Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([NH2:20])[N:10]=1.[C:21]([O:25][C:26]([NH:28][C:29](N1C=CC=N1)=[N:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].O>C(Cl)Cl>[NH2:20][C:11]1[N:10]=[C:9]([NH:8][C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH:1][C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3N)c2c1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of 4.53 g of N4-[(1S,2R)-2-aminocyclohexyl]-6-methylquinazoline-2,4-diamine in 90 ml of methylene chloride, 5.18 g of N,N′-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine was added, and then the mixture was stirred at room temperature for 15 hours. The reaction solution was mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 8.50 g of the desirable compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18]O)[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[Br-:20].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CC(=O)OCC>[Br:20][CH2:18][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: [Br-]
Reactant: COc1ccc(CNc2cc(F)cc(CO)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(F)cc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A mixture of [3-fluoro-5-(4-methoxy-benzylamino)-phenyl]-methanol (522 mg, 2 mmol) and triphenylphosphine dibromide (1.27 g, 3 mmol) in dichloromethane (6 ml) was stirred in an ice bath for 30 min. The mixture was then warmed up to room temperature, diluted with EA (20 ml), washed with saturated aqueous sodium bicarbonate solution followed by brine, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexane (1:10)) to afford 570 mg (88%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 3.86 (3H, s), 4.30 (2H, s), 4.40 (2H, s), 6.41 (1H, m), 6.56-6.60 (2H, m), 6.90-6.96 (2H, m), 7.31-7.35 (2H, m).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[O:11])=[C:8]([N:19]2[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:21]=[C:20]2[CH2:31]O)[CH:7]=[CH:6][CH:5]=1)=[O:2].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([NH:3][C:4]1[C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[O:11])=[C:8]([N:19]2[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:21]=[C:20]2[CH2:31][N:37]2[C:36](=[O:38])[C:35]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]3[C:33]2=[O:43])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=CNc1cccc(-n2c(CO)nnc2Cc2ccccc2)c1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=CNc1cccc(-n2c(Cc3ccccc3)nnc2CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, a mixture of 6-formamido-2'-chloro-2-[3-(hydroxymethyl)-5-benzyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 6-formamido-2'-chloro-2-[3-(phthalimidomethyl)-5-benzyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH2:16][CH2:17][NH2:18])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C(Cl)Cl>[C:30]([O:29][C:27]([NH:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:5]3[NH:1][N:2]=[N:3][N:4]=3)[CH:8]=2)[NH:12][CH:11]=1)=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCc1c[nH]c2ccc(Cc3nnn[nH]3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(Cc3nnn[nH]3)cc12
Reaction time: 16 h
Yield: 64.3 %

Procedure:
To a stirred suspension of 2-(5-tetrazol-5-ylmethyl-1H-indol-3-yl)ethylamine (1.76 g, 7.27 mmol) in dry CH2Cl2 (40 ml) was added triethylamine (1.5 g, 14.9 mmol) and (BOC)2O (1.9 g, 7.3 mmol) and the mixture stirred for 16 h. The solvent was removed under vacuum and the residue chromatographed on silica-gel eluting with EtOH/Et2O/H2O/NH3 (20:60:8:1) to give the title product (1.6 g, 64%); δ (360 MHz, CD3OD) 1.41 (9H, s, 3 of CH3); 2.87 (2H, t, J=7.4 Hz, CH2); 3.30 (2H, t, J=7.4 Hz, CH2); 4.32 (2H, s, CH2); 6.99 (1H, d, J=8.3 Hz, Ar--H); 7.04 (1H, s, Ar--H); 7.26 (1H, d, J=8.3 Hz, Ar--H); 7.49 (1H, s, Ar--H).
Reaction SMILES: CO.[CH:3]([O:8]C)([O:6][CH3:7])OC.OS(O)(=O)=O.[C:15]([C:23]1C(=O)[O:25][C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:30]1([C:26]2[O:25][C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][C:28](=[O:29])[C:27]=2[C:3]([O:6][CH3:7])=[O:8])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(OC)OC
Reactant: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Yield: 84 %

Procedure:
A 200 ml flask was fitted with a N2 inlet, a magnetic stirring bar and a condenser. 50 mls of methanol, 8.0 gms of trimethyl orthoformate, 5.2 gms of concentrated H2SO4 and 5.0 gms of 3-benzoyl-4-hydroxy-6-phenyl-pyr-2-one were added. The resulting mixture was then refluxed for 3 days, cooled, poured into water and extracted with methylene chloride (300 mls). The organic extracts were combined and washed with water. Removal of the solvent provided 4.4 gms of 2,6-diphenyl-3-methoxycarbonyl-pyr-4-one (85%). Recrystallization from methylene chloride/ether provide material with a melting point=150°-1°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH:49]([C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH:59]([CH3:61])[CH3:60])=[CH:54][CH:53]=1)[CH2:50][CH3:51]>ClCCl>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:15]=1)[CH:49]([C:52]1[CH:53]=[CH:54][C:55]([CH2:58][CH:59]([CH3:60])[CH3:61])=[CH:56][CH:57]=1)[CH2:50][CH3:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCn1cc(C(=O)c2cccc(NCc3ccccc3)c2)c2ccccc21)OCc1ccccc1
Reactant: CCC(Br)c1ccc(CC(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1ccc(CC(C)C)cc1)N(Cc1ccccc1)c1cccc(Cc2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of benzyl 4-[3-(3-benzylaminobenzoyl)indol-1-yl]butyrate (88 mg) and diisopropylethylamine (45 mg) in dichloromethane (3 ml) was added a solution of 1-bromo-1-(4-isobutylphenyl)propane (90 mg) in dichloromethane (1 ml). The mixture was stirred at room temperature for 24 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (5 g) eluting with a mixture of n-hexane and ethyl acetate (4:1) to give benzyl 4-[3-[3-[N-benzyl-N-[1-(4-isobutylphenyl)propyl]amino]benzyl]indol-1-yl]butyrate (30 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH2:51]([NH:54][CH2:55][C:56]#[CH:57])[CH2:52][CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([N:54]([CH2:55][CH2:56][CH3:57])[CH2:51][C:52]#[CH:53])=[O:19])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Reactant: C#CCNCCC
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(CCC)C(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which N-propylpropargylamine (0.804 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether with addition of ethanolic hydrochloric acid gave 0.25 g of the title compound as the dihydrochloride sesquihydrate, m.p. 172°-4° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=O)C.O.[NH2:31][NH2:32]>CO>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)(=[O:3])[NH:31][NH2:32]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A solution of 2-ethoxycarbonyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 5) (1.0 g, 2.5 mmol) in methanol (50 ml) was added hydrazine hydrate (500 μl, 10.3 mmol) in methanol (20 ml). The reaction mixture was stirred at 60° C. for 16 h and then concentrated in vacuo. The residue was added ether and the solid isolated by filtration to yield 860 mg (88%) of the title compound. M.p. >250° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21][C:22]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[O:24][N:23]=1>CN(C=O)C>[ClH:18].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH2:19][CH2:20][CH2:21][C:22]2[C:26]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[O:24][N:23]=2)=[CH:5][CH:4]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COc1cc2onc(CCCCl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2onc(CCCNCCc3ccc(F)cc3)c2cc1OC
Reaction time: 0.08 h

Procedure:
To 100 ml of dry DMF were added 2-(4-fluorophenyl)-ethylamine hydrochloride (10 g) and milled K2CO3 (20 g). After five minutes of stirring, 3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g) and KI (0.01 g) were added.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:56]=[CH:55][CH:54]=[CH:53][C:24]=1[O:25][C:26]1[CH2:30]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:28](=[O:52])[CH:27]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:11]1[CH2:30][C:26]([O:25][C:24]2[CH:53]=[CH:54][CH:55]=[CH:56][C:23]=2[Cl:22])=[CH:27][C:28]1=[O:52])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C[C@H]1C[C@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 80 °C
Yield: 34.5 %

Procedure:
In a small pressure bottle was placed a mixture of 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (147 mg, 0.86 mmol), acetonitrile (6 mL) and N,N-diisopropylethylamine (220 μL, 1.03 mmol) which was heated to 80° C. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 276 mg, 0.86 mmol) and the tube sealed and heated at 100° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 16% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (108 mg, 35%) as an amber oil: HR-ES-MS m/z calculated for C19H22NO4Cl [M+H]+ 364.1310, observed 364.1310.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>O>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: C=CC(=O)O
Reactant: Cc1ccccc1N
Solvent: O
Product: Cc1ccccc1NCCC(=O)O

Procedure:
3-(2-Methylanilino)propionic acid is prepared in a manner similar to that described in Example 1, but starting from o-toluidine (64.3 g; 0.60 mol), acrylic acid (11.6 g; 0.16 mol) and water (36.6 cc). A white powder (23.85 g) is thus obtained which, after recrystallisation in a toluene/hexane mixture (70:30 by volume), gives a pure product (21.7 g; 0.12 mol), m.p. 87° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]2[C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>CC#N>[CH3:37][O:36][C:32](=[O:35])[CH:33]=[CH:34][C:21]1[CH:20]=[CH:19][C:18]([CH:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][CH:22]=1
Reactant: O=S(=O)(Oc1ccc(C2c3ccccc3CCCC2c2ccccc2)cc1)C(F)(F)F
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2c3ccccc3CCCC2c2ccccc2)cc1

Procedure:
Prepared by Heck coupling 8c and methyl acrylate in accordance with the general method described in Example IV. Yield (14%); APcI m/z: 424 (M+H+CH3CN+, 100%).
Reaction SMILES: C([O:4][CH:5]([CH2:43][O:44]C(=O)C)[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:21][CH2:20][CH:19]([O:22]C(=O)C)[C:18]2=[O:26])[C:13]([I:27])=[C:12]([C:28]([NH:30][CH2:31][CH:32]([O:38]C(=O)C)[CH2:33][O:34]C(=O)C)=[O:29])[C:11]=1[I:42])=[O:9])(=O)C.C[O-].[Na+].CO.CCC1(C2C=CC(N)=CC=2)C(=O)NC(=O)CC1>O>[OH:4][CH:5]([CH2:43][OH:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[C:18]2=[O:26])[C:13]([I:27])=[C:12]([C:28]([NH:30][CH2:31][CH:32]([OH:38])[CH2:33][OH:34])=[O:29])[C:11]=1[I:42])=[O:9]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(OC(C)=O)C2=O)c1I)OC(C)=O
Agent: CCC1(c2ccc(N)cc2)CCC(=O)NC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2CCC(O)C2=O)c1I
Yield: 71.2 %

Procedure:
N,N'-Bis-[2,3-diacetyloxypropyl]-5-[3-acetyloxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 5b (4.20 g, 4.20 mmol) was treated with a 0.105 M solution of methanolic sodium methoxide [prepared by the addition of Na metal (48 mg, 2.10 mmol) to dry methanol (20 ml)] under a nitrogen atmosphere for 2.5 hours. The pH was then adjusted to 6.70 using Dowex-50 resin (H+ form) and AG-1 (OH- form) as necessary. The resin was removed and the solvents evaporated to give a yellow oil. This product was dissolved in 20 ml of deionized water and the pH adjusted to 6.98 by the addition of AG-1 (OH- 1 form) resin. The resin was filtered off and the filtrate containing the crude product was purified by low pressure reverse phase column chromatography using a CHP-20 resin to obtain N,N'-bis-[2,3-dihydroxypropyl]-5-[3-hydroxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white foam (2.36 g, 71% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To as solution of Example 220B (20 g, 41.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.85 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium (4.84 g, 4.19 mmol) in N,N-dimethylformamide (500 mL) was added a solution of sodium bicarbonate (7.04 g, 84 mmol) in water (40 mL) and the mixture was stirred at 80° C. for 12 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 532 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:8][CH2:7]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[C:32]([O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:10][CH2:11]1)(=[O:34])[CH3:33]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc(O)c2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of 207 mg (0.5 mmol) of 3-[1-(3-hydroxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)quinazolinone in 3 mL of pyridine was added 61 mg (0.6 mmol) of acetic anhydride, and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on sodium sulfate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 187 mg (0.41 mmol) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH:28]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 8-amino-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one (1) (200 mg, 0.98 mmol) in anhydrous MeOH (20 ml) was added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (191 mg, 1 mmol), AcOH (0.14 ml), and NaBH3CN (123 mg, 1.96 mmol). Resulting reaction mixture was stirred at room temperature for 2 hr. The solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (150 ml). The solution was washed with 1 N NaOH (20 ml) and H2O, Sat. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was purified on silica gel eluting with EtOAc/Hexane (4:1) to yield (3) (304 mg, 82%) as a white solid. MS (APPI) m/z 380.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Br[CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C([O-])=O.[Na+].C(=O)=O>C(#N)C.O>[OH:2][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: O=C=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(O)C(=O)c1ccccc1
Yield: 98 %

Procedure:
There was added 10.08 parts of sodium bicarbonate and about 60 parts of water to a mixture of 21.3 parts of α-bromopropiophenone, 6.8 parts of sodium formate and about 90 parts of acetonitrile. The resulting mixture was stirred vigorously for 48 hours at 65° C during which time carbon dioxide evolved. After cooling, the acetonitrile solution was separated from the aqueous layer and evaporated to dryness. The residue was dissolved into chloroform which was extracted once with water, dried over sodium sulfate, and evaporated to produce analytically pure (<98%) α-hydroxy-propiophenone. The yield of this isolated product was 77.1%,
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH-].[Na+].[CH2:11]([O:13][C:14](Cl)=[O:15])[CH3:12].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:11]([O:13][C:14]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Nc1ccc(O)cc1

Procedure:
p-aminophenol 33.36 g (0.3 mole) and 12 g NaOH were dissolved in 120 ml water and cooled to ice salt bath temperature. To the stirring solution, 24 ml ethylchloroformate were slowly added. A white precipitate was found. One gram sodium dithionite was added and mixed. The solid was filtered by suction and washed with cold water (50 ml). Recrystallization from hot water gave a crystalline powder, 48.3 g (89%), MP 120-123°.