Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[N:14](C(=O)C2C=CC=CC=2)[N:13]=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:13][N:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(-c2ccccc2)nn1C(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(Nc1cc(-c2ccccc2)[nH]n1)c1ccccc1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A suspension of 100 mg (0.27 mmoles) of 5-benzoylamino-3-phenyl-1-benzoylpyrazole in 4 ml of 10% (w/v) aqueous potassium hydroxide was heated in a water bath maintained at 100° C. for five minutes. During this time the reaction mixture remained a suspension. The cooled suspension was filtered and washed with water, then air-dried. There was obtained 48 mg (0.18 mmoles, 67%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH:19]=[C:20]([CH:22]=O)[CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: CC(=O)N1c2ccc(-c3cc(C=O)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cc(CN4CCCCC4)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(4-formyl-2-furanyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 20) (28 mg, 0.073 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with piperidine (8.65 μL, 0.087 mmol) and acetic acid (8.34 μL, 0.146 mmol) and stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (20.07 mg, 0.095 mmol) was added and the mixture was stirred again under nitrogen. After 16 hours reaction time the mixture was loaded onto a 2 g Flash SCX-column, eluting with MeOH (60 mL) followed by 2M MeOH/NH3 (60 mL). The product-containing fraction was evaporated to dryness to give a light brown solid (19 mg).
Reaction SMILES: CC([CH2:4][C:5]([OH:7])=[O:6])=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9].C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:5]([OH:7])(=[O:6])[CH3:4].[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9]
Reactant: CC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Oc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O

Procedure:
The preparation of monoacetates of hydroquinone and catechol has been investigated, according to early publications, with varying results. Oltcott (J. Am. Chem. Soc. 59, 1937, 392-393) has found, that the monacetylation of these two dihydroxybenzenes can be performed by careful reaction with an acetylating agent, e.g. acetic anhydride, in aqueous alkaline solution. The desired mono-acetate was obtained in a yield of only 20-30%, whereas the major product obtained was the diacetate. Johnston (Chem. Ind. 1982, 1000) has succeeded in improving the formation of the mono-acetate of hydroquinone from hydroquinone and acetic anhydride by using triethyl amine as a base and 4-dimethylaminopyridine (DMAP) as a catalyst, in a polar organic solvent, viz. in ethyl acetate solution. Under such reaction conditions, Johnston has succeeded in obtaining hydroquinone mono-acetate in yields of 58-65%.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=1)#[N:2].[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:20][C:19]1[C:14]([NH:13][C:7]2[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:22])=[N:15][C:16]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=3[CH:25]=2)=[N:17][CH:18]=1
Reactant: Cc1cccc(C(=O)NCC#N)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: Cc1cccc(C(=O)NCC#N)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 12.4 %

Procedure:
N-Cyanomethyl-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-benzamide (50.0 mg, 0.000149 mol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (30.4 mg, 0.000149 mol) and 10-Camphorsulfonic acid (34.6 mg, 0.000149 mol) were suspended in Isopropyl alcohol (3.0 mL, 0.039 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The reaction mixture was then reduced under nitrogen and the crude residue was isolated and purified by Gilson prep HPLC to afford 9.33 mg (12%) of 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-cyanomethyl-3-methyl-benzamide. LC/MS (ESI): 504.15. 1H NMR (400 MHz, DMSO, d6) δ 9.15 (s, 1H), 9.08 (m 1H), 8.93 (m, 1H), 8.80 (m, 1H), 8.11 (s, 1H), 7.50 (m, 2H), 7.34 (m, 3H), 6.61 (d, 1H, J=8.59 Hz), 4.21 (d, 2H, J=5.05 Hz), 2.32 (s, 3H), 2.12 (m, 2H), 1.93 (m, 2H), 1.22 (s, 6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:29])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[N:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#N)=[CH:15][CH:14]=2)[N:10]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:51])C>CCCCCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:29])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[N:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=[O:51])=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a mixture of 2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrile (4.50 g) and anhydrous toluene (150 mL) was dropwise added a solution (0.95 M, 25.5 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 15 min. To this mixture was added ethyl acetate and the mixture was stirred at room temperature for 30 min., and then insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.60 g, 57%) of 2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3S(C3C=CC=C(F)C=3)(=O)=O)=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:34](OC(=O)C1C=CC(N)=CC=1F)[CH3:35]>>[CH2:34]([O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:35]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CCC2
Reactant: CCOC(=O)c1ccc(N)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1F

Procedure:
2-Fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 473.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester, which was reduced to 2-fluoro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15]I.Cl>CO>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:15])[C:11]([O-:13])=[O:12].[Na+:2]
Reactant: CI
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) and 40 ml of methanol were added to 1.64 g (10.0 mmoles) of phenylpyruvic acid to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellowish white solid. To the solid was added 3 ml of a 3N aqueous solution of sodium hydroxide, and the mixture was concentrated under reduced pressure. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-phenylbutanoate was isolated as a white solid (1.62 g; yield 81 %) by filtration.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](=[O:42])[NH:36][C:37]4[NH:38][CH2:39][CH2:40][N:41]=4)=[CH:27][CH:26]=3)[C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>FC(F)(F)C(O)=O.O>[C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](=[O:42])[NH:36][C:37]4[NH:41][CH2:40][CH2:39][N:38]=4)=[CH:29][CH:30]=3)[C:17]([OH:19])=[O:18])=[O:14])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)cc1)NC1=NCCN1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
188 mg (0.32 mmol) of (5.1) were dissolved in 10 ml of trifluoroacetic acid/H2O (95:5). After 30 min, the solvent was removed in vacuo and the residue was digested with diisopropyl ether. After freeze-drying, 168 mg of an amorphous powder of (5.2) were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=3)[CH:14]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:32][C:33]1[CH:34]=[C:35]([C:40]2[N:44]=[C:43]([CH:45]3[CH2:48][N:47]([C:49]([O:51][CH3:52])=[O:50])[CH2:46]3)[O:42][N:41]=2)[CH:36]=[CH:37][C:38]=1[CH3:39]>ClCCl.N1C=CC=CC=1>[CH3:39][C:38]1[CH:37]=[CH:36][C:35]([C:40]2[N:44]=[C:43]([CH:45]3[CH2:46][N:47]([C:49]([O:51][CH3:52])=[O:50])[CH2:48]3)[O:42][N:41]=2)=[CH:34][C:33]=1[NH:32][C:18]([C:15]1[N:13]2[CH:14]=[C:9]([CH2:8][CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH:10]=[CH:11][C:12]2=[N:17][CH:16]=1)=[O:20]
Reactant: O=C(O)c1cnc2ccc(CCN3CCOCC3)cn12
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCN6CCOCC6)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(2-morpholinoethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24l) (50 mg, 0.182 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (17 uL, 0.200 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (26 mg, 0.0908 mmol) in anhydrous pyridine (1.5 mL) was stirred at room temperature for 2 hours. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(4-methyl-3-(6-(2-morpholinoethyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F66). 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 9.46 (s, 1H), 8.61 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 2H), 7.52-7.49 (m, 2H), 4.39-4.36 (m, 2H), 4.31-4.26 (m, 1H), 4.21-4.17 (m, 2H), 4.03-4.00 (m, 2H), 3.69-3.63 (m, 2H), 3.59 (s, 3H), 3.54-3.44 (m, 4H), 3.14-3.10 (m, 4H), 2.38 (s, 3H). MS m/z 546.24 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:17][CH2:18][CH3:19].C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C1COCC1.O.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>[CH3:15][C:6]1([CH3:16])[C:5]2[C:10](=[CH:11][C:2]([C:25](=[O:27])[CH3:26])=[C:3]([O:17][CH2:18][CH3:19])[CH:4]=2)[C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH2:7]1
Reactant: CCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CCC2(C)C
Temperature: 25 °C

Procedure:
To a solution 7-bromo-4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalene (Compound A-32, 284 mg, 0.879 mmol) in THF (5 mL) was tributyl(1-ethoxyvinyl) tin (0.445 mL, 1.32 mmol), and the resulting solution was purged with dry argon for 15 min. Dichlorobis(triphenylphosphine)palladium(II) (0.031 g, 0.044 mmol) was added and the solution was refluxed until the reaction was complete by TLC analysis. The reaction was cooled to room temperature. The mixture was diluted with water, extracted with ethyl ether, washed with brine, dried over MgSO4, and filtered. The solvent was removed under reduce pressure, and the residue was purified by flash column chromatography (silica gel, 95:5 hexane/ethyl acetate) to produce the title compound as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:18]=1)[N:9]=[C:8]2[NH:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]2.[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C=O)C.C1COCC1>[CH3:16][O:15][C:14]1[CH:13]=[C:12]2[C:7]([C:8]([NH:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]4)=[N:9][C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)=[N:11]2)=[CH:6][C:5]=1[O:4][CH2:3][CH2:2][N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C1CCNC1
Reactant: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCC1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.280 g, 0.407 mmol) in DMF (2 mL) and THF (3 mL) was added pyrrolidine (0.8 mL). The resultant mixture was heated at 85° C. for 2 h, upon which it was allowed to cool to RT, the volatiles were removed in vacuo and the residue was taken up in ice-water (200 mL). The resulting precipitate was collected via filtration and subjected to preparative TLC (SiO2, CH2Cl2:MeOH 83:17) to give tert-butyl 5-(7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g, 0.118 mmol, 29%). HPLC retention time 3.81 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:45]3[CH:46]=[CH:47][S:48][C:44]=3[CH2:43][CH2:42][NH:41]2)=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH:40]2[C:45]3[CH:46]=[CH:47][S:48][C:44]=3[CH2:43][CH2:42][N:41]2[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])=[CH:38][CH:39]=1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(O)cc1)N1CCc2sccc2C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Hydroxybenzoic acid (1.3 g, 9.6 mmol) was dissolved in N,N-dimethylformamide (25 ml) and 1-hydroxybenzotriazole (1.3 g, 9.6 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.8 g, 9.6 mmol), 4-(4-chlorophenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (2.0 g, 8 mmol) and N,N-diisopropylethylamine (2.5 ml, 16 mmol). The resulting mixture was stirred at room temperature for 16 hours. Water (200 ml) was added and the mixture was extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (150 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluting with a mixture of ethyl acetate and heptane (1:1). The pure fractions were pooled and concentrated in vacuo to afford 3.14 9 (100%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])=[CH:4][C:5](OCC)=[O:6].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])=[CH:4][CH2:5][OH:6]
Reactant: CCOC(=O)C=C(C)C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=CCO)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4.5 g of ethyl 4,4,4-trifluoro-3-methyl-2-butenoate in 50 ml of tetrahydrofuran was added dropwise 48 ml of diisobutylaluminum hydride (1.02M solution in hexane) under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added diluted sulfuric acid and then extracted with t-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain crude 4,4,4-trifluoro-3-methyl-2-buten-1-ol.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8][Br:9])[CH:7]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1.O>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH:8]([Br:12])[Br:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(CBr)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: c1ccccc1
Product: COc1ncc(C(Br)Br)cc1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-bromomethyl-2-methoxy-pyridine (6.03 g, 21.5 mmol), N-bromosuccinimide (4.09 g, 23.0 mmol), and azobisisobutyronitrile (one scoop) were combined in benzene (40 mL) and stirred at 80° C. for 4 hours. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-Bromo-5-dibromomethyl-2-methoxy-pyridine.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:10]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[Si:14]([O:13][C@H:11]1[C@H:10]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:9][NH:8][CH2:12]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(Cc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
A mixture of (3R,4R)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine (13.4 g, 31.8 mmol) and Pd(OH)2/C (2.23 g, 3.18 mmol, 20%) in MeOH (134 mL) was stirred for 20 h under H2 atmosphere (balloon). The reaction mixture was filtered through a Celite plug and concentrated under reduced pressure to afford 10.5 g (91%) of the crude (3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine that was used directly without further purification.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N:19][C:18]=2[CH:23]=1.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[C:25]1=[O:34])[CH2:31]2>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22][C:25]3([OH:34])[CH:26]4[CH2:32][CH:30]5[CH2:29][CH:28]([CH2:33][CH:24]3[CH2:31]5)[CH2:27]4)=[N:19][C:18]=2[CH:23]=1
Reactant: COc1ccc2sc(C)nc2c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1ccc2sc(CC3(O)C4CC5CC(C4)CC3C5)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 mL of a 1.6 M n-butyllithium solution is hexane are added dropwise to a solution of 358 mg of 5-methoxy-2-methylbenzothiazole (formula VIII) in 5 ml of dry THF, cooled to about −78°and the mixture obtained is stirred for about one hour. Solid 2-adamantanone (formula VI) is added and the mixture is kept at −78° for about one hour. The mixture is allowed to warm to room temperature and 400 μl of acetic acid are added. The resultant mixture is diluted with 600 ml of ethyl acetate and extracted with saturated NaH2PO4 solution. The solvent of the organic phase is evaporated off and the residue obtained is subjected to chromatography. The title compound is obtained (m.p. 140-142°).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[C:5]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>C1COCC1>[Cl:12][C:10]1[N:9]=[CH:8][C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:3](=[O:19])[N:4]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[C:5]=2[CH:11]=1
Reactant: CCCOCCn1c(=O)c(Cl)nc2cnc(Cl)cc21
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOCCn1c(=O)c(N2CCNCC2)nc2cnc(Cl)cc21
Yield: 72 %

Procedure:
A solution of 3,7-dichloro-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one (193 mg, 0.64 mmol), piperazine (118 mg, 0.91 mmol, Aldrich) and triethylamine (0.15 mL, 1.07 mmol) in THF (3 mL) was stirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give a brown oil. This was passed through a column of silica gel with 80-100% ethyl acetate/hexane to give 7-chloro-3-(piperazin-1-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one. (183 mg, 72% yield).