Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[Cl:14][C:15]1[C:20](=O)[O:19][C:18](=O)[N:17](C)[C:16]=1[CH3:24]>O1CCCC1>[Cl:14][C:15]1[C:20]([OH:19])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:5](=[O:7])[N:17]([CH3:18])[C:16]=1[CH3:24]
Reactant: Cc1c(Cl)c(=O)oc(=O)n1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To 0.43 g of sodium hydride (60%) was added 35 ml of tetrahydrofuran, 2.5 ml of a solution of 1.76 g diethyl malonate in tetrahydrofuran was further added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1.74 g of 5-chloro-3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione, and this was stirred for 3.5 hours under heat refluxing condition. The reaction mixture was concentrated under reduced pressure. To the residue, 20 ml of water and 15 ml of 1 mol/L hydrochloric acid were sequentially added, followed by extraction with 85 ml of chloroform twice. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was washed with n-hexane to obtain 1.52 g of ethyl 5-chloro-1.6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1N1CCCCC1)C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using piperidine as a reagent in the absence of a solvent, the same procedure of Example 264 gave 1.524 g of the titled compound (yield, 98%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11](=[O:14])([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[CH:29]([CH3:31])O.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.C1C=CC=CC=1>[C:37]1([CH2:36][O:14][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([O:13][CH:29]([CH3:31])[C:28]([O:33][CH2:34][CH3:35])=[O:32])=[O:12])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)O
Reactant: OCc1ccccc1
Reactant: O=P(O)(O)CCCCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)OP(=O)(CCCCc1ccccc1)OCc1ccccc1
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 4-phenylbutyl phosphonic acid from Part A (0.70 g, 3.27 mmole), benzene (10 ml), and PCl5 (1.36 g, 6.54 mmole) was refluxed under argon for 30 minutes. The benzene and POCl3 were removed in vacuo and the residue taken up in CH2Cl2 (5 ml). After cooling to 0° C. (ice-bath), triethylamine (1.3 ml, 9.39 mmole) was added followed by dropwise treatment with d,l ethyl lactate (0.39 ml, 3.3 mmole) in CH2Cl2 (3 ml) over a 5 minute period. After 1 hour benzyl alcohol (0.35 ml, 3.3 mmole) in CH2Cl2 (3 ml) was added dropwise over 2 minutes, the ice-bath removed, and the reaction mixture allowed to stir for 2 hours. The reaction mixture was diluted with EtOAc then washed with H2O, 5% KHSO4, saturated NaHCO3, brine, dried (MgSO4 ), and evaporated. The residue (1.3 g) was chromatographed on silica (70 g) eluting with 2/1 hexane/EtOAc to obtain the title compound (0.80 g, 1.98 mmole; 60% yield) as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13].[CH3:31][O:32][C:33]1[CH:61]=[CH:60][C:36]([C:37](C2C=CC=CC=2NC(=O)CNC(NC2C=C(C)C=CC=2)=O)=[O:38])=[CH:35][CH:34]=1>>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:37](=[O:38])[C:36]1[CH:60]=[CH:61][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(C(=O)c2ccccc2NC(=O)CNC(=O)Nc2cccc(C)c2)cc1
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2I)c1
Product: COc1ccc(C(=O)c2ccccc2N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)cc1

Procedure:
According to the synthesis method of the compound 24, the compound 42a is used to synthesize the titled compound. Mp, 228°-230° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[I-:46].[Na+]>C(#N)C>[I:46][CH2:2][O:3][C:4](=[O:45])[CH2:5][CH:6]([CH2:26][O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:7][O:8][C:9](=[O:25])[C@H:10]([CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCI

Procedure:
3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid chloromethyl ester (900 mg, 1.38 mmole) was dissolved in acetonitrile (5 ml). Sodium iodide (289 mg, 1.93 mmole) was added to the solution. After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 800 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH:17]([OH:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[N:5]([CH3:16])[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)CCCN>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH:17]([O:28][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:22][CH:23]=1)[N:5]([CH3:16])[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: COCOc1ccc(C(O)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)CCCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C(OC(=O)c2ccccc2)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine methyl ester (erythro isomer) (3.85 g) in dichloromethane (30 ml) were added triethylamine (1.38 g), 4-dimethylaminopyridine (0.45 g) and benzoyl chloride (1.92 g). After stirring for 16 hours at room temperature, 3-dimethylaminopropylamine (3.3 g) was added to the mixture and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with dil. hydrochloric acid, sodium bicarbonate aqueous solution and water. After evaporating, the residue was put on a column of silica gel (MERCK 7734, 150 g) and eluted with n-hexane-ethyl acetate (5:2, V/V) to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-benzoyloxytyrosine methyl ester (erythro isomer) (4.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](C=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(OC([CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][NH2:43])=O)(C)(C)C.Cl.[C:45](=[O:48])(O)[O-:46].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:43][O:42][CH2:41][CH2:40][N:39]([C:45]([O:46][C:10]([CH3:15])([CH3:11])[CH3:9])=[O:48])[CH2:38][CH3:37])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CC(C)(C)OC(=O)CCNCCON
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In tetrahydrofuran (1.5 ml) were dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1, 120 mg) and N-(t-butoxycarbonyl)ethylaminoethoxyamine (110 mg), and 134 μl of 2 mol/L hydrochloric acid was added, then the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into aqueous ice-cooled saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting residue was purified by amino column chromatography (eluting with hexane:ethyl acetate=1:1), and further re-purified by silica gel chromatography (eluting with hexane:ethyl acetate=1:1) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-(N-(t-butoxycarbonyl)-N-ethylamino)ethyloxyimino)quinazoline (V-16, 96 mg) as a yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([N:13]([CH2:21][CH3:22])[C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:21]([N:13]([CH2:11][CH3:12])[C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[S:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:22]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCN(CC)c1cccc(S)c1
Product: CCN(CC)c1cccc(Sc2ncccc2[N+](=O)[O-])c1

Procedure:
Thus, for example, a compound of the formula ##STR16## is obtained by reaction of 2-chloro-3-nitro-pyridine with 3-diethylaminothiophenol to give 2(3'-diethylaminothiophenoxy)-3-nitro-pyridine, reduction to the 3-amino compound, diazotisation and intramolecular coupling. The oxadiazepine derivative ##STR17## is obtained, for example, by reaction of 3-chloro-4-nitroanisole with 1-diethylamino-3-hydroxynaphthalene to give 1-diethylamino-3-(5'-methoxy-2'-nitro-phenoxy)-naphthalene, reduction to the 2'-amino compound, diazotisation and internal coupling.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:28][CH2:29][CH3:30])[C:17](=[O:27])[C:18]2[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=2)=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.[OH-].[Na+].C(Cl)Cl.CO>C1(C)C(C)=CC=CC=1>[CH2:28]([N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]2[NH:46][N:45]=[N:44][N:2]=2)=[CH:14][CH:13]=1)[C:17](=[O:27])[C:18]1[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=1)[CH2:29][CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)c1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: CO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 2.76 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-isophthalic acid monoamide and 8.68 g of tributyltin azide in 75 ml of xylene is heated under reflux for 2 hours. When cool, the mixture is stirred with 50 ml of 2N sodium hydroxide solution at room temperature for 1 hour, and is then acidified and extracted with 100 ml and twice with 50 ml of CH2Cl2. After customary treatment, the combined dichloromethane phases yield a crude product that, after chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (9:1) as eluant, yields N-propyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-isophthalic acid monoamide that has an Rf value of 0.10 [CH2Cl2 /CH3OH (4:1)]. ##STR10##
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=2[F:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].O.O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:13]=2[F:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(CCC(=O)O)c3F)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of ethyl 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluoropyrimidin-4-yl)propanoate (300 mg) in methanol (2.0 mL) and THF (4.0 mL) were added water (2.0 mL) and lithium hydroxide monohydrate (123 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (30 mg) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]2[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([O:13][C:8]1[C:7]([C:14]2[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][C:9]=1[CH:10]=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
step 2—A mixture of 48 (737 mg, 2.59 mmol), benzyl bromide (0.625 mL, 5.26 mmol) and K2CO3 (734 mg, 5.31 mmol) in DMF (10 mL) was stirred overnight at RT then partitioned between EtOAc and water. The organic layer was thrice washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 10% EtOAc) to afford 812 mg (84%) of 2-benzyloxy-5-tert-butyl-3-(2-methoxy-pyridin-3-yl)-benzaldehyde (50) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH3:8][C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1[N:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cn1ccc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1ccn(C)n1
Temperature: 115 °C
Yield: 94.3 %

Procedure:
A solution of 1-methyl-1H-pyrazol-3-ylamine (0.92 g, 9.5 mmol) in benzene (4.8 mL) was treated with hexane-2,5-dione (1.34 mL, 11.4 mmol) and para-toluenesulfonic acid (182 mg, 0.95 mmol) and was heated to 115° C. under Dean-Stark conditions for 4 h. After this time, the reaction was cooled to 25° C., concentrated in vacuo and dried under high vacuum overnight. The resulting residue was dissolved in methylene chloride (100 mL) and was washed with water (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 1:4 ethyl acetate/hexanes) afforded 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.57 g, 94%) as a green oil; ES+-HRMS m/e calcd for C10H13N3 [M+H+] 176.1182, found 176.1182.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.C[Si]([C:25]#[N:26])(C)C>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]2[C:25]#[N:26])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Reactant: c1ccc2ncccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CC1C=Cc2ccccc2N1C(=O)c1ccc(F)cc1
Yield: 150 %

Procedure:
The title compound was prepared by the procedure described in step 1 of Example 1 using 13.0 g of quinoline, 39.0 g of 4-fluorobenzoyl chloride, 0.1 g of aluminum chloride, 30.0 g of trimethyl silyl cyanide, and 500 mL of methylene chloride. The title compound (42.0 g) was obtained as a solid, m. p. 111-113° C. This product was used for the preparation of the title compound described in step 2, and for preparation of the title compound described in Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[CH3:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[CH3:45]>CO.C(Cl)Cl.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>[CH3:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:3]=[CH:4][C:5]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:42]=[CH:43][C:44]=1[CH3:45]
Reactant: N#Cc1cc(Br)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Cc1ccc(B(O)O)cc1C
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: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C#N)c2)cc1C
Temperature: 105 °C
Yield: 118.2 %

Procedure:
5-Bromo-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (300 mg, 0.777 mmol), Pd(Ph3P)4 (44.9 mg, 0.039 mmol), aqueous 2M Na2CO3 (0.882 mL, 1.763 mmol) were mixed with toluene (4 mL) in a sealed microwave tube. 3,4-dimethylphenylboronic acid (163 mg, 1.087 mmol) in MeOH (2.00 mL) was added to the above mixture. The mixture was heated at 105° C. for 4 hrs in an oil bath. The crude was diluted with CH2Cl2 (100 ml) and washed with water (2×50 ml), brine, dried with MgSO4 and concentrated. 378 mg of crude product (77% purity) was obtained and it will be used as it is.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([C:19]1[N:20]([CH2:32][C:33]#[CH:34])[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=1)[CH3:18]>CN(C=O)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.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:17]([C:19]1[N:20]([CH2:32][C:33]#[C:34][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=1)[CH3:18]
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (64 mg, 0.03 eq.), 4-iodoanisole (531 mg, 1.1 eq.), triethylamine (862 μL, 3.0 eq.), and copper (I) iodide (23.6 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (485 mg, 2.06 mmol, 1.0 eq.) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 3 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2/98 methanol/chloroform) to provide 0.34 g of 2-ethyl-1-[3-(4-methoxyphenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a clear oil that partially crystallized on standing.
Reaction SMILES: C(O[C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C.C(N(CC)CC)C.Cl.[F:33][CH2:34][CH2:35][NH2:36]>CO>[F:33][CH2:34][CH2:35][NH:36][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Reactant: NCCF
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1C=CN(c2ccc(N3C[C@H](C(=O)NCCF)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (5R)-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 72, Step 5, 226 mg, 0.68 mmol) in MeOH (2 mL) is added triethylamine (0.48 mL, 5.0 equiv.). Then 2-fluoroethylamine hydrochloride (136 mg, 2.0 equiv.) is added to the solution. The reaction mixture is heated at 50–60° C. for 5 h, followed by stirring overnight at room temperature. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by column chromatography (10% MeOH/CH2Cl2). The title compound is obtained as a yellow solid (100 mg, 42,%), 1H NMR (300 MHz, DMSO) δ 8.69 (t, 1H), 7.75–7.27 (m, 5H), 5.09 (dd, 1H), 4.98 (d, 1H), 4.55 (t, 1H), 4.39 (t, 1H), 4.29 (t, 1H), 4.02–3.93 (m, 3H), 3.51–3.37 (m, 2H), 2.50–2.45 (m, 2H); MS for C17H18FN3O4 m/z 348.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17]N(C)C)[CH2:11]2)=[CH:6][CH:5]=1.[C:22](=O)(O)O.[NH2:26][C:27]([NH2:29])=[NH:28].O.O.O.C([O-])(=O)C.[Na+]>CCO>[CH2:1]([O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[N:28]=[C:27]([NH2:29])[N:26]=[CH:17][C:12]=3[CH2:11]2)=[CH:6][CH:5]=1)[CH3:22]
Reactant: O=C(O)O
Reactant: COC(=O)c1ccc(N2CCC(=O)C(=CN(C)C)C2)cc1
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N2CCc3nc(N)ncc3C2)cc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
A solution of methyl-4-(3-dimethylaminomethylene-4-oxopiperidin-1-yl)-benzoate (3.00 g, 10.40 mmol) in EtOH (200 mL) was treated with guanidine carbonate (7.50 g, 41.60 mmol), followed by sodium acetate trihydrate (11.32 g, 83.20 mmol). The reaction mixture was refluxed for 16 hours and allowed to cool to room temperature. The insolubles were filtered off and the filtrate was concentrated. The residue was partitioned between water and ethyl acetate and the solid was filtered off, washed with water, ethyl acetate, and dried to give the title compound (258 mg). The filtered insoluble material from the reaction mixture was suspended in water, stirred for 30 minutes, and the remaining light yellow, amorphous solid was collected, washed with water, ethyl acetate, and dried to give an additional amount of the title compound (1.95 g, total yield 71%).