Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(C(=CNC1C=CC(CCCC)=CN=1)C(OCC)=O)#N>>[C:22]([C:16](=[CH:15][NH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCCCc1cccnc1N
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1
Product: CCCCc1cccnc1NC=C(C#N)C(=O)OCC
Yield: 84 %

Procedure:
The title compound (m.p. 98.5°-99.5°, 84% yield) was prepared from 2-amino-3-n-butylpyridine and ethyl ethoxymethylenecyanoacetate in a manner similar to that described for the preparation of ethyl 2-cyano-3-(5-n-butyl-2-pyridylamino)acrylate in Preparation 3D of U.S. Pat. No. 4,122,274.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:14]([C:25]([OH:27])=O)=[CH:13]1)[CH3:11].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:63]([NH2:84])=[N:64][CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([O:74][CH2:75][C@H:76]4[CH2:81][O:80][CH2:79][CH2:78][O:77]4)=[C:70]([O:82][CH3:83])[CH:69]=3)[CH:67]=2)=[CH:58][CH:57]=1>CN(C=O)C.O>[NH2:84][C:63]1[C:62]([C:59]2[CH:58]=[CH:57][C:56]([NH:55][C:25]([C:14]3[C:15](=[O:24])[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][N:12]([CH2:10][CH3:11])[CH:13]=3)=[O:27])=[CH:61][CH:60]=2)=[CH:67][C:66]([C:68]2[CH:73]=[CH:72][C:71]([O:74][CH2:75][C@H:76]3[CH2:81][O:80][CH2:79][CH2:78][O:77]3)=[C:70]([O:82][CH3:83])[CH:69]=2)=[CH:65][N:64]=1
Reactant: CCn1cc(C(=O)O)c(=O)c(-c2ccccc2)c1
Reactant: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OC[C@H]1COCCO1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1cc(C(=O)Nc2ccc(-c3cc(-c4ccc(OC[C@H]5COCCO5)c(OC)c4)cnc3N)cc2)c(=O)c(-c2ccccc2)c1
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
DIPEA (240 μl) was added to a solution of 1-ethyl-4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylic acid (168 mg) and COMU (384 mg) in DMF (2.3 ml) at room temperature, and the mixture was stirred for 20 minutes. The compound obtained in Step 1 of Example 42 (295 mg) was added at room temperature. The mixture was stirred for 15 hours, followed by the addition of water. The organic layer was extracted with ethyl acetate, and then washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 235 mg of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:24].O>CS(C)=O>[CH2:23]([O:25][C:26](=[O:27])[NH:28][C:29]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[CH:9]=2)=[CH:16][N:17]=1)=[S:30])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl{3-[(6-aminopyridin-3-yl)oxy]phenyl}carbamate (4.60 g, 15.2 mmol) in dimethyl sulfoxide (90 mL) was added ethoxycarbonyl isothiocyanate (2.00 mL, 16.7 mmol), and the mixture was stirred at room temperature for 5 days. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with 5% aqueous ammonium chloride solution (200 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50), and fractions containing the object product was concentrated under reduced pressure to give the title compound (4.56 g, 69%) as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[CH2:17][N:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]2=[O:33])=[O:8])=[CH:5][CH:4]=1.[CH3:36][N:37]([CH3:39])[CH3:38]>C(#N)C.C(OCC)(=O)C>[Cl-:1].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]([C:6]2[CH:34]=[CH:35][C:3]([CH2:2][N+:37]([CH3:39])([CH3:38])[CH3:36])=[CH:4][CH:5]=2)=[O:8])=[C:11]([CH2:17][N:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]2=[O:33])[CH:12]=1
Reactant: CN(C)C
Reactant: O=C(Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O)c1ccc(CCl)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[N+](C)(C)Cc1ccc(C(=O)Oc2ccc(Cl)cc2Cn2nc(-c3ccc(C(F)(F)F)cc3)oc2=O)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
A solution of 4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl]methyl]phenyl 4-(chloromethyl)benzoate (0.3 g, 0.573 mmol) in acetonitrile/ethyl acetate (20 mL) was saturated with anhydrous trimethylamine. The reaction mixture was stirred at room temperature for two days. The precipitate was collected and purified by recrystallization from acetonitrile-ether to afford the title compound as a white solid (0.24 g, 72%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[F:35])[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[F:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 54 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.62–7.57 (m, 3H), 7.27 (s, 8H), 7.23–7.19 (m, 1H), 6.94 (dd, 1H, J=8.8, 10.0 Hz), 4.78 (s, 1H), 3.39 (dd, 2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.77 (m, 1H), 2.48 (m, 1H), 2.42 (t, 2H, J=6.0 Hz), 1.99 (dt, 2H, J=1.6, 11.6 Hz), 1.77 (d, 2H, J=11.2 Hz), 1.69–1.61 (m, 4H), 1.22 (d, 6H, J=6.8 Hz); ESMS m/e: 584.2 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[NH2:13][C:14]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]2[C:26]([CH3:31])=[N:27][O:28][C:29]=2[CH3:30])=[CH:20][C:15]=1[C:16]([O:18]C)=O.CN1C2C(N=C(N)NC=2NCC1CNC1C=CC([C:53]([NH:55][CH:56](C(O)=O)[CH2:57][CH2:58][C:59](O)=O)=O)=CC=1)=O>>[NH2:13][C:14]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]2[C:26]([CH3:31])=[N:27][O:28][C:29]=2[CH3:30])=[CH:20][C:15]=1[C:16]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:53][N:55]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[OH:18]
Reactant: COC(=O)c1cc(-c2c(C)noc2C)cc(N)c1N
Reactant: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Product: Cc1noc(C)c1-c1cc(N)c(N)c(C(O)(c2ccccn2)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (1.6M solution in hexanes, 24 mL, 38 mmol) was added dropwise over 20 minutes to a solution of 2-bromopyridine (3.7 mL, 38 mmol in methyl-THF (100 mL) at −78° C. The reaction mixture was stirred for 1 hour and a solution of methyl 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoate (2.0 g, 7.7 mmol) in 20 mL of methyl-THF was added. The reaction mixture was warmed to room temperature, stirred for 30 minutes and quenched with water. The reaction mixture was extracted with ethyl acetate and purified by silica gel chromatography (90:9:1 ethyl acetate/methanol/ammonium hydroxide) to give (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol as an orange powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:14][OH:15])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(=NO)c2ccccc21
Temperature: 80 °C
Yield: 97.4 %

Procedure:
To a solution of 3,3-dimethylindan-1-one (1.16 g, 7.21 mmol) and hydroxylamine hydrochloride (1.31 g, 18.8 mmol) in MeOH (20.0 mL) was added a solution of sodium hydroxide (765 mg, 19.1 mmol) in water (10.0 mL). The mixture was heated to 80° C. for 2 h. The cooled reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was separated and concentrated in vacuo to afford the title compound as an oil (1.23 g, 97%). LC/MS: Rt=1.61 min, ES+ 176 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(F)c(Cl)cc(Cl)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2c(F)c(Cl)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 359 mg (1.0 mmole) of ethyl 6,8-dichloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 7 mLs of THF and 2 mL of methanol was added a solution of 90 mg of lithium hydroxide monohydate in 1.0 mL of water. The mixture was heated to reflux for 60 min and allowed to cool to rt. After stirring overnight, the mixture was treated with 75 mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were concd and purified by reverse phase chromatography to afford 240 mg of an impure white solid. Recrystallization from acetonitrile afforded 51 mg (15%) of a white, crystalline solid: 1H NMR (d6-acetone/400 MHz) 6.08 (q, 1H, J=7.0 Hz), 7.74 (d, 1H, J=7.7 Hz), 7.94 (s, 1H); 19F NMR (d6-acetone/400 MHz) −122.1 (d, 1F, J=7.7 Hz), −79.4 (d, 3F, J=6.8 Hz); MS (ES+) 331 (M+1, 100), 333 (M+3, 57); MS (ES−) 329 (M−1, 100), 331 (79); HRMS (ES−) m/z calcd for (C11H4C12F4O3) 328.9401, found 328.9357.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:32]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][CH:45]([CH3:47])[CH3:46])[CH:38]=1)[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:44]([O:43][C:39]1[CH:38]=[C:37]([O:36][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:42]=[CH:41][C:40]=1[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14]2)=[O:17])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1CC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)c3ccc(OCC(C)C)cc3OCC(C)C)ccc2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In 3 ml of methylene chloride is dissolved 0.12 g of 2-(ethoxycarbonyl)-1-isobutyl-1H-indole-5-carboxylic acid, to which are successively added 50 μl of oxalyl chloride and 20 μl of N,N-dimethylformamide at ambient temperature. The mixture is stirred at ambient temperature for one hour. Then, at 5-10° C., 0.12 g of aluminum chloride and 0.13 g of 1,3-diisobutoxybenzene are successively added and stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to obtain 0.18 g of ethyl 5-(2,4-diisobutoxybenzoyl)-1-isobutyl-1H-indole-2-carboxylate as a colorless oily product.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20][CH2:21][C:22]([O:24]CC)=O)[C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:31].O.C([O-])(O)=O.[Na+]>CC(O)=O.CCOC(C)=O>[OH:24][C:22]1[N:31]=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)=[N:20][CH:21]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CNC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1nc(-c2ncc(O)nc2-c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 24.8 %

Procedure:
A mixture of ethyl {[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]amino}acetate (14.0 g) and ammonium acetate (21.0 g) in AcOH (60 ml) was refluxed with stirring for 2 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(5-hydroxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (3.0 g) as white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/S(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[N+:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C-:23].CCO>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:23][NH:22][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step.
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23].C([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: C=CCC(O)C1=C(C)CCCC1(C)C
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCC(O)C12OC1(C)CCCC2(C)C

Procedure:
A mixture of 40 % peracetic acid (105 g.) and anhydrous sodium acetate (3.0 g.) was added at 25° with stirring to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (97g.) and anhyd. sodium acetate (60 g.) in 175 ml. of CH2Cl2 (1.5 h.). Stirring was continued for one night and 500 ml. of water were then added to the reaction mixture. The organic layer was separated and, after the usual treatments, distilled to give 98 g. (83 %) of two diastereoisomers of the epoxy product. V.p.c. enabled the separation of the two isomers (Carbowax, 170°, 3 m)
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[N:25]2[CH2:26][CH2:27][N:28]=[C:24]2[C:23]2[CH:22]=[CH:21][C:20]([OH:29])=[C:19]([O:30][CH3:31])[C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:43][C@@H:44]1[O:46][CH2:45]1)(=O)=O>CN(C=O)C>[CH3:31][O:30][C:19]1[C:18]2[N:17]=[C:16]([NH2:15])[N:25]3[CH2:26][CH2:27][N:28]=[C:24]3[C:23]=2[CH:22]=[CH:21][C:20]=1[O:29][CH2:43][C@H:44]1[CH2:45][O:46]1
Reactant: COc1c(O)ccc2c1N=C(N)N1CCN=C21
Reactant: CS(=O)(=O)OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
To a solution of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(trifluoroacetate) (Intermediate E, 0.30 g, 0.65 mmol) in DMF (8 mL) was added caesium carbonate to generate a white suspension. The suspension was stirred at room temperature for 1.5 hr, then (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 3.9 mL of 0.34 M solution in DMF, 1.30 mmol, 2.0 equiv.) was added, and the resulting solution was stirred at 60° C. for 20 h. The resulting suspension was concentrated under reduced pressure and the residue was treated separated between a saturated sodium bicarbonate solution (30 mL) and a 4:1 CH2Cl2/isopropanol solution (30 mL). The aqueous phase was extracted with a 4:1 CH2Cl2/isopropanol solution (30 mL). The combined organic phases were dried (anh. sodium sulfate) and concentrated under reduced pressure. The residue was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2Cl2 for 5 min., gradient to 95% CH2Cl2: 5% MeOH over 15 minutes; gradient to 90% CH2Cl2: 10% MeOH over 15 min.; gradient to 80% CH2Cl2: 20% MeOH over 15 min.; and gradient to 75% CH2Cl2: 25% MeOH over 15 min.) to give 7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (0.080 g, 43%): 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.71 (dd, J=2.5, 4.8 Hz, 1H), 2.85, (t, J=4.6 Hz, 1H), 3.34-3.40 (br m, 1H), 3.75 (s, 3H), 3.82 (s, 3H), 4.30 (dd, J=6.6, 11.4 Hz, 1H), 4.10 (br t, J=9.7 Hz, 2H), 4.31 (br t, J=9.7 Hz, 2H), 4.54 (dd, J=2.3, 11.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 7.84 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][C:6]=1[CH:7]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][C:6]=1[CH:7]([CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccccc3)oc2C)C2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methanol (545 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (365 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (1.0 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.0 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give methyl 4-[(2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methoxy]benzoate as an oil. The obtained methyl 4-[(2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methoxy]benzoate was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). 2N Lithium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (361 mg, 47%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=C(C#N)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:25]([C:24]([OH:27])=[O:26])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(Cl)cc1C=C2

Procedure:
550 Mg. 8-chloro-3-cyanodibenzo[b,f]thiepin is refluxed for 16 hours in a mixture of 15 cc. acetic acid and 15 cc. 50% aqueous sulfuric acid. The reaction mixture is cooled down and the product filtered, washed with water, and dried to yield 485 mg. (82% of the pure acid, m.p. 302°-304° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5]1.[CH:16]1[C:20]2[N:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[NH:18][CH:17]=1.[C:26](O)(=O)C.C=O>O1CCOCC1>[CH3:1][N:2]([CH2:26][C:16]1[C:20]2[N:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[NH:18][CH:17]=1)[CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5]1
Reactant: CC(=O)O
Reactant: CNCC1CCOC(c2ccccc2)O1
Reactant: O=c1[nH]cnc2cc[nH]c12
Agent: C=O
Solvent: C1COCCO1
Product: CN(Cc1c[nH]c2c(=O)[nH]cnc12)CC1CCOC(c2ccccc2)O1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
A mixture of 4-methylaminomethyl-2-phenyl-1,3-dioxane (0.368 g, 1.775 mmol), 9-deazahypoxanthine (0.288 g, 2.131 mmol), acetic acid (0.508 ml, 8.88 mmol) and 37% aq formaldehyde (0.264 ml, 3.55 mmol) in dioxane (10 mL) was stirred and heated in stoppered flask at 80° C. More 37% aq formaldehyde (0.132 ml, 1.775 mmol) was added and the stoppered flask was heated again at 80° C. for ˜24 h. The solution was concentrated to dryness and chromatography (10% 7M NH3/MeOH in CH2Cl2) separated the less polar byproducts, but the product and deazahypoxanthine eluted together. Chromatography of this material eluting with CHCl3/EtOAc/MeOH 5:2:1, then 4:2:3 followed by 20% 7M NH3/MeOH, gave the title compound as a white solid (0.406 g, 1.146 mmol, 64.5% yield). 1H NMR (CDCl3/CD3OD) δ 7.84 ((1H, s), 7.48-7.45 (2H, m), 7.39 (1H, s), 7.37-7.28 (3H, m), 5.56 (1H, s), 4.30-4.11 (2H, m), 4.02 (1H, dt, J=11.9, 2.5 Hz), 3.91 and 3.83 (1H each, d, J=13.8 Hz), 2.73 (1H, dd, J=13.5, 7.5 Hz), 2.57 (1H, dd, J=13.5, 3.4 Hz), 2.39 (3H, s), 1.74 (ddd, J=12.5, 4.9 Hz), 1.53 (1H, d, J=12.4 Hz); 13C NMR δ 156.8, 146.2, 143.2, 140.6, 130.6, 130.5, 129.8, 128.0, 119.7, 113.9, 103.0, 77.4, 68.7, 62.5, 52.0, 44.3, 31.5.