Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(CCCC2)CCC1.[C:11]1([S:17][C:18]2[C:19](C(O)=O)=[N:20][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>Cl>[C:25]1([S:24][C:21]2[CH:22]=[CH:23][C:18]([S:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:19][N:20]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1nc(Sc2ccccc2)ccc1Sc1ccccc1
Agent: Cl
Solvent: C1CCC2CCCCC2C1
Product: c1ccc(Sc2ccc(Sc3ccccc3)nc2)cc1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
In a reaction flask was placed 100 ml of decahydronaphthalene which was then heated to 190° C. To the decahydronaphthalene was added 3,6-bis(phenylthio)-2-pyridinecarboxylic acid (51 g) in small portions. Heating was continued for 1 hour. After cooling, 60 ml of 6 N HCl was added resulting in the formation of a solid. The solid was collected and made alkaline with NaOH and extracted with diethyl ether. The organic layer was dried, concentrated and distilled using a Kugelrohr apparatus to give 37 g of 2,5-bis(phenylthio)pyridine, b.p. 190° C. (0.05 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:16]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:17])=[O:6]
Reactant: O=C=NC1CC1
Reactant: NNC(=O)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1cccc(Cl)c1)NC1CC1

Procedure:
Under an argon atmosphere, 430 mg (2.52 mmol) of 3-chlorobenzoic acid hydrazide are placed in 6 ml tetrahydrofuran. 209 mg (2.52 mmol) of cyclopropyl isocyanate, dissolved in 2 ml tetrahydrofuran is added dropwise and further stirred overnight at room temperature. It is concentrated and purified by stirring the residue with diethyl ether, filtration, further washing with diethyl ether and drying in vacuo. 514 mg (80% of theory) of the target compound are thus obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[N+:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[S:61](Cl)(=[O:63])=[O:62])([O-:54])=[O:53]>>[N+:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[S:61]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])(=[O:63])=[O:62])([O-:54])=[O:53]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 48 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 2-nitrobenzenesulfonyl chloride as described in example 2, affording the title compound in 48% yield.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([O:11][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCC(C)(O)CC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCC(C)(CC)OC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
40.0 G. (0.25 mole) of 3-methylnonan-3-ol, 20. g. of pyridine and 60 ml. of toluene are combined and cooled to 5° C. under agitation. To the resulting solutin is added, under agitation, over a period of 1 to 2 hours while maintaining the reaction temperature between 5°-15° C., a solution of 35.15 g. (0.25 mole) of benzoyl chloride, dissolved in 30 ml. of toluene. The source of cooling is removed and the reaction mixture is agitated overnight, permitting the temperature of the reaction mixture to rise to room temperature (25°-30° C.). After completion of the reaction, the formed pyridine hydrochloride is removed by successive washings with 100 ml. of warm water. The solvent is removed by distillation and the desired ester is rectified by fractional distillation in a vacuum, preferably at 1 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][N:8]=1.[CH2:18](Br)[CH3:19].C(=O)([O-])[O-].[K+].[K+].C1C(O)=CC(O)=C(C2C(=O)C3C(=CC(O)=C(CC=C(CO)CO)C=3O)OC=2)C=1>[Cl-].[Na+].O.CN(C)C=O>[CH2:18]([N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8]1)[CH3:19]
Reactant: O=c1[nH]nc(-c2ccccn2)c2ncccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: O=c1c(-c2ccc(O)cc2O)coc2cc(O)c(CC=C(CO)CO)c(O)c12
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccccn2)c2ncccc2c1=O
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one 8 (50 mg, 0.22 mmol), ethyl bromide (20 μL, 0.27 mmol), potassium carbonate (303 mg, 2.2 mmol), and dimethylformamide (1.5 mL) was heated in a sealed tube at 60° C. for 30 minutes. After cooling to ambient temperature, the reaction mixture was poured into 15 mL of saturated brine and extracted with 3×20 mL of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over 16 minutes Like fractions containing product were pooled, concentrated under reduced pressure, and dried at 60° C. overnight to give 6-ethyl-8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one (46 mg, 0.19 mmol), RL-6. 1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 9.02 (s, 1H), 8.80 (d, J=8.3 Hz, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.71 (dd, J=8.1, 4.6 Hz, 1H), 7.56 (s, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.52 (t, J=7.2 Hz, 3H). LCMS: (M+H)+, 253.
Reaction SMILES: C(N(CC)CCOC1C=C(N)C=CC=1)C.[CH3:16][O:17][C:18](=[O:48])[C:19]1[CH:24]=[CH:23][C:22]([NH:25]C2N=CC(C3C=CC(OC)=CC=3)=CN=2)=[CH:21][C:20]=1[O:40][CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45]>CO.[Pd]>[CH3:16][O:17][C:18](=[O:48])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:40][CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45]
Reactant: CCN(CC)CCOc1cc(Nc2ncc(-c3ccc(OC)cc3)cn2)ccc1C(=O)OC
Agent: [Pd]
Agent: CCN(CC)CCOc1cccc(N)c1
Solvent: CO
Product: CCN(CC)CCOc1cc(N)ccc1C(=O)OC
Reaction time: 2 h

Procedure:
3-(2-Diethylamino-ethoxy)-phenyl-amine can be prepared by the following procedure. In a Parr pressure bottle, a solution of diethyl-[2-(3-nitro-phenoxy)-ethyl]-amine (2.72 mmol) (from Example 1i) in MeOH (10 mL) is added Pd (5% on carbon, 50% wet, 10% weight). The suspension is shaken at 40 psi of H2 for 2 h. The reaction is filtered through celite. The solvent is removed under reduced pressure to afford the title compound in quantitative yield. MS (m/z) (M+1)+ 267.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.Cl.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([CH:26]([CH3:28])[CH3:25])[CH2:15][C:13]=2[N:14]=1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 20) as a HCl salt (455 mg, 1.6 mmol) in anhydrous THF (5 ml) was added anhydrous acetone (500 μl) and glacial acetic acid (two drops). The reaction was stirred at RT for 30 minutes after which time sodium triacetoxyborohydride (696 mg, 3.3 mmol) was added. After stirring for a further 2 hours at RT the reaction was partitioned between water and DCM. The aqueous phase was extracted into DCM and the organic extracts were combined and concentrated in vacuo to afford the title compound as a brown oil which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:25]([F:28])([F:27])[F:26])=[N:19][C:20]([C:21](=[O:24])[NH:22][CH3:23])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:40]>C(OCC)(=O)C>[ClH:40].[CH3:23][NH:22][C:21]([C:20]1[N:19]=[C:18]([C:25]([F:28])([F:26])[F:27])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:13][C:14]=12)=[O:24]
Reactant: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 90 %

Procedure:
(R)-[3-(1-Methylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 8a (0.15 g, 0.27 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 5 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methylamide hydrochloride 8 (0.135 g, yield 90%) as a white solid.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][C:16]([F:24])([F:15])[CH2:17][CH2:18]1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCC1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(Br)cc2CN1CC1CCC(F)(F)CC1
Yield: 62.1 %

Procedure:
4-Bromo-2-bromomethyl-6-chlorobenzoic acid methyl ester (3.5 g, 9.35 mmol), (4,4-difluorocyclohexyl)methylamine (1.7 g, 11.39 mmol) and K2CO3 (3.15 g, 22.78 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2—SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford the title compound as a yellow foam (2.2 g, 45%), 1H NMR (300 MHz, CDCl3): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H), 2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=[O:9])=[O:4].COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.CC1CCCCC1>CC(C)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:7][C@@H:6]1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CC(C)=O
Solvent: CC1CCCCC1
Product: COC(=O)[C@H]1C[C@@H]1C(=O)O

Procedure:
Add trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester, Example 3a, (19.46 g) in acetone to quinine (43.8 g) in one portion. Heat the reaction to reflux, and then add methylcyclohexane (150 mL). After crystallization (5 times) from acetone/methylcyclohexane, collect 6.2 g of the diastereomeric salt (αD: +173, c: 7.3 CHCl3)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[N:5]=1)[CH3:2].C(N(CC)CC)C.[NH2:25][CH:26]([CH2:28][CH3:29])[CH3:27]>C(O)C>[CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH:25][CH:26]([CH2:28][CH3:29])[CH3:27])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[N:5]=1)[CH3:2]
Reactant: CCC(C)N
Reactant: CCNc1nc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNc1nc(C(F)(F)F)nc(NC(C)CC)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 73.2 %

Procedure:
5.4 g (0.02 mol) of 4-ethylamino-6-chloro-5-nitro-2-trifluoromethyl-pyrimidine are dissolved in 100 ml of abs. ethanol. The solution is treated with 2.3 g of triethylamine (0.023 mol) and 1.7 g (0.023 mol) of 2-amino-butane and the mixture is stirred overnight. After the mixture has been evaporated, the product is taken up in water and extracted with ether to yield 4.5 g of 4-ethylamino-5-nitro-6-(2-butylamino)-2-trifluoromethyl-pyrimidine; nD20 = 1.5209.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[S:31])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Yield: 109.4 %

Procedure:
Estrone methyl ether (2, 17.64 g, 62.2 mmol) was dissolved in 500 mL of dry tetrahydrofuran (THF) and a first portion of Lawesson's reagent (13 g, 32 mmol) was added. The reaction mixture containing suspended solid was heated to reflux for 18 h when all solids dissolved and the solution became salmon red. A second portion of Lawesson's reagent (13 g, 32 mmol) was added and heating continued at reflux temperature for another 18 h. Similarly, a third portion of Lawesson's reagent (13 g, 32 mmol) was added; and after being heated for 18 h, the reaction mixture was cooled and the THF evaporated to give a thick slurry. The slurry was dissolved in a minimum amount of CH2Cl2 and passed through a pad of silica gel to remove a polar by-product of Lawesson's reagent. The eluent was concentrated to afford a bright orange solid which was further purified by column chromatography on silica gel with EtOAc-Hexanes (1:3) as eluent to afford a bright orange solid product (10.5 g, 35 mmol) in 56% yield as the first fraction and then starting material (4 g, 14.0 mmol) in 23% recovery. Crude thione 3 can be further purified by crystallizing from boiling EtOAc, although after column purification it is pure enough for subsequent reactions. 1H NMR (250 MHz, CDCl3) δ 0.94 (s, 3, C-S 8 CH3), 3.78 (s, 3, --OCH3), 6.64-6.75 (m, 2, ArH), 7.22 (d, J=10 Hz, 1 ArH); 13C NMR (250 MHz, CDCl3) δ 273.3 (C=S).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=O)[CH:4]=[CH:3]1.[CH3:9][N:10]1[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[N:11]1>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:13]2[C:12]([CH3:16])=[N:11][N:10]([CH3:9])[C:14]=2[NH2:15])=[CH:4][CH2:3]1
Reactant: Cc1cc(N)n(C)n1
Reactant: Cn1ccc(=O)cc1
Product: Cc1nn(C)c(N)c1C1=CCN(C)CC1
Reaction time: 8 h

Procedure:
1-Methyl-4-pyridinone (1.1 mole) is added to 1,3-dimethyl-5-pyrazolamine (1 mole). The reaction mixture is kept at a temperature between 70° C. and 80° C. for a period of about 8 hours. After distillation under vacuum the residue is poured into water and neutralized with NaOH 10%. The compound of the title is recovered by filtration. M.p. 262°-265° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([N:47]=[C:48]=[S:49])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][C:48]([NH:47][C:37]6[C:46]7[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=7)[CH:40]=[CH:39][CH:38]=6)=[S:49])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: S=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)Nc4cccc5ccccc45)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-naphthyl isothiocyanate (148 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hour and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2→2:1→4:1→1:0 as the eluant to afford the title compound (301 mg, mp 185.8-188.1° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:13][C:14](=[O:15])[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[CH:6]=[O:7]
Reactant: O=C(CCl)N1CCCC1
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)N2CCCC2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-2,6-dimethyl-benzaldehyde (87 mg), 2-chloro-1-pyrrolidin-1-yl-ethanone (102 mg), and Cs2CO3 (375 mg, 1.15 mmol) in acetone (4 mL) was stirred at room temperature for 16 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 2,6-dimethyl-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzaldehyde: MS (m/z) 262 (M+1).
Reaction SMILES: OC[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5](CO)[C:4]=1[OH:12].C(O)(=O)C(O)=O.[CH3:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23](=[CH:25][CH:26]=1)[OH:24]>O>[CH:3]1[C:4]([OH:12])=[CH:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH3:19][C:20]1[CH:21]=[C:22]([OH:27])[C:23](=[CH:25][CH:26]=1)[OH:24]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: Cc1ccc(O)c(O)c1
Agent: O=C(O)C(=O)O
Solvent: O
Product: Cc1ccc(O)cc1
Temperature: 70 °C

Procedure:
To a 1 liter, 3 necked round bottomed flask equipped with a paddle stirrer, condenser, thermometer and heating source, were added 135 g (0.80 mole) of 2,6-bis(hydroxymethyl)-4-methylphenol, followed by 9 g (0.10 moles) of oxalic acid and 200 g (1.61 moles) of 4-methylcatechol. To this mixture were added 400 g of water. The reaction mixture was stirred and heated to 70° C. Solution occurred when the temperature reached approximately 60° C. Then, the reaction mixture was heated to reflux and held at reflux for 4 hours. After 1 hour at reflux, the product began to separate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([O:27][CH2:28][CH3:29])[N:18]=1.Cl>C(O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:19]1[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=1)[CH3:29]
Reactant: CCOc1cc(C(C)(C)O)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C(C)(C)O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 10.4 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (102 mg, 0.5 mmol), 2-(2-chloro-6-ethoxy-pyrimidin-4-yl)-propan-2-ol (108 mg, 0.5 mmol) and 1 N aqueous hydrochloric acid (0.025 mL) in ethanol (0.8 mL) was heated in a sealed tube in a microwave oven to 170° C. for 45 min. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% ethanol as eluent to give the title compound (20 mg, 10%) as yellow foam. MS ISP (m/e): 384.3 [(M+H)+].)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 7.16 (s, 1H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: Cl[Si](Cl)(C)C.[O:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17](Cl)(=O)=O)[CH:15]=2)[CH2:10][CH2:9][NH:8]1.CN1CCN(C)C1=O>ClCCCl.[Zn]>[SH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][NH:8][C:7]2=[O:6])=[CH:12][CH:13]=1
Reactant: O=C1NCCc2ccc(S(=O)(=O)Cl)cc21
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CN1CCN(C)C1=O
Solvent: ClCCCl
Product: O=C1NCCc2ccc(S)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a zinc powder (2.79 g, 42.7 mmol) and Dichlorodimethylsilane (5.15 mL, 42.7 mmol) in DCE (45 mL) is added a solution of 1-Oxo-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (3 g, 12.2 mmol) and 1,3-dimethylimidazolidin-2-one (3.96 mL, 36.6 mmol) in DCE (5 mL). After stirring at rt during 2 h, the mixture is concentrated.
Reaction SMILES: [Cl-].[CH2:2]([Zn+])[C:3]([CH3:6])([CH3:5])[CH3:4].[F:8][C:9]1[CH:10]=[C:11]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:12][C@H:13]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:14]([OH:28])[CH2:15][NH:16][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=2)[O:20][CH2:19][CH2:18]1>C1COCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:9]1[CH:10]=[C:11]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:12][C@H:13]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[C@H:14]([OH:28])[CH2:15][NH:16][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])[CH:25]=2)[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)C[Zn+]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To neopentyl zinc chloride (prepared as previously described) (51 ml, 11 mmol, 0.2 M in THF) under a nitrogen atmosphere at r.t. was added tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}propylcarbamate (1.3 g, 2.2 mmol) and Pd(dppf)Cl2 (0.09 g, 0.1 mmol) as solids. The reaction mixture was stirred at r.t. for 12 h and then heated to 50° C. for 8 h. The reaction was cooled to r.t. then quenched with 20 ml of aqueous NH4Cl and extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a brown oil. The residue was dissolved in CH2Cl2 and absorbed onto 6 g of silica gel. Flash chromatography (3-5% MeOH/CHCl3 with 20 drops of NH4OH/L, Biotage 40M) yields the desired product, which is identical to the material prepared by the previously described methods.