Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[NH:20])[CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>O1CCCC1>[NH2:20][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][C:14]([CH2:15][CH3:16])([OH:17])[CH2:18][CH3:19]
Reactant: CCC(O)(CC)CC(=N)C1(c2ccc(Cl)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(CC)CC(N)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-ethyl-1-iminopentan-3-ol (1.6 g) in dry tetrahydrofuran (20 ml) was treated under nitrogen with boranetetrahydrofuran complex (1M solution in tetrahydrofuran 10 ml) and the mixture was heated under reflux for 24 hours. The mixture was cooled in ice and water and then 2N sodium hydroxide solution were added. The resulting mixture was extracted with ether and the extracts were washed, dried and evaporated to give 1-amino-1-[1-(4-chlorophenyl)cyclobutyl]-3-ethylpentan-3-ol which was then converted into the corresponding dimethylamino compound by heating a mixture of the primary amine (1.5 g), 98% formic acid (4 ml) and 37-40% aqueous formaldehyde (2 ml) at 90°-95° C. for 16 hours. The reaction mixture was cooled and poured into a mixture of 16N sodium hydroxide solution (7 ml) and ice. The mixture was extracted with ether and the extract washed, dried and evaporated to give a residue which was dissolved in ether. Addition of a solution of maleic acid in ether gave 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-3-ethylpentan-3-ol maleate (m.p. 110°-111° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:32]([N:34]([CH2:35][CH3:36])[CH:17]1[CH2:16][CH2:15][CH:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:21][C:22]([C:24]3[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=3)=[O:23])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:1])([CH3:31])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:19][CH2:18]1)[CH3:33]
Reactant: CCNCC
Reactant: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(CC)C1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1

Procedure:
The title compound is prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-oxo-cyclohexyl)-phenyl]-amide (as prepared in Example 23) and diethylamine using NaBH(OAc)3 according to literature procedure (J. Org. Chem., 61, 3849-62 (1996)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([OH:26])=[C:21]([Cl:27])[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:25][C:23]1[CH:24]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:20]=[C:21]([Cl:27])[C:22]=1[OH:26]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cc(Cl)c(O)c(Cl)c3)c2cc1OC

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 213.6 mg (1.2 mmol) of 4-amino-2,6-dichlorophenol and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 1 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether/ ethyl acetate (1:1). After drying in vacuo this yielded 346.7 mg (88.8%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 389.8, 391.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[C:27]([O-])([O-])=O.[K+].[K+].IC.O>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)cn1C
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A solution of 3-(4-benzyloxy-phenyl)-4-cyano-1H-pyrrole-2-carboxylic acid ethyl ester (266.70 g, 0.770 mol) in DMSO (2,000 mL) is treated with K2CO3 (117.06 g, 0.847 mol). The resulting solution is allowed to stir at room temperature for several minutes, then treated with iodomethane (58.00 mL, 0.931 mol). The resulting reaction mixture is allowed to stir at room temperature overnight. An additional 0.5 eq of iodomethane (24.00 mL, 0.385 mol) and 0.6 eq of K2CO3 (63.85 g, 0.462 mol) are added to the reaction. The reaction mixture is allowed to stir at room temperature for 2 hours. The reaction mixture is divided into 2 equal portions and each portion is poured into water (2,000 mL) and extracted with EtOAc (3×700 mL each). The combined organics are washed with H2O (2×1000 mL each), dried over anhydrous MgSO4, filtered, then concentrated in vacuo to afford a residue. The residue is slurried in EtOAc (300 mL), then treated with excess hexanes, causing a solid to precipitate. The solid is recovered by vacuum filtration, washing with hexanes, and drying under vacuum filtration to afford the title compound, 3-(4-benzyloxy-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester, (184.73 g, 66% yield) as a light-brown solid: 1H NMR (500 MHz; CDCl3) δ 7.46 (d, 2H), 7.39 (m, 2H), 7.32 (m, 3H), 7.24 (s, 1H), 7.00 (d, 2H), 5.10 (s, 2H), 4.13 (q, 2H), 3.95 (s, 3H), 1.06 (t, 3H); MS(ES): m/z 361.1 (M++H).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:19])[CH2:13][C:14](=[O:18])[C:15]=1[O:16][CH3:17])([O:3][CH3:4])=[O:2]>[C].[Pd].[H][H]>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:19])[CH2:13][CH:14]([OH:18])[C:15]=1[O:16][CH3:17])([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCC1=C(OC)C(=O)CC1=O
Agent: [Pd]
Product: COC(=O)CCCCCCC1=C(OC)C(O)CC1=O

Procedure:
An isopropanolic solution (190 ml) of 24 g of 2-(6'-carbomethoxyhexyl)-3-methoxy-4-oxo-2-cyclopenten-1-one prepared in Step 1 and 2.85 g. of a 5% palladium carbon catalyst was subjected to catalytic hydrogenation under atmospheric pressure at room temperature until 2.3 liter of hydrogen gas was absorbed. The reaction mixture was treated according to a conventional method to give the desired compound, 2-(6'-carbomethoxyhexyl)-3-methoxy-4-hydroxy-2-cyclo-penten-1-one.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11](Br)[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:29]1([N:28]([C:4]2[CH:5]=[CH:6][C:1]3[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:16]4[C:17]([C:2]=3[CH:3]=2)=[CH:18][C:19]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:14][CH:15]=4)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc3c(c2)c2cc(N(c4ccccc4)c4ccccc4)ccc2n3-c2ccccc2)cc1

Procedure:
In the present embodiment, raw materials, 12.03 g (30 mmol) of N-phenyl-3,6-dibromocarbazole and 12.18 g (72 mmol) of diphenylamine are used to obtain 3,6-bis(N,N-diphenylamino)-9-phenylcarbazole (hereinafter, referred to as PhCzP2), that is the carbazole derivative represented by the above structural formula (76), in the same way as in Embodiment 2 described above. The obtained PhCzP2 is purified by sublimation at a higher temperature of 270° C. and a lower temperature of 175° C. The yield after the sublimation purification is approximately 50%. FIG. 21 shows a 1H NMR spectrum of the obtained PhCzP2, FIG. 22 shows a 13C NMR spectrum of the obtained PhCzP2, and FIG. 23 shows an enlarged view of a region (A) surrounded by a dashed line in FIG. 22. In FIGS. 21 to 23, a longitudinal axis indicates relative intensity of signals, and a lateral axis indicates the dimensionless value δ which is the difference of resonant frequency between a sample and an authentic sample divided by frequency of an oscillator. Data of 1H NMR and 13C NMR of the obtained PhCzP2 is as follows:
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:33]([CH:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][O:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:34]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a suspension of methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) and potassium carbonate (13.9 g, 100 mmol) in DMF (120 mL) was added dropwise under ice-cooling 2-ethylhexyl 3-sulfanylpropanoate (12.1 g, 55.2 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:1) to give the title compound (20.0 g, quantitative).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35]([O:37][P:38]([C:43]1[CH:48]=[C:47]([OH:49])[CH:46]=[CH:45][C:44]=1[CH3:50])(=[O:42])[O:39][CH2:40][CH3:41])[CH3:36]>CN(C=O)C>[CH2:40]([O:39][P:38]([C:43]1[CH:48]=[C:47]([O:49][C:9]2[N:8]([CH2:7][C:4]3[CH:5]=[CH:6][C:1]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:2][CH:3]=3)[C:12]3[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=3[N:10]=2)[CH:46]=[CH:45][C:44]=1[CH3:50])(=[O:42])[O:37][CH2:35][CH3:36])[CH3:41]
Reactant: CCOP(=O)(OCC)c1cc(O)ccc1C
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-biphenyl-4-ylmethyl-6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (1.2 g, 2.3 mmol) in DMF (10 ml) at rt was added K2CO3 (635 mg, 4.6 mmol), followed by (5-hydroxy-2-methyl-phenyl)-phosphonic acid diethyl ester (630 mg, 2.6 mmol). The mixture was stirred overnight at rt. The solvent was then removed on a rotary evaporator. The resulting residue was partitioned between EtOAc and a solution of half-saturated ammonium chloride. The EtOAc layer was washed with H2O, brine, and then dried with MgSO4. After rotary evaporation, the residue was purified by flash chromatography (SiO2, 12 g). The title compound was eluted with a gradient up to 50% EtOAc in Hexane as a mixture of the two protected regioisomers.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].Cl[C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:28](C)[C:29](=O)C2C=C(C(F)(F)F)C=C(S(C)(=O)=O)C=2)=[CH:20][CH:19]=[CH:18][N:17]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:29][NH:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:16]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cnccc1-c1cccnc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (81.1 mg, 468 μmol, Fluorochem) in DMF (1 mL) was added sodium hydride (approx. 55% in mineral oil) (18.6 mg, 426 μmol) and the resulting suspension was stirred at room temperature for 30 minutes until gas evolution ceased. To the turbid solution was added N-(2-chloro-3,4′-bipyridin-3′-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.1 g, 213 μmol) in one portion. The light brown reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed twice with water and once with brine, dried over MgSO4, filtered and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless oil (0.027 g; 35%). MS (ESI): m/z=357.19 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]([CH3:22])[CH2:14][C:15]3([CH3:21])[CH3:20])=O)[C:4]([CH3:23])=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](=[S:25])[NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]([CH3:22])[CH2:14][C:15]3([CH3:21])[CH3:20])[C:4]([CH3:23])=[N:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1C(C)CC2(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nn(C)c(C)c1C(=S)Nc1cccc2c1C(C)CC2(C)C
Temperature: 0 °C
Yield: 128.9 %

Procedure:
1.1 g of 1,3,5-trimethyl-N-(1,1,3-trimethyl-4-indanyl)pyrazole-4-carboxamide, 0.79 g of phosphorus pentasulfide and 15 ml of hexamethylphosphoramide (HMPA) were stirred at 100° C. for 8 hours. After cooling, the reaction mixture was poured into ice water and extracted with ether. The extracts ether layer were dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residue was chromatographed on silica gel to obtain 0.75 g of 1,3,5-trimethyl-N-(1,1,3-trimethylindane-4-yl)pyrazole-4-carbothioamide (yield 65%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[CH2:16]([N:15]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Ethyl bromoacetate (19.52 mL, 176 mol) was added in a single portion to a chilled (0° C.) solution of dibenzylamine (33.84 mL, 176 mmol) and triethylamine (27 mL, 193.6 mmol) in THF. The reaction mixture was stirred overnight at ambient temperature. Additional triethylamine (30 mL) and THF (100 mL) were added and the reaction mixture was heated at 50° C. for 1.5 hours. Additional ethyl bromoacetate (13 mL) was added and the reaction mixture was heated for 1 hour and then stirred at ambient temperature overnight. About half of the THF was removed under reduced pressure. The mixture was diluted with water (300 mL) and then extracted with ethyl acetate (2×400 mL). The combined extracts were washed sequentially with water and with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (700 g of silica gel, eluting with 20% ethyl acetate in hexanes) to provide 37.12 g of ethyl dibenzylaminoacetate as a colorless oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O>[CH2:31]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(O)cc1

Procedure:
To a room temperature mixture of 40 g of hydroquinone, 62.76 g potassium carbonate, 3.02 g potassium iodide and 700 ml acetone is added, dropwise, 113.5 ml of 1-bromotetradecane. The reaction is heated at reflux temperature for 20 hours, cooled, filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-10% ethyl acetate/hexane) to give 36.5 g of the desired product as colorless crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[C:20]3=[O:35])[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[C:20]3=[O:35])[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN=C(c4ccc5c(cnn5C)c4)C3=O)sc2c1-c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3=O)sc2c1-c1ccc(Cl)cc1
Reaction time: 12 h

Procedure:
To the solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-5,6-dihydropyrazin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate (64 mg, 0.1 mmol) in THF (1 mL) was added acetic acid (6 μL, 0.1 mmol), followed by sodium cyanoborohydride (10 mg, 0.2 mmol). The mixture was stirred for 12 hours, and diluted with ethyl acetate. Sodium hydroxide solution (1 N, 5 mL) was added, and the mixture was stirred for 30 minutes. Organic phase was separated, and was washed water and brine, and was dried over sodium sulfate. Concentration and purification with flash column chromatography (hexanes/EtOAc) gave (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C34H37ClN5O4S: 646.2 (M+H+); Found: 646.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[CH2:9][C:10]([OH:12])=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Nc1cc(Cl)ccc1CC(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Cl)cc1NC(=O)Nc1cccc(Br)c1
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
6-Chlorooxindole (2.5 g, 14.9 mmol) was suspended in 50 ml 4 M aqueous NaOH and the mixture was refluxed for 6 hours. The reaction mixture was allowed to cool and the product precipitated and filtered off with suction. The solid was dissolved in water (100 ml) and precipitated with 4 M aqueous HCl at 0° C. The solid was then filtered with suction and dried under vacuum to yield 2.0 g (72%) of white crystalline solid. (2-Amino-4-chloro-phenyl)-acetic acid (700 mg, 3.8 mmol) was then dissolved in 25 ml pyridine and 1-bromo-3-isocyanato-benzene (811 mg, 4.1 mmol) was added drop-wise and the solution was stirred for 90 minutes. The reaction mixture was diluted with 150 ml ethyl acetate and washed twice with 1 M aqueous HCl. The organic phase was reduced under vacuum and the product recrystallised from ethyl acetate/heptane to yield 680 mg of white crystalline solid (47%) (m.p. 195-196° C.)
Reaction SMILES: C[S:2]([C:4]1[CH:5]=[C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH:7]=[C:8]([F:10])[CH:9]=1)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClC(Cl)C>[F:10][C:8]1[CH:7]=[C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH:5]=[C:4]([SH:2])[CH:9]=1
Reactant: CS(=O)c1cc(F)cc(C(=O)c2nccs2)c1
Solvent: CC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(c1cc(F)cc(S)c1)c1nccs1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of the sulfoxide from Step 2 (0.35 g, 1.29 mmol) in dichloroethane (2.6 mL) was added TFAA (2.6 mL). The mixture was stirred at 80° C. for 0.5 h, cooled and evaporated. The residue was dissolved in MeOH: Et3N (1:1, 5 mL). The solvent was evaporated and taken up again in MeOH/Et3N. After evaporation of the solvent and chromatography using hexane:EtOAc (70:30) 0.28 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])NC2SC=CC=2C=1Cl)=[O:5])[CH3:2].[CH3:17][O:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[NH2:26])=[O:20].C(C(C(Cl)=O)C(Cl)=O)C>>[CH3:17][O:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[NH:26][C:11](=[O:12])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20]
Reactant: COC(=O)c1ccsc1N
Reactant: CCOC(=O)c1c(Cl)c2ccsc2[nH]c1=O
Agent: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)CC(=O)Nc1sccc1C(=O)OC

Procedure:
A preferred intermediate in the preparation of compounds of structure (III) is 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (42) below. To prepare this intermediate, methyl-2-amino-thiophene-3-carboxylate was reacted with ethylmalonyl chloride to yield intermediate 2-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester, depicted by formula (39). This intermediate was converted to 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (40), by reacting it with sodium ethoxide, and then converting it into 4,6-dichloro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (41). Hydrolysis of 4,6-dichloro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (41), yielded 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (42), as shown in Scheme 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(Cl)Cl.[NH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl.[O-]S([O-])(=O)=O.[Mg+2]>CCN(CC)CC>[C:18]([CH2:17][N:16]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Temperature: 20 °C

Procedure:
Alternatively, one may prepare compounds of the invention via the procedures of Scheme IV. In the first step, a benzaldehyde derivative is treated with ethyl glycinate hydrochloride in CH2Cl2, Et3N, and MgSO4 at room temperature to produce an imine ester of formula 24 (step 1). For example, 3,4-dimethoxybenzaldehyde is suspended in a CH2Cl2 solution of H2NCH2COOEt.HCl, Et3N and MgSO4 and stirred at 20° C. to produce 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24).