Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([Cl:27])=[O:18])=[CH:10]1
Reactant: O=C(O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(=O)n(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a suspension of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (795 mg) in CH2Cl2 (8 mL) were added DMF (0.025 mL) and ethanedioyl dichloride (603 mg) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. The volatile materials were removed by evaporation in vacuo to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarbonyl chloride (810 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20](=[N:28]O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=3)=[N:28][C:20]=2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:15][CH:14]=1
Reactant: NCc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(CCO)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
4-(2-Hydroxyethyl)phenylmethylamine and tert-butyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate are dissolved in pyridine, and the mixture is treated in the same manner as in Starting Material Synthetic Example 170 to give the objective tert-butyl 5-(4-chlorophenyl)-2-[4-(2-hydroxyethyl)phenyl]imidazole-4-carboxylate.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([S:27]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)(=[O:29])=[O:28])[CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:22]=[N:23][CH:24]=[C:25]([S:27]([N:30]3[CH2:33][C:32]([F:35])([F:34])[CH2:31]3)(=[O:29])=[O:28])[CH:26]=2)[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1cncc(Br)c1)N1CC(F)(F)C1
Product: N#Cc1ccc(OCC(=O)O)c(C#Cc2cncc(S(=O)(=O)N3CC(F)(F)C3)c2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 3-bromo-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]pyridine (Intermediate 34), the title compound was obtained as an off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:11](OC)=[O:12])([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:12][CH2:11][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1(C(=O)OC)CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CCOCC1
Temperature: 25 °C

Procedure:
Under an atmosphere of argon, to a solution of lithium aluminum tri(tert-butoxy)hydride (1.93 g) in tetrahydrofuran (15 mL) was added a solution of dimethyl tetrahydro-2H-pyran-4,4-dicarboxylate (606 mg) in tetrahydrofuran (5 mL) and the mixture was stirred at room temperature for an hour. To the reaction mixture was added an an aqueous saturated sodium sulfate solution till being cloudy. An insoluble matter was filtered and the filtrate was concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→1:2→1:4→ethyl
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3cccc(F)c3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccc(F)c2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 7.5 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.68 g of methyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2,3-difluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetate in 6 cm3 of a water/methanol (30/70 by volume) mixture and 0.08 g of potassium hydroxide. The crude product (0.45 g) is dissolved in 7.5 cm3 of 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 10 cm3 of diethyl ether, brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution, then extracted with 2 times 20 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The product obtained is purified by chromatography on silica [eluent:methylene chloride/methanol (80/20 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.05 g of (2R,4R)-3-{3-{2-[4-tert-Butoxycarbonyl-2-(2,3-difluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetic acid is thus obtained in the form of an amorphous product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:10])=[O:9].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([N:11]2[C:22](=[O:23])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[O:20][CH3:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(NS(=O)(=O)c2ccccc2N)cnc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1OC
Yield: 49 %

Procedure:
The title compound (257 mg, 0.77 mmol) was prepared from 2-amino-N-(5,6-dimethoxypyridin-3-yl)benzenesulfonamide (486 mg, 1.57 mmol), 1,1′-carbonyldiimidazole (1.02 g, 6.29 mmol) and triethylamine (0.44 mL, 3.14 mmol) in DMF (3 mL) using the methods of (IntA14), step 3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:15]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[O:28][CH3:29])=[CH:14][NH:13][N:12]=1)=O>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[C:15]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([C:24]([CH3:25])([CH3:26])[CH3:27])[CH:21]=[CH:20][C:19]=2[O:28][CH3:29])=[CH:14][NH:13][N:12]=1
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccccc1N
Solvent: CC(=O)O
Product: COc1ccc(C(C)(C)C)cc1C(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Temperature: 140 °C
Yield: 61.7 %

Procedure:
4-(5-tert-Butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (2-amino-phenyl)-amide (848 mg, 2.08 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140° C. for 3 hours. The solution was left to cool, the solvent removed in vacuo and the resulting solid dried through azeotrope with methanol and toluene. The crude product was purified by column chromatography [SiO2, EtOAc/petrol (2:1)] to give N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-5-tert-butyl-2-methoxy-benzamide (500 mg, 62% yield) as a pale yellow powder. (LC/MS: Rt 3.44, [M+H]+ 390, acidic method.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH:11]=[CH:10]2
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 130 °C
Yield: 52 %

Procedure:
To a solution of 2-chloro-6-fluoroquinoline (6.8 g, 37.4 mmol) in N,N-dimethylformamide (200 ml) in a round-bottomed flask was added potassium carbonate (10.4 g, 75.2 mmol) and piperazine (19.2 g, 222.9 mmol) at room temperature. After heating the contents to 130° C. for 5 hours, the reaction mixture was concentrated under vacuum to a minimum volume and then quenched with water (300 ml) and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-2.5% methanol in dichloromethane to elute. The product containing fractions were combined and concentrated to afford 6-fluoro-2-(piperazin-1-yl)quinoline as a brown solid (4.5 g, 52%); (ES, m/z): [M+H]+ 232; 1H NMR (300 MHz, CDCl3): δ 7.86 (d, J=9.3 Hz, 1H), 7.62-7.72 (m, 1H), 7.32-7.36 (m, 1H), 7.24-7.29 (m, 1H), 7.01 (d, J=9.3 Hz, 1H), 3.73 (t, J=5.1 Hz, 4H), 3.05 (t, J=5.1 Hz, 4H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:40])[CH2:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[CH3:40][N:30]([CH3:29])[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:38][CH:39]=1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)CCc1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline Rf value: 0.2 (silica gel, methylene chloride/ethanol=5:1) C28H29N3O3
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Yield: 67.2 %

Procedure:
15 g of methyl 2-hydroxyphenylacetate are refluxed with 11.4 g of benzyl chloride and 6.2 g of potassium carbonate in 90 ml of absolute methanol for 24 hours. The mixture is filtered, the filtrate is evaporated down, 400 ml of ether are added to the residue, and the solution is washed with water, dried with MgSO4 and evaporated down. Distillation of the residue at about 200° C. and under 18 mbar gives 15.5 g of pale oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])[C:7]([OH:9])=[O:8].[CH2:21](Br)[C:22]#[CH:23]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])[C:7]([O:9][CH2:23][C:22]#[CH:21])=[O:8]
Reactant: C#CCBr
Reactant: C#CCOc1cc(C(=O)O)cc(Cl)c1OCC#C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(Cl)c(OCC#C)c(OCC#C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Sodium hydride (0.23 g; 60% dispersion in mineral oil) was added to a solution of 3-chloro-4,5-dipropargyloxybenzoic acid (1.50 g) in N,N-dimethylformamide (50 ml) at 0° C., followed by stirring at room temperature for 1 hour. Propargyl bromide (0.80 g) was added thereto, and the resultant mixture was stirred at 90° C. for 5 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with an aqueous potassium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography using toluene as an eluent to give propargyl 3-chloro-4,5-dipropargyloxybenzoate (1.03 g). m.p. 98°-99° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH2:32][CH2:33][NH2:34])[CH3:30].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:30]
Reactant: CCOCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 25.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (27 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (90 mg), 2-ethoxyethylamine (20 mg), DPPA (61 mg), and DIEA (28 mg). LC/MS: m/z 481.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 7.35 (s, 1H), 3.62 (bs, 3H), 3.54-3.37 (m, 6H), 1.11 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.C1(O)C=CC=CC=1.[CH3:23][O:24][C:25](=[O:29])[CH:26](Br)[CH3:27]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[C:5]([O:12][CH:26]([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: COC(=O)C(C)Br
Reactant: CCC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Solvent: Oc1ccccc1
Product: CCC(=O)c1cc(Br)cc([N+](=O)[O-])c1OC(C)C(=O)OC

Procedure:
Using 1-(5-bromo-2-hydroxy-3-nitrophenyl)propan-1-one as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted 2-nitrophenols gives the title compound as a gold oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.10 (m, 3H) 1.44 (d, J=6.82 Hz, 3H) 3.00-3.12 (m, 2H) 3.59 (s, 3H) 4.56 (q, J=6.82 Hz, 1H) 8.07 (d, J=2.53 Hz, 1H) 8.34 (d, J=2.53 Hz, 1H). ESI-MS: m/z 361.1 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[C@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Reactant: CCOC(=O)[C@H](N)CC(C)CC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A suspension of (R)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.57 g, 7.50 mmol) in acetonitrile (9 mL) was treated with N,N-diisopropylethylamine (1.62 mL) and stirred at 60° C. for 15 min. At this time the solution was treated with N,N-diisopropylethylamine (1.62 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 2.39 g, 7.49 mmol) in acetonitrile (4 mL) via a dropping funnel and refluxed for 20 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (1.26 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.Cl[CH2:14][C:15](=[O:17])[CH3:16].[I-].[K+]>CC(C)=O>[CH2:14]([O:11][C:4]1[C:3]([F:12])=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:15]([CH3:16])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(F)c1O
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1c([N+](=O)[O-])ccc(Cl)c1F
Yield: 54.5 %

Procedure:
A mixture of 3 g (15.7 mmols) of 3-chloro-2-fluoro-6-nitrophenol, 3 ml of chloroacetone and 300 mg of potassium iodide in 50 ml of acetone was refluxed for 6 hours while vigorously stirring. After cooling, any insoluble substance was removed by filtration, and the filtrate was concentrated and purified by silica gel (20 g) column chromatography using chloroform as an eluant to provide 2.5 g (54.5% yield) of 2-acetonyloxy-4-chloro-3-fluoronitrobenzene as an oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=2)O)=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:28][O:27][CH2:26][O:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:15][C:14]2[C:9](=[O:8])[NH:10][C:11]([CH3:30])=[CH:12][C:13]=2[CH3:29])=[CH:18][CH:19]=1
Reactant: COCOCCc1ccc(C(O)c2c(C)cc(C)nc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COCOCCc1ccc(Cc2c(C)cc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91 %

Procedure:
To a solution of 4-(2-methoxymethyloxyethyl) bromobenzene (0.60 g) in tetrahydrofuran (6 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 2.0 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. Then, a solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.49 g) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours at 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dimethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-(2-methoxymethyloxyethyl)phenyl methanol (0.74 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-(2-methoxymethyloxyethyl)phenyl methanol (0.11 g) in ethanol (5.3 mL) was added 10% palladium carbon powder (0.065 g), and the mixture was stirred for 11 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-[4-(2-methoxymethyloxy-ethyl)benzyl]-4,6-dimethyl-1H-pyridin-2-one (0.074 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]([O:25]C)=[O:24])[O:20][N:19]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[O:20][N:19]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cc(C(=O)O)on2)CC1

Procedure:
A solution of 3-6 (580 mg, 1.6 mmol), 1N NaOH (3.1 mL, 3.1 mmol), and CH3OH (8 mL) was stirred at ambient temperature for 1.0 h. The reaction was then concentrated and the resulting gum acidified with 1M NaHSO4. The aqueous layer was saturated with NaCl and then extracted with ether. The extracts were combined, dried (MgSO4) and concentrated to give 3-7 as a viscous gum. Rf 0.20 (silica, 9/0.5/0.5 CH2Cl2/CH3OH/HOAc).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:15])[C:6]=2[N:16]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:31][CH2:32][CH2:33][C:34](ON2C(=O)CCC2=O)=[O:35])C=CC=CC=1>ClCCl>[NH2:15][C:7]1[C:6]2[N:16]=[C:3]([CH2:2][NH:1][C:34](=[O:35])[CH2:33][CH2:32][SH:31])[N:4]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: NCc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CNC(=O)CCS)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(aminomethyl)-1-benzyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.3 mmol) and succinimido 3-(triphenylmethylthio)propanoate (2.2 g, 4.9 mmol) in dichloromethane (33 mL) was stirred overnight at room temperature. The reaction mixture was warmed and the solvent was removed under reduced pressure. Dichloromethane (30 mL) and trifluoroacetic acid (3 mL) were added and the mixture was stirred over the weekend. Additional trifluoroacetic acid was added. After 4 hours, the mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) followed by crystallization from ethyl acetate/acetonitrile. HRMS (ESI) calcd for C21H21N5OS+H 392.1545, found 392.1534.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)C.O.O[Li].O>C1COCC1>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (120 g, 0.29 mol) in THF (1.2 L) was added water (240 mL), LiOH.H2O (16 g, 0.32 mol) and stirred at room temperature for 16 h. The solution was filtered and concentrated in vacuo to remove THF. The resulting thick liquid was acidified to pH 2 by adding 2N aqueous HCl solution and the white suspension was mechanically stirred for 1 h at room temperature. The wet white product was recovered after filtration and dissolved in EtOAc (500 mL). The organic layer was separated from water, dried (MgSO4) and concentrated in vacuo to obtain (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (105 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)co3)cc2OC)nc1Cl
Yield: 62.4 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxyphenyl)-1,3-oxazole-4-carboxylate obtained in Example (102e) (0.26 g, 0.64 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 156 mg of the title compound as a colorless solid (62%).