Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=O)[C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2]>O1CCCC1>[N+:1]([C:4]1[CH:35]=[CH:34][C:7]([C:8](=[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](=[C:23]([C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)[CH2:6][CH2:7][CH3:8])[CH2:19][CH:18]=3)=[CH:12][CH2:11]2)[CH2:5][CH2:4][CH3:35])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc(Cc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCCC(=C1C=CC(CC2=CCC(=C(CCC)c3ccc([N+](=O)[O-])cc3)C=C2)=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
Then, a solution of 30.0 g (0.064 mole) of 1,1-bis(4-(4-nitrobenzoyl)phenyl)methane in 1 liter of tetrahydrofuran was added dropwise for 1 hour, and stirred for 8 hours with maintaining at 3° to 5° C. At that time, hue was changed to dark purple. After the end of the reaction was confirmed by a liquid chromatography, the solution was poured in 400 milliliters of ice water, and extracted with 800 milliliters of chloroform after adding 400 milliliters of a 4N-HCl aqueous solution. Thereafter, the solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and then removed off chloroform by a rotary evaporator. The residue was dissolved in toluene and treated with a silica gel (800 g) column, to obtain 17.1 g of 1,1-bis(4-(1-(4-nitrophenyl)butylidene)phenyl)methane as highly viscous oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[C@@H:32]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][C@H:35]2[C@@H:33]1[CH2:34]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CO>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[C@H:36]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][C@H:33]2[C@@H:35]1[CH2:34]2
Reactant: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of triphenylphosphine (6.4 g, 24.292 mmol), phthalimide (6.2 g, 42.511 mmol) and benzyl (1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hexan-3-ylcarbamate (3.0 g, 12.146 mmol) in toluene (250 mL) was stirred at −78° C. for 30 minutes under nitrogen protection, followed by the addition of diisopropyl azodicarboxylate (8.6 mL, 42.511 mmol) dropwise. The resulting mixture was stirred at −78° C. for another 1 hour and then at room temperature overnight. The reaction mixture was treated with 10 mL of methanol, and the solvents were removed under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to afford the title compound (3.0 g, 65%) as a light yellow oil. MS (ES+) C22H20N2O4 requires: 376, found: 399 [M+23]+.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9](=[O:15])[NH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:7])(C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]CCC1C=CC(C(O)=O)=CC=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:14][C:11]1[NH:10][C:9](=[O:15])[C:8]([C:6]([OH:5])=[O:7])=[CH:13][CH:12]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)c(=O)[nH]1
Reactant: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCc2ccccc2OCc2ccccc2)[nH]c1=O
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
3-tertbutoxycarbonyl-6-methyl-2(1 H)-pyridinone (1.49 g, J. Het. Chem., 1981, 18, 1611) was added to a THF (20 ml) solution of lithium diisopropylamide (14.3 mmol, prepared by the standard method) and stirred under argon, at -30° C., for 2.5 hours. 2-Benzyloxybenzyl bromide (2 g, prepared as described in Example 1) in THF (10 ml) was added and the mixture stirred, at -30° C., for 1 hour, then warmed to ambient temperature. The mixture was poured into saturated aqueous ammonium chloride (200 ml) and extracted with dichloromethane. The solvent was evaporated and crystallised from isopropranol. There was thus obtained 6-(2-[2-benzyloxyphenyl)ethyl]-3-tertbutoxycarbonyl-2(1 H)-pyridinone (1.85 g) m.p. 146°-147° C.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[N:18]1([CH2:24][CH:25]([OH:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([CH2:24][C:25](=[O:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1OCC(O)CN1CCOCC1
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(COc1ccccc1[N+](=O)[O-])CN1CCOCC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A five liter round bottom flask was charged with 63.8 ml (0.45 mole) of trifluoroacetic anhydride and 400 ml of MDC under nitrogen. The resulting solution was cooled to -65° C. with a dry ice bath, treated with 42.6 g (0.54 mole) of dimethylsulfoxide over a period of 15 minutes, stirred for 30 minutes, and then treated with a solution of 90 g (0.32 mole) of 2-[3-(4-morpholinyl)-2-hydroxy-1-propyloxy]nitrobenzene in 200 ml of MDC over a 35 minute period. The reaction mixture was stirred for 30 minutes, quenched with 261 ml of diisopropylethylamine, the reaction temperature allowed to rise to -10° C. and the mixture treated with one liter of diethyl ether. The pale yellow solid which separated was collected by filtration, slurried in 1.5 liters of diethyl ether and the product collected and dried to give 73.7 g of 2-[3-(4-morpholinyl)-2-keto-1 -propyloxy]nitrobenzene.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=C.[O:12]=[O+][O-]>ClCCl>[Cl:11][C:5]1[C:4]([CH2:1][CH:2]=[O:12])=[C:9]([Cl:10])[N:8]=[CH:7][N:6]=1
Reactant: C=CCc1c(Cl)ncnc1Cl
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: O=CCc1c(Cl)ncnc1Cl
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of 5-Allyl-4,6-dichloro-pyrimidine (Preparation 207, 30 g, 0.159 mole) in dry dichloromethane (400 mL) was bubbled ozone at −70° C. for 30 min. After excess ozone was purged by nitrogen gas, dimethyl sulfide (10 mL) was added at −5° C., and the reaction was stirred for 2 hours. The mixture was washed with water, brine, dried over sodium sulfate, and evaporated in vacuo. The crude material was purified by trituration from pentane-diethyl ether to afford the title compound as a colorless solid in 84% yield, 10 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>N1C=CC=CC=1>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Solvent: c1ccncc1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4ccccc4[N+](=O)[O-])c2)c1=O)CCCC3
Temperature: 80 °C
Yield: 100.2 %

Procedure:
A mixture of 4-(3-aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (228 mg, 0.74 mmol), 2-nitrobenzenesulfonyl chloride (247 mg, 1.11 mmol), and dry pyridine (5 mL) was refluxed at 80° C. for 4 hours. After cooling on standing, the solvent was removed by evaporation under reduced pressure. The obtained residue was extracted with chloroform, washed with water and a dilute hydrochloric acid aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the titled compound as a brown crystal (365 mg, yield 100%).
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:2][CH2:1][CH:3]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH2:4][CH3:5]
Reactant: CCC(N)CC
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCC(CC)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-ethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 mL) was added a solution of 1,3-propane sultone (13.7 g, 110 mmol) in 20 mL of THF. The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×50 mL), and dried in vacuo., to afford compound DD (18.1, 80%): 1H NMR (D2O, 500 MHz) δ ppm 3.08 (t, 2H, J=7.3 Hz), 3.01 (m, 1H), 2.87 (t, 2H, J=7.3 Hz) 2.00 (m, 2H), 1.59 (m, 4H), 0.82 (t, 6H, J=7.3 Hz). 13C NMR (D2O, 125 MHz) δ ppm 60.87, 48.14, 43.68, 21.81.21.60, 8.25. ES-MS 208 (M−1).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(OC)C(CC)=CC=2)=[O:8])C=CC=CC=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([O:51][CH3:52])=[C:32]([C:40]([CH2:43][S:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:41][CH:42]=2)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:26]1>>[C:45]1([S:44]([CH2:43][C:40]2[C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:31]([O:51][CH3:52])[C:30]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)=[CH:42][CH:41]=2)=[O:8])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OC(C)(C)C
Product: COc1c(-c2ccoc2)ccc(CS(=O)c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from t-butyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoate (Intermediate 222).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(C(C)=O)C>[CH3:7][C:2]1[NH:1][C:2]2[C:7]([C:3]=1[CH3:4])=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Nc1ccccc1
Solvent: CCC(C)=O
Product: Cc1[nH]c2ccccc2c1C
Yield: 93 %

Procedure:
Aniline was reacted with methyl ethyl ketone in the same way as in Example 3. 2,3-Dimethylindole was formed in a yield of 93% of the theoretical yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@H:18]([CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=2)=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccc(F)c(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)c(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (150 mg, 0.62 mmol), 2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (207 mg, 0.65 mmol)[prepared according to the procedure of Preparation 6] and N,N-diisopropylethyl amine (0.33 ml, 1.87 mmol) in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (436 mg, 0.94 mmol). After stirring at ambient temperature for 20 h, the mixture was concentrated and purified using silica gel and eluting with a gradient of 0-50% ethyl acetate/hexane to afford the title compound as an off-white foam (200 mg, 0.35 mmol, 57% yield): LC-MS (ES) m/z 539 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=[C:9]2[N:8]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])C.BrCCC1C=CC(C(F)(F)F)=CC=1>>[CH:16]1([C:14]2[CH:15]=[C:9]3[N:8]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11](=[O:12])[N:10]3[N:13]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cn(CCc2ccc(C(F)(F)F)cc2)c2cc(C3CC3)nn2c1=O
Agent: FC(F)(F)c1ccc(CCBr)cc1
Product: O=C(O)c1cn(CCc2ccc(C(F)(F)F)cc2)c2cc(C3CC3)nn2c1=O

Procedure:
The expected compound was obtained according to general procedure G using 2-cyclopropyl-7-oxo-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester. The starting material was obtained according to general procedure D using Key Intermediate II and 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene. The expected compound was isolated as white powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:13](Cl)(Cl)=[S:14].C(N(CC)CC)C>ClCCl.[OH-].[Na+].CO>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[O:5][C:13]([SH:14])=[N:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Sc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
To a solution of 2-amino-4′-chloroacetophenone hydrochloride (1.48 g) in 30 ml of dichloromethane were added 1.65 g of thiophosgene and 3.63 g of triethylamine at 0° C. and the mixture was stirred over night at room temperature. To the reaction mixture were added IN sodium hydroxide solution and methanol. The resulting mixture was stirred at room temperature and partitioned between ethyl acetate and water. The aqueous layer was neutralized by adding dil. hydrochloric acid and the resulting crystal was collected and dried to give 220 mg of 5-(4-chlorophenyl)-2-mercaptooxazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([CH:8]2[CH2:13][C:12]([NH:14][NH:15]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([CH:8]2[CH2:13][C:12]3[N:14]=[N:15][CH:37]=[C:38]([CH3:39])[C:11]=3[C:10](=[O:26])[CH2:9]2)[CH:7]=1
Reactant: CC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(F)ccc3C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc(F)cc1C1CC(=O)c2c(C)cnnc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of 5-(5-fluoro-2-methylphenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.63 g), anhydrous potassium carbonate (1.45 g), methanol (20 ml) and 1,2-dimethoxyethane (10 ml) was added under ice-cooling 1-bromopropan-2-one (0.75 g), and the mixture was stirred at room temperature for 2 hours and then at 80° C. for 5 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (70 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.265 g) as yellowish brown crystals.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:23])[C:3]=1[O:24]CC1C=CC=CC=1.O1CC=CC1=O>>[OH:24][C:3]1[C:4](=[O:23])[O:5][C:6]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: CC(C)Cc1ccc(C2(c3ccccc3)OC(=O)C(OCc3ccccc3)=C2O)cc1
Agent: O=C1C=CCO1
Product: CC(C)Cc1ccc(C2(c3ccccc3)OC(=O)C(O)=C2O)cc1
Yield: 51.4 %

Procedure:
Hydrogenolysis of 500 mg (1.2 mmol) of 4-hydroxy-5-(4-isobutylphenyl)-5-phenyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H-furanone to provide 200 mg (51% yield) of 3,4-dihydroxy-5-(4-isobutylphenyl)-5-phenyl-2(5H)-furanone as a white powder: mp 138-139° C. (CHCl3/hexanes). 1H NMR (acetone-d6) δ 7.40-7.15 (m, 9H), 2.49 (d, J=7.1 Hz, 2H), 1.94-1.74 (m, 1H), 0.89 (d, J=6.5 Hz, 6H). Anal Calcd for C20H20O4: C, 74.1; H, 6.2. Found: C, 73.7; H, 6.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(C)n1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(C)n1
Yield: 28 %

Procedure:
The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g, 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2,4 g, 10.48 mmol) in the presence of a base K2CO3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.
Reaction SMILES: [NH2:1][C:2](=[O:15])[CH:3]([CH3:14])[O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11](O)=[O:12].Cl.C(N=C=NCCCN(C)C)C.FC1C=C(C2C3OCCNCC=3SC=2)C=CC=1.CN(C=O)C>O>[Br:10][C:9]1[C:5]2[O:4][CH:3]([CH3:14])[C:2](=[O:15])[NH:1][C:11](=[O:12])[C:6]=2[S:7][CH:8]=1
Reactant: CC(Oc1c(Br)csc1C(=O)O)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Fc1cccc(-c2csc3c2OCCNC3)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2c(Br)csc2C(=O)NC1=O
Yield: 77.2 %

Procedure:
A solution of 3-(2-amino-1-methyl-2-oxoethoxy)-4-bromothiophene-2-carboxylic acid (400 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (521 mg), 1-hydroxybenzotriazole 1 hydrate (417 mg) and DMF (4 mL) was stirred at room temperature for 1.5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (290 mg, 77%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2([CH:13]([C:14](O)=[O:15])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:20](C)C=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[C:14]([CH:13]1[C:11]2([CH2:17][CH2:18][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:12]1)(=[O:15])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC2C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2C(N)=O
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
To a mixture of 165d (400 mg, 1.57 mmol) and N,N-dimethylformamide (0.1 mL) in DCM (5 mL) was added oxalyl chloride (397 mg, 3.13 mmol) dropwise. See FIG. 6. The reaction mixture was stirred at 15° C. for 2.5 h and then concentrated. The residue was dissolved in tetrahydrofuran (20 mL) and added dropwise to aqueous ammonia (10 mL, 28%). The mixture was stirred at 15° C. for 4 h and then diluted with water (15 mL). The reaction mixture was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate 165e (260 mg, 65%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.58 (s, 1H), 5.34 (s, 1H), 3.48-3.39 (m, 4H), 1.73-1.70 (m, 2H), 1.48 (s, 9H), 1.47-1.41 (m, 2H), 1.40-1.22 (m, 2H), 0.89-0.87 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][CH2:3]1.O1CCCC1.O.[OH-].[K+]>CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(N[C@H]2CC[C@H](O)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N[C@H]2CC[C@H](O)CC2)c1

Procedure:
To a solution of methyl 3-[(trans-4-hydroxycyclohexyl)amino]benzoate (0.25 g, 1.00 mmol) in a mixture of methanol (20 mL), terahydrofuran (10 mL) and water (10 mL) was added a 4M aqueous solution of potassium hydroxide (0.5 mL, 2.00 mmol), and the reaction mixture was heated to reflux for five minutes. The organic portion of the solvent was evaporated, and the pH of the aqueous solution was adjusted to 2 by the addition of 2M aqueous hydrochloric acid. The aqueous mixture was partitioned with ethyl acetate, the organic layer was separated and washed with brine, dried over sodium sulfate, filtered, and the solution was concentrated to give 3-[(trans-4-hydroxycyclohexyl)amino]benzoic acid (40 mg, 17%). MS (EI) for C13H17NO3: 234 (M−H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (2 g, 5.69 mmol) and potassium carbonate (1.967 g, 14.23 mmol) were suspended in DMF (20 ml) and heated to 50° C., under nitrogen for 30 mins. The mixture was cooled to room temperature, 1-bromo-4-chlorobutane (0.656 ml, 5.69 mmol) was added and stirring continued at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between DCM (40 ml) and water (40 ml). The layers were separated using a hydrophobic frit and the aqueous layer washed with DCM (10 ml). The combined organic extracts were concentrated in vacuo to give crude material that was purified by silica chromatography using the FlashMaster (70 g cartridge) eluting with a cyclohexane:ethyl acetate 0-100% gradient over 30 mins. The product-containing fractions were combined and evaporated to give the title compound as a white solid (1.4 g).