Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([P:16](=[O:23])([O:20]CC)[O:17]CC)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C1COCC1.Cl>[C:24]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][C:13]([P:16](=[O:17])([OH:20])[OH:23])=[CH:12][CH:11]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(OCC)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=P(O)(O)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
0.40 g (10.0 mmol) of NaOH in 7 ml of water are added dropwise at 23° C. to a solution of 2.00 g (5.0 mmol) of diethyl 4-diphenylphosphinophenylphosphonate in 7 ml of THF. After refluxing for 6 hours, the mixture is diluted with a further 7 ml of THF, 4.0 ml of 2N hydrochloric acid are added dropwise at 23° C. and the mixture is stirred for 20 min at 23° C. After phase separation, the aqueous phase is extracted twice, each time with 25 ml of dichloromethane, and the combined organic phases are washed with 25 ml of water. After drying over Na2SO4, complete evaporation on a rotary evaporator and drying under reduced pressure, 1.54 g of 4-diphenylphosphinophenylphosphonic acid (90% of theory) are obtained in the form of a pale yellow solid having an m.p. of 87° C.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[SH:12][CH2:13]C(O)=O.[C:17]([O:20]C(=O)C)(=O)[CH3:18].C([O-])(=O)C.[Na+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[C:17]([O:11][C:1]1[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][S:12][CH:13]=1)(=[O:20])[CH3:18]
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: O=C(O)CS
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1cscc1-c1ccccc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Atropic acid (149 mg, 1.10 mmol) and mercaptoacetic acid (80 μl, 106 mg, 1.15 mmol) were combined and stirred 18 hours at 130° C. under a nitrogen atmosphere. The resulting crude Michael addition product was dissolved in acetic anhydride (2.4 mL, 2.6 g, 25 mmol) and sodium acetate (115 mg, 1.4 mmol) was added. The reaction was warmed in an oil bath, increasing the temperature to 150° C. over 1 hour. The mixture was maintained at that temperature for 2.5 hours, then cooled to 25° C. and evaporated. The residue was dissolved in 3.0 mL of dioxane and DDQ (200 mg, 0.88 mmol) was added in portions over 10 minutes. The reaction was stirred 1 hour at 25° C., then for 0.5 hour at 50°-55° C. The mixture was allowed to stand at room temperature overnight, diluted with 3 mL of dichloromethane, and filtered. The precipitate was rinsed with an additional 3 mL of dichloromethane. The solution was evaporated, taken up in 25 mL of ethyl acetate, and washed with 2×15 mL of saturated aqueous sodium bicarbonate followed by 15 mL of saturated aqueous sodium chloride. The residue was dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in a mixture of ethyl acetate and dichloromethane and evaporated onto 1.5 g of silica gel. Flash column chromatography on 5 g of silica gel eluted with 4% ethyl acetate in hexane gave 84 mg (44% yield) of 3-acetoxy 4-phenylthiophene as an almost colorless oil. A similarly prepared sample was further purified by bulb-to-bulb distillation, bp 85°-90° C. (0.2 mm).
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[N:10]=2)[CH2:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:27]([O:26][C:24]([N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[N:10]=2)[CH2:4][CH2:3]1)=[O:25])[CH3:28]
Reactant: CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOCCn1c(N2CCCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Combine 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20 mL). Heat to 80° C. After 2 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.87 (silica gel, dichloromethane/methanol, 90/10).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[C:15]2[C:10]3[C:11](=[CH:16][CH:17]=[CH:18][C:9]=3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2.C(Br)C#C.C(O)(=O)C>CN(C)C=O>[CH2:3]([N:7]1[C:15]2[C:10]3[C:11](=[CH:16][CH:17]=[CH:18][C:9]=3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2)[C:2]#[CH:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C1Nc2cccc3cccc1c23
Agent: C#CCBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Potassium-t-butoxide, 6.17 g (0.055 mol) was added to a solution of 8.46 g (5 mmol) of benz[cd]indol-2(1H)-one in 100 ml of dimethylformamide. After stirring for 10 minutes at room temperature, 4.9 ml (0.055 mol) of propargyl bromide was added and the mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified with acetic acid and partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from tetrahydrofuran/ethanol to leave 8 g (77%) of product with m.p. 183°-186° C. The title compound was recrystallized for analysis twice from methylene chloride/ethyl acetate and had m.p. 185°-187° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:45][C@@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[S:52]([C:55]1[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53]>C(Cl)Cl.CN(C=O)C>[CH:8]([OH:10])=[O:9].[CH3:45][C@@H:46]1[CH2:51][N:50]([C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:49][CH2:48][N:47]1[S:52]([C:55]1[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=1)(=[O:54])=[O:53]
Reactant: Cc1ncccc1C(=O)O
Reactant: C[C@@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@H](C)C1
Product: O=CO
Yield: 98 %

Procedure:
To a solution of 2-methyl-3-pyridinecarboxylic acid (47.7 mg, 0.348 mmol) in DCM (2.000 ml) was added HATU (132 mg, 0.348 mmol) and DIPEA (0.152 ml, 0.870 mmol) and the mixture stirred for 15 minutes before addition of (2R)-2-methyl-l-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride (Description 6) (100 mg, 0.290 mmol) in DMF (2 ml). The resultant mixture was stirred for 16 h at room temperature then the reaction mixture was then concentrated and the residue taken up in DMSO and purified by reverse phase MDAP. The collected fractions were concentrated in vacuo giving the the title compound (80.7 mg) as a white solid.
Reaction SMILES: [CH3:1]N(C=O)C.[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([NH:22][CH:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:21])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[H-].[Na+].IC>C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([N:22]([CH:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH3:1])=[O:21])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(/C=C/c1ccc(-n2ccnc2)c(F)c1)NC1CCc2ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CN(C(=O)/C=C/c1ccc(-n2ccnc2)c(F)c1)C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DMF (1.0 mL) solution of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide (30.0 mg) obtained in Example 324, sodium hydride was added at 0° C. (10.0 mg), and the reaction solution was allowed to be warmed to room temperature. Iodomethane (54.0 μL) was added to the reaction solution, the reaction solution was agitated at room temperature for 3 hours, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent heptane-ethyl acetate=1:1), and 8.5 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:9][Br:17])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(Br)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cc1Br
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a solution of 52A (1.25 g, 4.98 mmol) in CCl4 (7 ML) was added NBS (0.89 g, 4.98 mmol) followed by catalytic AIBN and the mixture was heated to reflux for 4 hours. The reaction was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 10% CH2Cl2/Hexane then 50% CH2Cl2/Hexane) to give 52B (0.90 g, 55%). HPLC Rt=2.85 min.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]1=[O:11])[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH2:1]([N:3]1[C:8]([CH2:9][O:10][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][CH:6]=[CH:5][C:4]1=[O:11])[CH3:2]
Reactant: CCn1c(CO)cccc1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCn1c(COS(C)(=O)=O)cccc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
1-Ethyl-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine (1.51 g, 9.86 mmol) obtained in Step 2 and triethylamine (2.06 mL, 14.8 mmol) were dissolved in dichloromethane (40 mL), and at 0° C., methanesulfonyl chloride (0.920 mL, 11.8 mmol) was added dropwise thereto, followed by stirring at 0° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 1-ethyl-6-(methanesulfonyloxymethyl)-2-oxo-1,2-dihydropyridine (2.29 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C=O.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:16])=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)[CH3:21]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CNC
Agent: C=O
Product: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Upon intermixing of 2,6-di-tert.butyl-4-methylphenol, formaldehyde and dimethylamine in an alcoholic medium at a temperature within the range of from 80° to 90° C. a condensation reaction occurs resulting in the formation of N,N-dimethyl-3,5-di-tert.butyl-4-hydroxybenzylamine. Along with the latter, formed are readily-volatile reaction products, i.e., water and bis-amine. In addition, alcohol is contained in the reaction mass. The thus-selected temperature range is optimal. When temperature is decreased below the lower limit, the reaction rate of condensation is substantially reduced. Upon increasing temperature above 90° C., decomposition of the Mannich base is observed.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[C:19]([C:29](=[O:43])[NH:30][CH2:31][C:32]3[C:33](=[O:42])[NH:34][C:35]([CH3:41])=[CH:36][C:37]=3[CH2:38][CH2:39][CH3:40])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:41][C:35]1[NH:34][C:33](=[O:42])[C:32]([CH2:31][NH:30][C:29]([C:19]2[C:20]3[CH:21]=[CH:22][N:23]([CH:26]([CH3:27])[CH3:28])[C:24]=3[CH:25]=[C:17]([O:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[O:43])=[C:37]([CH2:38][CH2:39][CH3:40])[CH:36]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)cc2c1ccn2C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCNCC2)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a stirred solution of 4-(2-{1-isopropyl-4-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-carbamoyl]-1H-indol-6-yloxy}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.472 mmol; prepared following the procedure of Example xx) in dichloromethane (15 mL) was added TFA (1.5 mL) at room temperature and then stirred for 3 h at room temperature. Reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and washed the resulting aqueous layer with diethyl ether (2×15 mL). The aqueous layer was basified with (pH ˜8) with saturated aqueous NaHCO3 solution and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine solution (2×25 mL) and concentrated. Purification by preparative HPLC afforded 1-isopropyl-6-(2-piperazin-1-yl-ethoxy)-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (48 mg, 20%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (t, 3H), 1.42 (d, 6H, J=6.8 Hz), 1.57 (m, 2H), 2.14 (s, 3H), 2.45-2.2 (m, 4H), 2.68 (t, 2H), 2.75 (t, 4H), 4.15-4.19 (m, 2H), 4.35 (d, 2H), 4.78-4.72 (m, 1H), 5.91 (s, 1H), 6.73 (d, 1H), 7.03 (s, 1H), 7.24 (s, 1H), 7.42 (d, 1H), 8.12 (t, 1H), 11.58 (bs, 1H). LCMS (ES+): m/z=494.57[M+H].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:19]1CCC[CH2:20]1>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:20]=[O:19])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2-tert-Butylphenol 7.51 g (50 mmol) and THF (tetrahydrofuran) 54 ml were charged in a sufficiently dried 500 ml reactor purged with argon, ethylmagnesium bromide 18.53 ml (an ether solution, 3.0N, 55.6 mmol) was added dropwise to the reactor at 0° C. in 15 minutes and after that, the temperature was gradually raised to a room temperature and the resultant mixture was stirred for 1 hour at a room temperature. Toluene 180 ml was added, the resultant mixture was heated to 100° C., and about 40 ml of the mixed solvents of ether and THF were evaporated off to obtain a slightly opaque slurry. After the slurry was cooled to a room temperature, p-formaldehyde 3.75 g (125 mmol) and triethylamine 10.45 ml (75 mmol) were added and the resultant mixture was stirred at 88° C. for 1 hour. After being cooled to a room temperature, the mixture was quenched with 10% hydrochloric acid and an organic layer was concentrated and purified by a silica gel column to obtain 3-tert-butylsalicylaldehyde 6.22 g (yield 70%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:29][C@H:17]1[N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=[C:2]1[Cl:1])(=[O:22])[CH3:21]
Reactant: Clc1cc(Cl)c2[nH]c(Cl)nc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
To a suspension of 1.362 g (6.15 mmol) of 2,4,6-trichlorobenzimidazole in 31 mL of MeCN, was added 1.52 mL (6.15 mmol) of BSA. The reaction mixture was stirred at 80° C. for 15 min to give a clear solution. This solution was treated with 2.153 g (6.675 mmol) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.426 mL (7.380 mmol) of TMSOTf at 80° C. for 1 hr. The reaction mixture was cooled and diluted with EtOAc (150 mL). The EtOAc solution was washed with sat. NaHCO3 solution (150 mL×2), sat. NaCl solution (150 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with MeOH and then suspended in 50 mL of hot MeOH. The suspension was cooled, filtered, and the solid product was washed with MeOH to give 2.103 g of 80 as white crystals (This product showed one spot TLC). The mother liquor was evaporated and the residue was chromatographed on a silica column (2.5×20 cm, eluted with CHCl3 and 0.5% MeOH/CHCl3). Evaporation of fractions 20-24 (20 mL per fraction) and recrystallization from MeOH gave an additional 0.258 g of 80 as white crystals. The total yield of 80 was 2.361 g (80%). MP: 198°-200° C. MS: (EI) m/e 480.0069 (4%, for C18H1735Cl237ClN2O7 : M+ =480.0072). 1H NMR (DMSO-d6): δ 7.89 (d, 1, 7-H, J7-5 =2.0 Hz), 7.58 (d, 1, 5-H), 6.26 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.54 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (dd, 1, 3'-H. J3'-4' =4.5 Hz), 4.48, 4.38 (2×m, 3, 4'-H and 5'-H), 2.14, 2.02 (2×s, 9, 3×Ac). 13H NMR (DMSO-d6): δ 169.84, 169.37, 169.09 (3×COCH3), 140.91 (C2), 137.39 (C3a), 134.14 (C7a), 128.47 (C6), 123.66 (C4), 123.25 (C5), 111.06 (C7), 86.91 (C1'), 79.58 (C4'), 70.54 (C2'), 68.55 (C3'), 62.47 (C5'), 20.48, 20.19, 19.90 (3×COCH3). Anal. Calcd. for C18H17Cl3N2O7 : C, 45.07; H, 3.57; N, 5.84. Found: C, 45.08; H, 3.62; N, 5.87.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1)=O.[C:30](O)(=[O:32])C>>[O:32]1[CH:30]=[CH:9][CH:10]=[C:11]1[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8]
Reactant: Nc1n[nH]cc1-c1ccco1
Reactant: CC(=O)N(C)c1ccc(C(=O)C=CN(C)C)cc1
Reactant: CC(=O)O
Product: CC(=O)N(C)c1ccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)cc1

Procedure:
A solution of 1.77 g of 3-amino-4-furanylpyrazole and 2.46 g of N-[4-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylacetamide in 50 ml of glacial acetic acid was refluxed for 8 hours. Evaporation of the reaction mixture gave a gum which was partitioned between an aqueous saturated sodium bicarbonate solution and methylene chloride. The methylene chloride extract was dried and passed through a short column of hydrous magnesium silicate adsorbent. The eluate was refluxed on a steam bath with gradual addition of hexane until turbidity. On cooling, the desired compound was collected by filtration, mp 202°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[CH2:35]([NH2:38])[CH2:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:38][CH2:35][CH2:36][CH3:37])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCNC(=O)c1cccc(-c2nc(NCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 32.7 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added propylamine (0.003 mL, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (5 mg, 31%). LC-MS m/z 510 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.67 (m, 2H), 2.80 (s, 6H), 3.25 (m, 2H), 3.40 (m, 2H), 3.62 (m, 2H), 4.52 (s, 2H), 7.19 (m, 1H), 7.53 (m, 1H), 7.65 (m, 1H), 7.76 (d, 1H), 7.98 (d, 1H), 8.05 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1.C([O:23]CC)C>>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:23])[C:5]=2[CH:14]=1)#[N:19]
Reactant: CCOCC
Reactant: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from (+)-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained (+)-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 143°-44° C. (from diethyl ether); [α]58920 =+78.8° (c=1.001 in ethanol).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH:13]([C:14]([O:16]C)=[O:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.Cl>C1COCC1.CO>[O:3]=[C:4]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: COC(=O)C1Cc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
1N Aqueous sodium hydroxide solution (80 ml) was added dropwise to the mixed solution of methyl 2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (8.322 g) in THF (80 ml) and methanol (80 ml) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid (90 ml) was added dropwise to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated to obtain crude crystals of the entitled compound (7.032 g). The obtained crude crystals were put to use in the following reaction without purification.
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:8])OC)C.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH2:21]>CO>[CH3:19][C:17]1[CH:16]=[C:15]2[C:4](=[C:13]([CH3:12])[CH:18]=1)[CH:5]=[N:8][C:20]([NH2:21])=[CH:14]2
Reactant: CCOC(OCC)C(=N)OC
Reactant: Cc1ccc(CN)c(C)c1
Solvent: CO
Product: Cc1cc(C)c2cnc(N)cc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of methyl 2,2-diethoxyacetimidate (1.5 g, 9.3 mmol) in methanol (4.9 mL) was added (2,4-dimethylphenyl)methanamine (1.2 g, 8.9 mmol) dropwise at ambient temperature. The reaction flask was then placed into a preheated oil-bath and stirred at 70° C. for 16 h, then cooled and the volatiles removed under reduced pressure. The crude material was added dropwise to sulfuric acid (19.7 mL) at ambient temperature and stirred for 72 h. The flask was then placed into an ice-water bath, diluted with water (50 mL), and slowly neutralized to pH=10 with sodium hydroxide (10 N). As the reaction mixture became basic, an orange precipitate formed. This precipitate was filtered, washed with water, and dried to afford 6,8-dimethylisoquinolin-3-amine (1.37 g, 7.95 mmol, 90%). 1H NMR (400 MHz, MeOD) δ ppm 8.82 (s, 1H), 7.17 (s, 1H), 6.90 (s, 1H), 6.72 (s, 1H), 2.61 (s, 3H), 2.37 (s, 3H). MS (LC/MS) R.T.=0.77; [M+H]+=173.15.