Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[CH3:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25]>>[N+:11]([C:4]1[C:3]([CH3:14])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[O:16][CH3:15])([O-:13])=[O:12]
Reactant: COc1ccc(OC)c(O)c1
Reactant: Cc1c([N+](=O)[O-])ccc([N+](=O)[O-])c1F
Product: COc1ccc(OC)c(Oc2c([N+](=O)[O-])ccc([N+](=O)[O-])c2C)c1

Procedure:
The process was carried out as indicated in point 5.4. above, using 0.366 g (1.83 mmol) of the 2-fluoro-3,6-dinitrotoluene prepared in point 7.4. above and 0.282 g (1.83 mmol) of 2,5-dimethoxyphenol prepared in point 7.5. above. The title product was isolated in the form of a yellow solid, using a 70:30 mixture of light mineral spirit (60-80° C.):diethyl ether as eluent (0.400 g, 65.5%).
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)[OH:4].P(=O)(O)(O)O.[Al:12]>O>[CH3:2][CH:3]([CH3:5])[O-:4].[Al+3:12].[CH3:2][CH:3]([CH3:5])[O-:4].[CH3:2][CH:3]([CH3:5])[O-:4]
Reactant: OCC(O)CO
Reactant: [Al]
Agent: O=P(O)(O)O
Solvent: O
Product: CC(C)[O-]
Product: [Al+3]

Procedure:
Into the shell of a 500 mL Autoclave Engineers reactor are placed 45 g of a propoxylate of glycerin that has an average molecular weight of 450 (Voranol® CP450, The Dow Chemical Company). 1.7 microliters of a 0.15 M phosphoric acid solution in water, and 0.0030 g of the Arcol 3 catalyst. 0.037 mole of Aluminum isopropoxide/gram of DMC catalyst complex (enough to provide 10 parts per million of aluminum based on the expected mass of the product) is added and stirred in. The shell of the reactor is then placed on the reactor frame, and the reaction mixture is stirred and heated at a temperature of 145° C. for 90 minutes with a slow purge of nitrogen (0.5 standard cubic feet (14 liters) per hour) passing through the reactor contents. The reactor contents are heated to 150° C., and, while maintaining that temperature, propylene oxide (PO) is introduced into the reactor at a rate of 1.0 mL/min. The reactor initially climbs to an internal reactor pressure of 16.8 psig (116 kPa), at which time the pressure begins to decline slowly to a pressure of 6.2 psig (43 kPa) with a constant feed of PO at 1.0 mL/min. There is no pause in PO feed for catalyst activation. Eventually the pressure in the reactor begins to rise due to the compression of nitrogen gas in the reactor. The feed is continued until a total of 309.1 mL (255.0 g) of PO has been fed into the reactor. The time required to complete the PO feed is 5 hrs and 24 minutes. After all the PO has been fed into the reactor, the reaction mixture is cooked down at 150° C. until a steady internal reactor pressure (indicative of complete polymerization of the charged PO) is achieved. The PO digest time for this reaction is 12 minutes. A 3000 number average molecular weight product is obtained. The final DMC catalyst concentration in the reactor is 10 ppm.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]1[C:43]([NH2:45])=[O:44]>>[NH2:45][C:43]([C@H:38]1[CH2:39][CH2:40][CH2:41][CH2:42][C@H:37]1[NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18])=[O:44]
Reactant: NC(=O)[C@H]1CCCC[C@H]1N
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@@H]2C(N)=O)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and (1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtained in 92% purity by HPLC. MS(ESI+): m/z=491.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:25]=[C:24]4[CH2:32][CH2:33][C:34]([O:36]CC(C)C)=[O:35])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH:25]=[C:24]4[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)COC(=O)CCc1cn(CC(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Sodium hydroxide (114 mg) was added to a solution of 2-methylpropyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoate (D124) (77 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoic acid (E30) (42 mg). δH (DMSO-d6, 400 MHz): 0.52 (6H, d), 1.37 (6H, d), 1.51 (1H, m), 2.61 (2H, t), 2.99 (2H, t), 3.99 (2H, d), 4.89 (1H, m), 7.19 (1H, t), 7.22 (1H, s), 7.45 (2H, m), 7.82 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 12.04 (1H, br s); MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:19]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:12]([OH:16])(=[O:19])[CH3:13].[C:12]([OH:16])(=[O:19])[CH3:13].[CH:3]1[C:4]2[C:5](=[O:17])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:16])[C:13]=2[CH:14]=[CH:15][C:2]=1[CH:1]=[O:19]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methylanthraquinone (16.0 g, 72.0 mmol) in a mixture of acetic acid (400 ml) and acetic anhydride (400 ml) was added concentrated sulfuric acid (16 ml) at 5° C. Chromium trioxide (18.0 g, 0.18 mmol) was added over a period of 1 hour at 5° C. The reaction mixture was then stirred at 5° C. for 4 hours, poured into ice water, and extracted with chloroform. The organic extract was dried over MgSO4 and concentrated under vacuum to give anthraquinone-2-aldehyde diacetate (16.0 g, 65%.) To a solution of the anthraquinone-2-aldehyde diacetate (16.0 g, 47.3 mmol) in acetic acid (400 ml) was added dropwise 35% aqueous hydrochloric acid (170 ml) at room temperature. The reaction mixture had been stirred while refluxing for 15 min, cooled to room temperature, filtered off with suction, and washed with water. After drying, anthraquinone-2-aldehyde (10.0 g, 89%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[C:5]([C:9]1[CH:10]=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]2[O:16][C:15](=[O:17])[CH:14]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:13]=2[CH:25]=1)([CH3:8])([CH3:7])[CH3:6].Cl>[OH-].[Na+]>[C:5]([C:9]1[CH:10]=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]2[O:16][C:15](=[O:17])[CH:14]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:2][CH2:3][OH:4])=[CH:22][CH:23]=3)[C:13]=2[CH:25]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: OCCCl
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
1.0 ml (15.0 mmol) of 2-chloroethanol is added to a solution of 3.38 g (10.0 mmol) of 5,7-di-tert-butyl-3-(4-hydroxyphenyl)benzofuran-2-one in 30 ml of 1N sodium hydroxide solution heated to 80° C. The reaction mixture is then maintained at 80° C. for 2 hours, 50 ml of 1N hydrochloric acid are added, stirring is continued for 1 hour, the mixture is cooled, and the product is extracted with dichloromethane. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from 8 ml of ethanol and 2 ml of water gives 2.34 g (61%) of 5,7-di-tert-butyl-3-[4-(2-hydroxyethoxy)phenyl]-benzofuran-2-one m.p. 132°-135° C. (compound (105), Table 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])CO)[CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>CO.CCOCC>[F:17][C:14]([F:15])([F:16])[C:10](=[O:13])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 4.9 g (15.8 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol in 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. The mixture was stirred for 4 hours and was then diluted with 100 mL of ether and 100 mL of hexanes, filtered through diatomaceous earth, and concentrated in vacuo. The crude residue was dissolved in hexanes and passed through a pad of silica gel, eluting first with hexanes then with EtOAc-hexanes (2:98, then 4:96) to afford 3.85 g (87%) of the title compound as a clear oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH:23]1[C:35]2[N:34]([C:36](Cl)=[O:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.O>C(Cl)Cl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:36]([N:34]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:35]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:37])[CH2:3]2)=[CH:14][CH:13]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)n1c2ccccc2c2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)n1c2ccccc2c2ccccc21
Yield: 47.3 %

Procedure:
(S)-3-Amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) and triethylamine (0.28 ml) were dissolved in methylene chloride (10 ml), and carbazole-N-carbonyl chloride (0.46 g) was added under ice-cooling. After the completion of the reaction, water was added, and the mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)carbazole-9-carboxamide (0.38 g), melting point 107-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[N:15]=[N+]=[N-])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([F:14])[CH:8]=1)[CH3:2]>CC1C=CC(C)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:12]2[C:7]([CH:6]=1)=[CH:8][C:9]([F:14])=[C:10]([CH3:13])[CH:11]=2)=[O:18])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(C)c(F)c1)N=[N+]=[N-]
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1cc2cc(F)c(C)cc2[nH]1
Temperature: 15 °C
Yield: 37.1 %

Procedure:
(Z)-2-Azido-3-(3-fluoro-4-methyl-phenyl)-acrylic acid ethyl ester (9.7 g, 0.039 mol) was dissolved in 80 ml p-xylene and divided into four portions which were refluxed for 1 h. The oil bath was removed and the yellow solutions were cooled to 15° C. The resulting suspensions were filtered, washed with n-hexane and the solid material collected. The combined mother liquors were evaporated and the resulting oil was purified on silical gel (0.030-0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent. The purified fractions together with the first precipitates were combined and chromatographed again to yield the desired product as a colorless solid (3.2 g, 37.2%). EI-MS: m/e=249.1 (M).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[C:9]3[C:12](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][S:14](=[O:17])(=[O:16])[CH2:15][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([N:11]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:15][S:14](=[O:16])(=[O:17])[CH2:13][C:12](=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]2=[N:10]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=S1(=O)CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1N=C2C(=Cc3ccccc3)CS(=O)(=O)CC2C1c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 1.6g of 2,3,3a,4,6,7-hexahydro-3-phenyl-7-(phenylmethylene)thiopyrano[4,3-c]pyrazole-5,5-dioxide in 2ml of acetic anhydride and 30ml of acetic acid is heated on a steam bath for 15 minutes. Hot water (50ml) is added with stirring and the solution is allowed to cool to room temperature. The solids are collected and washed well with water and dried in vacuo over phosphorus pentoxide at 50°C to yield 1.65g of the title compound, melting point 218°-219.5°C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([F:35])[C:19]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:24][C:20]=1[C:21](O)=[O:22].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:21](=[O:22])[C:20]3[CH:24]=[C:25]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[N:27][C:19]=3[CH:18]([F:35])[F:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(NC(C)(C)C)ncnc23)c1
Yield: 5.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 150 mg, 0.55 mmol), oxalyl chloride (104 mg, 0.83 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH2Cl2 (2 mL) to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.71 (s, 1H), 8.63 (m, 1H), 8.49 (m, 2H), 8.16 (d, 1H), 8.05 (m, 1H), 7.46 (m, 2H), 7.22 (t, J=54 Hz, 1H), 4.42 (d, 2H), 1.55 (s, 9H), 1.05 (d, J=6.6 Hz, 6H); MS [M+H]+: 471.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1.C(OCC)(=O)C>[C:29]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])(=[O:31])[CH3:30]
Reactant: COc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2coc3ccc(C(=O)NNC(C)=O)cc23)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-1-benzofuran-5-carbohydrazide (565 mg, 2.00 mmol) and triethylamine (0.418 mL, 3.00 mmol) in tetrahydrofuran (30 mL) was added acetyl chloride (0.213 mL, 3.00 mmol) at room temperature, and the resulting mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) to give the title compound (613 mg, yield 94%) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CC(=O)CC>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:20][CH:22]2[CH2:23][O:24]2)[CH:8]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(-c2cccc(OCC3CO3)c2)cc1
Temperature: 80 °C

Procedure:
7.4 g of 3-phenylphenol, 52.7 g of 2-butanone and 21.5 g of potassium carbonate were initially charged to a three-neck flask equipped with KPG stirrer and stirring motor and also drier tube. After conditioning to 22° C. 23.8 g of epibromohydrin were added dropwise within about 2 hours, the temperature increased to 80° C. and then the mixture was stirred at about 75° C. for a further 45 hours. This was followed by filtration and removal of the solvent in a rotary evaporator to obtain a clear yellowish thinly liquid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH2:18]C)[CH2:12][C:13]([OH:15])=[O:14].C([Mg]Br)CC>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH3:18])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCC(CC(=O)O)c1ccc(OC)cc1OC
Agent: CCC[Mg]Br
Product: CCCC(CC(=O)O)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 42a, but using propylmagnesium bromide instead of butylmagnesium bromide, the title compound was obtained as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(Cl)n1
Reactant: c1ccc2c(c1)CCN2
Solvent: C1COCCO1
Product: Nc1nccc(N2CCc3ccccc32)n1
Yield: 89.2 %

Procedure:
A suspension of 2-amino-4-chloropyrimidine (1.3 g; 10 mM) in dioxan (30 ml) was treated with indoline (2.4 g; 20 mM) and the mixture was heated for 18 hours at 95°-100° C. The precipitated product was separated from the cooled mixture by filtration and suspended in a mixture of 2-propanol (30 ml) and a solution of potassium hydroxide flake (6 g) in water (10 ml). This mixture was stirred and heated at 95°-100° C. for one hour. The hot 2-propanol solution was separated from the aqueous layer and allowed to cool. The solid product was recrystallised from 2-propanol to give 2-amino-4-(indolin-1-yl)pyrimidine as a solid (1.9 g, 89.6%), m.p. 177°-179° C.; microanalysis, found: C,62.2; H,6.2; N,23.8%; C12H12N4.H2O requires: C, 62.6; H,6.1; N,24.3%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH:13]([CH3:15])[CH3:14])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH:13]([CH3:14])[CH3:15])[C:9](=[O:12])/[CH:10]=[CH:11]/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(I)c1
Reactant: C=CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.6 %

Procedure:
To a solution of ((R)-1-Isopropyl-2-oxo-but-3-enyl)-carbamic acid tert-butyl ester (13.54 g, 59.6 mmol) in dry acetonitrile (150 mL) under argon, was added 3-iodoanisole (113.96 g, 59.6 mmol), triethylamine (9.1 mL 65.6 mmol) followed by palladium (II) acetate (335 mg, 1.49 mmol). The resulting clear yellow solution was heated to 80° C. Upon heating, the reaction darkened and the precipitation of palladium black occurred. After 15 h, the reaction mixture was allowed to cool to room temperature, quenched with water (150 mL) and diluted with ether (150 mL). The ether layer was washed with brine (100 mL) and the combined aqueous layers were extracted with ether (two 50 mL portions). The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was immediately purified by silica gel chromatography (9:1 hexanes/EtOAc) to provide 17.6 g (88%) of [(R)-(E)-1-Isopropyl-4-(3-methoxy-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester as a yellow oil. MS(ES+) m/e 334.0 [M+H]+.
Reaction SMILES: [C:1]1(/[C:7](/[CH2:34][CH3:35])=[C:8](\[C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]#[N:33])=[CH:26][CH:25]=2)/[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20]O2)[N:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:37][OH:38].C(N(CC)CC)C.[OH2:46]>CS(C)=O>[OH:38]/[N:37]=[C:32](\[NH2:33])/[CH:31]=[CH:30]/[C:27]1[CH:28]=[CH:29][C:24](/[C:8](/[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:46]2)[N:13]=[CH:12]3)=[C:7](\[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)/[CH2:34][CH3:35])=[CH:25][CH:26]=1
Reactant: O
Reactant: NO
Reactant: CC/C(=C(/c1ccc(/C=C/C#N)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC/C(=C(/c1ccc(/C=C/C(N)=N/O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Temperature: 75 °C

Procedure:
To a solution of (E)-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylonitrile (380 mg, 0.83 mmol) and hydroxylamine hydrochloride (265 mg, 3.8 mmol) in DMSO (8 mL) was added triethylamine (0.5 mL, 3.8 mmol), and the mixture was heated at 75° C. for 24 h. After cooling, water was added, and the solution was extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried (MgSO4) and concentrated. Purification by silica gel chromatography (0 to 65% EtOAc/hexanes) provided 116 mg of the title compound as a yellow foam. LCMS: 409 [(M-THP+H)+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[H-].[Na+].[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[CH3:12].C([Li])CCC.CCCCCC.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH3:12][C:11]([CH3:13])([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]([OH:15])=[O:14]
Reactant: CC(C)C(=O)O
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(CCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21.5 %

Procedure:
To a stirring mixture of diisopropylamine (2.2 mL, 15 mmol) and sodium hydride [60% in mineral oil] (0.66 g, 16.5 mmol) in dry THF (50 mL), isobutyric acid (1.4 mL, 15 mmol) was dropwise added. The mixture was refluxed for 15 min, cooled to 0° C., and 2.5M n-butyllithium (BuLi) in hexane (5.45 mL, 14 mmol;) was added. After 20 min at 0° C., the mixture was heated to 30-35° C. for 30 min. The solution was then cooled to 0° C. and (2-bromoethyl)-benzene (2.8 mL, 15 mmol) was slowly added over 20 min. After ca. 1 h at 30-35° C. the reaction was quenched by adding water (40 mL), while keeping the temperature below 15° C. The aqueous layer was separated, and the organic layer washed with a mixture of Et2O/H2O (1:1). The aqueous layers were combined, extracted with Et2O (20 mL), acidified with 2M HCl solution, and the product was further extracted with Et2O (2×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (0.619 g, 21%) as a colorless oil. 1H NMR (CDCl3): δ 1.31 (s, 6H), 1.86-1.95 (m, 2H), 2.59-2.68 (m, 2H), 7.17-7.33 (m, 5H).