Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.ClC(Cl)C.[CH3:36][N:37]([CH3:48])[C:38](=[O:47])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[CH:41]=1>>[CH3:36][N:37]([CH3:48])[C:38]([O:39][C:40]1[CH:41]=[C:42]([NH:46][C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:43]=[CH:44][CH:45]=1)=[O:47]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
1-(tert-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (67 mg, 0.28 mmol), EDC (64 mg, 0.33 mmol), HOBT (45 mg, 0.33 mmol) and dichloroethane (2.0 mL) were combined in a pressure rated sealed tube and stirred for 45 min. 3-Aminophenyl dimethylcarbamate (50 mg, 0.28 mmol) was added, and the mixture was heated at 85° C. for 18 hours. The mixture was concentrated and chromatographed (SiO2, 0-2% MeOH:CH2Cl2) to give the title compound in 50% yield. MS (ES+) [M+H]+=406.
Reaction SMILES: BrC1C=CC2[C:6](C3C=CC(O)=CC=3)=[N:7]OC=2C=1.BrCCCCCCBr.[Br:26][C:27]1[CH:49]=[CH:48][C:30]2[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)=[CH:36][CH:35]=3)=[N:32][O:33][C:29]=2[CH:28]=1.C(NC)C=C>>[Br:26][C:27]1[CH:49]=[CH:48][C:30]2[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:7][CH3:6])=[CH:36][CH:35]=3)=[N:32][O:33][C:29]=2[CH:28]=1
Reactant: BrCCCCCCOc1ccc(-c2noc3cc(Br)ccc23)cc1
Reactant: Oc1ccc(-c2noc3cc(Br)ccc23)cc1
Agent: BrCCCCCCBr
Agent: C=CCNC
Product: CNCCCCCCOc1ccc(-c2noc3cc(Br)ccc23)cc1

Procedure:
Analogously to Example 1, from 4-(6-bromo-benzo[d]isoxazol3-yl)-phenol and 1,6-dibromohexane via 6-bromo-3-[4-(6-bromo-hexyloxy)-phenyl]-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained allyl-[6-[4-(6-bromo-benzo[d]-isoxazol-3-yl)-phenoxy]-hexyl-methyl-amine which is converted into the fumarate, MS: m/e 442 (M+H+, 1 Br).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H].C1(C2C=CC(O)=CC=2)C=CC=CC=1>>[C:2]1([OH:1])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2=CCC(O)CC2)cc1
Reactant: [H][H]
Agent: Oc1ccc(-c2ccccc2)cc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
It was found that a novel compound 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol can be obtained in good yield by conducting a decomposition reaction in the initial stage of a reaction in the absence of a dehydrogenation catalyst and a hydrogen acceptor, and that by-products such as p-phenylphenol can be virtually inhibited by conducting the dehydrogenation reaction of the novel compound to give 4,4'-biphenol of high purity.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11](=[O:18])C1C=CC=CC=1.N1CCCC1>CO>[O:18]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][CH2:11]1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CCOc2ccccc21
Temperature: 50 °C

Procedure:
2-Hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII under suitable conditions to provide chroman-4-one compounds of structure XXXXIII. In some embodiments, 2-hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII, pyrrolidine, and methanol, with heating to about 50° C. for about 2 days to provide chroman-4-one compounds of structure XXXXIII. Chroman-4-one compounds of structure XXXXIII are then reacted tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate, potassium bicarbonate, a suitable arylbromide, and 1,4-dioxane/water (4:1,) at about 110° C. to provide chroman-4-one compounds of structure XXXXIV. Chroman-4-one compounds of structure XXXXIV are then treated with methyl magnesium chloride in tetrahydrofuran at about 0° C., followed by 80% AcOH/H2O with warming to about 90° C. to provide compounds of structure XXXXV.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)([F:4])[CH3:3].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccccc1Br
Reactant: C1CNCCN1
Product: CC(F)(F)c1ccccc1N1CCNCC1

Procedure:
A solution of diethylaminosulfur trifluoride (560 mg, 3.47 mmol, 3 eq) and 2-bromoacetophenone (230 mg, 1.16 mmol, 1.0 eq) was heated to 40° C. for about 72 hours. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate, water, brine, dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (35 g SiO2, linear gradient 0-10% ethyl acetate/Hexanes, 30 mL/minute, over 30 minutes) afforded about 125 mg (0.57 mmol, 49%) of 2-(1,1-difluoroethyl)-1-bromobenzene. GC/MS (EI): 220 (M+H). 2-(1,1-Difluoroethyl)-1-bromobenzene was coupled to piperazine in a manner similar to Preparation 1A. LRMS (ESI+): 227.2 (M+1)
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](O)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:20])=O.CN(C)C=O>>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([Cl:20])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (600 mg, 2.5 mmol) in thionyl chloride (5400 L, 7.4 mmol) was added N,N-dimethylformamide (60 L, 0.60 mmol). The reaction mixture was stirred at room temperature for one hour. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OCCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(OCCCc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenylpropanol and DBU in THF. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.O>CCOC(C)=O>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([S:18]([CH3:19])=[O:28])[N:3]=1
Reactant: CSc1ncc(C(=O)OCc2ccccc2)c(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(S(C)=O)ncc1C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (3.6 g) and m-chloroperbenzoic acid (P=75%) (2.72 g) in AcOEt (30 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with saturated NaHCO3 solution, brine and dried over MgSO4. The solvent was evaporated in vacuo to give benzyl 4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate (3.2 g)
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: CC(C)(O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(C)(C)O)c1

Procedure:
Prepared from 285 mg (0.648 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide, 268 mg of potassium carbonate and 150 μL of methoxymethyl chloride in 2 mL THF using procedure x. Yield: 153 mg of a white solid. LC-MSD, m/z for C16H17BrCl2N2O4S [M+H]+=482.9, 484.9, 486.9
Reaction SMILES: [C:1]([C@H:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:1]([C@H:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2C(C)(C)C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (S)-6-tert-butyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (1.35 g, 3.31 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 12, step b; and yielded, after chromatographic purification and crystallization from a mixture of diethyl ether-hexane, 4-{[(S)-6-tert-butylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.975 g, 2.48 mmol, 75%) as a homogeneous, colorless, crystalline (prisms), single enantiomer*, m.p. 187-189° C.;
Reaction SMILES: C(=O)(O)O.[Na].CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[Na].[CH:25]([NH:28][N:29]1[C:33]([SH:34])=[N:32][N:31]=[N:30]1)([CH3:27])[CH3:26].[Na].C(=NN1C(S)=NN=N1)(C)C>O>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:34][C:33]3[N:29]([NH:28][CH:25]([CH3:27])[CH3:26])[N:30]=[N:31][N:32]=3)[CH2:20][S:19][C@H:14]12
Reactant: CC(C)Nn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)=Nn1nnnc1S
Agent: O=C(O)O
Agent: [Na]
Solvent: O
Product: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 66.1 %

Procedure:
To a solution of sodium hydrogen bicarbonate (1 g, 12 mmol) in water (80 ml) were added 7β-aminocephalosporanic acid (3 g, 11 mmol) and 1-isopropylamino-5-mercapto-1H-tetrazole sodium salt (4 g, 22 mmol). The mixture was treated in a manner similar to that described in Example 6, (a) to give pale brown powder of 7β-amino-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.7 g, 66%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH:47]([OH:50])[CH2:48][CH3:49])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([O:44][CH3:45])=[N:41][C:42]=4[CH3:43])[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([C:47](=[O:50])[CH2:48][CH3:49])=[CH:26][CH:25]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
Dess-Martin reagent (207 mg, 0.487 mmol) was added to a stirred solution of 1-[9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido [1,2- a]benzimidazol-6-yl]propan-1-ol (178 mg, 0.443 mmol) in dimethyl sulfoxide (1.0 mL) and acetonitrile (3.0 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (172 mg, 0.430 mmol, 97%).
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.FC1(F)C(F)=CC=C(OCC2C3C=NC(C(OCC)=O)=CC=3N(CC)C=2)C1.[F:59][C:60]1[C:61]([OH:85])=[C:62]([CH:80]=[C:81]([F:84])[C:82]=1[F:83])[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([O:75]CC)=O)=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1>>[CH2:78]([N:66]1[C:67]2[CH:72]=[C:71]([C:73]([NH:21][OH:22])=[O:75])[N:70]=[CH:69][C:68]=2[C:64]([CH2:63][C:62]2[CH:80]=[C:81]([F:84])[C:82]([F:83])=[C:60]([F:59])[C:61]=2[OH:85])=[CH:65]1)[CH3:79]
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)c(F)c(F)c1O)cn2CC
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2c(cn1)c(COC1=CC=C(F)C(F)(F)C1)cn2CC
Product: CCn1cc(Cc2cc(F)c(F)c(F)c2O)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(3,4,5-trifluoro-2-hydroxybenzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 2,3,4-trifluorophenol using a methods similar to that set forth in Example 55. (b) 1-Ethyl-N-hydroxy 3-(3,4,5-trifluoro-2-hydroxybenzyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from a mixture of ethyl 3-(3,3,4-trifluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3,4,5-trifluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]([NH:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:35])[CH3:36])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)CC1CCc2cc(OCc3ccc(NC(=O)c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (0.14 ml) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; ethyl acetate), and recrystallized (THF-IPE) to give the titled compound (240 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>CN(C=O)C.O>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: ClCCCI
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 26.0 mmol) in DMF (100 ml), cooled to 0° C. was added sodium hydride (3.12 g, 78 mmol). The mixture was stirred until bubbling had ceased, then 1-chloro-3-iodopropane (8.23 ml, 78 mmol) was added. The reaction was kept in an ice bath and allowed to warm to room temperature slowly, then stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with a 1:1 mixture of brine and water (3×), then brine (1×). The organic phase was dried, filtered and concentrated then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.22 g, 19.43 mmol, 74.7% yield).
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:23](=[O:25])[NH:22][C:21]([CH2:26][CH3:27])=[N:20][C:19]=3[N:18]=[C:17]([S:28][CH2:29][C:30]3[N:31]=[C:32]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[S:33][CH:34]=3)[C:16]=2[C:42]#[N:43])=[CH:11][CH:10]=1)(=O)CC.[OH-].[Li+]>O1CCOCC1.O>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[S:33][CH:34]=[C:30]([CH2:29][S:28][C:17]3[C:16]([C:42]#[N:43])=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][OH:5])=[CH:10][CH:11]=4)[C:24]4[C:23](=[O:25])[NH:22][C:21]([CH2:26][CH3:27])=[N:20][C:19]=4[N:18]=3)[N:31]=2)=[CH:40][CH:39]=1
Reactant: CCC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc3nc(CC)[nH]c(=O)c23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccc(OCCO)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 mg (0.063 mmol) of 2-{4-[7-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-6-cyano-2-ethyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-5-yl]phenoxy}ethyl propanoate were initially charged in 4 ml of a dioxane/water mixture 2:1, 3 mg (0.127 mmol) of lithium hydroxide were added and the mixture was stirred at RT. After 3 h, the reaction mixture was purified by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5, with 0.1% TFA added). This gave 27 mg (70% of theory) of the target compound.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:2][NH2:3])[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: NN
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: NN=C(C(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Benzoin, 60 g, is suspended in 600 ml acetic anhydride and 60 ml concentrated sulfuric acid is added under ice cooling. Under continued ice cooling, 33 g potassium nitrate is added in small portions. The reaction is stirred at room temperature for two days and poured over ice. The aqeuous portion is decanted off and the remaining oil is taken up in ether, washed with water, sodium bicarbonate solution, dried over potassium carbonate and stripped. The oil residue is added dropwise to concentrated nitric acid at 0°, followed by heating gently on a steam bath for 2 hours. After cooling, the solution is poured over ice. The solid which forms is removed by filtration (~40 g) and recrystallized three times from glacial acetic acid, to yield 5.5 g of a yellow solid, 4-nitrobenzil. To a solution of 0.7 g hydrazine hydrate in 50 ml ethanol is added a suspension of 4-nitrobenzil, 5.1 g, in 150 ml of ethanol. The reaction is heated on a steam bath for 1 hour and cooled. Plate-like crystals separate out and are removed by filtration. Yield 3.5 g. The product is recrystallized from 200 ml ethanol. M.P. 166°-173°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[NH2:14][OH:15].[OH-].[K+].Cl>C(O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[N:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)CCCCC
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(CCCCC)=NO
Temperature: 0 °C
Yield: 100.2 %

Procedure:
To a solution of 5.11 g of 6-undecanone in 20 ml of ethanol were successively added a solution of 3.47 g of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The resulting mixture was heated under reflux for 3 hours. The reaction mixture was then poured into 150 ml of ice-containing water. The resulting aqueous mixture was made acidic by addition of 2N hydrochloric acid, and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride and evaporated under reduced pressure to remove the solvent. There was obtained 5.57 g (corresponding to theoretical amount) of 6-undecanone oxime as a pale yellow solid,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:22]1[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.9 %

Procedure:
To a cold (0° C.) solution of 5-hydroxyindole-2-carboxylic acid ethyl ester (purchased at Biosynth, ref H-6350, 20 g, 1.0 eq.), 1-isopropylpiperidin-4-ol (intermediate 1, step 1, 16.75 g, 1.2 eq.) and triphenylphosphine (30.68 g, 1.2 eq.) in tetrahydrofuran (500 mL) was slowly added a solution of di-tert-butylazodicarboxylate (26.93 g, 1.2 eq.) in tetrahydrofuran (100 mL). The reaction mixture was stirred at room temperature for 48 h then evaporated to dryness in vacuo and purified on silica, eluting with a gradient of solvent from dichloromethane/ethyl acetate 19:1 to dichloromethane/methanol/ammonium hydroxide 95:5:0.25. One fraction was isolated and dried in vacuo, to yield 21.53 g (66%) of the desired product as white solid. MS (m/e): 331.1 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][OH:40]>CC(C)=O>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:38][CH2:39][OH:40])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OCCBr
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCN(CCO)CC4)c3)cc12
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 282 (50 mg, 0.122 mmol) in acetone was added potassium carbonate (25 mg, 0.244 mmol) and 2-bromo ethanol (18.3 mg, 0.146 mmol) and stirred for 12 h at 60° C. The reaction was filtered through celite bed and washed with ethyl acetate. The organic layer was concentrated to get the crude, which was purified by neutral alumina and the compound was eluted at 2% methanol in chloroform as half white coloured solid 2-(4-(4-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol 347. 1HNMR (400 MHz, DMSO) δ: 12.04 (s, 1H), 8.54 (d, 1H), 8.31 (s, 1H), 8.18 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.22 (m, 2H), 4.39 (m, 1H), 4.10 (m, 1H), 4.00 (m, 1H), 3.60 (s, 3H), 3.50 (m, 2H), 2.96 (d, 2H), 2.42 (m, 2H), 2.13 (m, 2H), 1.99 (m, 3H), 1.16 (t, 1H) and MS ES+454.0.