Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].C(O[C:17]1(OCC)[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH:13]=[C:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])([O-:3])=[O:2]
Reactant: CCOC1(OCC)CCCN1C
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: c1ccccc1
Product: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 34.6 %

Procedure:
Stir 7.0 g of 2,4-dinitrotoluene and 9.65 g of 2,2-diethoxy-1-methylpyrrolidine for 5 hours at 40° in 50 ml of benzene. Allow the resulting reaction mixture to cool to ambient temperature. Filter off the precipitate and wash it with a little benzene and hexane to obtain 3.5 g of the title compound (m.p. 188° to 190°) in the form of black-violet crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC=C)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:19]1(OC2C=CC=CC=2)[CH:24]=CC=C[CH:20]=1>>[CH3:18][C:2]([CH3:1])([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([CH2:24][CH:19]=[CH2:20])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CCOc1ccc(CC(C)(C)C(=O)OC)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(CC(C)(C)C(=O)OC)ccc1O
Temperature: 25 °C

Procedure:
A solution of methyl 2,2-dimethyl-3-(4-allyloxyphenyl)propionate (1.56 g) in diphenyl ether was heated at reflux for 15 minutes. The reaction mixture was cooled to ambient temperature and the reaction mixture was filtered through a silica gel pad. Elution with a 4:1 (v/v) mixture of hexane and ethyl acetate gave methyl 2,2-dimethyl-3-(3-allyl-4-hydroxyphenyl)propionate (1.53 g) as a yellow oil; microanalysis, found: C, 72.2; H, 7.80%; C15H20O3 requires: C, 72.6; H, 8.12%; NMR(CDCl3): 1.15(6H,s), 2.73(2H,s), 3.35(2H,m), 3.63(3H,s), 4.87(1H,s), 5.10(2H,m), 5.95(1H,m), 6.67(1H,m) and 6.83(2H,m); m/z 249 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-]CC.[Na+]>C(O)C>[OH:28][C:21]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]2[CH:10]=[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]3=[N:3][C:2]=2[N:1]=1
Reactant: Cc1ccc(C(=O)c2cc3ccccc3nc2N)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2nc3ccccc3cc2c1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a solution of (2-aminoquinolin-3-yl)(p-tolyl)methanone (0.525 g; 2 mmol) and diethyl malonate (1.22 mL; 8 mmol) in ethanol (10 mL) under nitrogen atmosphere was added a solution of sodium ethoxide 21% (w/w) in ethanol (2.24 mL; 6 mmol). The mixture was stirred in a sealed tube and heated to 100° C. for 48 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash-chromatography on silica gel column using a gradient of ethyl acetate (1-60%) in dichloromethane as eluent to furnish 0.217 g (30%) of ethyl 2-hydroxy-4-p-tolylbenzo[b][1,8]naphthyridine-3-carboxylate as a bright yellow solid. ESI/APCI(+): 359 (M+H). NMR 1H (DMSO-d6) (ppm): δ 12.54 (s, 1H, NH); 8.21 (s, 1H, Harom.); 8.03 (d, 1H, Harom.); 7.93-7.80 (m, 2H, 2×Harom.); 7.51-7.46 (m, 1H, Harom.); 7.41-7.32 (m, 4H, 4×Harom.); 4.02 (q, 2H, OCH2CH3); 2.43 (s, 3H, CH3); 0.94 (t, 3H, OCH2CH3).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6]OCC1.[CH3:8][NH:9][C:10](=[O:30])[C@@H:11]([NH:22][C:23]([O:25]C(C)(C)C)=O)[CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>>[CH3:8][NH:9][C:10](=[O:30])[C@@H:11]([NH:22][C:23](=[O:25])[C@H:11]([CH3:10])[CH2:12][S:13][C:7](=[O:2])[C:6]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)[CH2:12][S:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: CNC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: CNC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)[C@H](C)CSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 N hydrogen chloride/dioxane (1.5 ml) is added to (2R)-2-(tert-butoxycarbonylamino)-3-(4-methylbenzylthio)propionic acid methylamide (reference compound No. 4-1, 200 mg), and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure, and the obtained residue is dissolved in methylene chloride (5 ml). To the solution are added N-methylmorpholine (0.119 ml), 1-hydroxybenzotriazole (109 mg), (2S)-3-(benzoylthio)-2-methylpropionic acid (182 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and N-methylmorpholine (0.077 ml) successively under ice-cooling, and the mixture is stirred overnight at room temperature. A 5% aqueous sodium hydrogencarbonate solution is added to the system of reaction, and the whole is extracted with ethyl acetate. The organic layer is washed with a 5% aqueous sodium hydrogencarbonate solution and a saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5](O)=O)O.S(=O)(=O)(O)O.[C:19]1(O)C=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1>>[OH:25][C:21]1[CH:22]=[C:23]2[C:5]([C:3]([CH2:2][C:1]([OH:13])=[O:12])=[CH:8][C:9](=[O:10])[O:11]2)=[CH:19][CH:20]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(=O)oc2cc(O)ccc12
Temperature: 70 °C

Procedure:
84 g of citric acid and 112 ml of concentrated sulfuric acid were stirred for one hour at ambient temperature and then heated progressively to 70° C. and maintained there for 35 minutes. The mixture was cooled to 0° C. and 34.56 g of 1,3-benzene diol and 44.8 ml of concentrated sulfuric acid were added. The mixture was maintained for 16 hours at 0° C. and then poured over ice. The crystallized product was separated off and dried under reduced pressure to obtain after crystallization from water, 22.77 g of the expected product melting at 210° C.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].[OH-].[Na+].Cl>CO>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 47.5 °C
Yield: 61.4 %

Procedure:
To a solution of methyl 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoate (155 mg, 0.26 mmol) in MeOH (3 mL) was added 2M NaOH (5 mL). The mixture was heated (45-50° C., 16 h), and then cooled to RT. 2M HCl was added dropwise to adjust pH=1. The mixture was then extracted by EA (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica chromatography (MeOH/DCM, 0-10%) to afford of 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid as light yellow oil (92 mg, 61%). Mass calculated for C35H48N2O5=576.77. found: [M+H]+=577.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:10])[N:7]([CH3:9])[CH:8]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Br)=[N:27][C:26]([Br:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>>[Br:30][C:26]1[N:27]=[C:28]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6](=[O:10])[N:7]([CH3:9])[CH:8]=2)[C:23]([NH:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:24][CH:25]=1
Reactant: Cn1cc(CO)ccc1=O
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Product: Cn1cc(COc2nc(Br)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)ccc1=O

Procedure:
Prepared by the method of Example 31 using 5-hydroxymethyl-1-methyl-1H-pyridin-2-one (0.1 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16 g). Yield 0.035 g.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1I.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])#[CH:20]>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:20]#[C:19][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(C#Cc2ccccc2F)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.2 ml, 1.43 mmol) was added to a suspension of 1-Chloro-2-iodo-4-nitro-benzene 69 (Step 1) (100 mg, 0.354 mmol), 1-ethynyl-2-fluorobenzene (100 mg, 0.832 mmol), copper iodide (100 mg, 0.525 mmol), Pd(PPh3)2Cl2 (100 mg, 0.142 mmol) in dimethylformamide (2 ml) at room temperature, then stirred at 70° C. for 2 hours. Reaction was cooled to room temperature and extracted with ether (50 ml), washed with water (20 ml), dried (MgSO4), filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 20% v/v MeCl2/hexanes yielding title product 70 as pale yellow solid (80 mg, 82%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@@H](CCl)NC(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To the compound (500 mg) obtained in Step 3 were added 3-fluorophenol (84 μl), potassium carbonate (250 mg) and DMF (2 ml), and the mixture was stirred overnight at 95° C. The reaction mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound as a crude product.
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21].C(=O)(O)[O-].[Na+].C(OC)(C)(C)C>C(OCC)(=O)C.O>[CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:21][C:20]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:18]([O:17][CH3:16])[CH:19]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: COc1cc(NS(=O)(=O)c2ccc3c(c2)CCN3C=O)cc(OC)c1OC
Reaction time: 1 h
Yield: 95677.1 %

Procedure:
A room temperature mixture of Example 1 (153.5 g, 0.625 mol), 3,4,5-trimethoxyaniline (109 g, 0.595 mmol), and sodium bicarbonate (75 g, 0.895 mol) in ethyl acetate (1.1 L) and water (1.05 L) was stirred for 20 hours, treated with methyl tert-butyl ether (1 L), stirred for 1 hour, filtered, washed with water (2×500 mL) and methyl tert-butyl ether (2×300 mL), and dried under vacuum at 50° C. for 20 hours to provide 223.4 g of the desired product (95.7%) as a mixture of rotamers.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[O:8]1)=[O:6])[CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Oc1ccccc1
Reactant: CC(C)NC(=O)C1OC1c1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccccc1)c1cccc(Cl)c1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(3-chlorophenyl)-2-oxiranecarboxamide (7.2 g.), phenol (3.0 g.), sodium hydride (50% oil dispersion, 1.6 g.), 18-crown-6 (0.9 g.) and acetonitrile (250 ml.) as described in Example 12. The crude product was recrystallized from ether. The compound melted at 160°-162°, and weighed 1.7 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([CH2:34][CH2:35][C:36](=O)[CH2:37][CH3:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]([CH2:37][CH3:38])[CH2:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CCC(=O)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(CC)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-pentan-3-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[N:11]=1
Reactant: COC(=O)CCCCCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCCCCc1ccc2c(n1)NCCC2

Procedure:
To a stirred suspension of 10% palladium on carbon (600 mg) in ethanol (25 mL) was added a solution of 7-[1,8]naphthyridin-2-yl-heptanoic acid methyl ester 29-3 (3.6 g) in ethanol (75 mL) and the mixture was subjected to an atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure to give 29-4 as an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22](O)=[O:23])=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.O[NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:39])(=[O:38])[NH2:37])[CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22]3[O:23][N:40]=[C:29]([C:30]4[CH:31]=[C:32]([S:36]([NH2:37])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=4)[N:28]=3)=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnc4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)cn34)n2)c1

Procedure:
The title compound was prepared from 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.32) (187 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as an off-white solid (117 mg, 42%). MS (ISN) 552.0 [(M−H)−]; mp 297° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]=[O:20])=[CH:11]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1c(Cc2ccc(F)cc2)[nH]c2ccccc12
Yield: 91.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.74 g of 4-fluorobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.18 g of (4-fluorobenzyl) indole-3-carbaldehyde as colorless crystals. The yield thereof was found to be 91%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH2:14][CH:13](Cl)[C:12]2=[O:18])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:18])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(N2C(=O)CC(Cl)C2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
N-(4-Allyloxyphenyl)chlorosuccinimide (265.5 g, 1 mole) was dissolved in dichloromethane (1300 ml) and cooled to 10° C. Triethylamine (101 g, 1 mole) was added in 10 min and the reaction was stirred for 10 min. The reaction mixture was washed with 1M hydrochloric acid and dried over sodium sulfate. The organic solvent was removed under reduced pressure and the solid was recrystallized from methanol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([N:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([N:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1cc(NS(=O)(=O)N(C)C)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(NS(=O)(=O)N(C)C)cc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 2.8 %

Procedure:
N′-[3-Methoxy-4-(4-{[(1S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-N,N-dimethylsulfamide (73 mg, 0.06 mmol, 57% purity) was treated with boron tribromide (1M in dichloromethane, 2.0 ml, 2.0 mmol) with dichloromethane (1.0 ml) as a solvent according to the method described in Example 23. and then with a solution of ammonia (7N in methanol, 5.0 ml, 35.0 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water-acetonitrile/methanol 1:1) to obtain 1 mg (2% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:28][NH:29][CH3:30]>C1COCC1>[Br:1][C:2]1[C:3](=[O:27])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:29]([CH3:30])[CH3:28])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1ccc(CCl)cc1
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)cc1
Reaction time: 15 h
Yield: 46 %

Procedure:
To a sealed tube containing 3-bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one (0.49 g, 1.1 mmol) was added a solution of dimethylamine (5.5 mL of a 2.0 M solution in THF, 11 mmol), and the reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 92:7.2:0.8 methylene chloride/methanol/ammonia) provided 3-bromo-4-(2,4-difluorobenzyloxy)-1-(4-dimethylaminomethylbenzyl)-1H-pyridin-2-one as a light yellow solid (0.23 g, 46%): mp 111-113° C.; 1H NMR (500 MHz, CDCl3) δ 7.50-7.49 (m, 1H), 7.26-7.22 (m, 5H), 6.90-6.88 (m, 1H), 6.82-6.78 (m, 1H), 6.04 (d, J=6 Hz, 1H), 5.16 (s, 2H), 5.11 (s, 2H), 3.37 (s, 2H), 2.19 (s, 6H). ESHRMS m/z 463.0782 (M+H C22H22BrF2N2O2 requires 463.0827)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:31][C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C@@H:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:45][CH:44]=3)=[CH:17][CH:18]=2)[C:24]([OH:26])=[O:25])=[O:43])=[CH:34][CH:35]=1)([CH3:40])([CH3:41])[CH3:42]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)O)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A crude solution of (S)-4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl 4-(heptyloxy)benzoate in DCM (1 mL) was treated with TFA (0.15 mL) and stirred overnight at 30° C. The solvent was evaporated and the residue was purified by preparative HPLC to give 12.3 mg (33%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-((4-(heptyloxy)benzoyl)oxy)phenyl)propanoic acid 57. LCMS-ESI (m/z) calculated for C34H41NO6: 559. Found 560 [M+H]+, tR=12.14 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 8.65 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 4.63 (ddd, J=10.8, 8.2, 4.4 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.22 (dd, J=13.9, 4.3 Hz, 1H), 3.10 (dd, J=13.8, 10.8 Hz, 1H), 1.81-1.66 (m, 2H), 1.50-1.20 (m, 8H), 1.29 (s, 9H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:15])[CH:11]=[C:12]([CH3:14])[CH3:13]>O=[Mn]=O.CCCCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CC(O)C1=C(C)CCCC1(C)C
Agent: O=[Mn]=O
Solvent: CCCCC
Product: CC(C)=CC(=O)C1=C(C)CCCC1(C)C
Yield: 63 %

Procedure:
2,6,6-Trimethyl-1-[1-hydroxy-3-methyl-2-butenyl]-1-cyclohexene, prepared according to Example 6, (1.0 g.) with activated MnO2 (10 g.) in 30 ml. of pentane was mixed at room temperature during 63 h. After filtration and distillation 630 mg. (63 %) of the desired ketone, B.p. 67° /0.001 Torr, were obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2[C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1ccco1
Product: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccco2)C1=O

Procedure:
5-{4-(Aminosulfonyl)phenyl}-2-ethyl-4-iodo-2-methyl-3(2H)-furanone was coupled with 2-furanboronic acid according to a procedure similar to the procedure in Example 44. mp: 154-155° C. NMR: δ0.92 (t, J=7.5 Hz, 3H), 1.52 (s, 3H), 1.95 (m, 2H), 5.03 (br s, 2H), 6.51 (dd, J=3.0, 1.8 Hz, 1H), 6.87 (d, J=3.0 Hz, 2H), 7.37 (d, J=1.5Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H). IR (cm−1): 3347, 3257, 1692, 1545, 1341, 1164.