Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44]CO)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCN4CCOCC4)cc3C)c2cc1OC
Yield: 73.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-morpholino-1-propanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water: and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (56 mg, yield 66%).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]([NH:10][C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:9])[CH3:8]>C(OCC)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:11]2[O:21][CH2:6][C:7]([CH3:8])([CH3:9])[N:10]=2)[CH:17]=1
Reactant: COc1ccc(Br)cc1C(=O)NC(C)(C)CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(Br)cc1C1=NC(C)(C)CO1
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Thionyl chloride (36.5 ml) was added dropwise to N-(1-hydroxy-2-methylpropan-2-yl)-5-bromo-2-methoxybenzamide (36.34 g). The resulting solution was stirred for 15 minutes and mixed with diethyl ether. The diethyl ether was decanted off and the resulting residue dissolved in 20% NaOH solution. The aqueous solution was extracted with diethyl ether. The extract was washed with brine, dried (MgSO4) and evaporated to give 2-(5-bromo-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (32.02 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].[CH3:19][C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:15]([O:17][C@H:20]([CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reactant: C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, the acid of Step D of Example 1 and (R)α-methyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-methyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+108.5°±2° (c=1% in CHCl3).
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:23]=[CH:22][C:7]2[O:8][CH2:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])([OH:13])[C:6]=2[CH:5]=1.C(=O)(O)[O-:25].[Na+].[OH2:29].C(OCC)(=O)C>FC(F)(F)C(O)=O>[ClH:1].[CH3:2][S:3]([C:4]1[CH:23]=[CH:22][C:7]2[O:8][CH2:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])([OH:13])[C:6]=2[CH:5]=1)(=[O:25])=[O:29]
Reactant: CSc1ccc2c(c1)C(O)(CN(C)C)c1ccccc1CO2
Reactant: O=C([O-])O
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CN(C)CC1(O)c2ccccc2COc2ccc(S(C)(=O)=O)cc21
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
2-Methylthio-11-dimethylaminomethyl-6,11-dihydrodibenz(b,e)oxepin-11-ol, hydrochloride (1.404 g, 4 mmole) is dissolved in 8 ml of trifluoroacetic acid and cooled to -30° C. 8.6 ml of 4M solution of peroxytrifluoro acetic acid in trifluoroacetic acid is added dropwise. The solution is allowed to stay at room temperature. A controlled exothermic reaction starts. After 30 minutes the reaction is complete (the reaction is readily followed by NMR). The solvent is poured into an excess solid sodiumbicarbonate-water mixture and ethyl acetate. The organic extract is washed with 10% sodium bicarbonate and dried over anhydrous sodium sulphate. The desired compound, 2-methylsulfonyl-11-dimethylaminomethyl-6,11-dihydrodibenz(b,e)oxepin-11-ol, hydrochloride, is isolated. M M.p. 247° C. (compound 7:1)
Reaction SMILES: [OH:1][C:2]1[CH:3]=N[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][C:12]1[S:20][C:19]2[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:17][C:16]([Cl:27])=[N:15][C:14]=2[CH:13]=1.[CH2:28]1COCC1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:19]2[S:20][C:12]([CH2:11][O:1][C:2]3[CH:3]=[CH:28][CH:5]=[CH:6][CH:7]=3)=[CH:13][C:14]=2[N:15]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: C1CCOC1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: Clc1nc(N2CCOCC2)c2sc(COc3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxypyridine (102 mg) in THF (10 mL) was added sodium hydride (43 mg) and the reaction stirred at room temperature for 1 h. Then, 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (150 mg) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([N:20]([O:21][CH3:22])[CH3:19])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)ccc1F
Reaction time: 6 h

Procedure:
To a suspension of 20.0 g (91.3 mmol) 5-bromo-2-fluorobenzoic acid in 1 L CH2Cl2 was added 12.0 mL (137 mmol) oxalyl chloride and 3 drops of DMF. After stirring for 6 h, the reaction was concentrated by rotary evaporation, the residue was dissolved in 1 L of CH2Cl2, 11.6 g (119 mmol) N,O-dimethylhydroxylamine hydrochloride and 63.6 mL (456 mmol) triethylamine were added and the reaction was stirred overnight. The reaction was dumped into a separatory funnel with 1 M HCl, the layers were separated, the organic was washed with 1M NaOH, then water, dried over Na2SO4 and concentrated to provide 3-1 as a colorless oil. Data for 3-1: LC/MS: rt=1.76 min; m/z=262 (M+1).
Reaction SMILES: C([O:8][CH:9]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:11][CH2:10]1)C1C=CC=CC=1.[H][H]>O1CCCC1.[C].[Pd]>[OH:8][CH:9]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OCc1ccccc1)CO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)CO2
Reaction time: 8 h
Yield: 89.1 %

Procedure:
6.47 g of tert-butyl 3-(benzyloxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was dissolved in 100 ml tetrahydrofuran, 1.3 g palladium carbon was added thereto, and the mixture was stirred overnight in a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, 1.3 g of palladium carbon was added thereto, and the solution was stirred overnight in a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, 2.6 g of palladium carbon was added thereto, and the solution was stirred overnight in a hydrogen atmosphere at 4.2 atmospheric pressure. The catalyst was filtered off from the reaction solution, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give 4.27 g of tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][CH3:12].B(F)(F)F>F>[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:11]([CH3:12])[CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC
Reactant: CC(C)c1ccccc1
Agent: F
Agent: FB(F)F
Product: CC(C)c1ccccc1C(C)C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
12 g (0.1 mol) cumene is dissolved in 150 ml anhydrous hydrogen fluoride and while keeping the stirred solution at -20° C. to 0° C., 0.05 mol of propylene is introduced and stirring continued for 15 min. The reaction mixture is then saturated with boron trifluoride and stirring continued for another 15 min. After workup, 41% diisopropylbenzene was obtained, comprised of 99.6% of meta and 0.4% para isomer, together with about 15% 1,3,5-triisopropylbenzene, which can be recycled under conditions of Example 6 to produce more meta-diisopropylbenzene.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH:12]([O-])([O-])[O:13]C.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CO>[CH:26]1([NH:17][C:18](=[O:8])/[CH:19]=[C:20](\[O:13][CH3:12])/[CH3:21])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccc2ncccc2c1
Solvent: CO
Product: CO/C(C)=C\C(=O)NC1CCCC1
Temperature: 145 °C
Reaction time: 72 h

Procedure:
84 g of diketene were added over 10 minutes at 10° C. to a mixture of 85 g of cyclopentylamine and 500 ml of tetrahydrofuran and after stirring the mixture for 6 hours at 20° C., the mixture was evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and was cooled and vacuum filtered to obtain 107 g of N-cyclopentyl-acetylacetamide melting at 52° C. 56 g of the latter product and 1.6 g of p-toluene sulfonic acid were added to a mixture of 40 g of methyl orthoformate and 80 ml of methanol and the mixture was held at 50° C. for 8 hours and 72 hours at 25° C. 4 ml of quinoline were added and the mixture was evaporated to dryness under reduced pressure. The residue was added to toluene and the mixture was heated at 145° C. for 4 hours while distilling a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 40 g of N-cyclopentyl-3-methoxy-crotonamide melting at 94° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[N:7]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:32]3[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30][CH2:31]3)[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:30][CH2:31]4)[C:10]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCCBr)CC1
Reactant: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting mixture was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture 5-[1-(t-butoxycarbonyl)piperidin-4-yl)pentyl bromide (4.0 mmol, 2.2 eq) was added and the resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined and washed with water (2×10 ml), and then brine (1×10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was further purified by flash chromatography. There is some substitution at the 7-position of the benzimidazole present, although the 4-substituted is the major isomer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI.O.CN(C)[CH:23]=[O:24]>>[CH3:12][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:24][CH3:23])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Hydroxy-4-methylbenzoic acid (3 g) was dissolved in N,N-dimethylformamide (60 ml) to prepare a solution. Potassium carbonate (6.81 g) and methyl iodide (6.14 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give methyl 3-methoxy-4-methylbenzoate (3.48 g, yield 98%).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](Cl)(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C>[NH:18]([C:2]1[C:10]([S:11](=[O:13])(=[O:12])[NH:15][C:3]2[CH:4]=[CH:5][CH:9]=[CH:10][CH:2]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1

Procedure:
To a solution of 4-chloro-3-nitro-5-chlorosulphonyl-benzoic acid (6 g) in ethyl acetate (50 ml), aniline (7.5 g) was added, while stirring. The reaction mixture was stirred for a further 8 hours and filtered. The filtrate was evaporated, and the residue was dissolved in a mixture of aqueous sodium hydrogen carbonate and diethyl ether. The aqueous layer was separated, and the 4-anilino-3-nitro-5-phenylsulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid. After recrystallization from aqueous ethanol (25% ethanol in water), the melting point was 249°-250° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:12](=O)[CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NN1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NN1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
To a solution of 191 mg of cis-8-tert-butoxycarbonyl-5-[(1R)-1-phenylethylamino]-4-oxo-2-oxa-5,8-diazabicyclo[4.3.0]nonane 13a in 6 ml of tetrahydrofuran was added 1 ml of 1M diborane tetrahydrofuran complex dropwise. The mixture was stirred at 5° C. for 3 days. To an ice-cooled reaction mixture was added 15 ml of water and 10 ml of saturated potassium carbonate aqueous solution, and the mixture was stirred. The mixture was extracted by chloroform and the organic layer was separated. The organic layer was washed by saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (3:1 by volume), the titled compound 14a weighing 103 mg was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 90 °C
Yield: 85.2 %

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (10.0 g, 61 mmol) in methanol (100 ml) is treated sequentially with 1-methylpiperazine (6.7 g, 67 mmol) and platinum (5%) on sulfided carbon (0.5 g). The resulting solution is then heated at 90° C. and is subjected to a pressure of 5 bar of hydrogen for a period of 4 hrs until the hydrogen uptake is complete. The reaction mixture is cooled to room temperature and filtrated over a pad of Celite. The methanol is removed under reduced pressure and replaced with toluene (100 ml). The resulting organic solution is extracted with aqueous HCl (2N, 2×50 ml). The aqueous layer is treated with concentrated aqueous NaOH (30%) to set the pH to 12 and is back-extracted with toluene (2×50 ml). The combined organic layers are concentrated in vacuo to give 12.9 g (85%) of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester as a pale yellow oil which may be further purified by distillation under reduced pressure.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][C:1]1[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3][C:2]2=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Product: COc1ccc2[nH]c3c(c2c1)CCc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using 3,4-dihydro-2H-naphthalen-1-one (2.90 g, 20 mmoL) and 4-methoxy-phenylhydrazine HCl salt as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Br[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (200 mg) in N,N-dimethylformamide (5 mL) is added tert-butyl 2-bromoethylcarbamate (270 mg) and Cs2CO3 (810 mg). The mixture is stirred for 20 hours at room temperature. tert-Butyl 2-bromoethylcarbamate (110 mg) and Cs2CO3 (325 mg) are added and the mixture is stirred for 4 hours. Again tert-butyl 2-bromoethylcarbamate (110 mg) and Cs2CO3 (325 mg) are added and the mixture is stirred for 12 hours. The mixture is partitioned between water and diethylether. The organic phase is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20) to give the title compound. Yield: 320 mg; LC (method 8): tR=0.66 min; Mass spectrum (ESI+): m/z=344 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:6]=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[N:8]1([CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: C=O
Reactant: c1cn[nH]c1
Solvent: CCO
Product: c1cnn(CN2CCCC2)c1
Yield: 71.4 %

Procedure:
To a mixture of pyrazole (88.3 g, 1.297 mol) and formalin (116 ml, 33%, 1.4 mol) in 450 ml of ethanol at 0° C. was added pyrrolidine (101.2 g, 1.425 mol) dropwise, and the mixture was heated to reflux under nitrogen for 5 h. The reaction mixture was cooled, and concentrated in vacuo. The residue was distilled (57°-58° C./0.05 mm) to afford 140 g (55.12%) of 1-(1-pyrrolidinomethyl)-pyrazole.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:29]([NH2:31])=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]([C:29]([NH2:31])=[O:30])[CH2:25][N:26]([CH3:34])[CH2:27][CH:28]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CNCC3)cc1OCC2
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C)CC3C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide from Example 414 (0.15 g, 0.35 mmol) in DCM (16 mL) and methanol (8 mL) was added formaldehyde (0.053 mL, 37% aq., 0.7 mmol), sodium triacetoxyborohydride (0.11 g, 0.52 mmol) and acetic acid (24 μL, 0.42 mmol). The reaction mixture was stirred at RT for 16 h. Sodium hydrogen carbonate (aqueous) and 10% methanol in DCM were added to the mixture and the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give the title compound. The product was triturated with diethyl ether, filtered and dried to give the title compound (24 mg, 16%). LCMS: RT=2.39 min, [M+H]+=434. 1H NMR 400 MHz (DMSO-d6) δ: 8.33 (1 H, d, J=8.48 Hz), 7.92 (1 H, s), 7.91 (1 H, s), 7.32 (1 H, br, s), 7.27 (1 H, dd, J=8.51, 1.92 Hz), 7.11 (1 H, d, J=1.86 Hz), 6.90 (1 H, br, s), 6.35 (1 H, d, J=3.82 Hz), 5.90-5.89 (1 H, m), 4.51-4.49 (4 H, m), 3.53 (1 H, s), 3.31 (1 H, m), 2.97 (1 H, m), 2.85 (1 H, m), 2.64 (1 H, m), 2.33 (3 H, s), 1.48 (6 H, dd, J=6.60, 3.70 Hz)