solution of 4-benzyloxybenzaldehyde (85 g, 0.4 mol) and methyl methoxyacetate (52 g, 0.5 mol) in THF (0.5 L) was added dropwise at −70° C. over 2 hours, and the mixture was stirred for an hour. A solution of concentrated HCl (85 mL) and water (85 mL) was added at −70° C. The resulting solution was allowed to warm to ambient temperature and was extracted with MTBE (2×0.5 L). The combined extracts were washed with brine (0.5 L), dried (MgSO4), filtered, and concentrated under to give 133 g of a red oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([SH:29])=[N:27][N:28]=2)[CH:25]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>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].COCCOC>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([S:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=4)[N:7]=3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Sc1nnc2ccc(Cl)cn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccc(Cl)cn34)ccc2n1
Temperature: 120 °C
Yield: 102.6 %

Procedure:
Combined compound 7B (50 mg, 0.14 mmol), 6-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (28 mg, 0.15 mmol), Tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.01 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (14 mg, 0.025 mmol), DIEA (48 uL, 0.28 mmol) and DME (1.4 mL) and heated in a microwave unit at high absorbance, 120° C. for 30 min. The resulting crude material was purified by silica gel using 5% MeOH in DCM. The cleanest fractions were concentrated to give compound 7 (0.06 g; quantitative yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (br. s., 1 H), 8.86-8.82 (m, 1 H), 8.11-8.05 (m, 1 H), 7.89 (d, J=9.3 Hz, 1 H), 7.73 (s, 1 H), 7.66 (dd, J=1.9, 9.7 Hz, 1 H), 7.09 (d, J=9.6 Hz, 1 H), 1.48-1.41 (m, 9 H), ESI-MS:m/z 418.2.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@@H:10]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:11]([CH3:13])[CH3:12])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2].Br[C:51]1[NH:55][C:54]([C@@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C=O)C.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>[CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:14][C:15]([O:16][CH3:17])=[O:18])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36]([C:51]2[NH:55][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2]
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
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: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CCCN4C(=O)OC(C)(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 85 °C
Reaction time: 6 h
Yield: 33.7 %

Procedure:
To a solution of methyl [(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (0.16 g, 33%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCc1ccccc1
Product: c1ccc(CCN(N=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-phenylhydrazine (200 mg, 0.735 mmol; Example 79A) and (2-bromoethyl)benzene (1.29 g, 6.9 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 391 (M+H)+.