Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:21][NH:20][C:22]([C:24]3[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=3)=[O:23])[CH3:19])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Yield: 59.7 %

Procedure:
2-(4-t-Butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (80 mg, 0.29 mmol) and methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (58 mg, 0.29 mmol) were stirred in dimethylformamide (2.9 mL) at 120° C. under heating overnight. The resulting reaction solution was concentrated, and chloroform/n-hexane was added. The precipitated solid was recovered by filtration to give the desired product as a yellow solid (79 mg, yield 60%).
Reaction SMILES: C(OC([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[CH:11]2[CH2:19][CH2:20][CH2:21][C:10]2([F:22])[C:9]1=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O.C(OCC)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][C:17]2[NH:8][C:9](=[O:23])[C:10]3([F:22])[CH2:21][CH2:20][CH2:19][CH:11]3[C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(F)CCCC2c2cc(Cl)ccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C2CCCC12F
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A solution of 2.20 g (6.5 mmol) of 5-tert-butoxycarbonyl-8-chloro-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 10 ml of dichloromethane is mixed with 10 ml of trifluoroacetic acid at room temperature. After 2 hours, the batch is diluted with water and ethyl acetate. The organic phase is separated, washed with water, saturated NaHCO3 and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 0.83 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([NH2:13])[NH:10][N:9]=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:22][CH:23]=2)[CH:18]=[N:17]1)[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]2[NH:13][C:25]([C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[N:16]([CH2:14][CH3:15])[N:17]=[CH:18]4)=[CH:26][C:27](=[O:28])[N:10]2[N:9]=1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2CC)c1
Reactant: Nc1nc(-c2ccccc2Cl)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CCn1ncc2cc(-c3cc(=O)n4nc(-c5ccccc5Cl)nc4[nH]3)ccc21
Yield: 40.4 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1H-1,2,4-triazol-5-amine (50 mg, 0.25 mmol) in n-BuOH (0.2 mL) was added ethyl 3-(1-ethyl-1H-indazol-5-yl)-3-oxopropanoate (100 mg, 0.37 mmol) and p-TsOH (10 mg) at room temperature. After refluxing overnight, the solids were collected by filtration and washed with methanol (3×2 mL) to afford 2-(2-chlorophenyl)-5-(1-ethyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid (39.5 mg, 40%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[O-2].[Mn+4].[O-2]>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH:26]=[O:27])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccc(C=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 95.5 %

Procedure:
To a solution of (3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)methanol (6.96 g) in THF (37 mL) was added manganese(IV) oxide (8.03 g), and the mixture was stirred at room temperature for 5.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.61 g) as a pale-yellow oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([S:11][CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[N:8][C:5]2=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+].[OH-].[Na+]>O>[OH:24][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([S:11][CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1c(C)cnc(CSc2nc3ncc(N)cc3[nH]2)c1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ncc(O)cc3[nH]2)c1C
Temperature: 0 °C

Procedure:
0.2 Gram of 6-amino-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine was dissolved in a mixture consisting of 3 ml of water and 0.1 ml of concentrated sulfuric acid. This mixture was stirred at 0° C., and 59 mg of sodium nitrite was added, then the mixture was further stirred at the same temperature for 1 hour. The reaction solution was neutralized by adding 4N-sodium hydroxide aqueous solution, and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 0.2 g of 6-hydroxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine in the form of yellow powdery crystals. Melting point: 178°-179.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1>>[CH:8]1([C:2]2[CH:3]=[C:4]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:5]=[C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:1]=2[OH:7])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1=CCCC1
Reactant: Oc1ccccc1
Product: Oc1c(C2CCCC2)cc(C2CCCC2)cc1C1CCCC1
Reaction time: 15 h
Yield: 11.6 %

Procedure:
To 470 g of phenol and 100 g of an acid-activated fuller's earth 1020 g of cyclopentene are added dropwise at 140° C whereupon the mixture is stirred at the same temperature for 15 h. After elimination of the catalyst by filtration the reaction mixture is distilled by fractionation. Besides 2,4,6-tricyclopentylphenol 173 g of a fraction are obtained having a boiling range of 205° to 212° C at 1.4 mm Hg which are recrystallised from ligroin. Yield: 143 g of 2,4,5-tricyclopentylphenol. Melting point: 104° C.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][N:20]([C:23]3[S:24][C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH:28]=O)[N:27]=3)[CH2:19][C@H:18]2[O:35][CH3:36])=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.[Cl-].[Na+].O>[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][N:20]([C:23]3[S:24][C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH:28]=[CH2:1])[N:27]=3)[CH2:19][C@H:18]2[O:35][CH3:36])=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13]
Reactant: [Li]CCCC
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1C(=O)OCC
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 20 %

Procedure:
Methyltriphenylphosphonium bromide (0.19 g, 0.53 mmol) was suspended in THF (4 mL), followed by cooling to −78° C. An n-butyllithium/1.58 M hexane solution (0.34 mL, 0.54 mmol) was added dropwise, followed by stirring for 25 minutes. Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (28a) (74 mg, 0.16 mmol) was added, and the mixture was heated to room temperature and stirred for one hour. Brine was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 3/1, 1/1) to obtain 15 mg of the title compound as a pale yellow solid (21%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[C:9]([N:8]([CH3:12])[C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of N-(5-aminopyridin-2-yl)-N-methylacetamide (1.00 g, 6.06 mmol) and pyridine (1.47 ml, 18.2 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.09 mmol) with ice-cooling, the mixture was stirred for 0.5 hour with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (1.08 g, 52.4%) as a solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:34]=[C:33]([OH:35])[C:26]3[CH2:27][CH:28]([CH:30]([F:32])[F:31])[O:29][C:25]=3[CH:24]=2)=[O:22])=[N:16]1>>[CH3:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:34]=[C:33]([O:35][C:10]3[CH:11]=[CH:12][C:7]([C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[CH:8][CH:9]=3)[C:26]3[CH2:27][CH:28]([CH:30]([F:32])[F:31])[O:29][C:25]=3[CH:24]=2)=[O:22])=[N:16]1
Reactant: O=C(c1ccc(F)cc1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)c3c(c2)OC(C(F)F)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 33, from azetidin-1-yl(4-fluorophenyl)methanone (57.4 mg, 0.32 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (99 mg, 0.32 mmol) to give a white solid (12 mg, 8% yield). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1 H) 7.55-7.71 (m, 2 H) 7.22-7.31 (m, 1 H) 7.13-7.19 (m, 1 H) 7.06-7.12 (m, 1 H) 6.96-7.03 (m, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 5.75-6.08 (m, 1 H) 4.93-5.19 (m, 1 H) 4.35 (br. s., 2 H) 4.24 (br. s., 2 H) 3.79 (s, 3 H) 3.57-3.63 (m, 1 H) 3.14-3.31 (m, 2 H) 2.30-2.42 (m, 1H.); LCMS for C24H22F2N4O4 m/z 469.00 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[C:7]([C:10](Cl)=[O:11])[N:6]=[CH:5][C:4]=2[CH2:3][O:2]1.[C:13]([O:17][C:18](=[O:44])[N:19]([CH:21]([C:23](=[O:43])[NH:24][C:25]1[CH:30]=[C:29]([C:31]2[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]3[C:32]=2[CH:33]=[CH:34][CH:35]=[N:36]3)[CH:28]=[C:27]([NH2:42])[N:26]=1)[CH3:22])[CH3:20])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[C:13]([O:17][C:18](=[O:44])[N:19]([CH:21]([C:23](=[O:43])[NH:24][C:25]1[CH:30]=[C:29]([C:31]2[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]3[C:32]=2[CH:33]=[CH:34][CH:35]=[N:36]3)[CH:28]=[C:27]([NH:42][C:10]([C:7]2[N:6]=[CH:5][C:4]3[CH2:3][O:2][CH2:1][C:9]=3[CH:8]=2)=[O:11])[N:26]=1)[CH3:22])[CH3:20])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C(Cl)c1cc2c(cn1)COC2
Reactant: Cc1ccc2ncccc2c1-c1cc(N)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc2ncccc2c1-c1cc(NC(=O)c2cc3c(cn2)COC3)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1H,3H-furo[3,4-c]pyridine-6-carbonyl chloride M1 (33 mg, 0.2 mmol) is added to tert-butyl-N-(1-{[6-amino-4-(6-methylquinolin-5-yl)pyridin-2-yl]carbamoyl}ethyl)-N-methyl-carbamate J1 (60 mg, 0.14 mmol) and DIPEA (59 μl, 0.34 mmol) in THF (1 ml) and the mixture is stirred at 50° C. for 2 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 17 mg (21%). HPLC-MS: M+H=583; tR=1.01 min (Method—2).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:5]([Al](CC)CC)C.[H][H]>C1CCCCC1.[Co].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2].[Co].[Al]>[CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH2:1]=[CH:2][CH:3]=[CH2:4]
Reactant: CC[Al](CC)CC
Reactant: [H][H]
Agent: [Co+2]
Agent: [Co]
Agent: C=CC=C
Solvent: C1CCCCC1
Product: C=CC(=C)C

Procedure:
Part of the polymeric solution (195 g) described in Example V was introduced into a 0.5 L Fischer-Porter reactor. The total amount of polymer added to the reactor was 31.4 g which represents 0.540 moles of butadiene unsaturation. The hydrogenation catalyst was prepared by adding 35.1 mL of a 1.7M triethylaluminum solution (59.6 mmol) to a solution of 19.9 mmol of cobalt octoate in 153.0 mL (119.2 g) of cyclohexane. The final catalyst solution was 0.1M in cobalt and had an aluminum-cobalt ratio of 3:1. A portion of this catalyst (5.0 mL, 0.50 mmol Co) was syringed into the reactor which had been purged/vented three times with nitrogen, then hydrogen, and pressured to 55 psig with hydrogen. The reaction exothermed to 34° C. and was maintained at 30°-35° C. The progress of the hydrogenation was monitored by infrared (FTIR) analysis of hourly samples. After 4 hours an additional 4 mL (0.40 mmol) of catalyst was added. The reaction was terminated after 6.25 h, when the IR showed minimal trans unsaturation (968 cm-1) and complete disappearance of vinyl (910, 990 cm-1). The catalyst was then removed by washing the polymer in the same type of reactor described in Example I with 300 mL of a 0.5M citric acid aqueous isopropanol (2:1 water-IPA) solution. The mixture was vigorously mixed at 70° C. for 20 minutes and allowed to settle. The pink aqueous layer was removed and the entire wash step was repeated using an aqueous isopropanol (2:1 water-IPA) solution. After addition of 0.2 g of Irganox 1076, the polymer was isolated by removing the volatiles under reduced pressure. Gel permeation chromatography of a sample revealed little change in the polydispersity index of the polymer had occurred as a result of hydrogenation.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:19]=[CH:18][C:7]=3[N:8]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2nc3ccc([N+](=O)[O-])cc3o2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3ccc(N)cc3o2)cc1
Yield: 3.8 %

Procedure:
To 6-nitro-2-p-tolylbenzo[d]oxazole (2.1 g, 8.27 mmol) in ethanol:water 2:1 v/v (60 mL) at 70° C. was added iron powder (2.14 g, 38.3 mmol) and ammonium chloride (819 mg, 15.3 mmol). The suspension was stirred at reflux for 16 h. After cooling, the solution was filtered through a pad of Celite® and washed with ethanol. After evaporation of the solvent, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate:hexanes 1:3 v/v to afford 70 mg (4%) of the title compound (LCMS RT=6.12 min, MH+ 223.1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.[Sn].Cl.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NCC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-chloro-2-nitro-phenyl)-(tetrahydro-pyran-4-ylmethyl)-amine (1.28 g; 4.729 mmol) in tetrahydrofuran (25 mL) was added tin metal (1.740 g; 14.660 mmol) and 1N hydrochloric acid (32.157 mL; 32.157 mmol) and the reaction is stirred at room temperature overnight. After this time, the mixture is diluted with 1N sodium hydroxide solution (1.6 g NaOH/40 mL water; 40 mmol) and filtered through Celite®, washing with ethyl acetate. The filtrate is extracted with ethyl acetate and the combined organics are washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford title compound which was used without further purification. ESI m/z 241 [M+H]+
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4cccc(F)c4)s3)ccc2C1
Temperature: 100 °C
Yield: 26.7 %

Procedure:
To a solution of the bromide from Step 2 (20 mg) in toluene (0.5 mL), ethanol (0.25 mL) and water (0.25 mL) were added 3-fluorophenylboronic acid (8 mg), potassium carbonate (26 mg) and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (3 mg). The mixture was heated in a microwave at 100° C. for 5 min. Additional catalyst was added and the mixture was heated at 100° C. for a further 10 min. The reaction mixture was poured into satd. NaHCO3(aq) and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. Chromatography on silica eluting with 25% ethyl acetate in hexane gave the title compound (5.5 mg, 27%). δ (1H, 400 MHz, CDCl3) 1.31–1.41 (2H, m), 1.71–1.77 (2H, m), 2.47–2.51 (2H, m), 2.72–2.84 (2H, m), 3.25–3.29 (2H, m), 3.45 (2H, s), 3.70 (2H, q, J=8.7 Hz), 4.93 (1H, s), 7.01–7.06 (1H, m), 7.18 (1H, d, J=7.8 Hz), 7.28–7.31 (1H, m), 7.37–7.41 (2H, m), 7.68 (1H, dd, J=7.8, 1.6 Hz), 7.73 (1H, d, J=1.2 Hz), 8.00 (1H, s); MS (ES+) 538 ([MH]+).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])=[CH:4][N:3]=[CH:2]1.Cl.CN.C(Cl)CCl.C1C=[N:26][C:25]2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CCOC(C)=O.CO.CN(C=O)C>[CH3:25][NH:26][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([C:5]2[O:1][CH:2]=[N:3][CH:4]=2)[CH:7]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)c1cccc(-c2cnco2)c1
Agent: CN
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cnco2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
DMF (15.9 mL) was added to a round bottom flask containing 3-(oxazol-5-yl)benzoic acid (0.99 gm, 5.23 mmol), methylamine hydrochloride (0.39 gm, 5.76 mmol), EDC (1.10 gm, 5.76 mmol), and HOAt (0.78 gm, 5.76 mmol). DIPEA (2.29 mL, 13.08 mmol) was then added. The reaction mixture was stirred at rt overnight. After 24 h the mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes then 15% MeOH in EtOAc to give the product, N-methyl-3-(oxazol-5-yl)benzamide, (0.50 gm, 2.49 mmol, 48% yield) as a white solid. Anal. Calcd. for C11H10N2O2 m/z 202.1, found: 203.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19]CC#C)([CH3:16])([CH3:15])[CH3:14].CO>N>[Si:17]([O:18][CH2:19][CH2:11][C:10]#[C:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:24])[CH3:23]
Reactant: OCCCc1cccc(CO)c1
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1cccc(CO)c1

Procedure:
Prepared by the method of Aromatic Intermediate 18, step a using tert-butyldimethyl(but-3-ynyloxy)silane (0.92 g) in place of tert-butyl dimethyl(prop-2-ynyloxy)silane. The preparative HPLC conditions were changed to XBridge™, Gradient: 75-99% methanol in 0.2% aqueous ammonia to avoid cleavage of the silyl protecting group. Yield 0.79 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([O:24][CH3:25])=[N:22][NH:23][C:17]=2[CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C(=O)N([Br:33])C(=O)C1.O>CN(C=O)C>[Br:33][C:16]1[C:17]2[NH:23][N:22]=[C:21]([O:24][CH3:25])[C:18]=2[CH:19]=[N:20][C:15]=1[NH:14][C:12]([NH:11][C@@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][O:2][CH3:1])=[O:13]
Reactant: COC[C@@H](NC(=O)Nc1cc2[nH]nc(OC)c2cn1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H](NC(=O)Nc1ncc2c(OC)n[nH]c2c1Br)c1ccccc1

Procedure:
(S)-1-(2-Methoxy-1-phenylethyl)-3-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (Example 41, 53 mg, 0.155 mmol) and NBS (35.5 mg, 0.199 mmol) were stirred in DMF (1 mL) at room temperature for 6 hours. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave (S)-1-(7-bromo-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(2-methoxy-1-phenylethyl)urea MS: [M+H]+ m/z 420. 1H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.08 (d, J=7.0 Hz, 1H), 8.67 (s, 1H), 7.98 (s, 1H), 7.35-7.30 (m, 4H), 7.25-7.21 (m, 1H), 5.03-4.98 (m, 1H), 4.01 (s, 3H), 3.63-3.56 (m, 2H), 3.27 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16]Cl)[C:9]=2[CH3:18])[CH2:5][C:4](=[O:19])[C:3]=1[C:20](=[O:23])[CH2:21][CH3:22].[C-:24]#[N:25].[Na+]>>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16][C:24]#[N:25])[C:9]=2[CH3:18])[CH2:5][C:4](=[O:19])[C:3]=1[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: [C-]#N
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CCl)c2C)CC1=O
Agent: [Na+]
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Reaction time: 4 h
Yield: 81.8 %

Procedure:
A solution of 3-hydroxy 2-propionyl-5-(3-chloromethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (3.32, 9.96 mmol) in dmf (15 ml) was added to a suspension of sodium cyanide (0.98, 19.9 mmol) in dmf (10 ml). The mixture was stirred at 70° for 4 h, then cooled and partitioned between methylene choride and water. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (elution with an increasing gradient of ethyl acetate in methylene chloride) gave 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl) cyclohex-2-en-1-one (2.65 g, 81%) plus a further impure fraction. Proton magnetic resonance spectrum (CDCl3, δ in ppm): 1.18 (3H,t,J7 Hz); 2.33 (3H,s); 2.37 (3H,s); 2.42 (3H,s); 2.5-4.1(7H,m); 3.62 (2H,s); 7.90 (1H,s); 18.20 (1H,s). Infrared spectrum: ν (CHCl3) 2250 m cm-1.