Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[CH2:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[O:54][CH3:55]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])[CH:45]([C:38]1[C:39]([O:43][CH3:44])=[CH:40][CH:41]=[CH:42][C:37]=1[O:36][CH3:35])[C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[O:54][CH3:55]
Reactant: COc1cccc(OC)c1C(O)c1c(OC)cccc1OC
Reactant: COc1cccc(OC)c1Cc1c(OC)cccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1cccc(OC)c1C(c1c(OC)cccc1OC)C(c1c(OC)cccc1OC)c1c(OC)cccc1OC
Reaction time: 1 h

Procedure:
To a solution of bis(2,6-dimethoxyphenyl)methanol (1.52 g, 0.005 mol) in acetonitrile (50 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.95 g, 0.005 mol). To the resulting deep red solution was added bis(2,6-dimethoxyphenyl)methane (1.44 g, 0.005 mol). The reaction mixture decolored within about one hour and was stirred for an additional 17 hours. The reaction was quenched by the addition of water (10 mL), extracted with dichloromethane and dried over anhydrous magnesium sulfate. Evaporation of the solvent and hot filtration using hexane/benzene gave 1,1,2,2-tetrakis(2′,6′-dimethoxyphenyl)ethane as a mixture of rotational isomers after evaporation of the solvents and washing with diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][C:9](=[O:11])[C:8]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([OH:20])[CH2:6]1)=[O:4].C(N)(=O)C.BrC1CC(=O)NC1=O.BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([OH:20])[CH:6]=1
Reactant: COC(=O)C1CC(=O)C(N=Nc2ccccc2)=C(O)C1
Agent: BrBr
Agent: CC(N)=O
Agent: O=C1CC(Br)C(=O)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(O)c(N=Nc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
54.8 G. of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid methyl ester, 12.0 g. of acetamide and 2.0 g. of bromosuccinimide were stirred in 600 ml. of chloroform and treated dropwise with 32.0 g. of bromine in 400 ml. of chloroform (the reaction temperature being held below 35° C.). Soon, the separation of acetamide hydrobromide began. The mixture was stirred for an additional 30 minutes at room temperature. Then, the acetamide hydrobromide was removed by filtration and the filtrate evaporated to dryness. The residue was taken up in a small amount of ethanol, filtered under vacuum and washed with ethanol, whereby there was obtained 3,5-dihydroxy-4-phenylazo-benzoic acid methyl ester having a melting point of 216°-218° C.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:19])[C@H:6]([CH2:15][S:16][CH2:17][CH3:18])[NH:7]C(OC(C)(C)C)=O)[CH3:3]>C(OCC)(=O)C>[ClH:1].[CH2:2]([NH:4][C:5](=[O:19])[C@H:6]([CH2:15][S:16][CH2:17][CH3:18])[NH2:7])[CH3:3]
Reactant: CCNC(=O)[C@H](CSCC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@@H](N)CSCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To 14.92 g (100 mmole) of S-methyl-L-cysteine were added 55 ml of water and 21 ml (110 mmole) of triethylamine and the mixture was dissolved in 55 ml of dimethylformamide at room temperature. Thereafter, 26.4 g (110 mmole) of t-butyl-S-4,6-dimethylpyrimidin-2-ylthiol carbanate was added and the mixture was stirred for about 10 hours at room temperature. After addition of 150 ml of water, the mixture was extracted with 2×200 ml of ethyl acetate. The aqueous layer was ice-cooled, adjusted to pH 2 with addition of 6 N hydrochloric acid and extracted with 1×150 ml and 2×80 ml of ethyl acetate. The organic layers were washed with 3×100 ml of 5% hydrochloric acid and 2×100 ml of aqueous saturated sodium chloride and then dried over magnesium sulfate. The solution was concentrated in vacuo to give 24.5 g (98% yield) of S-ethyl-N-butyloxycarbonyl-L-cysteine as an oil. ##STR10## To a solution of 6.23 g (25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine dissolved in 60 ml of tetrahydrofuran was added 3.48 ml (25 mmole) of triethylamine. To the resulting mixture cooled to -15° C. was added dropwise 3.28 ml (25 mmole) of isobutyl chloroformate and the mixture was stirred at that temperature for 20 minutes. After cooling to -40° C., 3.2 g of aqueous 70% ethylamine solution (50 mmole) was added in a portion and the mixture was stirred for 2.5 hours under ice cooling. After addition of 70 ml of ethyl acetate, the organic layer was washed successively with 30 ml of aqueous 5% sodium bicarbonate, 2×30 ml of aqueous 10% citric acid, 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline and dried over anhydrous magnesium sulfate. The solution was then concentrated in vacuo, resulting in precipitation of crystals, which were recrystallized from ethyl acetate-n-hexane to give 4.93 g of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide, 71% yield, m.p. 109°-110° C. ##STR11## To 40 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate was added dropwise a solution of 2.00 g (7.25 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine ethylamide in 50 ml of ethyl acetate over 20 minutes. After stirring for 2.5 hours at room temperature, the mixture was concentrated in vacuo and the residual oil was treated with ethyl ether to give 1.31 g (85% yield) of S-ethyl-L-cysteine ethylamide hydrochloride as powder.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:8]2[CH:20]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-chloro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 424 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:30].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:2]2=[O:1])=[CH:32][CH:33]=1
Reactant: CCCc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propyl-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.4 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.076 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.63 g, 81%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH:11]([CH3:15])C(O)=O)[C:3]1=2.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:16](=[O:17])[CH2:15][CH2:11][C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)[CH2:31][CH2:30]1
Reactant: CC(C(=O)O)c1c[nH]c2c1C(=O)CCC2
Reactant: CN1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a suspension of 10 g of 3-(4-oxo-4,5,6,7,tetrahydro-1H-indol-3-yl-propionic acid (48 mmol) in 60 mL of dichloromethane was added 9.3 g (57.6 mmol) of carbonyldiimidazole. After stirring at room temperature for 2 hours, 5.3 mL (48 mmol) of 1-methylpiperazine and 8.4 mL (48 mmol) of N,N-diisopropylethylamine were added. The dark red reaction mixture was stirred at room temperature overnight. The reaction was poured into water and the organic layer washed with brine, dried and concentrated to give 8 g (57% yield) of 3-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1,5,6,7-tetrahydro-indol-4-one. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.97 (br s, 1H, NH), 6.47 (d, 1H), 3.43 (m, 4H, 2×CH2), 2.67–2.75 (m, 4H, 2×CH2), 2.51 (m, 2H, CH2), 2.27 (m, 2H, CH2), 2.20 (m, 4H, 2×CH2), 2.15 (s, 3H, CH3), 1.97 (m, 2H, CH2). MS m/z 289 [M+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[N:14]1([CH2:19][CH2:20]O)[CH:18]=[CH:17][N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:14]1([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]3)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cc1cc2c(cc1O)CCCC2=O
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1OCCn1ccnc1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Under N2, a solution of 2.08 g (11.8 mmol) of 6-hydroxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 25 mL of THF was treated with 1.46 g (13.9 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.1 g (11.8 mmol) of triphenylphosphine. The solution was cooled in ice and treated with a solution of 1.9 mL (11.8 mmol) of diethyl azodicarboxylate in 5 mL of THF. The solution was allowed to stir at room temperature overnight. The mixture was diluted with EtOAc and washed twice with H2O, twice with saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (95/5) gave the product which was recrystallized from EtOAc/hexane to give 1.05 g (32.9% yield) of the product as a tan solid, mp 118-120° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 271 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:22][CH3:23])[C:11](=[O:21])[N:12]([CH3:20])[C:13]=3[C:17](O)=[O:18])[C:8]2=[O:24])=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:22][CH3:23])[C:11](=[O:21])[N:12]([CH3:20])[C:13]=3[C:17]([Cl:29])=[O:18])[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reactant: O=S(Cl)Cl
Product: COc1c2c(c(C(=O)Cl)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O

Procedure:
To 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (0.213 g, 0.6 mmol) was added thionyl chloride (5 mL) and the mixture was heated to reflux for 2 hours, then evaporated to dryness, suspended in toluene and evaporated three times to give the crude product.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]([O:17]C(=O)C)(=O)[CH3:15].[N+:21]([O-])([O-:23])=[O:22].[K+]>S(=O)(=O)(O)O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][C:14](=[O:17])[CH3:15])=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1ccc(C2CCCCC2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 4-cyclohexylaniline (10.0 g, 57.1 mmol) and acetic anhydride (50 ml) was stirred at 50° C. for 1 hour. The resultant mixture was cooled in an ice-bath and a solution of potassium nitrate (10.0 g, 99.0 mmol) in conc. sulphuric acid (25 ml) was added drop-wise keeping the temperature at 15-18° C. After the addition, the mixture was poured into ice-water (400 g). The precipitate was filtered off, washed with water and dried. This crude product (12 g) contained a 1:1 mixture of mono- and dinitrated product. The desired product was isolated by column chromatography on silica gel, using a mixture of petroleum ether and ethyl acetate (9:1, v/v) as the eluent (6.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH3:23])[C@@H:9]([OH:22])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH3:23])[C@@H:9]([OH:22])[CH2:10][N:11]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CNCCCc1ccc(F)cc1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CN(CCCc1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The material from step d (623 mg, 1.83 mMol) and cyclohexanone (179 mg, 1.83 mMol) were dissolved in methanol (5 ml), 4 A molecular sieves were added, and the mixture was stirred at room temperature for 2 hours. To this mixture, sodium cyanoborohydride (173 mg, 2.75 mMol) was added, and the mixture was stirred overnight. Analysis of the reaction mixture by ESI MS showed an M+H which was two AMU higher than that of the desired product, indicating that the imine or aminal hadn't been reduced by sodium cyanoborohydride. The reaction mixture was filtered, the solids were rinsed with EtOAc, and the combined filtrates were concentrated in-vacuo. The residue was dissolved in EtOAc (30 ml), washed with water (2×10 ml), dried over sodium sulfate, and concentrated in-vacuo. The residue was dissolved in methylene chloride (5 ml), sodium triacetoxyborohydride (583 mg, 2.75 mMol) followed by two drops of glacial acetic acid were added, and the mixture was stirred at room temperature for three days. The reaction was worked up by diluting with water (50 ml), adjusting the pH of the mixture to >10 with 1N NaOH, and extracting with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, and concentrated to a yellow oil. This oil was purified via flash chromatography, eluting with EtOAc to yield 310 mg of a colorless oil as product. ESI+MS detects 423 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[Cl:26][C:27]([O:29]C)=[O:28].Cl.N1C=CC=C[CH:33]=1>>[ClH:26].[CH3:33][N:1]([C:2]1[CH:3]=[CH:4][C:5]([S:20]([CH:23]([CH3:24])[CH3:25])(=[O:21])=[O:22])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1)[C:27](=[O:28])[OH:29]
Reactant: COC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: c1ccncc1
Agent: Cl
Product: CC(C)S(=O)(=O)c1ccc(N(C)C(=O)O)cc1[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 40A (0.1 g, 0.27 mmol) in pyridine (1 mL) at 0° C. was added methyl chloroformate (57 μL, 0.54 mmoL). After 2.0 h of stirring at rt the reaction was acidified with 1M HCl to pH 3-4. The product was extracted with ethyl acetate and was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was redissolved in ethyl acetate (1.5 mL) and hydrogen chloride (2 mL, 4M in dioxane) was added. The reaction was stirred for 3 h at rt. The solvent was removed and placed on the lyophilizer to give 0.15 g white solid 44A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.25 (t, J=7.09 Hz, 3H) 1.37 (d, J=6.85 Hz, 3H) 2.13-2.31 (m, 1H) 2.31-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.36-3.56 (m, 3H) 3.73-3.91 (m, 3H) 5.43 (t, J=7.70 Hz, 1H) 7.66 (dd, J=8.80, 2.20 Hz, 1H) 7.97 (d, J=8.80 Hz, 1H) 8.11 (d, J=1.96 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[C:4]#[N:5].O.NN>C(O)C.[Ni]>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([CH3:10])=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(O)c1CN
Temperature: 55 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
2-hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 0.43 mmol) was dissolved in ethanol (10 mL) and was warmed to 55° C. before it was treated with Raney nickel (0.5 mL slurry in water) followed by addition of hydrazine monohydrate (2 mL). The resulting mixture was allowed to stir at 55° C. for 2 hours. The cooled reaction mixture was filtered through diatomaceous earth, rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (40 mg, 56% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 6.04 (s, 1H), 4.87 (br s, 3H), 3.77 (s, 3H), 3.42 (s, 2H), 2.15 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:30])[CH2:27][O:28][CH3:29])[CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH3:7].[NH2:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:30])[CH2:27][O:28][CH3:29])[CH:20]=2)[CH2:10][CH2:9]1
Reactant: COCC(=O)Nc1cc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)c3ccccc32)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)Nc1cc(O[C@H]2CC[C@H](N)c3ccccc32)ccn1
Product: N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.5 %

Procedure:
To a solution of Intermediate 10c (272 mg, 0.64 mmol) in DCM (6 mL) was added TFA (2 mL), and the mixture stirred at RT for 30 min. The mixture was concentrated in vacuo. The residue was purified on an Isolute SCX-2 cartridge, eluting with MeOH then 0.4-1M NH3 in MeOH, to give the title compound as a colourless gum (208 mg, 100%). LCMS (Method 3): Rt 0.44 min, m/z 350.2 [MNa+].
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:19])[O:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[CH3:18])=[O:5])C.[NH2:20][CH2:21][C:22]([O-:24])=[O:23].[Na+]>COC(O)C>[OH:16][C:15]1[C:14]2[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[CH:12][CH:13]=2)[O:8][C:7](=[O:19])[C:6]=1[C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5]
Reactant: CCOC(=O)c1c(O)c2ccc(C)c(C)c2oc1=O
Reactant: NCC(=O)[O-]
Agent: COC(C)O
Agent: [Na+]
Product: Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)oc2c1C
Yield: 79.6 %

Procedure:
A mixture of 4-hydroxy-7,8-dimethyl-2-oxo-2H-chromene-3-carboxylic acid ethyl ester (18 mg, 0.069 mmol) and sodium glycinate (34 mg, 0.34 mmol) in methoxyethanol (5 mL) was refluxed for 16 h; then cooled, the solvent was removed, the residue was redissolved in water, acidified with 2 M HCl, the precipitates were collected and freeze dried to give the desired title product (16 mg). ESI (m/z): 292 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]2[N:10]=[C:11]([S:13]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:14])[N:12]=[C:6]2[N:5]=1.CS(O)(=O)=O>CS(C)=O>[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([S:13]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:14])[N:12]=[C:6]2[NH:5]1
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1CCn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2N1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
Sodium borohydride (0.6 g, 16 mmol) was added to a solution of 3.0 g (8.3 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in 25 ml of dry DMSO. An exothermic reaction occured and 2.0 ml (31 mmol) of methane sulfonic acid in 5 ml of DMSO was added at a rate to maintain the temperature of the reaction mixture at 60° C. After the addition was complete the reaction mixture was stirred for 10 minutes and carefully quenched with 0.5N aqueous NaOH. The clear yellow solution was filtered, and the filtrate was acidified with 3N aqueous HCl. The resulting 7recipitate was treated with dilute aqueous NaOH and filtered to remove insoluble material. The filtrate was acidified with aqueous HCl to precipitate a solid. The solid was collected by filtration and dried to yield 1.11 g (37%) of the desired product as a solid, mp 230°-235° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:5].C(=O)(O)[O-].[Na+].[CH2:28]([O:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH:9]2[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:2]([F:1])[CH:3]=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1c1ccc(N)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCNCC1c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 18 h
Yield: 135.3 %

Procedure:
To 3-Fluoro-4-(N-tert-butoxycarbonylhomopiperazinyl)aniline (2.6 g, 8.4 mmol) in THF (25 ml) cooled to 5° C., sodium bicarbonate (0.85 g 10.1 mmol), was added and then benzylchloroformate (1.72 g, 10 mmol) was added dropwise. The reaction mixture was stirred for 18 hrs. at R.T. and then filtered. The filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and brine water. The organic layer was dried over anhyd Na2SO4 and evaporated in vacuo to give 5.04 g of final product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C(C)C)=[C:20]([I:28])[CH:19]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([I:28])[CH:19]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1OCC
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1OCC
Yield: 84 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 84% yield, as a creamy solid. 1H-NMR (CDCl3) 8.48 (d, 1H, J=2.05 Hz); 8.04 (dd, 1H, J=8.46, 1.98 Hz); 7.76 (dd, 1H, J=8.43, 2.0 Hz); 7.65 (d, 1H, J=1.98 Hz); 7.07 (d, 1H, J=8.5 Hz); 6.96 (d, 1H, J=8.46 Hz); 5.63 (bs, 1H); 4.24-4.09 (m, 4H); 1.56-1.42 (m, 6H).