Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)C(C)C)(C)C.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.CCOC(C)=O>CN1CCN(C)C1=O.O>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:3]2[C:2]([Cl:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=2)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CN1CCN(C)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
To a solution of ethyl 5,6-dichloronicotinate (10.0 g) and N,N-diisopropylethylamine (17.4 mL) in 1,3-dimethyl-2-imidazolidinone (100 mL) was added tert-butyl (3R)-3-amino-1-piperidinecarboxylate (10.9) at ambient temperature and the mixture was stirred at 100° C. for 9 hr. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was added ice-water and the mixture was adjusted to pH 3.5 with 1N-NCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate (16.74 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22]Cl)[O:19][CH2:18][CH2:17][O:16]1>CN(C)C=O>[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:12]=[O:13])=[CH:4]2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC1(CCCCl)OCCO1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CCCn2cc(C=O)c3ccccc32)OCCO1
Reaction time: 1 h

Procedure:
A suspension of 10.6 g. (0.44 mole) of sodium hydride in 50 ml. of dry dimethylformamide is treated dropwise with a solution of 58 g. (0.40 mole) of indole-3-carboxaldehyde in 200 ml. of dimethylformamide. An exothermic reaction is observed with the temperature rising to 70° C. The resulting mixture is stirred for one hour. To the resulting mixture there is added 69 g. (0.42 mole) of 2-methyl-2(3-chloropropyl)-dioxolane, and the mixture is maintained overnight at room temperature. The solvent is evaporated and the residue is extracted with ether, washed with water and dried over anhydrous magnesium sulfate. Following the evaporation of the solvent, the residue is crystallized from ether/hexane to give 1-[3-(2-methyl-2-dioxolanyl)propyl]-3-indolecarboxaldehyde, m.p. 52°-55° C.
Reaction SMILES: [N:1]1([C:9]([O:11]C(C)(C)C)=O)[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Cl.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([NH-:29])[CH:20]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.CN1CCCC1=O>[CH2:22]1[CH2:21][NH:29][C@H:24]([C:9]([N:1]2[C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][CH2:8]2)=[O:11])[CH2:23]1.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([NH-:29])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: COc1cc([NH-])cc2ccccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Pro (32 mg, 0.15 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluoronium tetrafluoroborate (53 mg, 0.15 mmol) and Pro-4-methoxy-β-naphthylamide hydrochloride (46 mg, 0.15 mmol) were dissolved in anhydrous N,N-dimethylformamide/tetrahydrofuiran 1:1 (4 ml). N-ethyldiisopropylamine (0.26 ml, 0.44 mmol) dissolved in N-methylpyrrolidone (1.7 molar) was added and the mixture was stirred at room temperature overnight.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:8]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: BrCc1ccsc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1ccsc1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one hydrochloride (502 mg), 3-bromomethylthiophene (1.069 g), anhydrous sodium carbonate (955 mg) and benzyltrimethylammonium chloride (12 mg) in dry N,N-dimethylformamide (15 ml) was stirred at room temperature. After 22 h the reaction mixture was diluted with water (120 ml) and the resulting precipitate was collected, washed with water and dried to give a pale yellow solid (233 mg). The solid was crystallised from ethanol to give white crystals of the title thiophene (184 mg), m.p. 194°-195° C., λmax 229 nm (ε 14,410), 233 nm (ε 3,080), λinf 246 nm (ε 5,210).
Reaction SMILES: [O-][N+:2]1[O:3][N:4]=[C:5]2[CH:14]=[C:13]3[C:8]([CH2:9][CH2:10][CH:11]([N:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)[CH2:12]3)=[CH:7][C:6]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:2]1[O:3][N:4]=[C:5]2[CH:14]=[C:13]3[C:8]([CH2:9][CH2:10][CH:11]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]4)[CH2:12]3)=[CH:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3cc4c(cc3C2)no[n+]4[O-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc4nonc4cc3C2)CC1

Procedure:
A solution of tert-Butyl 4-(1-oxido-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazol-6-yl)piperazine-1-carboxylate (100 mg, 0.27 mmol) and triphenyl phosphine (140 mg, 0.53 mmol) in THF (3 mL) was heated to 140° C. in a microwave reactor for 30 minutes. LC showed formation of the desired product, which was separated by reverse phase HPLC (water: Acetonitrile with 0.1% TFA). LC-MS (IE, m/z): 359 [M+1]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH:26]([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40]4[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=4)[CH:34]=3)=[CH:31][N:32]=2)[OH:27])[CH2:25][CH2:24]1>ClCCl.C(OCC)(=O)C>[CH:23]1([C:26]([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40]4[N:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][N:41]=4)[CH:34]=3)=[CH:31][N:32]=2)=[O:27])[CH2:25][CH2:24]1
Reactant: OC(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
Dess-Martin periodinane (110 mg, 0.260 mmol) was added to a stirred, cooled (room temperature) mixture of cyclopropyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol (Example 4A-5, 85 mg, 0.217 mmol) in dichloromethane (0.72 mL) and the mixture was stirred at room temperature for 30 min. The mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium sulfite then brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to give cyclopropyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanone (43 mg, 0.110 mmol, 50.8%) as a colorless solid. APCI: [M+H]+ m/z 391.0. 1H NMR (400 MHz, CDCl3): δ 8.71 (d, J=4.90, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.58-7.50 (m, 2H), 7.46 (t, J=7.87, 1H), 7.42-7.38 (m, 1H), 7.13 (d, J=4.91, 1H), 3.28-3.23 (m, 1H), 1.39-1.34 (m, 2H), 1.22-1.17 (m, 2H). rhSYK activity=+++
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15](=[O:27])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH2:26])[N:24]=1)([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1>>[C:10]([O:14][C:15](=[O:27])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH:26][C:29]2[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=2)[N:24]=1)([CH3:18])[CH3:17])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CN)cs1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
N,N-Diisopropylethylamine (2.24 g) was added to 2-{[4-(aminomethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 13 and 2-chloro-5-ethylpyrimidine (2.47 g), and the mixture was stirred at 130° C. for 8 hr. The reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (5.0 g) as a slightly yellow oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(hydroxymethyl)phenyl]-1H-indole-7-carboxamide (52.0 mg, 0.120 mmol) in THF (10 mL), MnO2 (360.0 mg, 3.5 mmol) was added at ambient temperature. The resulting suspension was stirred overnight, filtered through celite, and the solid rinsed with THF (3×10 mL). The filtrate was concentrated to give the title compound (51.0 mg, 98%) which was used in the next step without purification.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH:27]([OH:33])[CH2:28][CH2:29][CH2:30][CH2:31]O)[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O>ClCCl>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:33]2)[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CCCCO)C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C2CCCCO2)C1=O

Procedure:
A solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,8-dihydroxyoctan-3-yl)-3-methylpiperidin-2-one (31 mg, 0.060 mmol; diastereomeric mixture; Example 224, Step B) and triphenylphosphine (31.4 mg, 0.12 mmol) in dichloromethane (1.5 mL) was treated with (E)-diethyl diazene-1,2-dicarboxylate (0.02 ml, 0.12 mmol) at ambient temperature for 2 hours. Purification by silica chromatography eluting with ethyl acetate/hexane provided the title compound as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([OH:10])[C@H:2]1[O:7][C:5](=[O:6])[C@H:4]([OH:8])[C@@H:3]1[OH:9].CO.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>CC(C)=O>[O:6]=[C:5]([NH2:19])[C@@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:10])[OH:7])[OH:9])[OH:8].[NH2:19][CH2:18][CH2:17][C:16]1[CH:20]=[CH:21][C:22]([OH:23])=[C:14]([OH:13])[CH:15]=1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: NCCc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(C)=O
Product: NC(=O)[C@H](O)[C@H](O)[C@H](O)CO
Yield: 188.1 %

Procedure:
D-(+)-Ribonic acid gamma-lactone (2.0 gm, 13.5 mmol) was added to methanol (25 mL) in a 100 mL round bottom flask with stirring until dissolved, and then an additional 5 min. 3-Hydroxytyramine (2.6 gm, 13.5 mmol) was added slowly, allowing it to dissolve, with stirring, over the course of about 10 minutes. Triethylamine (1.4 gm, 13.5 mmol) was then added and the reaction mixture refluxed for 4 hr. in the dark, during which time the solution acquired a slight yellow color. Solvents were removed by rotary evaporation using anhydrous ethanol as an azeotrope to remove any residual water. The resultant dried product constituted a thick syrup which solidified upon standing (1 hr.) to give a white solid. The white solid product was stirred (1 hr.) with acetone (40 mL), again resulting in a white solid as a product. The resultant solid was collected by filtration and dried in vacuo for 6 hrs. yielding dopamine ribonamide (3.83 gm, 12.7 mmol, 94.1% yield.) 1H and 13C-NMR results and CHN analyses were consistent with structure. Molting point was 90-91° C. Predicted C13H19N1: (301.30): C, 51.82; H, 6.36; N, 4.65; Analysis results of synthesis product: C, 51.67; H, 6.40; N, 4.69.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[F:17][C:18]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)[CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(CN4CCOCC4)c(F)c3)cnc2N)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (250 mg, 0.77 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (690 mg, 2.12 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (40 mg, 0.03 mmol) was added and allowed to stir at 110° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 80% EtOAc in hexanes to afford 100 mg (yield: 35.71%) of the title compound as pale yellow solid.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[S:1]1[C:5]([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1cncs1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCC(Cc1cncs1)C2
Yield: 76.2 %

Procedure:
3.92 g of ethyl 6-(5-thiazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was added to a mixture of 10 ml of a 10 % aqueous solution of sodium hydroxide and 30 ml of methanol and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in water. A small amount of insoluble material was removed by filtration and the filtrate was adjusted to pH 6 with hydrochloric acid. The precipitate formed was collected by filtration to give 2.71 g of 6-(5thiazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid as a powder. The powder was suspended in 20 ml of water and 0.42 g of sodium hydroxide was added thereto. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was recrystallized from a mixture of ethanol and diethyl ether to give 1.92 g of sodium carboxylate of the above product as a colorless powder with m.p. above 280° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:14]([O:16]C)=O)[C:3]=1[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45]>C1COCC1.C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6](=[O:8])[N:45]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:14]2=[O:16]
Reactant: CN(C)CCN
Reactant: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(CCN(C)C)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a solution of 4-amino-2-(methoxycarbonyl)-3-methyl-5-nitrobenzoic acid (0.43 g, 1.69 mmol), EDCI hydrochloride (0.36 g, 1.86 mmol), and HOBt (0.23 g, 1.69 mmol) in 22 mL of anhydrous THF was added 1.18 mL of triethylamine and stirred for 10 min at rt under an argon atmosphere. N1,N1-dimethylethane-1,2-diamine (0.16 g, 1.86 mmol) was added into above mixture and the reaction mixture was heated at reflux for 14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.44 g (90%) of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, ArH), 8.12 (br s, 2H, NH2), 3.64 (t, J=6.5 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 2.45 (t, J=6.5 Hz, 2H, CH2), 2.15 (S, 6H, 2×CH3); Mass (ESI, positive) m/z 293.0 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([OH:9])([CH3:8])[CH3:7].CC1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[C:13](C)([CH3:20])[CH:12]=1.C1CCCCC=1>O>[CH3:7][C:6]12[CH2:18][CH2:17][CH:14]([C:13]([CH3:20])([CH3:12])[CH2:8]1)[CH:15]([CH3:16])[O:9]2
Reactant: CC1=CC(C)(C)C(CCO)CC1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1=CCCCC1
Product: CC1OC2(C)CCC1C(C)(C)C2
Temperature: 25 °C

Procedure:
Into a 500 ml reaction flask equipped with reflux head, thermometer and stirrer is added 50 g of 40% sulfuric acid and 50 g of anhydrous isopropyl alcohol. The resulting mixture is heated to reflux and 1,3,3-trimethyl-1-cyclohexene-4-ethanol, prepared according to Example II (50 g) (fraction 2 according to Example II) is added slowly to the reaction mass while maintaining the temperature thereof at 86°-88° C. The addition takes place over a period of one hour. At the end of the addition of the cyclohexene derivative, the reaction mass is cooled to room temperature and water is added. The reaction mass now exists in two phases. The phases are separated and the organic phase is washed with aqueous sodium carbonate and saturated sodium chloride. The organic phase is then distilled using a microdistillation set-up (micro Vigreux column) yielding the following fractions:
Reaction SMILES: ClC1C=C(N/C=C2\C(=O)NC(=O)C3C\2=CC=CC=3)C=CC=1SC1N(C)C=CN=1.CO/[CH:31]=[C:32]1/[C:33](=[O:46])[NH:34][C:35](=[O:45])[C:36]2[C:41]/1=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2.[N:47]1([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[CH2:50]1[CH2:51][CH2:52][N:47]([CH2:53][C:54]2[CH:55]=[CH:56][C:57]([NH:60]/[CH:31]=[C:32]3/[C:41]4[CH:40]=[C:39]([N+:42]([O-:44])=[O:43])[CH:38]=[CH:37][C:36]=4[C:35]([NH:34][C:33]/3=[O:46])=[O:45])=[CH:58][CH:59]=2)[CH2:48][CH2:49]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc([N+](=O)[O-])cc21
Agent: Cn1ccnc1Sc1ccc(N/C=C2\C(=O)NC(=O)c3ccccc32)cc1Cl
Product: O=C1NC(=O)c2ccc([N+](=O)[O-])cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Yield: 73.3 %

Procedure:
Using the procedure described for (4Z)-4-[({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione, 115 mg (0.46 mmol) of (4E)-4-(methoxy)methylene-6-nitroisoquinoline-1,3(2H,4H)-dione is reacted with 93 mg (0.49 mmol) of 4-piperidin-1-ylmethyl-phenylamine to give 137 mg (73%) of brown solid, mp 225-235 (dec); MS (ES−) m/z 405.2 (M−H)−1.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)(=[O:16])[CH2:13][CH2:14][CH3:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:12]([O:17][CH2:18][C@H:19]([OH:21])[CH2:20][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: Oc1cccc2ccccc12
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCCC(=O)OC[C@H](O)COc1cccc2ccccc12
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 144 g (1 mol) of 1-naphthol and 7.4 g (0.02 mol) of tetrabutylammonium iodide in 200 ml of toluene was added 144 g (1 mol) of (R)-glycidyl butyrate over a period of 15 min at a temperature of 120° C., and the mixture was kept at this temperature for a further 4 h. Conventional subsequent treatment of the reaction mixture gave the required compound as an oil, yield about 75%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[C:5]([NH:6][CH2:12][CH2:11][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Cl)cc1I
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNc1c(F)cc(Cl)cc1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.5 g, 1.8 mmol), vinylmethylsulfone (0.2 g, 1.8 mmol), Cs2CO3 (1.17 g, 3.6 mmol) and DMF (15 mL) was heated with stirring at 50° C. overnight. The resulting mixture was poured into water and then extracted with EA (50 mL×3). The combined organic phases were dried over Na2SO4 and then concentrated. The residue was purified by column chromatography (EtOAc:PE=1:40) to give 4-chloro-2-fluoro-6-iodo-N-[2-(methylsulfonyl)ethyl]aniline (0.42 g, yield: 61%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18].C(O)(C(F)(F)F)=O>O>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])=[O:1]
Reactant: COC(=O)Nc1ccc(C2OCCO2)c([N+](=O)[O-])c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
5C (5.00 g, 18.64 mmol) was added to a solution of TFA (27 mL) and H2O (3 mL) and stirred at rt for 3 h. After 3 h, the reaction mixture was concentrated and the residue was partitioned between H2O and EtOAc. The organic layer was then washed with saturated sodium bicarbonate solution followed by brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated to give a light yellow solid as 5D (3.83 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.09 (s, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.86-7.81 (m, 1H), 3.74 (s, 3H) ppm.