Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O.[Cu](I)I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][N:9]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nn(-c2cncc(C(F)(F)F)c2)c1C
Temperature: 160 °C
Yield: 22.3 %

Procedure:
3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.10 g, 1 mmol) (prepared as described in Tett 2002, 58, 18, p 3639), 3-bromo-5-trifluoromethyl-pyridine (0.16 g, 1 mmol), copper iodide (0.02 g, 0.2 mmol) and cesium carbonate (1.0 g, 3 mmol) were suspended in DMA (0.5 ml) and heated to 160° C. for 16 h. The reaction was diluted with EtOAc, washed repeatedly with ammonium hydroxide, brine and dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (EtOAc:n-heptane 1:9-2:8 gradient affording the title compound (0.07 g, 35%) as a yellow oil. MS: 314.2 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([C:27]#[N:28])[N:10]=1>COCCOC>[N:1]1([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27]#[N:28])[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(-n3ccnc3)nc(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of imidazole (15 mg) in 2 mL DME was added NaH (12 mg, 60% dispersion in mineral oil); a precipitate formed immediately. The mixture was stirred at room temp for 5 min, then heated to 75 C. A solution of 1-chloro-4-phenyl-6-methoxyisoquinoline-3-carbonitrile (60 mg) in 1 mL DME was added via cannula. Heating continued at 75 C for 45 min. The reaction was cooled to room temp and quenched by adding a few drops of water, then partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic solution was washed with brine (1×), dried over MgSO4 and concentrated. Flash chromatography (0% to 10% MeOH (10% NH4OH) in EtOAc) gave a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:7][CH:6]=1)#[N:4].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([N:21]([CH2:20][CH2:19][N:14]1[CH2:15][CH:16]2[O:18][CH:12]([CH2:11][N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=3)[CH2:17]2)[CH2:13]1)[S:22]([CH3:25])(=[O:24])=[O:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a suspension of NaH (60% in oil, 0.039 g, 1.64 mmol) in dry DMF (10 mL) was added N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethyl}methanesulfonamide (0.3 g, 0.82 mmol; see Preparation M above) at 0° C. The reaction mixture was stirred for 1 h at room temperature. Benzyl bromide (0.155 g, 0.9 mmol) was added at 0° C. and the reaction mixture stirred at rt for 2 h. The reaction quenched with water, extracted with dichloromethane, washed with water, brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography of the residue over silica gel (using 5% methanol in chloroform as eluent) gave 160 mg of the title compound as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]([N:18]=[C:19]=[O:20])=[O:17]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:19]([NH:18][C:16]([O:15][CH3:14])=[O:17])=[O:20])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)N=C=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(=O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 79.1 %

Procedure:
To 4-nitrobenzenesulfonamide (2.1 grams, 0.01 mole) in 100 milliliters dry toluene was added 1.2 grams (0.012 mole) methoxycarbonyl isocyanate. Three drops of pyridine were added. The mixture was refluxed for four hours. After cooling the precipitate was filtered off and washed with toluene. The solid material was dried. There was obtained 2.4 grams of the title compound, m.p. 150°-158° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([N:6]1[C:14]2[C:13]([O:15][CH3:16])=[CH:12][CH:11]=[C:10]([C:17]([O:19]C)=[O:18])[C:9]=2[CH:8]=[CH:7]1)[CH3:5]>C(O)C>[CH3:5][CH:4]([N:6]1[C:14]2[C:13]([O:15][CH3:16])=[CH:12][CH:11]=[C:10]([C:17]([OH:19])=[O:18])[C:9]=2[CH:8]=[CH:7]1)[CH3:3]
Reactant: COC(=O)c1ccc(OC)c2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)c2ccn(C(C)C)c12
Yield: 92.7 %

Procedure:
Added 1 N sodium hydroxide (6.47 mL, 6.47 mmol) to a solution of methyl 1-(1-methylethyl)-7-(methyloxy)-1H-indole-4-carboxylate (400 mg, 1.618 mmol) in ethanol (30 mL) and heated at reflux for 3 h. The EtOH was removed in vacuo and the residue dissolved in 20 ml of water. Acidifed solution by addition of 1 N HCl and extracted with DCM. the combined DCM extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give 350 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (d, 6H), 4.03 (s, 3H), 5.47 (dt, J=13.39, 6.69 Hz, 2H), 6.70 (d, J=8.34 Hz, 2H), 7.23 (d, J=3.28 Hz, 2H), 7.37 (d, J=3.03 Hz, 2H), 7.99 (d, J=8.34 Hz, 2H). MS(ES) [M+H]+ 234.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:36]3[CH2:35][CH2:34][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
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: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg) in DMF (5 mL) was added tert-butyl piperazine-1-carboxylate (77.5 mg, 0.42 mmol), DIEA (89.6 mg, 0.69 mmol), HATU (158.3 mg, 0.42 mmol). The resulting solution was stirred at room temperature for 3 h and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM to afford 279 mg of tert-butyl 4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylate as a yellow solid. LCMS (Method 22) [M+H]+=631.4, RT=1.49 min.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[CH:27][CH:28]=2)[O:17]1.C=O>C(Cl)Cl>[CH3:1][N:32]1[CH2:31][CH2:30][N:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([B:18]3[O:17][C:16]([CH3:35])([CH3:15])[C:20]([CH3:21])([CH3:22])[O:19]3)[CH:24]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1(C)OB(c2cccc(N3CCNCC3)c2)OC1(C)C
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (0.066 g, 0.31 mmol) was added to a solution of 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (60.0 mg, 0.208 mmol, from Boron Molecular) and 11.0 M aqueous formaldehyde (0.057 mL, 0.62 mmol) in methylene chloride (0.8 mL, 10 mmol) and then the reaction was stirred at r.t. for 1 hour. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated to provide the product which was used in the next step. LCMS calculated for C17H28BN2O2 (M+H)+: m/z=303.2. Found 303.2.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:41])[CH2:12][N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[CH2:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:41])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)CN2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(CC(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester (30.0 mg, 0.05 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid (29.0 mg, 98.9%). LC-MS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.5; Found: 602.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH3:18].[OH-].[NH4+]>C(O)C>[OH:1][CH2:2][C:3]1[NH:18][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(CO)[nH]cc1OCc1ccccc1

Procedure:
A mixture of 2-(hydroxymethyl)-5-[(phenylmethyl)oxy]-4H-pyran-4-one (9.65 g, 41.59 mmole), 95 ml of concentrated ammonia and 20 ml of ethanol were heated at reflux overnight. An additional 75 ml of ammonium hydroxide was added, the mixture was refluxed for 2 hours and cooled. The resulting brown solid was filtered and washed with water until the washings were neutral. The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8])(=[O:11])[CH3:10]
Reactant: N#Cc1ccsc1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1sccc1C#N
Reaction time: 3 h

Procedure:
2-Amino-3-cyanothiophene (12 g) was heated at reflux in acetic anhydride (34 ml) for 15 minutes, cooled and refrigerated for 3 h. The crystalline product was filtered off (13.6 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: BrCCCc1ccccc1
Product: c1ccc(CCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 1-bromo-3-phenylpropane, to produce the above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][CH2:25][CH3:26])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCCC(=O)CCl
Product: CCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with 1-chloro-2-pentanone to give 7-chloro-2-[(2-chloro-1-propylethylidene) hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=3)=[O:15])[C@H:11]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][O:28]2>>[CH3:21][N:17]1[C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:31]4[CH2:32][C@@H:27]5[CH2:33][C@H:30]4[CH2:29][O:28]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[N:18]1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cn1nccc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Product: Cn1nccc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
230 mg (0.61 mmol) of (8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 107.90 mg (0.79 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 160 mg of (8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:33][C:34]([O:36]C)=[O:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of methyl ({6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (271 mg, 0.555 mmol), prepared in the previous step, and 1N NaOH (1.11 mL, 1.11 mmol) in 35 mL of THF plus 20 mL of H2O was stirred at room temperature for 15 h (overnight). The reaction was acidified by the addition of 1.2 mL of 1N HCl and then concentrated under reduced pressure to remove the THF. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (236 mg, 90%) as a white solid, mp 238-242° C. Elemental Analysis for C30H22N2O4+0.32 mole of H2O. Calc'd: C, 75.03; H, 4.75; N, 5.83. Found: C, 74.67; H, 5.34; N, 5.19.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: CCc1nc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
3-Bromo-2-ethyl-6-nitropyridine (2.6 g, 11.3 mmol) and 2-chloro-4-hydroxypyridine (2.9 g, 22.5 mmol) were dissolved in DMA (20 mL). The solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.7 g, 33.8 mmol) was added and the reaction mixture was stirred at 110° C. for 12 h. EtOAc (80 mL) was added and the suspension was washed with 10% K2CO3 (aq) (2×50 mL), 5% LiCl (aq) (2×50 mL), and brine (2×50 mL). The solution was dried (Na2SO4), concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (1.3 g, 37.2%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.16 (dd, J=5.7, 2.3 Hz, 1H), 2.79 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([C:19]1([NH2:34])[C:25](=[O:26])[N:24]([CH3:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[N:21]([CH3:32])[C:20]1=[O:33])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:34][C@H:19]([C:25]([NH:34][CH:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[N:24]([CH3:27])[C:25]2=[O:26])=[O:26])[CH3:20])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-R), the title compound was prepared as a white solid (melting point=206-207° C.). Purification was by flash chromatography eluting with straight EtOAc gradient to EtOAc/Acetone (95:5). Rf=0.32 (EtOAc).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15](Br)[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.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]>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:19])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Zn]C
Reactant: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Temperature: 22 °C
Yield: 95 %

Procedure:
A solution of the product from step j) (284 mg, 0.86 mmol) in dioxane (4.3 ml) was treated with Pd(dppf)2Cl2 (42 mg, 0.051 mmol) and a 2M solution of dimethylzinc in toluene (0.86 ml, 1.72 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) passed through a plug of silica-gel eluting with 50:50 hexanes:EtOAc to provide the subtitle compound (216 mg, 95% over 3-steps). MS calculated for C14H19NO2S +H 266, observed 266.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]1[Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution (7 M) of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate in DMF at 0° C. was treated with NaH (1.2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min then it was treated with benzyl bromide (1.2 eq.). The reaction mixture was stirred at RT for 90 min then poured into water and extracted with AcOEt. The combined organic phase was washed with water and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:8 AcOEt/petroleum ether) to afford the title compound (71%) as a solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:23])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13].CO.O1CCOCC1.[OH-].[Na+]>>[Cl:22][C:17]1[CH:16]=[C:15]([S:12]([N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3]([OH:24])=[O:2])[CH3:23])(=[O:13])=[O:14])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)Cc1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CN(c1ccccc1CC(=O)O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)acetic acid methyl ester (13.7 g, 34.26 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1) (266 ml, 52.92 mmol NaOH), and then further 4 M NaOH (39.7 ml, 158.76 mmol) was added. The resulting clear solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 0.5 M KHSO4. The aqueous phase was then extracted several times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over sodium sulfate and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34](Cl)(=[O:36])[CH3:35].C(OCC)(=O)C>O1CCCC1>[C:34]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:21])[CH3:22])[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[O:11])[C:5]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(N)c1=O)C(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(-c2cccs2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[5-amino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.3 g) in tetrahydrofuran (7 mL) was added sodium carbonate (0.4 g) and the mixture cooled in an ice bath to 0° C. Acetyl chloride (0.11 mL) was added and the solution warmed to room temperature and let stir for 1 h. The mixture was poured into ethyl acetate and washed (1N HCl, a saturated solution of sodium carbonate, and H2O). The resulting solution was dried and the solvent removed by evaporation. The resulting material was purified by chromatography, eluting with methanol:dichloromethane (gradient, 5:95, 12:88) to give the title compound (0.46 g) as a light yellow powder; TLC: Rf =0.47, methanol:dichloromethane (5:95); NMR (DMSO/D2O): 8.77 (s,1), 7.81 (d,1), 7.36 (d,1), 7.09 (t,1), 4.83 (m,2), 4.09 (d,1), 2.26 (m, 1), 2.13 (s,3), 0.93 (d,3), 0.80 (d,3).