Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].[CH3:15][CH2:16][C:17](=O)[CH2:18][CH2:19][C:20](=O)[CH2:21][CH3:22]>C(O)(=O)C>[CH2:21]([C:20]1[N:2]([NH:1][C:3]2[N:4]=[N:5][C:6]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:7][CH:8]=2)[C:17]([CH2:16][CH3:15])=[CH:18][CH:19]=1)[CH3:22]
Reactant: CCC(=O)CCC(=O)CC
Reactant: NNc1ccc(N2CCOCC2)nn1
Solvent: CC(=O)O
Product: CCc1ccc(CC)n1Nc1ccc(N2CCOCC2)nn1
Temperature: 67 °C
Yield: 85.7 %

Procedure:
To 1.95 g (10 m moles) of 3-hydrazino-6-morpholino-pyridazine dissolved in 12 ml of acetic acid, 1.71 g (12 m moles) of 3,6-octanedione dissolved in 4 ml of acetic acid are added at room temperature. The mixture is heated at 67° C. for 2 hours and then evaporated to dryness under vacuum. The oily residue is dissolved in toluene and the solution is evaporated to dryness. The residue is slurried with ice-water and neutralized with sodium bicarbonate to yield 2.58 g of a solid product. Said material, after crystallization from isopropanol gives 1.25 g (42%) of the title product, melting at 186°-9° C. Elemental analysis, I. R., N.M.R. and mass spectra are in agreement with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.[C:39](Cl)([Cl:41])=[O:40]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:39]([Cl:41])=[O:40])[C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)(=[O:28])=[O:29])[CH:24]=[CH:23][C:22]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidine-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[CH:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C(c2ccc([N+](=O)[O-])cc2Cl)C(=O)C1
Temperature: 75 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution containing 42.05 g (0.300 mol) of 5,5-dimethyl-1,3-cyclohexanedione and 100 g (0.718 g-atom) of anhydrous potassium carbonate in 300 ml of dry dimethylformamide was heated to 75° C. under nitrogen and stirred for one hour. The 3,4-dichloronitrobenzene, 57.60 g (0.300 mol) was dissolved in 100 ml dimethylformamide and added dropwise to the reaction mixture while stirring and maintaining the temperature of the reaction mixture at 75° C. A deep red-colored solution formed, and when the addition was complete the reaction temperature was raised to 100° C. and held at this temperature for 3 hours. Most of the dimethylformamide was removed by vacuum distillation. The residue was poured into 21 of ice water and extracted three times with 500 ml of benzene. Nitrogen was then passed through the aqueous solution while warming to remove dissolved benzene. The aqueous solution was cooled in an ice bath and acidified to give a tacky precipitate, which, upon warming solidified and was collected by suction filtration. The product was recrystallized from acetone to give 31.7 g (36%) of 2-(2'-Chloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione as a white powder, m.p. 250°-253° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6]([N:7]1[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:9][O:10][C:21]1([CH3:23])[CH3:22])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(I)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of (RS)-[2-hydroxy-1-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (7.97 g) in dichloromethane (400 ml) were added sequentially 2,2-dimethoxypropane (36 ml) and p-toluenesulphonic acid monohydrate (0.75 g) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with 0.5 N aq NaOH, the phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated in vacuo to afford (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.05 g, 89%) as a yellow solid. MS (EI): 403 (M+), 388 ([M-CH3]+), 332 ([M-CH3—C4H8]+), 288 ([M-CH3—C4H8—CO2]+), 57 ([C4H9]+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:26][N:25]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:20][NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[N:26][N:25]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CNc1cc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyridin-2-amine (0.070 g, 0.24 mmol) and 1-chloro-4-phenylphthalazine (0.048 g, 0.20 mmol) was added tBuOH (1.0 mL). The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine as an off-white solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.58.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][C:33]=1[C:34](O)=[O:35]>>[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:34]([C:33]4[CH:37]=[C:38]([O:41][C:42]([F:43])([F:44])[F:45])[CH:39]=[CH:40][C:32]=4[CH3:31])=[O:35])[CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)(F)F)ccc4C)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B6) and 2-methyl-5-(trifluoromethoxy)benzoic acid (compound F5) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[CH:17][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]=3[CH:32]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[CH:17][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]=3[CH:32]=2)=[O:9])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc(N)cc3)cc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (241 mg, 526 μmol) in a mixture of ethanol and water (6:1, 14 mL) was added palladium on carbon (48 mg, 10% w/w Pd) and ammonium formate (200 mg, 3.18 mmol). The suspension was heated to reflux for 2 hours, and was then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=4.61 min, MH+ 429].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1.[Li].C([Li])CCC.CCCCCC.[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[O:30][C:31]3[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=3[CH2:33][N:34]([C:35](Cl)=[O:36])[C:28]=2[CH:27]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][O:12][C:35]([N:34]2[CH2:33][C:32]3[CH:38]=[CH:39][CH:40]=[CH:41][C:31]=3[O:30][C:29]3[CH:42]=[CH:43][C:26]([Cl:25])=[CH:27][C:28]2=3)=[O:36])=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: OCCCNCc1ccncc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCCCNCc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 40.9 %

Procedure:
By the procedure described in Example 11, 3-(4-pyridylmethylamino)-1-propanol (1.0 g, 3.4 mmol) in 30 mL of THF was converted to its lithium salt with 1.6M n-butyllithium in hexane (2.1 mL, 3.4 mmol) and reacted with the product of Example 2 (1.0 g, 3.4 mmol) to yield 590 mg of the title product.
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.C(N(CC)CC)C.[C:57](Cl)(=[O:66])[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:27]2[CH:28]=[CH:29][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH3:34])=[CH:31][CH:32]=2)[C:57](=[O:66])[O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:12][CH2:11]1)=[O:43]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
The compound (257 mg, 0.383 mmol) obtained in Example 83b was dissolved in dichloromethane (4 mL), triethylamine (107 mL, 0.766 mmol) and benzyl chlorocarbonate (0.082 mL, 0.58 mmol) were added, and the mixture was stirred at 50° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride (×3), and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in tetrahydrofuran (4 mL), 55% sodium hydride-paraffin (25.0 mg, 0.573 mmol) and benzyl chlorocarbonate (0.082 mL, 0.58 mmol) were added, and the mixture was stirred. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and dichloromethane was further added to separate the layers. The resulting organic layer was separated and dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography to give the title compound (235 mg; yield, 76%) as a brown oily substance.
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].O>CCCCCC>[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:21]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCCCCC(=O)OCc1ccc2c(c1)OCO2
Temperature: 50 °C
Yield: 84.4 %

Procedure:
Piperonyl alcohol (442 mg, 2.90 mmol), 8-methylnonanoic acid (500 mg, 2.90 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (25 ml) was added, and Novozyme 435 and the precipitated piperonyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (preparative thin layer chromatography, Merch Art. 13895) (n-hexane:ethyl acetate=4:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give piperonyl 8-methylnonanoate (0.75 g, yield 84.3%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11](O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:29][CH2:30][CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1.CO>O1CCCC1>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11]([NH:29][CH2:30][CH2:31][C:32]2[N:36]=[CH:35][NH:34][CH:33]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]cn1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To stirred solution of the product of step 1 (1.50 g, 4.34 mmol) in tetrahydrofuran (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.210 g, 5.25 mmol). After gas evolution ceased,p-toluenesulfonyl chloride (0.990 g, 5.20 mmol) was added and the mixture was stirred for 2 hours. At this time, histamine (1.93 g, 17.4 mmol) was added followed by methanol (10 mL). The reaction was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a pasty white solid. Flash chromatography over silica (methylene chloride/methanolic ammonia solution) provided 1.08 g (57%) of product as a colorless tacky foam: 1H NMR (CDCl3) δ 7.52-7.43 (m, 1H), 7.40-7.00 (m, 15H), 6.78-6.69 (m, 1H), 4.36-3.97 (m, 4H), 2.92-2.20 (m, 7H) ppm.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:11]=2[O:10]1.CO.Cl>O>[OH:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:11]=2[O:10]1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)CCC(CO)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a stirred solution of 27 parts of N-[3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-yl]-acetamide in 240 parts of methanol were added 100 parts of a hydrochloric acid solution 10% in water. The whole was stirred for 30 minutes at room temperature. The reaction mixture was evaporated till all traces of methanol were removed. After cooling, the product was filtered off from the aqueous phase, washed with water and crystallized from acetonitrile. The product was filtered off and dried, yielding 14.4 parts (74%) of N-[3,4-dihydro-2-(hydroxymethyl)-2H-1-benzopyran-6-yl]acetamide; mp. 156.5° C. (intermediate 12).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCC.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:25]=[CH:26][C:21]([OH:27])=[CH:22][CH:23]=2)[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2cccc3ccccc23)cc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc(C(c2ccc(O)cc2)c2cccc3ccccc23)cc1
Reaction time: 3 h

Procedure:
A solution of compound (4-methoxyphenyl)-naphth-1-yl-carbinol of formula II (3.0 gm, 0.011 mol) and phenol (5.4 gm, 0.057 mol) in a mixture of anhydrous benzene and anhydrous hexane (40.0 ml), 1:1) was gradually added to a mixture of phenol (1.5 gm, 0.061 mol) and anhydrous aluminum chloride (1.5 gm, 0.011 mol) at 0° C. under stirring. After the addition was over, the stirring was continued at room temperature for 3 hrs, the reaction was decomposed by adding crushed ice with conc. HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed with water, 5% NaOH, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel to yield the title compound of formula I. Yield 2.3 gm (59.3%).
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C1COCC1.[NH2:33][C:34]1[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=1.[H-].[Na+]>C(OCC)(=O)C>[CH:25]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:26][CH2:27]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)Nc3cc(C)nn3C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 41A, 0.0342 g, 0.090 mmol) was added THF (0.449 mL). 5-Amino-1,3-dimethylpyrazole (0.012 g, 0.108 mmol) was added followed by sodium hydride (3.60 mg, 0.090 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was used without further purification.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:14][CH3:15])[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH2:14][CH3:15])[CH3:13]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCC(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCC(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and sec-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2.5 hours. Using the same procedure as in Example 1, 4'-sec-butylbenzoin was obtained as crystal (200.6 mg, 37.3% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]2[C:9]([CH3:20])=[N:10][O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:3][CH2:2]1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OCC1CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OCC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid cyclopropylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C)C=O>[Br:46][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one (1.10 g, 3.20 mmol) in anhydrous N,N-dimethylformamide (16 mL) were added triphenylphosphine (0.92 g, 3.50 mmol) and carbontetrabromide (1.17 g, 3.50 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one as an off-white solid. Yield: 0.60 g (46%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[N:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
Prepared in analogy to example 1.6 (d) from 4-quinolin-2-yl-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.