Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][NH:6]2.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29]2)[CH2:25][CH2:24][CH:23]([CH3:33])[N:22]3[CH:21]=1)=O>>[CH3:33][CH:23]1[CH2:24][CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:4]4[C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[F:1])[NH:6][CH:5]=4)=[CH:21][N:22]13)[CH:29]=[C:28]([F:32])[CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)CCC2C
Product: CC1CCc2cc(F)cc3c(C4=C(c5c[nH]c6cccc(F)c56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (4-fluoroindol-3-yl)acetamide and (4-methyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Cl:10])=[CH:7][C:8]=1[Cl:9])#[N:2].[OH-:17].[Na+]>O>[C:1]([C:3]1[C:4]([Cl:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Cl:10])=[CH:7][C:8]=1[Cl:9])(=[O:17])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1c(Cl)cc(Cl)c(CCC(=O)O)c1Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Cl)cc(Cl)c(CCC(=O)O)c1Cl
Temperature: 60 °C
Yield: 90 %

Procedure:
16 g of 3-(3-cyano-2,4,6-trichlorophenyl)propionic acid is dissolved in a solution of 5 g of solution of caustic soda in 80 ml of water. The mixture is maintained at 60° C. for 3 hours, filtered over active carbon, and the filtrate is brought to pH 1 under cooling by the addition of concentrated hydrochloric acid under agitation. After several hours of stirring, the precipitate is vacuum-filtered, washed with water, and dried at 50° C. Recrystallization from five times the amount of toluene yields 15.5 g (90% of theory) of 3-(3-carbamoyl-2,4,6-trichlorphenyl)propionic acid as a white powder, mp 196°-198° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C([Sn](CCCC)(CCCC)[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:35](/[C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
Under inert atmosphere (Ar) a mixture of palladium(II)-acetate (0.45 g , 2 mmol) and triphenylphosphine (0.95 g, 3.6 mmol) in DMF (50 ml) was stirred for 0.5 hr at rt. Then 2-chloro-5-nitropyridine (3.2 g, 20 mmol) and tributyl-styryl-stannane (15.7 g, 40 mmol) was added and the mixture was stirred at 130° C. for 15 hr. The solvent was evaporated and the residue partitioned between AcOEt and 1N HCl. The aqueous phase was neutralized with 6N NaOH and extracted with AcOEt. The organic phase was dried with Na2SO4, concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH=97/3) to (give the title compound (0.90 g, 23%) as a yellow solid. Mp. 159-160° C. (AcOEt), MS: 196 (M+).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=[O:2].[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][OH:47])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.CN.O>C1COCC1>[CH3:4][NH:3][C:1](=[O:2])[O:47][CH2:46][CH2:45][C:41]1[N:40]([CH2:39][CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:26]3[N:27]=[C:23](/[CH:22]=[CH:21]/[C:18]4[CH:19]=[CH:20][C:15]([C:14]([F:48])([F:13])[F:49])=[CH:16][CH:17]=4)[O:24][CH:25]=3)=[CH:31][CH:32]=2)[CH:44]=[CH:43][N:42]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
1,1′-Carbonyldiimidazole (143 mg) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (300 mg) in THF (3 ml) at 0° C., and the mixture was stirred at the same temperature for 3 hr. A solution (2.0 M; 1.47 ml) of methylamine in THF was added to the reaction mixture at 0° C., and the mixture was stirred at the same temperature for 3 hr and at room temperature for 30 min. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and recrystallized from diethyl ether-acetone-hexane to give the titled compound (310 mg) as a colorless crystal powder.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[OH:31][C@H:32]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[CH2:33][NH:34][CH3:35]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]([CH2:33][C@H:32]([OH:31])[C:36]5[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=5)[CH3:35])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC[C@H](O)c1ccc(O)cc1
Product: CN(C[C@H](O)c1ccc(O)cc1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
(R)-5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-{[2-hydroxy-2-(4-hydroxy-phenyl)-ethyl]-methyl-amino}-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and (R)-4-(1-Hydroxy-2-methylamino-ethyl)-phenol following General Procedure B.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2].N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39].C(=O)(O)[O-].[Na+]>ClCCl>[C:38]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:20]2[CH:19]=[C:18]([N:15]3[CH2:14][C@H:13]4[N:9]([CH2:10][CH2:11][CH2:12]4)[C:8]4[N:31]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[CH:6][C:7]=4[C:16]3=[O:17])[CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCNCC3)c1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCN(C(C)=O)CC3)c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Compound 147 (50.0 mg, 0.118 mmol) obtained in Example 147 was dissolved in dichloromethane (3 mL), cooled to 0° C., and stirred at 0° C. for 30 minutes after adding pyridine (0.0110 mL, 0.142 mmol) and acetyl chloride (0.0100 mL, 0.142 mmol). A saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by preparative TLC to give the title compound (Compound 150) (54.2 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3F)CC12
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2-fluorophenylacetic acid (1.08 g) in dry dichloromethane (30 cc) cooled to +5° C. The mixture is stirred for 20 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (1.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 72 hours and then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (50 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-fluorophenyl)acetyl]-4-perhydroisoindolone (1.53 g) is obtained in the form of white crystals melting at 186° C.
Reaction SMILES: [OH-].[Na+].O.C([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[C:15](/[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)\[CH3:16])(=O)C.Cl>C(O)C>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1/[C:15](/[CH3:16])=[CH:14]/[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[OH:7]
Reactant: CC(=O)Oc1ccccc1/C=C(\C)c1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccccc1O)c1ccc2ccccc2n1
Temperature: 100 °C
Yield: 70.8 %

Procedure:
Aqueous sodium hydroxide (5%, 8.8 g), followed by water (88 mL) were added to a stirred solution of (E)-2-(2-(quinolin-2-yl)prop-1-enyl)phenyl acetate (2.2 g, 7.3 mmol, 1.0 eq.) in ethanol (110 mL). The resulting mixture was heated at 100° C. for 10 min. The mixture was allowed to cool down a little and the pH was adjusted to 7.0 by careful addition of aqueous hydrochloric acid (10%). The mixture was allowed to cool down to r.t. and was then placed in a freezer (−18° C.) over night. The precipitation formed was isolated by filtration yielding the product (1.35 g, 71%) as a tan solid; 1H NMR (400 MHz, DMSO-d6) δ 2.38 (s, 3H, CH3), 6.87 (t, J=7.5 Hz, 1H, Ar), 6.92 (d, J=7.5 Hz, 1H, Ar), 7.16 (t, J=7.5 Hz, 1H, Ar), 7.36 (d, J=7.0 Hz, 1H, Ar), 7.56 (t, J=7.0 Hz, 1H, Ar), 7.61 (s, 1H, C═CH), 7.74 (t, J=7.0 Hz, 1H, Ar), 7.95 (d, J=8.5 Hz, 2H, Ar), 8.00 (d, J=8.5 Hz, 1H, Ar), 8.34 (d, J=8.5 Hz, 1H, Ar), 9.66 (br s, 1H, OH).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]([Cl:18])([Cl:17])[CH2:12][C:13](Cl)([CH3:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCl>[Cl:10][C:11]([Cl:18])([Cl:17])[CH2:12][C:13]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH2:8][CH3:9])=[CH:2][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(Cl)CC(Cl)(Cl)Cl
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(C(C)(C)CC(Cl)(Cl)Cl)cc1
Reaction time: 4 h
Yield: 20.3 %

Procedure:
A mixture of 61 g (0.5 mol) of phenetole and 105 g (0.5 mol) of 1,1,1,3-tetrachloro-3-methyl-butane is added slowly with stirring at 0° C. to a suspension of 66.5 g (0.5 mol) of AlCl3 in 100 ml of dichloromethane. After stirring for 4 hours, 1,000 ml of water are added to the reaction mixture with ice-cooling. The mixture is extracted several times with dichloromethane and, after drying, the combined extracts are worked up by distillation. 30 g (=20% of theory) of 1,1,1-trichloro-3-p-ethoxyphenyl-3methyl-butane (b.p.: 145°-150° C./0.1 mbar) are obtained in addition to unreacted starting material.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:21])=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c(N)c(N)n(C)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To the stirring solution of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (1.13 g, 4.0 mmol) in glacial acetic acid (22.5 ml) and water (7.5 ml) at 65° C. was added sodium nitrite (345 mg, 5.0 mmol) in portions. The pink mixture was stirred at 65° C. for 1 hour and then cooled to 0-5° C. After filtration, the violet solid was washed with water (2×10 ml) and then suspended in water (20 ml) and heated at 65° C. while sodium hydrosulfite (2.78 g, 16.0 mmol) was added in portions. The pale yellow solution was stirred at 65° C. for an additional 1 hour, cooled to room temperature and extracted with chloroform (3×25 ml). The combined extracts were dried over magnesium sulfate and filtered to provide crude (R)-3-(5-acetoxyhexyl)-5,6-diamino-1-methyluracil in chloroform. To this clear solution was added 1,1′-carbonyldiimidazole (650 mg, 4.0 mmol). After stirring overnight at room temperature, the mixture was washed with water (2×25 ml), with 1 N aqueous hydrochloric acid (2×25 ml), with water (2×25 ml), with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-3-methyluric acid (280 mg) as a beige solid which was dissolved in 20 ml of ethanol. To this solution was added hydrogen chloride in ethyl ether (1 M, 2.0 ml, 2.0 mmol). After refluxing overnight, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyluric acid (210 mg, 19% yield) as a beige solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][CH:26](Br)[CH3:27]>CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([O:17][CH2:27][CH2:26][O:25][CH3:24])=[CH:7][C:8]=1[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(C)Br
Reactant: COc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(C)(C)C)c(OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2,5-di-tert-butyl-4-methoxyphenol (9 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml). Cesium carbonate (13 mmol) and 1-bromoethyl methyl ether (9 mmol) were added to the solution. The reaction mixture was then stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between dichloromethane (DCM) and aqueous NaHCO3 (0.1 M). The organic portion was separated and dried over Na2SO4 and then the solvent was removed under vacuum. The crude product was chromatographed (silica, hexanes/DCM from 5:1 to 1:1) to afford pure 1-methoxy-4-(2-methoxyethoxy)-2,5-di-tert-butyl-benzene in an 85% yield. 1H NMR (300 MHz, CDCl3): δ/ppm 6.84 (s, 1H), 6.83 (s, 1H), 4.11 (t, J=4.5 Hz, 2H), 3.78 (m, 5H), 3.45 (s, 3H), 1.38 (s, 9H), and 1.35 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:18]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCCC[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 25 °C
Yield: 131.2 %

Procedure:
(L)-Arginine (32.8 g., 0.19 moles) was dissolved in 188 mL of 2 N sodium hydroxide. Cyclopentanoyl chloride (22.9 mL, 0.19 moles) was added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 2 hours. The mixture was then acidified to pH 1.5 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide to pH 7.5 and dried by lyophilization to furnish 67.4 g of N-cyclopentanoyl-(L)-arginine. The product was a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[C:32]([Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:33]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Reactant: CN1CCN(Cc2ccc(N)cc2[Si](C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c([Si](C)(C)C)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid (0.22 mmol) in dry pyridine (5 mL) is added 4-(4-methylpiperazin-1-ylmethyl)-3-trimethylsilylaniline (60 mg, 0.22 mmol) and EDCl (62 mg, 0.325 mmol). The resulting mixture is stirred at r.t. overnight. The solvent is removed on rotavap and the residue is partitioned between DCM and aq. NaHCO3. The combined organic layers from extraction are dried (Na2SO4), filtered, concentrated, and the resulting residue is purified by silica gel flash chromatography [eluted with 5% MeOH (pre-saturated with NH3) in DCM] to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@H](C)Oc1cc(C)ccc1C=O
Yield: 35 %

Procedure:
A mixture (S)-(4-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (260 mg, 1.260 mmol), Dess-Martin periodinane (642 mg, 1.513 mmol) in DCM (10 mL) was stirred at rt for 1 h. It was then diluted with EtOAc, washed with sat. NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-4-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (90 mg, 35%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 6.87-6.78 (m, 2H), 5.88 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.21-5.10 (m, 2H), 4.59 (sxt, J=6.1 Hz, 1H), 2.63-2.51 (m, 1H), 2.51-2.42 (m, 1H), 2.40 (s, 3H), 1.40 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.6 %

Procedure:
A mixture of 100.0 g of methyl 2-methyl-3-nitrobenzoate, 100.0 g of N-bromosuccinimide, 3.0 g of dibenzoyl peroxide and 1000 ml of carbon tetrachloride was refluxed for 24 hours. The reaction mixture was cooled, 3.0 g of dibenzoyl peroxide added, and refluxing continued an additional 24 hours. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude reaction product was dissolved in ether and the organic solution washed sequentially with saturated sodium sulfite (500 ml), water (2×500 ml), 2.5% sodium hydroxide (500 ml), water (2×500 ml) and saturated brine (500 ml). The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated in vacuo giving a pale yellow oily solid. Recrystallization from 350 ml of 1-chlorobutane/cyclohexane (2:1) gave 73.9 g of methyl 2-bromomethyl-3-nitrobenzoate, m.p. 67°-70°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: NCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1ccc(CNc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.5 g, 9.6 mmol), 2-chloro-5-aminomethylpyridine (2.7 g, 19 mmol), acetonitrile (10 mL), and N,N-diisopropylethylamine (3.4 mL, 19 mmol) was subjected to microwave irradiation at 180° C. for 2 h. After standing at rt overnight, the precipitated solids were collected by filtration and washed with cold acetonitrile (5 mL×2), and dried to yield a yellow powder (2.8 g, 77%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: COCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
The resulting 1-acetamido-4-methoxymethoxy-2-nitro-benzene is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to afford 1-amino-4methoxymethoxy-2-nitrobenzene. This latter compound is treated in accordance with the first paragraph of Example VI to afford 1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethoxy-2-nitrobenzene. This latter compound is reduced in accordance with the iron reduction technique as set forth in the third paragraph of Example XIX to afford 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethoxybenzene. This latter compound is treated in accordance with the first paragraph of Example XVI to afford 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethoxybenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCC1CC1
Product: Brc1cccc(OCC2CC2)n1

Procedure:
Prepared according to the procedure described in Example 139, Step 1, using 2,6-dibromo-pyridine and cyclopropyl-methanol.