Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46].C(OCC)(=O)C>O>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 538 mg of (3RS,4RS)-2-{(1SR,2SR)-2-aminocyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 2.5 ml of pyridine was added 0.15 ml of methanesulfonyl chloride, followed by stirring at room temperature for 6 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform) and then recrystallized from ethyl acetate-hexane to obtain 206 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]1[CH2:5][O:4]1.[CH3:8][C:9]([NH2:12])([CH3:11])[CH3:10]>CO>[CH3:8][C:9]([NH:12][CH2:5][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N
Reactant: ClC(Cl)(Cl)C1CO1
Solvent: CO
Product: CC(C)(C)NCC(O)C(Cl)(Cl)Cl

Procedure:
The preparation of 2-(trichloromethyl)oxirane is reported by H. Gilman and R. K. Abbott, Jr., J. Org. Chem. 8, 224 (1943). 2-(Trichloromethyl)oxirane can be reacted with 1,1-dimethylethylamine at about -30° to +50° C. in a solvent such as methanol to produce 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.O1CCCCC1OCCCC(OC(=O)C)COC1C=CC(F)=CC=1>>[C:22]([O:21][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]#[C:9][CH2:8][OH:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCOC1CCCCO1)COc1ccc(F)cc1
Product: CC(=O)OC(C#CCO)COc1ccc(F)cc1

Procedure:
This compound is prepared by the procedure described in Example 4, Step B-5, except that 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-2-pentyne (Example 4, Step B-3) is substituted for 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)pentane. The title compound is obtained as a light yellow oil which is not distilled but used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:12]=1[NH2:13].C(N(C(C)C)CC)(C)C>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([NH:13][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (307 mg, 1.84 mmol), 2-methyl-5-t-butylaniline (300 mg, 1.84 mmol) and diisopropylethylamine (2 mL) in ethanol (2 mL) was heated at 80° C. for 16 h in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane to afford the product (369 mg, 68%) as a solid.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[S:3][N:2]1[NH:14][C:15]([N:17]1[CH:21]=[CH:20]N=C1)=[S:16])=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]1(CCN)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:22]1([CH2:20][CH2:21][NH:17][C:15]([NH:14][N:2]2[CH2:1][C:5]3[C:6]4[C:11]([CH:12]=[CH:13][C:4]=3[S:3]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[S:16])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C(NN1Cc2c(ccc3ccccc23)S1)n1ccnc1
Reactant: NCCc1ccccc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1)NN1Cc2c(ccc3ccccc23)S1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 1-[(2-naptho[1,2]thiazolyl)-thiocarbamoyl]imidazole (1.6 g, 5 mmol) and 2-phenylethylamine (0.62 g, 5.2 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.5 g (82%) of the titled product:
Reaction SMILES: [CH3:1][N:2]1C(=O)CCC1.Cl[C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(C)(C)C)=[C:11]([C:22]#[C:23][CH3:24])[C:10]=1[C:25]([F:28])([F:27])[F:26].C([Cu])#N.[OH-].[NH4+]>CCOCC>[CH3:24][C:23]1[NH:15][C:12]2[C:11]([CH:22]=1)=[C:10]([C:25]([F:26])([F:27])[F:28])[C:9]([C:1]#[N:2])=[CH:14][CH:13]=2
Reactant: CC#Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Temperature: 195 °C
Yield: 64 %

Procedure:
An NMP solution (150 mL) of N-[4-chloro-2-(1-propyn-1-yl)-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (10 g, 31.5 mmol) was treated with CuCN (11.3 g, 126 mmol) and the resulting mixture was heated at 195° C. for 90 h. Two reactions were carried out simultaneously. The combined dark brown reaction mixture was poured into crushed ice (250 mL) containing conc. ammonium hydroxide (100 mL). The resulting slurry was stirred with the addition of Et2O and filtered through celite. The filtrate was diluted with Et2O and partitioned. The aqueous portion was extracted with Et2O four times. The combined organic portions were washed with brine and dried (MgSO4). Filtration and concentration in vacuo followed by radial chromatography (SiO2, 0-60% EtOAc-hexanes gradient) afforded the title compound as a solid (9 g, 64%): 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 6.54 (s, 1H), 2.52 (s, 3H); MS (ES) m/z 225 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-])=O.C1C=CC=CC=1>O.C(O)C.[Fe]>[Cl:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:4]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(Cl)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1cc(F)c(F)c(Cl)c1Cl
Yield: 41.5 %

Procedure:
To a suspension of iron powder (1.9 g) in water (3 ml), with vigorous stirring at 50° to 60° C., was added concentrated hydrochloric acid (0.4 ml) slowly. After mixed with ethanol (7 ml), 2,3-dichloro-4,5-difluoronitrobenzene (2.47 g) in ethanol (3 ml) was added dropwise to the suspension at 54° to 66° C. during 20 minutes. After stirring for 4 hours at the same temperature, the hot reaction mixture mixed with benzene was filtered and the insoluble materials were washed with hot ethanol (5 ml) and with benzene (20 ml) successively. The filtrate and washings were combined and mixed with ice water. The resulting organic layer was collected, washed with water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:3) to give the title compound (0.89 g) as colorless needles, mp 94°-97.5° C.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH3:16])[O:15][C:7]2[C:8]([CH3:14])=[N:9][CH:10]=[C:11]([CH:12]=[O:13])[C:6]=2[CH2:5][O:4]1.CO>C(O)(C)C.[O-2].[O-2].[Mn+4]>[CH3:2][C:3]1([CH3:16])[O:15][C:7]2[C:8]([CH3:14])=[N:9][CH:10]=[C:11]([C:12]([NH2:1])=[O:13])[C:6]=2[CH2:5][O:4]1
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: N
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: CC(C)O
Product: Cc1ncc(C(N)=O)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
Ammonia gas was bubbled into a solution of 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (31.3 g, 151 mmol) in isopropyl alcohol (2.4 L) at 0° C. for about 30 minutes. Manganese (IV) dioxide (210 g, 7.96 mmol) was added, and the solution was stirred for about 15 hours at room temperature. Excess manganese (IV) dioxide was filtered through a celite pad and washed with isopropyl alcohol. The filtrate was evaporated and washed with diethyl ether, water, and then with methyl alcohol to give 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carboxylic acid amide (78) (23.1 g, 69% yield) as a light yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]2=[O:22])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOC(C)=O>[CH3:28][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: CI
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(CO)cc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
According to Scheme 24 Step 3: A mixture of 1-(4-(hydroxymethyl)benzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 0.25 mmol, 0.08 g), NaH (55%, 1.5 eq, 0.37 mmol, 18 mg) and iodomethane (3 eq, 0.75 mmol, 0.11 g) in DMF (2 mL) was stirred at room temperature overnight. The crude was diluted with AcOEt. The organic layer washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 5 g SiO2, CH2Cl2/MeOH 99/1), yielding the title compound (0.14 mmol, 46 mg, 55%) as white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[C:23]([NH2:29])=[C:22]([CH3:30])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[H][H].[CH:41](O)=O>[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:20]3[CH:21]=[C:22]([CH3:30])[C:23]4[NH:29][CH:41]=[N:26][C:24]=4[CH:25]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: O=CO
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c([N+](=O)[O-])c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]cnc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 2 h

Procedure:
1.2 g (2.3 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 50 mL formic acid and combined with 300 mg 10% Pd/C. The mixture was hydrogenated for 2 h in a Parr apparatus at 60° C. and 50 psi hydrogen pressure. Then the catalyst was filtered off, the filtrate was evaporated down i.vac. and the residue was purified by chromatography (Alox, gradient DCM/MeOH 40:1 to 30:1). Yield: 880 mg (76% of theory) ESI-MS: (M+H)+=506 Rf=0.40 (Polygram-Alox, DCM/MeOH 25:1)
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Br[C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].CCN(C(C)C)C(C)C.CS(C)=O>CCOC(C)=O.[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:1][S:2]([C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10])(=[O:4])=[O:3]
Reactant: Nc1cccc(Br)c1[N+](=O)[O-]
Reactant: CS(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(N)c1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a mixture of copper(II) triflate (0.83 g, 2.3 mmol), sodium methanesulfinate (2.8 g, 27.6 mmol), 3-bromo-2-nitroaniline (5.0 g, 23 mmol) under N2, was added DIEA (0.50 mL, 4.6 mmol) and DMSO (10 mL). The stirred mixture was heated in a pre-heated 110° C. oil bath for 18 h. The mixture was cooled to rt, diluted with EtOAc, and filtered through a pad of Celite™. The filtrate was washed with water, brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM with 0.2% NH4OH as eluent gave 3-(methylsulfonyl)-2-nitroaniline: 1H NMR (400 MHz, CDCl3) δ 7.44 (1H, dd, J=8.0, 4.0 Hz), 7.35 (1H, t, J=8.0 Hz), 7.02 (1H, dd, J=8.0, 4.0 Hz), 5.04 (2H, br), 3.36 (3H, s); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])/[CH:3]=[CH:4]/[CH:5]1[CH2:7][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[C:25]1(C)C=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C([O-])([O-])=[O:37].[Na+].[Na+]>O1C=CCCC1>[O:37]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:1][C:2]([CH3:23])([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])/[CH:3]=[CH:4]/[CH:5]1[CH2:7][C:6]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CCCCCC(C)(O)/C=C/C1CC1(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Agent: [Na+]
Solvent: O
Product: CCCCCC(C)(/C=C/C1CC1(C(=O)OCC)C(=O)OCC)OC1CCCCO1
Reaction time: 0.5 h

Procedure:
A solution of diethyl trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate (22.4 g), described in Example 31, dihydropyran (80 ml, distilled over sodium) and p-toluenesulfonic acid monohydrate (300 mg) is allowed to stand at room temperature for 30 min. After adding a few ml of 10% Na2CO3 solution the mixture is extracted with ether. The ether extract is washed with water, dried (Na2SO4) and evaporated. Purification of the residue by chromatography on silica gel gives the title compound, nmr (CDCl3) δ 0.87 (t, 3H), 2.48 (m, 1H), 4.6 (1H), 5.5 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[NH2:7].[N:17]#[C:18][NH2:19].Cl>C(O)C.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:7][C:18]([NH2:19])=[NH:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: N#CN
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline hydrochloride (3 g, 12.52 mmol), cyanamide (0.684 g, 16.27 mmol) and hydrochloric acid (1.564 mL, 18.77 mmol) in ethanol (20 mL) were heated to reflux o.n. The reaction mixture was concentrated under reduced pressure before the residue was poured on potassium carbonate (1.730 g, 12.52 mmol) in water (60 mL) and then put in refrigerator o.n. The formed carbonate-salt was filtered off, and dried in vacuum oven o.n. The solid was washed with several portions of DCM, dried and used as such in next step (52.3%). MS (ES+) m/z 246.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34](=[O:50])[N:35]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:36]2=[O:41]>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:35]2[C:34](=[O:50])[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[CH2:31][NH:30][C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[O:9])[C:36]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: Cn1cccc1C(=O)O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
A mixture of 1-methyl-1H-pyrrole-2-carboxylic acid (0.3 g, 2.6 mmol) and carbonyl diimidazole (0.5 g, 3.0 mmol) in DMF (30 mL) was stirred for 2 hours. Triethylamine (0.8 g, 6.0 mmol) was added, followed by 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol). The mixture was stirred at 75° C. (oil bath) overnight. The mixture was cooled to room temperature and concentrated. The residue was stirred with EtOAc (80 mL) and water (30 mL). The EtOAc solution was washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 1-methyl-1H-pyrrole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.2 g, 25%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H), 4.86 (d, J=5.8 Hz, 2H), 5.13-5.20 (dd, J=5.5 and 12.7 Hz, 1H), 6.04 (t, J=3.4 Hz, 1H), 6.88-6.93 (m, 2H), 7.70-7.86 (m, 3H), 8.63 (t, J=5.8 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.98, 30.93, 36.19, 37.47, 48.86, 106.75, 112.63, 121.73, 124.98, 126.95, 128.07, 131.49, 132.96, 134.76, 140.06, 161.56, 166.98, 167.58, 169.82, 172.74; Anal. calcd. for C20H18N4O5+0.18H2O+0.1 ether: C, 60.49; H, 4.82; N, 13.83. Found: C, 60.54; H, 4.74; N, 13.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([O:23]C)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:17])([F:16])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([OH:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 76A, 260 mg (0.72 mmol) were dissolved in 5 ml of methanol and admixed with 2.87 ml (2.87 mmol) of a 1M solution of lithium hydroxide in water. The mixture was stirred at RT for 1 h, then acidified with 1N hydrochloric acid and diluted with DMSO. The entire solution was purified by preparative HPLC (Method 10). This gave 215 mg (86% of theory) of the title compound.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:16][CH:17]3[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:24][C:23]4[C:18]3=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:13]C(=O)N[C:10]2=[O:15])=[CH:5][CH:4]=1)#N.[C:31]([OH:34])(=[O:33])C.[OH-:35].[Na+]>>[NH2:13][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:31]([OH:34])=[O:33])=[CH:8][CH:7]=1)([CH2:16][CH:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[S:24][C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]([OH:15])=[O:35]
Reactant: [OH-]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C2(CC3c4ccccc4Sc4ccccc43)NC(=O)NC2=O)cc1
Agent: [Na+]
Product: NC(CC1c2ccccc2Sc2ccccc21)(C(=O)O)c1ccc(C(=O)O)cc1

Procedure:
5-(4-Cyanophenyl)-5-(9H-thioxanthen-9-ylmethyl)hydantoin (2.3 g, 5.5 mmol) was hydrolysed in aqueous sodium hydroxide (16.5 ml) following the procedure described in Example 1 (vi) for 72 h at 150° C. The cooled reaction mixture was then acidified with acetic acid, the resulting solid precipitate was filtered and washed with diethylether to give an off white solid. The solid was redissolved in aqueous sodium hydroxide (2M), filtered through a celite pad and acidified with acetic acid, filtered, washed with water, diethylether and finally methanol and then dried in vacuo to give the title compound as a white solid, m.p. 251° C.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC=CC=1>O>[CH:9](=[N:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1C=CCCCC1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C1=CC(N=Cc2ccccc2)CCCC1
Yield: 83.8 %

Procedure:
A mixture of 2-cycloheptenylamine (11.1 g, 0.1 mole), benzaldehyde (10.6 g, 0.1 mole) and benzene (50 ml) was heated under reflux, and resulting water was removed by azeotropic distillation. The mixture was concentrated to obtain 16.7 g of N-benzylidene-2-cycloheptenylamine [Compound (280)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccc(F)cc2)cs1
Product: O=C(NCCc1nc(-c2ccc(F)cc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 86 %

Procedure:
This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 26 step 6 (180 mg, 86% yield). 1H NMR (CDCl3) δ 8.51 (1H, t), 8.22 (1H, dt), 8.04 (1H, dt), 7.85-7.81 (2H, m), 7.64 (1H, m), 7.59 (1H, t), 7.31 (1H, s), 7.06-7.02 (2H, m), 3.97 (2H, q), 3.35 (2H, t); MS (ESI) m/z: Calculated for C21H14F4N4O2S: 462.08. found: 463.1 (M+H)+.
Reaction SMILES: [H][H].C([O:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH:18]([O:23][C:24](=[O:42])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=3)[CH2:17][CH2:16][C:15]=2[CH:14]=1)=[O:12])C1C=CC=CC=1>[Pd].O1CCCC1>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH:18]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[O:42])=[CH:26][CH:27]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC2CCc3cc(C(=O)OCc4ccccc4)ccc3C2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)OC2CCc3cc(C(=O)O)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
Hydrogen gas was blown into a mixture of 0.53 g (1.0 mmol) of 6-(4'-decyloxybenzoyloxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid benzyl ester, 0.11 g of 5% palladium/carbon and 10 ml of tetrahydrofuran with stirring at room temperature and ordinary pressure for 15 hours. The reaction mixture was filtered using Celite as a filter aid, and the filtrate was concentrated to obtain 0.42 g (0.93 mmol) of 6-(4'-decyloxybenzoyloxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].N1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:14](O)[CH3:15]>>[CH2:9]([CH:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6])[CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: C1CCNCC1
Reactant: CCO
Reactant: O=C1CSC(=O)N1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC1SC(=O)NC1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
DHA aldehyde from Part C (1.50 g, 4.8 mmol) was dissolved in ethanol (30 mL) with thiazolidine-2,4-dione (0.81 g, 6.8 mmol), and a catalytic amount of piperidine (103 mg, 1.2 mmol). The mixture was heated under reflux for 2 h. The heat was turned off and the solution slowly cooled to RT over 1.5 h. The ethanol was removed under reduced pressure and dichloromethane (100 mL) was added. The dichloromethane was extracted with 5% HCl (100 mL) and water (100 mL). The dichloromethane was dried over sodium sulfate, filtered, and concentrated. The remaining orange oil (1.94 g) was purified on silica gel (100 g), eluting with 10-30% ethyl acetate in heptanes. The experiment produced DHA-TZ olefin intermediate (4 in Scheme 2) (1.45 g, 74% yield, purity 85-90% by NMR) as a light yellow oil and is further characterized by: