Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[F:21][C:22]([F:41])([F:40])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=[C:25]([C:36]([F:39])([F:38])[F:37])[N:24]=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].Cl>COCCOC.O>[F:41][C:22]([F:40])([F:21])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([O:34][CH3:35])[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:25]([C:36]([F:39])([F:38])[F:37])[N:24]=1
Reactant: CCOC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a cold (-78° C.) solution of LDA, from 0.02 mol (2.8 ml) of diisopropylamine, 0.0208 mol of n-BuLi, and 30 ml of DME was added a solution of 4.65 g (0.015 mol) of product of Example 4 in 20 ml of DME. The resulting greenish solution was stirred at -78° C. for 10 minutes and treated with 2.7 ml (0.035 mol) of ethyl chloroformate. The reaction mixture was warmed to room temperature in 40 minutes, then poured into a mixture of 20 ml of concentrated HCl and 50 ml of water. The mixture was extracted with ether (200 ml). The ether extract was dried and concentrated. The residue was kugelrohr distilled at 13 Pa. The earlier fraction (pot temperature 50°-65° C.) was discarded. The later fraction (pot temperature 90° C.) was an oil (5.47 g) which was crystallized from hexane at low temperature to give 4.4 g (75%) of product; mp 46.5°-47.5° C.
Reaction SMILES: C(OC(N1CCO[C@H](CC2C=CC=C(Br)C=2)C1)=O)(C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1Br.[CH2:33]([C@@H:35]1[O:37][CH2:36]1)[Cl:34]>>[Cl:34][CH2:33][C@H:35]([OH:37])[CH2:36][C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: ClC[C@H]1CO1
Reactant: COc1ccc(Br)c(OC)c1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Product: COc1ccc(C[C@@H](O)CCl)c(OC)c1

Procedure:
(R)-1-Chloro-3-(2,4-dimethoxyphenyl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but from 2,4-dimethoxybromobenzene and (R)-epichlorohydrin.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([OH:34])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:49](O)[CH:50]=[CH2:51]>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([O:34][CH2:51][CH:50]=[CH2:49])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1c2c(C(=O)O)ncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Reactant: C=CCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ncn2c1[C@@H](CC)N(C1CCCC1)c1nc(Nc3ccc(C(=O)NC)cc3OC)ncc1-2
Temperature: 42.5 °C
Reaction time: 0.67 h
Yield: 77.3 %

Procedure:
(R)-5-cyclopentyl-6-ethyl-3-(2-methoxy-4-(methylcarbamoyl)phenylamino)-5,6-dihydroimidazo[1,5-f]pteridine-7-carboxylic acid 1-2 (44 mg, 0.09 mmol) in DMF (0.5 mL) was treated with carbonyldiimidazole (19 mg, 0.12 mmol) and stirred at 40-45° C. for 40 minutes. Allyl alcohol (1 ml, 14.7 mmol) was then added and the reaction mixture was stirred at 40° C. for 18 hours. The mixture was partitioned between an aqueous solution of sodium carbonate and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to give the desired compound as a pale brown solid (37 mg, 77% yield); LC/MS M+1 (obs.) 532.68, LC/MS M-1 (obs.) 530.81.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12](Cl)=[O:13])=[CH:2]1.[NH2:15][C:16]([NH2:18])=[O:17]>C1C=CC=CC=1.S(=O)(=O)(O)O>[O:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH:2]=[C:3]1[C:12]([NH:15][C:16]([NH2:18])=[O:17])=[O:13]
Reactant: NC(N)=O
Reactant: O=C(Cl)c1coc2ccccc2c1=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: NC(=O)NC(=O)c1coc2ccccc2c1=O
Yield: 63 %

Procedure:
A hot solution of 10.4 g (0.05 mol) of chromone-3-carbonylchloride in 150 ml of benzene was added over two minutes to a stirred boiling mixture of 3.6 g (0.06 mol) of urea, 100 ml of benzene and two drops of conc. sulfuric acid. The mixture was stirred at reflux for 2 hrs., cooled and filtered; wt 12.3 g; mp 200°-217°. Recrystallization from dimethylformamide gave 63% yield of pure product, mp 247°-250°.
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH2:29]([NH:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:53][CH3:54])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[C:36]([NH2:55])[N:35]=1)[CH2:30][CH2:31][CH3:32].ICC>>[CH2:29]([NH:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:53][CH3:54])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:48][CH2:49][N:50]([CH2:1][CH3:2])[CH2:51][CH2:52]2)=[C:36]([NH2:55])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from N2-butyl-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purine-2,6-diamine and 2-iodoethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH3:2]
Reactant: CCOC(=O)COc1cc(OC)c(Cl)cc1C(O)C(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(=O)C(C)C
Temperature: 37.5 °C
Yield: 57.3 %

Procedure:
The above prepared [4-chloro-2-(1-hydroxy-2-methyl-propyl)-5-methoxy-phenoxy]-acetic acid ethyl ester (1.56 g, 4.92 mmol) was dissolved in 50 mL of CH2Cl2, treated with MnO2 (12.84 g, 30 eq.), and the reaction mixture vigorously stirred over night at 35-40° C. Cooling, filtration over a pad of Celite, copiously rinsing, and evaporation of the solvent, followed by flash chromatography (SiO2, heptane/AcOEt=72/28) and direct crystallization afforded 0.887 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](=O)[CH3:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>CO.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26](/[C:28](=[N:33]/[OH:34])/[CH3:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(C)=O)[nH]2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(/C(C)=N/O)[nH]2)c1
Yield: 41.9 %

Procedure:
1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)ethanone (117 mg, 0.26 mmol) synthesized in Example (15c) was dissolved in methanol (6 mL), and hydroxylamine hydrochloride (37 mg, 0.53 mmol) and sodium acetate (26 mg, 0.32 mmol) were added, followed by heating to reflux for 6 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 mL), washed with water and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired product (50 mg, yield 41%) as a white solid.
Reaction SMILES: Cl.[NH2:2]O.[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>N1C=CC=CC=1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:11]([CH3:15])=[N:2][O:24][C:9]=2[C:8]2[CH:7]=[C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([OH:4])=[CH:14][C:13]=2[OH:12])=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(-c4ccccc4)cc3c2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(O)cc2O)cc1
Yield: 73.9 %

Procedure:
Hydroxylamine hydrochloride (75 mg, 1.08 mmol) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-6-phenyl-chromen-4-one (105 mg, 0.29 mmol) in pyridine (2 ml) and the mixture heated under reflux for ˜6 hrs., to give a pale yellow solution. The solution was allowed to cool and water (20 ml) added. The mixture was extracted with diethyl ether (2×10 ml). The combined extracts were washed with water (2×20 ml) and saturated aqueous sodium chloride solution (10 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:1), to give the title compound as an off-white powder (80 mg)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[C:30]([CH:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:25]2[C:30]([CH:31]3[CH2:32][CH2:33][CH:34]([OH:37])[CH2:35][CH2:36]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:13][CH:12]=1
Reactant: OC1CCC(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: OC1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 200 °C

Procedure:
To a vial containing 4-(benzo[d]thiazol-2-ylamino)phenol (819 mg, 3.38 mmol) was added cesium carbonate (918 mg, 2.82 mmol) followed by 4-(2-fluoropyridin-3-yl)cyclohexanol (220 mg, 1.127 mmol) as a solution in NMP (7.5 mL). The reaction mixture was heated to 200° C. for 2.5 h with microwave irradiation. The reaction mixture was diluted with water and extracted with 15% IPA:chloroform before drying over magnesium sulfate, filtering, and concentrating to a dark brown residue under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH:11]=O)[CH:10]=1)=[O:5])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc(CNc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.2012 g (1.20 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester was dissolved in 4.8 mL (0.25 M) of 5% acetic acid in methanol. Aniline (0.13 mL g, 1.44 mmol) was added, and the reaction was stirred at room temperature under nitrogen for 45 minutes, then sodium cyanoborohydride (0.1244 g, 1.98 mmol) was added slowly and the reaction was allowed to stir at room temperature overnight. About 2 mL of saturated K2CO3 were added, and the reaction was extracted twice with ethyl acetate. The combined organics were washed with saturated NaHCO3 (˜3 mL) and brine (˜3 mL), then the combined organics were dried with Na2SO4, filtered and concentrated en vacuo. The crude product was purified by silica gel chromatography (Combiflash column, 85:15 Hexanes: Ethyl acetate) to obtain 0.2663 g (91%) of 4-phenylaminoethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (183) as a colorless viscous oil. Note: Starting material 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has an HPLC retention time=7.337 min. 1H (CDCl3, 400 MHz): δ 9.49 (1H, broad s), 7.19 (2H, dd, J=8.6, 7.3 Hz), 6.73 (1H, tt, J=7.3, 1.1 Hz), 6.66 (2H, dd, J=8.6, 1.1 Hz), 6.91 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=2.0 Hz), 4.33 (2H, q, J=7.2 Hz), 4.19 (2H, s), 3.90 (1H, broad s), 1.36 (3H, t, J=7.2 Hz) ppm. HPLC: 6.936 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:40])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28](C2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CN(C=O)C.O.C(OCC)(=O)C.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>[CH2:19]([O:21][C:22](=[O:40])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([O:9][CH2:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[CH:3]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: CCOC(=O)COc1ccc(C2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (Example I(a)) (2.2 g, 6.3 mmol), [4-(4,4,5,5-tetramethyl-(1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethyl ester (2.9 g, 1.5 eq.), bis(triphenylphosphine)palladium(II) chloride (136 mg) and sodium carbonate (1.93 g, 3.0 eq.) in ethylene glycol dimethyl ether (30 mL), DMF (5 mL) and water (8 mL) was heated to 90–100° C. under nitrogen for 7 hr. The reaction was cooled to rt and diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on silica column to afford (4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)acetic acid ethyl ester. This ester was treated with sodium carbonate and water at rt overnight. The reaction was diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on silica column to afford 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acid.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCOCC1>[CH2:16]([NH:19][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: O=C1Cc2c(cccc2OCC2CO2)N1
Solvent: C1COCCO1
Product: C=CCNCC(O)COc1cccc2c1CC(=O)N2

Procedure:
3 g of 4-(2,3-epoxypropoxy)oxindole, 30 cc of allylamine and 70 cc of dioxane are heated to the boil for 16 hours. The mixture is evaporated to dryness at reduced pressure and the crude title compound is recrystallized from ethanol/ethyl acetate. M.P. 124°-127° .
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])=[CH:15][CH:14]=1.O.NN.C(OCC)(=O)C>C(O)C>[NH2:3][CH2:12][C:13]1[N:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])=[CH:15][CH:14]=1
Reactant: CC(=O)OCCOc1ccc(CN2C(=O)c3ccccc3C2=O)nc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1ccc(CN)nc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a solution of 0.35 gm (0.97 mmol) of Acetic acid 2-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-nitro-pyridin-3-yloxy]-ethyl ester 97 in 5 mL of ethanol was added 0.051 mL (1.01 mmol) of hydrazine hydrate at room temperature. The reaction mixture was allowed to stir for 4 h. The mixture was then transferred with ethyl acetate and the solvent was removed at reduced pressure. The residue was taken up in CHCl3 (200 mL) and washed twice with water (100 mL), saturated brine, dried (Na2SO4), and the solvents removed under reduced pressure. This was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:29])([F:28])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:26][NH2:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:20]1([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:29])([F:28])[F:12])=[N:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=434.1, tR (minutes, Method F)=2.34
Reaction SMILES: CO.[CH:3]1([C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:13][CH:12]3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[C:20](O)=[O:21])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:3]1([C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:13][CH:12]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH2:20][OH:21])[CH2:5][CH2:4]1
Reactant: O=C(O)c1c(C2CC2c2ccccc2)noc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1c(C2CC2c2ccccc2)noc1C1CC1
Temperature: 0 °C

Procedure:
(5-cyclopropyl-3-2-phenylcyclopropyl)isoxazol-4-yl)methanol (rac-I-6F). To a solution of 5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole-4-carboxylic acid rac-I-6E (0.49 g, 1.82 mmol) in THF and cooled to 0°C. lithium aluminum hydride (4.5 mL, of a 1M solution in THF) was added dropwise. After stirring fo(12 h at rt, the reaction mixture was cooled back to 0°C. and quenched by dropwise addition of H2O (0.5 mL), 15% NaOH (0.5 mL), H2O (1 mL) followed by Na2SO4 and filtered through CELITE® under vacuum. The crude was purified by column chromatography on silica gel with DCM-EtOAc 0 to 5% gradient as eluent to give (5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methanol. 1H NMR (400 MHz, DMSO) δ 7.31-727 (m, 2H), 7.21-7.17 (m, 3H), 5.00 (t, J=5.2 Hz, 1H), 4.42-4.33 (m, 2H), 2.39-2.35 (m, 1H), 2.23-2.13 (m, 2H), 1.57-1.52 (m, 1H), 1.46-1.42 (m, 1H), 1.05-1.04 (m, 2H), 0.95-0.91 (M, 2H). MS m/z 256.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:13]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:34]([O:33][C:31]([O:30][C:26]1[CH:25]=[C:24]([OH:23])[CH:29]=[CH:28][CH:27]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)Oc1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)Oc1cccc(O)c1
Product: CC(C)(C)OC(=O)Oc1ccc(OCc2ccccc2)cc1

Procedure:
The objective compound was obtained in the same way with the step (2) (ii) of Example 21, except for using 1-benzyloxy-3-t-butoxycarbonyloxybenzene obtained in the step (i) instead of 1-benzyloxy-4-t-butoxycarbonyloxybenzene in the step (2) (ii) in Example 21.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:31]([O:33]C)=[O:32])[C:10]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[C:11]=3[CH:30]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[N:1]1([C:7]2[CH:8]=[C:9]([C:31]([OH:33])=[O:32])[C:10]3[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[C:11]=3[CH:30]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A suspension of methyl 6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 48 (1.28 g, 2.73 mmol) in Methanol (18 mL) and 1 M sodium hydroxide (15 mL, 15.00 mmol) was stirred overnight at rt, then at 50° C. for 5 h. The reaction was cooled to room temperature and acidified (pH 4) by the addition of 1 N HCl. The precipitate formed was collected by filtration, washed with water and dried to give the desired product (1.13 g, 2.233 mmol, 82% yield). A portion of this material (132 mg) was purified by reverse phase-HPLC (15-95% AcCN in water plus 0.1% TFA). The fractions containing product were combined and the volume was reduced to about ⅓ of the original. The precipitate formed was collected, washed with water and dried in a vacuum oven (50° C., overnight) to give the desired product (88.4 mg, 0.194 mmol, 7.12% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1H), 8.26 (d, J=8.59 Hz, 1H), 8.01 (d, J=7.33 Hz, 1H), 7.85 (d, J=8.34 Hz, 1H), 7.57-7.73 (m, 3H), 7.35 (d, J=2.53 Hz, 1H), 7.29-7.34 (m, 1H), 6.24 (d, J=7.07 Hz, 1H), 6.22 (s, 2H), 3.64-3.72 (m, 4H), 3.06-3.18 (m, 4H). MS (ES+) m/e 456 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)cnc1Cl
Solvent: ClCCl
Product: Cc1cc(C=O)cnc1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of (6-chloro-5-methyl-3-pyridinyl)methanol (300 mg, 1.904 mmol), CrO2 (Magtrieve) (2.398 g, 28.5 mmol), and DCM (15 ml) was stirred at 40° C. in a closed tube overnight. TLC showed some starting material remaining. Additional CrO2 (0.8 g) was added. After heating 4 additional hours, TLC showed full conversion. Filtration and concentration afforded 6-chloro-5-methyl-3-pyridinecarbaldehyde (204.8 mg, 69%) as a white solid.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:18]1([NH:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:2][C:1]1[N:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:29]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NNc1cccc2ccccc12
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nn(-c3cccc4ccccc34)c(N)c2C(N)=O)cc1
Yield: 27 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (464 mg, 2.0 mmol), 1-naphthyl hydrazine hydrochloride (389 mg, 2.0 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 50-60% ethyl acetate in hexane) and was recrystallised from diethylether to give the title compound as pink crystals (185 mg) m.p. 195°. δH (CDCl3) 8.00 (1H, d, J 8.3 Hz), 7.95 (1 H., m), 7.73-7.55 (7H, m), 7.30 (2H, d, J 8.3 Hz), 5.52 (2H, br s), 5.16 (2H, br s) and 2.42 (3H, s).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:19][C:20]1[CH:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:27]([C:22]3[NH:23][C:24]([CH2:25][CH3:26])=[C:20]([Cl:19])[CH:21]=3)=[O:28])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: CCc1[nH]c(C(=O)O)cc1Cl
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: CCc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 4-chloro-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 71).