Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[CH:8][CH:9]=1)[O:20][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (104 mg, 0.75 mmol) and 4-bromomethyl-benzenesulfonamide (125 mg, 0.5 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70° A) ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 33%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1(C)C=C[CH:15]=[CH:14][CH:13]=1.[OH2:19]>>[CH2:1]([C:6]1[C:5](=[O:19])[CH2:4][CH2:3][CH:2]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Product: CCCCCCC1=CCCC1=O
Yield: 97 %

Procedure:
The above prepared mixture (25 parts) was admixed with p-toluenesulfonic acid (1.25 parts) and toluene (75 parts) and refluxed for 2 hours, during which by-produced water was eliminated by azeotropic distillation. The reaction mixture was treated as in Example 1 to give 2-n-hexyl-2-cyclopentenone in a yield of 97 %.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[CH3:24][C@H:25]1[CH2:30][O:29][CH2:28][CH2:27][NH:26]1>CN1C(=O)CCC1.O>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][C@@H:25]5[CH3:24])[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: C[C@H]1COCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(N3CCOC[C@@H]3C)c2s1
Temperature: 165 °C

Procedure:
A mixture of 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide (90 mg, 262 μmol) and (S)-3-methylmorpholine (79 mg, 785 μmol) in NMP (2 ml) was heated to 165° C. for 48 hrs. The mixture was cooled to RT, diluted with H2O and filtered. The solids were washed with H2O and air-dried. The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS (ESI, pos. ion) m/z: 409 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[CH2:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCCc3ccccc32)cc1
Reaction time: 3 h

Procedure:
1,2,3,4-tetrahydroquinoline (2.66 g, 0.02 mol), benzaldehyde (3.12 g, 0.03 mol) and glacial acetic acid (0.67 ml, 0.012 mol) were dissolved in methanol (10 ml). Sodium cyanoborohydride (0.675 g, 0.0107 mol) was added portionwise, controlling the resulting vigorous gas evolution by the rate of addition. After 3 hours, the reaction mixture was poured into 50 ml 1N HCl and extracted 3×40 ml ether. The organic layers were combined, dried (MgSO4) and stripped to yield crude title product contaminated with benzyl alcohol. The crude product was dissolved in 50 ml ether, cooled to 0° C. and diffused with HCl gas until precipitation of hydrochloride salt was complete. The ether was decanted from the resulting semi-solid salt. The salt was washed with 20 ml fresh ether, the ether decanted, and the washed salt taken up in 50 ml of fresh ether and 50 ml of H2O. The pH was adjusted to 12 with 1N NaOH, and the ether layer separated, dried (K2CO3) and stripped to 2.47 g of product still containing some residual benzyl alcohol. Repeated conversion to hydrochloride salt and back to free base gave purified title product, 2.02 g.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[C:18]4[C:23](=[CH:24][C:14]=3[CH:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19]4>CCOC(C)=O.CCCCCC>[CH3:5][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:24]=[C:23]4[C:18](=[CH:17][C:15]=3[C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22]4
Reactant: CCOC(=O)c1cc2c(ccc3cc4ccccc4cc32)[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c3cc4ccccc4cc3ccc2n1C
Yield: 97 %

Procedure:
Using the procedure described in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[2,3-e]indole-2-carboxylate (H.G. Pars Pharmaceutical Laboratories, Inc.) gave a 97% yield of ethyl 3-methyl-3H-naphth[2,3-e]indole-2-carboxylate, mp 141°-144°, (EtOAc/hexane), (C,H,N).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=O)(C)(C)C.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:24]>CN(C)C=O.ClCCl.O1CCOCC1>[ClH:24].[CH2:6]([NH:8][C@H:9]([CH3:10])[C:11]([O:13][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-D-alanine (3 g) in dimethylformamide (5 ml) was added dropwise to a stirred solution mixture of 60% sodium hydride (1.4 g) in dimethylformamide (5 ml) at ice-bath temperature. After stirring for 30 minutes at the same temperature, benzyl bromide (4.14 ml) was added and then the mixture was stirred for 1 hour at the same temperature and then for 6 hours at room temperature. The reaction mixture was poured into a mixture of dilute hydrochloric acid and ice-water, and extracted with diisopropyl ether. The extract was washed with aqueous sodium bicarbonate solution and brine successively and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1) to give an oily product, which was dissolved in dichloromethane (40 ml). To the solution was added 4N hydrogen chloride in dioxane solution (7 ml) at ice-bath temperature. The resulting mixture was stirred for 1.5 hours at room temperature and then concentrated under reduced pressure to give benzyl (2R)-2-(N-benzylamino)propionate hydrochloride (2.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3ccncc3)nn12

Procedure:
The title compound, MS m/e (%): 292 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 4-pyridinecarboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.O=[C:23]([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:24]([OH:26])=[O:25])[CH2:27][CH2:28][CH3:29])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: CCCC(=O)C(=O)O
Product: CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 9, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with α-oxopentanoic acid at room temperature to give 7-chloro-2-[(1-carboxybutylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][C:65]=1[Cl:66]>ClCCl>[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[Cl:66]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: NCc1ccc(Cl)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in the dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromo-4-chlorophenyl)methyl]amine (441 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine. A substantial amount of solid would not dissolve in either the EtOAc or aqueous phases. This was filtered off and set aside. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (349 mg, 0.324 mmol, 16.20% yield). The solid that had been set aside was washed with water and ethyl acetate and dried under vacuum to give another batch of N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (993.7 mg, 1.488 mmol, 74.4% yield) as a white solid. LC-MS m/z 667.2 (M+H)+, 1.02 min (ret time); mp 212-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:56](=[O:61])[CH2:57][CH2:58][O:59][CH3:60]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH:55][C:56](=[O:61])[CH2:57][CH2:58][O:59][CH3:60])=[CH:15][CH:16]=1
Reactant: COCCC(=O)Nc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COCCC(=O)Nc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.458 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.32 g of N-(2-hydroxyphenyl)-3-methoxypropionamide are reacted. The title compound is obtained as a colourless oil. Rf=0.50 (1:1 EtOAc-heptane); Rt=5.70.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].CN(C)C=O.Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1ccc(C)cc1

Procedure:
A mixture of p-cresol and sodium hydroxide was stirred with dimethylformamide and water while 1-bromo-3-methylbut-2-ene (VII; R1 = R2 = CH3, Hal = Br) was added dropwise. The 1-(p-methylphenoxy-3-methylbut-2-ene was isolated as described under Example B(i).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH2:14]([C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[CH3:15].[Sn](Cl)Cl.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>>[CH2:14]([C:16]1[N:17]2[C:18]([C:25](=[O:26])[NH:8][C:7]3[C:6]([CH3:11])=[N:5][C:4]([S:12][CH3:13])=[N:3][C:2]=32)=[C:19]([CH3:21])[N:20]=1)[CH3:15]
Reactant: CSc1nc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1nc(C)c[nH]1
Agent: Cl[Sn]Cl
Product: CCc1nc(C)c2c(=O)[nH]c3c(C)nc(SC)nc3n12

Procedure:
Prepared by treatment of 4-chloro-6-methyl-2-(methylthio)-5-nitropyrimidine with 2-ethyl-4-methylimidazole, reduction with tin (II) chloride, and cyclization with carbonyidiimidazole.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[Br:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([F:14])([F:13])[F:15])[C:8]([C:16]([OH:18])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Yield: 71.9 %

Procedure:
Ethyl 8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-caboxylate (0.3 g), ethanol (15 mL), tetrahydrofuran (10 mL), and sodium hydroxide solution (10 mL, 2.5 N) were stirred at room temperature for 16 h. Hydrochloric acid (1 N) was added until the mixture was acidic to pH paper. The addition of water (50 mL) caused the formation of a precipitate which was collected by filtration yielding the title compound as a white solid (0.2 g, 72%): mp 227.8-228.9° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J=2.4 and J=28.8 Hz), 6.00 (q H−F, 1H, J=7.2 Hz). FABHRMS m/z 356.9134 (M+H, Calc'd 356.9141). Anal. Calc'd for C11H5BrClF3O3: C, 36.96; H, 1.41. Found: C, 37.05; H, 1.33.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:43]([Si:46](Cl)([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])([CH3:45])[CH3:44].O>O1CCCC1>[CH2:34]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[N:20]([Si:46]([CH:50]([CH3:52])[CH3:51])([CH:47]([CH3:49])[CH3:48])[CH:43]([CH3:45])[CH3:44])[CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Reaction time: 0.08 h

Procedure:
To (3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (55, 0.84 g, 1.6 mmol) in tetrahydrofuran (150 mL) was added sodium hydride (210.0 mg, 60% in mineral oil, 5.3 mmol) under an atmosphere of nitrogen. The reaction was stirred for 5 minutes. Triisopropylsilyl chloride (0.80 mL, 3.8 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to provide the compound (56, 420 mg, 39%). MS (ESI) [M+H+]+=687.4.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7]>C1CCCCC1>[C:6]1(=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1.[CH:6]1([OH:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: OCCCCCCO
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
The present invention relates to a process for preparing 1,6-hexanediol having a purity of at least 99% which is, in particular, essentially free of 1,4-cyclohexanediols, from a carboxylic acid mixture which is obtained in the oxidation of cyclohexane to cyclohexanone/cyclohexanol using oxygen or oxygen-containing gases by water extraction of the reaction mixture, by esterification of the acids, fractionation of the esterification mixture into an ester fraction free of 1,4-cyclohexanediols and a fraction comprising the 1,4-cyclohexanediols, hydrogenation of the ester fraction and purification of the 1,6-hexanediol by distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[N:29]([CH3:37])[C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[N:31][CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[N:29]([CH3:37])[C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[N:31][CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CN(C)Cc1ncc(C(=O)Oc2ccccc2)n1C
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnc(CN(C)C)n3C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester, the title compound was obtained as off-white solid (49% yield). MS: m/e=431(M+H+), mp 229-231° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:18]1[CH2:37][CH:19]1[CH2:20][O:21][C:22](=[O:36])[C:23]1[C:24](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)=[O:26].[OH-:38].[K+]>CN(C)C=O>[OH:18][CH:19]([CH2:37][N:6]1[C:5](=[O:38])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][C:22](=[O:36])[C:23]1[C:24](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([O:27][CH2:28][CH:29]([OH:31])[CH2:30][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])=[O:26]
Reactant: [OH-]
Reactant: O=C(OCC1CO1)c1ccccc1C(=O)OCC1CO1
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC(=O)c1ccccc1C(=O)OCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O

Procedure:
24.0 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 12.0 g of bis(2,3-epoxypropyl)phthalate and 0.5 g of potassium hydroxide were reacted in 200 ml of N,N-dimethylformamide, following substantially the same procedure as in Example 1. The desired Compound No. 130 was obtained in the form of a white powder, having an Rf value of 0.47 on thin-layer chromatography on silica gel using a 8:1:1:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine as developing solvent.
Reaction SMILES: O=C[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:17][O:16][CH:11]([O:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(OC)OC
Reactant: COC(=O)CCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCCCC(OC)OC
Reaction time: 48 h
Yield: 88 %

Procedure:
56 g (0.4 Mole) of cyclohexanone enolacetate in 500 ml of methanol was ozonised in a dry ice-acetone bath until the solution turned blue. 60 ml of dimethyl sulphide was added, and the cooling bath was removed. The temperature rose slowly to 48°, and after it had returned to room temperature, 40 ml of trimethyl orthoformate and 1 ml of acetyl chloride were added. The mixture was then left for 48 h at room temperature. Three identical batches were combined and the solvent was removed in vacuo. The residue was dissolved in ether, washed with brine containing a small amount of NaHCO3, dried (Na2SO4), and distilled to give 193 g of product, b.p. 56°-69°/0.1 Torr. The NMR spectrum indicated the presence of ca. 20% of methyl 6-oxohexanoate. The product was mixed with 100 ml of trimethyl orthoformate, 20 ml of methanol, and 0.5 g of p-toluene sulfonic acid. The mixture was left for 48 h at room temperature, then worked up as above yielding 201 g (88%) of methyl 6,6-dimethoxyhexanoate. b.p. 61°/0.1 Torr.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH:27]([CH3:29])[CH3:28])[C:23](=[O:26])[CH2:24]Cl)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C>[CH2:9]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]([CH:27]([CH3:29])[CH3:28])[C:23](=[O:26])[CH2:24][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCCCO
Reactant: CC(C)N(C(=O)CCl)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)N(C(=O)COCCCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
1,4-Butanediol (16 mL, 178 mmol) was refluxed with sodium hydroxide (970 mg, 24.3 mmol) in tert-butanol (8 mL) for 2 h at which time the solid sodium hydroxide had dissolved. The solution was then cooled to room temperature and a solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 2-chloroacetamide (5.0 g, 16.2 mmol) in tert-butanol (8 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. After removal of tert-butanol under reduced pressure, the residue was dissolved in dichloromethane and this solution washed with sodium bicarbonate, water and brine. The organic layer was then dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (dichloromethane/methanol/ammonium hydroxide: 90/9/1) to give 4.73 g of the title intermediate as a viscous oil (81% yield).