Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:6]([N+:16]([O-])=O)=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)[C:23]([CH3:35])=[CH:22][N:21]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:6]([NH2:16])=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)[C:23]([CH3:35])=[CH:22][N:21]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(C)c(-c2cnn3ccccc23)n1
Yield: 57.6 %

Procedure:
A mixture of N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-5-methyl-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 2, 279 mg, 0.59 mmol), iron (198 mg, 3.55 mmol) and NH4Cl (22.16 mg, 0.41 mmol) in ethanol (10.5 mL) and water (3.50 mL) was heated at reflux for 0.75 h. Further NH4Cl (22.16 mg, 0.41 mmol) and iron (198 mg, 3.55 mmol) were then added and the mixture was heated at reflux for a further 1.5 h. The mixture was then cooled, filtered, and the filtrate was concentrated in vacuo. Purification by FCC, eluting with 2-10% 7N methanolic ammonia in CH2Cl2 gave the title compound (150 mg, 57%) as a beige crystalline solid after trituration with THF and washing the resulting solid with diethyl ether; 1H NMR: 2.30 (3H, s), 2.40 (5H, m), 2.59 (2H, t), 3.01 (2H, d), 3.73 (3H, s), 4.27 (2H, s), 5.71 (1H, s), 6.63 (1H, s), 7.10 (1H, m), 7.35-7.49 (2H, m), 7.83 (1H, s), 8.27 (1H, s), 8.50-8.63 (2H, m), 8.81 (1H, d); m/z: ES+ MH+ 442.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9].[N+]([O-])(O)=O.[OH-].[Na+]>O>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])=[C:4]([CH3:29])[N:3]=1
Reactant: CC1=C(C(=O)OCCO)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCCO
Reaction time: 1 h

Procedure:
20 g (49.5 mmol) of 2-hydroxyethyl isopropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate were introduced into a mixture of 83 ml of 96% strength nitric acid in 660 ml of water and heated to boiling for 1 hour. The mixture was then cooled down to 5° to 10° C. and made weakly alkaline with dilute sodium hydroxide solution. The oil which had separated out was extracted with methylene chloride, the extracts were dried over sodium sulphate and evaporated in vacuo. The oily residue was induced to crystallize by trituration with ether/petroleum ether, filtered off with suction and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[N:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][N:12]3[CH:13]=[N:14][C:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])=[N:11]3)[CH2:28][CH2:27]2)[CH2:24][CH2:25]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(O)Cn1cnc(NC(=O)c2ccc(Cl)s2)n1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Cn3cnc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
Using general method A, using THF instead of DMF as solvent, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-acetic acid (example 61.3) was reacted with 1-(N-methyl-4-piperidyl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-[1,2,4]triazol-3-yl)-amide. Off-white solid. MS 452.3 ([M+H]+)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH2:14][C:15]([CH3:17])([OH:18])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)CCOc1ccccc1I
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of 2-iodophenol (6 g), 3-hydroxy-3-methylbutyl tosylate (7.4 g) and Cs2CO3 (13.3 g) in DMF (120 mL) was stirred at 0° C. for 2 h and at room temperature for 10 h. The mixture was diluted with EtOAc and washed with 1N HCl, saturated NaHCO3 aq., H2O, and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hexane/EtOAc=7/3) to obtain compound aa28-1 (8.02 g) as pale yellow oil.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>C(OCC)C>[C:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)OB(OC(C)C)C(C)(C)C
Temperature: -78 °C

Procedure:
The reaction was conducted as described in Example 1 with tert-butyllithium (30.9 mL, 51 mmol) which was added to triisopropoxyborane (9.59 mL, 51 mmol) in 51 mL ethyl ether cooled to -100° C. instead of -78° C. Solvents were removed at 0° C. and 15 mm Hg. The oil bath was maintained at 50° C. to furnish tert-butyldiisopropoxyborane: 8.44 g (45.3 mmol, 89%), bp 136°-138° (754 mm Hg); proton NMR (neat)δ+4.50 (septet, J=18 Hz, 2H), 1.12 (d, J=18 Hz, 12H), 0.95 (s, 9H); boron NMR (neat) δ+29.5 ppm (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:7][CH:8]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1ccc(OC)cn1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccccc2C(=O)O)nc1
Yield: 87.8 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 3-methoxypyridine-6-ylbenzoate (249 mg), which is the product of Reference example 33(b), and aqueous sodium hydroxide solution (1N, 1.20 ml) and the reaction mixture was treated to afford the title compound (206 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=O)(=O)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>CC(N(C)C)=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)(=[O:8])=[O:7])=[CH:22][CH:21]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(S(=O)(=O)NCC(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)CC(C)C)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 4.2 mmol) in anhydrous dimethylacetamide (20 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 186 mg, 4.6 mmol) until no more gas evolved then stirred for a further 10 minutes. 4-Chlorobenzylbromide (951 mg, 4.6 mmol) was added and the reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water was added, extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N-(4-chloro-benzyl)-N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 67%). LCMS (m/z, Method A)) ES+ 368 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=[O:22])[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][CH:31]=[CH2:32]>CN(C=O)C>[CH2:32]([O:22][C:5]1[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(SC)nc(C(=O)OCC)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 2-methylsulfanyl-1,6-dihydro-6-oxo-5-(phenylmethoxy)-4-pyrimidinecarboxylic acid, ethyl ester (4.28 g, 13.36 mmol) in DMF (70 mL) was added Cs2CO3 (4.35 g, 13.36 mmol) followed by 3-bromoprop-1-ene (1.156 mL, 13.36 mmol). The resulting mixture was stirred at 80° C. for 1 h, cooled to room temperature and partitioned between ethyl acetate and hexane. The organic phase was washed with water followed by brine, dried (Na2SO4) and filtered. Concentration gave an oil that was purified by flash column chromatography (Biotage flash chromatography system, 0%-40% ethyl acetate/hexane, 16 CV) to give the title compound as a yellow oil (1.8144 g, 38% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41-7.37 (2H, m), 7.36-7.28 (3H, m), 6.10-5.97 (1H, m), 5.40 (2H, dq, J=17.2, 1.5 Hz), 5.29 (2H, dq, J=10.5, 1.2 Hz), 5.03 (2H, s), 4.93 (2H, dt, J=5.6, 1.4 Hz), 4.32 (2H, q, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 2.50 (2H, q, J=7.1 Hz), 1.28 (3H, t, J=7.1 Hz). LCMS (M+H) calcd for C18H21N2O4S: 361.12; found: 361.21.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Reactant: C=CCc1c(O)ccc(C(=O)NC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy-N-methyl-3-(2-propenyl)benzamide (770 mg, 3.7 mmol), the compound of Example 23 (650 mg, 1.55 mmol), and potassium carbonate (321 mg, 2.32 mmol) were added to about 20 ml of DMF, and the reaction mixture was stirred overnight at room temperature in a 100 ml pear-shaped flask. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, concentrated under vacuum and chromatographed on silica gel using 40% ethyl acetate/hexane as eluant to give the product.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[C:13]([C:22]#[N:23])=[CH:12]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C>C(O)C>[CH:4]1([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[C:13]([C:22]([NH:2][OH:3])=[NH:23])=[CH:12]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: NO
Reactant: COc1cccc2c(C#N)cn(CC3CCCCC3)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c(C(=N)NO)cn(CC3CCCCC3)c12
Temperature: 25 °C
Yield: 33.8 %

Procedure:
Hydroxylamine hydrochloride (966 mg, 13.9 mmol) was added to a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbonitrile (2.48 g, 9.24 mmol), triethylamine (1.41 g, 13.9 mmol), and ethanol (50 ml), then the resulting mixture was stirred at reflux for 20 h. After being cooled to room temperature, the reaction mixture was concentrated in vacuo. The obtained residue was mixed with water (150 ml), adjusted to pH 10 by the addition of aqueous sodium hydroxide and extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 10% (v/v) acetone in dichloromethane to give 1-(cyclohexyl)methyl-N-hydroxy-7-methoxy-1H-indole-3-carboxamidine (940 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>>[Cl:11][C:4]1[N:3]=[C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1

Procedure:
2,6-Dichloro-3-nitropyridine was reacted with N-ethoxycarbonylpiperazine to give 6-chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine. The product, without purification, was heated with ethanolic ammonia in a sealed tube at 120°-125° C. to give 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (mp 132°-134° C.), which was treated with acetic anhydride in acetic acid to give 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (mp 168°-169° C.). This compound was catalytically hydrogenated in the presence of 5% palladium-carbon in acetic acid to yield 3-amino-6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine. The obtained 3-amino derivative, without further purification, was dissolved in a mixture of ethanol and 42% tetrafluoroboric acid, and to this solution was added a solution of isoamyl nitrite in ethanol at below 0° C. with stirring. Twenty minutes later, ether was added to the solution. The resulting precipitate was collected by filtration and washed with a mixture of methanol and ether and then with chloroform to yield 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-pyridine diazonium tetrafluoroborate; mp 117°-117.5° C. (dec.).
Reaction SMILES: [OH-].[K+].C1COCC1.C[O:9][C:10](=[O:28])[C:11]([N:17]([CH3:27])[C:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=[O:19])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:10]([C:11]([N:17]([CH3:27])[C:18]([C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)=[O:19])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])([OH:28])=[O:9]
Reactant: CNC(=O)C(C)(C(=O)OC)N(C)C(=O)c1ccc(I)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(C)(C(=O)O)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A 1.7 mol/L-potassium hydroxide aqueous solution (0.55 mL) was added to a THF (1.0 mL)-MeOH (1.0 mL) solution of 1-{[1-methoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 10-2, 0.12 g), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was adjusted to pH 5 with a 10% aqueous solution of citric acid, and extracted with a chloroform-methanol mixture. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered out, and then the solvent was distilled off under reduced pressure to obtain 1-{[2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 11, orange solid) (91 mg, 80%).
Reaction SMILES: C([O:8][C:9](=[O:26])[CH2:10][CH2:11][C:12]#[C:13][C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=[N:16][CH:15]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:22]([O:21][C:19]([N:18]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:26])=[O:8])=[CH:15][N:16]=[CH:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1cncc1C#CCCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)O
Yield: 99.4 %

Procedure:
Vigorously stir a 60° C. solution of tert-butyl 5-(5-benzyloxy-5-oxo-pent-1-ynyl)imidazole-1-carboxylate (0.17 g; 1.0 equiv; 0.48 mmoles) and palladium (10% on carbon; 0.030 g; 0.014 mmoles) in methanol (13 mL) under 1 atmosphere of hydrogen for 16 hours. Filter and concentrate to afford the desired 5-(3-tert-butoxycarbonylimidazol-4-yl)pentanoic acid (0.128 g; 99%) as a white solid: MS (m/z): 213(M-t-Bu+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)(C)OC(=O)C(=O)Cl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (50 mg, 0.13 mmol) and tert-butyl 2-chloro-2-oxoacetate (0.064 mL, 0.40 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 21 mmHg]. Yield 44 mg (66%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([Cl:16])=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([Cl:6])[C:8]([Cl:16])=[N:9][CH:10]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 4 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
4.45 mL of sulfuric acid was added to 5.0 g of 5,6-dichloronicotinic acid (26 mmol) dissolved in 50 mL of methanol, and refluxed under heating and stirring for 18 hours. The mixture was cooled to 4° C., neutralized with a saturated sodium bicarbonate solution, and methanol was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated to be dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 5.2 g of white solid, 5,6-dichloro-nicotinic acid methyl ester (yield 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:26])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)[C:11]([CH3:25])([CH3:24])[CH2:10]2)=[O:4]>C(O)C.Cl.[Fe]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:26])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[C:11]([CH3:24])([CH3:25])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc([N+](=O)[O-])c1)C(C)(C)C2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N)c1)C(C)(C)C2
Temperature: 95 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a mixture of 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1 g, 2.7 mmol) in ethanol 95% (100 mL) and 10% hydrochloric acid (5 mL) was added iron (0.23 g, 4 mmol). The reaction mixture was stirred at 95° C. for 4 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.8 g, 86%) as a white solid: LC/MS m/e calcd for C19H21ClN2O2 (M+H)+: 345.84, observed: 345.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])=[C:22]([F:34])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[O:25])=[C:22]([F:34])[CH:21]=1)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NCC(F)(F)F)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NCC(F)(F)F)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(2,2,2-trifluoroethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 8% of the corresponding Z isomer as a colorless waxy solid, MS (ESI+): m/z=510.2 [M+H]+.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[CH:11]=1.C(N(CC)CC)C>O1CCOCC1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([O:8][C:17](=[O:18])[NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)=[CH:2][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)Oc1ccc(O)cc1

Procedure:
Benzene-1,4-diol Compound 25a was reacted with 1-chloro-3-isocyanato-benzene Compound 28a and a catalytic amount of triethylamine in 1,4-dioxane at room temperature to provide (3-chloro-phenyl)-carbamic acid 4-hydroxy-phenyl ester Compound 28b.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:27][C:20]1[C:19]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2c(Cl)c3cccccc-3c2-c2ccccc2)cc1
Yield: 45.6 %

Procedure:
To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (0.20 g) in CCl4 (10.0 ml) was added N-chlorosuccinimide (0.08 g) and α,α'-azobis(isobuthyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The mixture was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/EtOAc, 20:1) to give the title compound (0.10 g) as green crystals; mp 140°-142° C.