Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[NH:10][C@H:9]2[CH3:14])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C:37]1[CH:38]=[C:39]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][C:46]=2[CH3:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:28]=3[C:37]3[CH:38]=[C:39]([C:45]4[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][C:46]=4[CH3:55])[CH:40]=[CH:41][C:42]=3[O:43][CH3:44])[C@H:9]2[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cccc(F)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cccc(F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of (4S,5R)-5-(3-fluorophenyl)-4-methyl-1,3-oxazolidin-2-one (16.2 mg, 0.0830 mmol) in DMA (1 mL) was added NaHMDS (83 μL, 0.083 mmol). Next, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (49 mg, 0.0996 mmol) in DMA (1 mL) was added via cannula. After 5 minutes, the reaction was quenched with saturated NH4Cl solution (10 mL) and diluted with EtOAc (20 ml). The aqueous layer was extracted with EtOAc (20 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded methyl 2″-{[(4S,5R)-5-(3-fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS=608.2 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.94 (d, J=5.9 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.71-7.61 (m, 2H), 7.41-7.36 (m, 2H), 7.33-7.24 (m, 2H), 7.14-7.12 (m, 1H), 7.07-7.05 (m, 1H), 7.02-6.90 (m, 3H), 5.46 (d, J=8.2 Hz), 5.24 (d, J=8.2 Hz), 4.90 (d, J=15.8 Hz), 4.82 (d, J=15.8 Hz), 4.20 (d, J=15.8 Hz), 3.97 (d, J=15.8 Hz), 3.92 (s, 3H), 3.95 (s, 3H), 3.75-3.69 (m, 1H), 2.36 (s), 2.31 (s), 0.53 (d, J=6.6 Hz), 0.43 (d, J=6.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:33][OH:34])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([F:32])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([F:32])[CH:23]=1)[CH2:33][O:34][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(Oc2cc(F)cc(C(F)(F)F)c2)c(F)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(Oc4cc(F)cc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluo-ro-4-(3-fluoro-5-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2ncccn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 22.3 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-chloropyrimidine (51 mg, 0.45 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (1 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 25.1 mg of the title compound as a white solid (22%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-benzyloxybenzoic acid (116 mg, 0.51 mmol) and PS-carbodiimide (500 mg, 0.66 mmol, 1.32 mmol/g) in 5% DMF in CH2Cl2 (5 mL) is added (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (80 mg, 0.51 mmol). The mixture is stirred at room temperature for 3 days. The reaction mixture is filtered, and the resin is washed with CH2Cl2. The filtrate is concentrated and applied to silica-gel column chromatography (in CH2Cl2 followed by 5% 2M NH3 in MeOH/CH2Cl2) to give the product. 62.7 mg (34%): Observed mass: 365 (M+1).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1OS(C)(=O)=O)([CH3:4])[CH3:3].[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C=O)C>[CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[N:29]=[N+:30]=[N-:31])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1OS(C)(=O)=O
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1N=[N+]=[N-]
Temperature: 80 °C
Yield: 73.2 %

Procedure:
2-(2-(((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl)-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)-1-O-methanesulfonylcyclobutanol (180 mg, 0.41 mmol) was mixed with 200 mg (4.1 mmol) of lithium azide in 4 mL of DMF. The reaction mixture was heated at 80° C. for 2 h then concentrated in vacuo. The residue was purified on a silica gel column eluted with 5% ethyl acetate in hexane to give 120 mg (73% yield) of the title compound; MS DCI-NH3M/Z: 400 (M+H)+, 417 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:21])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][C:10]([CH3:19])=[C:9]([CH3:20])[CH2:8]1)([O-])=[O:2].O.C(=O)([O-])[O-].[K+].[K+]>COCCO>[OH:2][NH:1][C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:21])[C:7]1[CH:8]=[C:9]([CH3:20])[C:10]([CH3:19])=[CH:11][C:12]=1[C:13]2=[O:18]
Reactant: CC1=C(C)CC2C(=O)c3c(cccc3[N+](=O)[O-])C(=O)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: Cc1cc2c(cc1C)C(=O)c1c(NO)cccc1C2=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 parts of 5-nitro-2,3-dimethyl-1,4,4a,9a-tetrahydroanthraquinone with 50 parts of water, 50 parts of methylcellosolve and 0.05 parts of potassium carbonate was stirred at 60°C for 1 hour, then cooled to 20°C and filtered to recover crystals. The crystals were washed with water and dried under reduced pressure to obtain 4.5 parts of 5-hydroxylamino-2,3-dimethylanthraquinone.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][CH2:42][C@@H:43]1[CH2:48][CH2:47][C@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:40])([CH3:37])[CH3:36]>>[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][N:20]2[C:49]([C@@H:46]2[CH2:45][CH2:44][C@H:43]([CH2:42][NH:41][C:39](=[O:40])[O:38][C:35]([CH3:36])([CH3:34])[CH3:37])[CH2:48][CH2:47]2)=[O:50])[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:16][CH3:17])=[O:18])=[CH:10][CH:9]=1
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)[C@H]3CC[C@@H](CNC(=O)OC(C)(C)C)CC3)nc2Cl)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 67 was treated with cis-4-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]4[CH:24]=[N:19][CH:20]=[N:21][CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1cncnc1
Product: N#Cc1cc(-c2cncnc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, off-white solid (13 mg, 17%), MS (ISP) m/z=304.5 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[CH3:5][C:6]([CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][CH2:9]1)=[O:7]>>[CH3:14][C:12]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([C:6]([OH:7])([CH2:3][CH:2]=[CH2:1])[CH3:5])[CH2:13]1
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: C=CCCl
Product: C=CCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with allyl chloride replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26](=[O:28])[NH2:27])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>CCO>[ClH:30].[C:26]([CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[CH:19]=1)[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:29])(=[O:28])[NH2:27]
Reactant: COc1cc(OCC(N)=O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(OCC(N)=O)cc(C(=O)NC2CCNCC2)c1
Temperature: 25 °C

Procedure:
2.20 g (5.4 mmol) of 4-(3-carbamoylmethoxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester was suspended under argon in 40 mL of EtOH at rt; while stirring, 6.75 mL of HCl/dioxane (4 molar) was added; the heterogeneous reaction mixture was heated up to reflux to achieve a clear solution. After cooling down to rt, the solvents were removed by evaporation i.V. and the residue was dried in high vacuum at rt for 5 hours. This crude product was recrystallised from MeCN to yield 1.53 g of 3-carbamoylmethoxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride as colorless solid [MS: 308.3 (MH+)]; the mother liquor contained 0.80 g of [3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-acetic acid ethyl ester hydrochloride as light yellow amorphous solid. MS: 337.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(=O)[C:30](Cl)=[O:31]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:30]=[O:31])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(N)(=O)=O)cc1-c1ccccc1
Solvent: Clc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(=O)(=O)N=C=O)cc1-c1ccccc1

Procedure:
A mixture of the resultant sulfonamide from Example 119A in chlorobenzene is treated with with oxalyl chloride according to the procedure of Franz et al. (J. Org. Chem, 1964, 29, 2592) to give the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([C:27]2[CH:32]=[N:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=2)=[O:5])=[CH:7]1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: COc1ncc(I)cc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ncc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 119 mg (0.33 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 183 mg (0.73 mmol) of 5-iodo-2-methoxy-3-methyl-pyridine in 1 mL THF with 0.38 mL 2M isopropylmagnesium chloride. Yield: 86 mg of a white powder. LC-MSD, m/z for C24H19ClN2O3 [M+H]+=419.1, 421.1; HPLC retention time: 3.1 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]([F:27])([F:26])[C:11]([F:25])([F:24])[C:12](=O)[CH2:13][C:14](=O)[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[OH-].[NH4+]>P(=O)(O)(O)O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:14]([C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])=[CH:13][C:12]=2[C:11]([F:25])([F:24])[C:10]([F:27])([F:26])[F:9])[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(CC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(C(F)(F)C(F)(F)F)cc(C(F)(F)C(F)(F)F)nc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-diamino pyridine (5.2 g., 4.76 mmole), 1,1,1,2,2,6,6,7,7,7-decafluoroheptan-3,5-dione (14.5 g., 4.80 mmole) and 85% phosphoric acid (50 ml.) is stirred at 90°-95° C. for 6 hours. When cool, the reaction mixture is poured into ice-water and neutralized with ammonium hydroxide to pH 7. The solid is collected, washed with water, dried, and can be purified by recrystallization from benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[N:17][CH:18]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Br)cn1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cn1

Procedure:
The-captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-amino-5-bromopyridine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (508 mg, 3.6 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (671 mg, 3.6 mmol) in N,N-dimethylformamide (7 mL) was heated at 55° C. for 1.5 hours and then stirred overnight at room temperature. The reaction mixture was poured into water and the suspension was filtered with water washes to provide the title compound after drying.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)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: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.1 g, 44%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:19]([N:21]([CH:35]([CH3:37])[CH3:36])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[O:20])[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=2[O:8][C:7]([CH3:39])([CH3:38])[C:6]1=[O:40])[CH2:2][CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:49])C=1.O>ClCCl>[CH3:39][C:7]1([CH3:38])[C:6](=[O:40])[N:5]([CH2:1][CH2:2][CH:3]2[CH2:4][O:49]2)[C:10]2[CH:11]=[C:12]([C:19]([N:21]([CH:35]([CH3:36])[CH3:37])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]3)=[O:20])[C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:9]=2[O:8]1
Reactant: C=CCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCC1CO1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-but-3-en-1-yl-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.7 g) in dichloromethane (15 ml) was added m-chloroperbenzoic acid (775 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (780 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2nc(Cl)ncc2Br)cc1
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22.0 mmol), 4-methoxyphenol (2.72 g, 22.0 mmol) and potassium carbonate (6.07 g, 44.0 mmol) in DMF (20 ml) was stirred for 24 hours. The mixture was added to water (100 ml) and the solid which separated out was collected by filtration, washed with water (50 ml) and dried under high vacuum to give the product (6.6 g, 96%). NMR: 3.8 (s, 3H), 7.0 (d, 2H), 7.2 (d, 2H), 8.8 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1(C)C23[C@@]4(ON4S(=O)(=[O:53])C2)C(Cl)(Cl)[C@H]1CC3>C1COCC1>[OH:53][CH:3]1[C:2](=[O:1])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: CC1(C)[C@@H]2CCC13CS(=O)(=O)N1O[C@]13C2(Cl)Cl
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)CC3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)C(O)C3)cc1
Temperature: -10 °C

Procedure:
To a solution of 7-(6-oxo-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid (Ex. 12.1) (100 mg, 0.219 mmol) in THF (2 ml), under a nitrogen atmosphere at −78° C., was treated dropwise with 1M lithium bis trimethylsilylamide in THF (0.5 ml, 0.500 mmol). Once the addition was complete, the mixture was stirred at −78° C. for 1 hour before a solution of (+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine (78 mg, 0.262 mmol) in THF (2 ml) was added. The resultant solution was stirred at −78° C. for 60 minutes. The cooling was removed and the mixture allowed to warm to around −10° C. The mixture was allowed to slowly warm to room temperature overnight. The mixture was cooled to −78° C., quenched with sat. NH4Cl (3 ml) and allowed to slowly warm to room temperature. The yellow solution was diluted with water and extracted with EtOAc (×2). The aqueous layer (pH-9) was acidified to pH ˜2 with 1M HCl and extracted with DCM (×2). The combined organic extracts were dried (MgSO4) and evaporated under vacuum to give a yellow gum. The residue was purified by chromatography on silica eluting with 1% MeOH/DCM followed by 10% MeOH/DCM to afford the title compound;
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Product: CC(=O)NN1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
The above compound is prepared by heating under reflux for 30 minutes a mixture of 14 gm. of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 280 ml. of acetic anhydride. The mixture is evaporated to dryness, and the solid residue is washed thoroughly with ether giving 16.4 gm. of a yellow solid having a melting point of 235° C. (decomposition).