Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[NH2:6][C:7]1[N:12]=[C:11](O)[C:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:9]([CH3:33])[N:8]=1>>[NH2:6][C:7]1[N:12]=[C:11]([Cl:3])[C:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:9]([CH3:33])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OCc2ccccc2)c1
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
POCl3 (25 ml) was added to the product from step (vi) (4.8 g) and stirred at 80° C. for 18 h. After cooling, the reaction was evaporated to dryness and the residue diluted with water (100 mL) and neutralized with solid NaHCO3. The mixture was heated at 50° C. for 30 min and left to cool. The subtitle compound was collected by filtration as a solid, 3.78 g.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]2[C:17]([CH:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[OH:19])=[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1([C:13]2[C:17]([C:18](=[O:19])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])=[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a solution of dry pyridine (0.237 g, 300 mmol) in anhydrous methylene chloride (5 mL) was slowly added chromium trioxide (0.15 g, 1.5 mmol) to give a wine colored mixture which was stirred at room temperature for 10 minutes. A solution of ethyl 3-phenyl4[(4-chloro-2-nitrophenyl)-(hydroxy)methyl]-1H-pyrazole-5-carboxylate (0.10 g, 0.25 mmol) in anhydrous methylene chloride (2 mL) was added to the wine red mixture in three portions over 25 minutes. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate extracted with 3×20 mL 3N HCl. The combined organic extracts were dried with sodium sulfate and concentrated via rotary evaporation to give an oil (0.1 g) which was triturated with hexane:ethyl acetate (4:1) to give the title compound as a tan solid (0.075 g, 75%).
Reaction SMILES: [Na].[CH3:2][C@H:3]([NH:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:13]=12)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:28]([OH:31])[CH2:29][CH3:30]>[Na+].[Cl-]>[CH3:2][C@H:3]([NH:11][C:12]1[N:17]=[C:16]([O:31][CH2:28][CH2:29][CH3:30])[N:15]=[C:14]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:13]=12)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Reactant: CCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CCCOc1nc(N[C@@H](C)Cc2ccccc2)c2cnn(-c3ccccc3)c2n1
Temperature: 90 °C

Procedure:
Next, 324 mg sodium was reacted with 10 ml of n-propanol. To this, 640 mg of (S)-N-(1-methyl-2-phenylethyl) -1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine in 5 ml of n-propanol was added with stirring and the reaction was heated to 90° C. for 2 hours. It was then cooled, diluted with 200 ml saturated NaCl, and extracted with 200 ml CHCl3. The organic layer was dried over MgSO4, filtered, and concentrated to yield an oil which was purified by radial chromatography (30-50% Et2O/hexane) to yield after recrystallization from 30% Et2O/hexane 382 mg of product (m.p. 134°-136° C.). Proton NMR indicated ether was still present. The compound was then oven dried under vacuum for 6 hours to yield 318 mg of (S)-N-(1-methyl-2-phenylethyl)-1-phenyl-6-propoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine (m.p. 134°-136° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[F:24][C:25]([F:44])([F:43])[C:26]1[CH:27]=[C:28]([C@@H:36]2[O:40][C:39](=[O:41])[NH:38][C@@H:37]2[CH3:42])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:38]2[C@H:37]([CH3:42])[C@H:36]([C:28]3[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:26]([C:25]([F:24])([F:43])[F:44])[CH:27]=3)[O:40][C:39]2=[O:41])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCCCCC.C(OCC)(=O)C.CN(C)C=O>[C:11]1([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-n2nnc3ccccc32)cc1
Yield: 95.3 %

Procedure:
Using the general procedure, benzotriazole (0.119 g, 1.00 mmol) was coupled with iodobenzene (134 μL, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %) and dimethylformamide (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 9:1) provided 0.186 g (95% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.17 (m, 1H), 7.78 (m, 3H), 7.62 (m, 2H), 7.55 (m, 2H), 7.42 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[C:27]([CH3:28])=[C:26]([C:29]([O:31][CH3:32])=[O:30])[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[C:14]([OH:33])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:32][O:31][C:29]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=3[O:33][CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])[C:20]=2[C:27]=1[CH3:28])=[O:30]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Bromopropionic acid tert-butyl-ester (1.4 g) was added to methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (Intermediate III) (2.00 g) and cesium carbonate (4.8 g) in ACN (50 ml) and stirred at 60° C. for 2 hours. The mixture was diluted with water, filtrated and washed with water.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[C:12]([F:30])=[C:13]([NH:18][S:19]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])=[N:4][N:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH2:7]([N:5]1[CH:6]=[C:2]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[C:3]([C:11]2[C:12]([F:30])=[C:13]([NH:18][S:19]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])=[N:4]1)[CH:8]([CH3:9])[CH3:10]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)Cn1cc(Br)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
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: [Na+]
Solvent: COCCOC
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol) in dimethoxyethane (1 mL), N-{3-[4-bromo-1-(2-methylpropyl)-1H-pyrazol-3-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (0.09 g, 0.18 mmol) in dimethoxyethane (1 mL) was added and the mixture was insufflated with nitrogen for 5 min. A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.4 mmol)) in dimethoxyethane (1 mL) was added and the mixture was insufflated with nitrogen for 10 min, then 2 M sodium carbonate solution (1 mL) was added and the mixture was heated at 110° C. in a microwave cavity for 1 h. More tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.016 g, 0.08 mmol) were added and the process was resumed for 0.5 h. The mixture was cooled and the organic phase was concentrated. The crude oil was purified by flash chromatography (eluant: dichloromethane/methanol 30:1). The title compound was obtained as a white solid (0.025 g, 28%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[CH:4]1)[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([C:5]=1[C:16]#[N:17])=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2
Reactant: CCn1cc(C#N)c2ccc(C(F)(F)F)cc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(Cl)c(C#N)c2ccc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure 1A, in anhydrous THF (20.0 mL), at −78° C. is added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture is continued for 0.5 h after the addition, followed by the addition of hexachloroethane and the mixture is then brought to room temperature slowly and stirred for 0.5 h. The solvent is then evaporated and the residue is treated with water. The organics are extracted with dichloromethane, washed with water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (silica gel, dichloromethane/hexanes, 3/2) to provide 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g, 64%).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[CH3:30][OH:31]>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[CH3:30][O:31][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1
Reactant: CO
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (1.10 g) was dissolved in methylene chloride (12 ml) and to this solution was added methanol (3 ml). And to the solution was added silver fluoroborate (0.45 g) under stirring under cooling at -10°C and the mixture was stirred for 2 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered and the filtrate was washed with sodium bicarbonate aqueous solution and then with water, dried over magnesium sulfate and thereafter concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of about 20 ml and the first and second fractions were collected. After distilling off the solvent, the residue was dried to give oily 2,2,2-trichloroethyl 2-methoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate. Infrared Absorption Spectrum (CHCl3) 3360, 1785, 1757, 1666 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[F:9])([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
1-Bromo-2,4-difluoro-benzene (0.67 g, 3.5 mmol) was dissolved in THF (5 mL) and cooled to 0° C. Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M, 2.5 mL, 3.2 mmol) was added. The mixture was stirred for 0.5 hours then added dropwise to a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in THF (10 mL) that had been cooled to −78° C. The mixture was allowed to warm to room temperature then cooled to −78° C. and a solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-50% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.7 g) as a clear, colourless oil. LCMS m/z 314.3 [M+H]+. R.T.=4.65 min (Analytical Method 4).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](Br)[CH3:10].O.N.C(O)(=O)C>O>[CH2:9]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])[CH3:10]
Reactant: CCBr
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCSC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
SEC is synthesized from L-cysteine hydrochloride (1.58 g, 0.01 mol) and ethyl bromide (1.09 g, 0.01 mol) with the following steps. The reaction mixture is diluted with water in a titration manner until a clear solution is formed. No more than necessary amount of water should be added to further dilute the mixture. Ammonia water was added to PH 9.5-10 with stirring at room temperature. After 2 hours reaction, the mixture is acidified with acetic acid to PH 5-5.5. The desired product was cooled in the refrigerator, filtered and washed successively with water and ethyl ether. The chemical structure of SEC is determined by Proton Nuclear Magnetic Resonance Spectroscopy.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([NH2:13])[CH3:12].CCN(CC)CC>C(O)CCC>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:13][CH2:11][CH3:12])[N:7]=1
Reactant: CCN
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCNc1nc(N)cc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloro-4-aminopyrimidine 18-1 (Avocado; 4.8 g, 29.3 mmol), ethylamine hydrochloride (7.0 g, 85.8 mmol), Et3N (20 mL, 144 mmol) and n-butanol (150 mL) was heated to 90° C. for 6 hours. After cooling, the solvent was removed in vacuo and the residue partitioned between saturated Na2CO3 solution and EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to give an orange solid. Purification by column chromatography (EtOAc/hexane 1:1) gave the title compound 18-2 as a white solid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15](=[O:30])[CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:26]([O:25][C:23]([NH:22][C@H:18]([C:19]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH2:9])=[O:20])[CH2:17][CH2:16][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:30])=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: NC(=O)c1cccn1N
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carboxamide (1.00 g, 7.99 mmol) and (5)-5-tert-butoxy-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2.91 g, 9.59 mmol) was dissolved in THF (80 mL). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.84 g, 9.59 mmol). The reaction was stirred at rt for 1.5 h, then concentrated in vacuo. CH2Cl2 (150 mL) was added, and the reaction mixture was washed with water (2×150 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The compound was purified by silica gel flash chromatography (0-35% 90:10:1 [CH2Cl2/MeOH/conc NH4OH]/CH2Cl2) to give 10A (2.90 g, 85%). 10A had an analytical HPLC retention time=2.05 min (Waters XBridge 4.6×50 mm, 5-95% aqueous acetonitrile over 5 min containing 10 mM ammonium acetate) and a LC/MS M−−1=409.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 77.6 %

Procedure:
4-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (46 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (67 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 592. 1H NMR (DMSO-d6, 400 MHz): δ 8.26 (d, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.74 (br, 1H), 7.47 (d, 1H), 7.35 (d, 1H), 3.97 (br, 1H), 3.91 (m, 2H), 3.66 (s, 3H), 2.82 (m, 2H), 1.81 (m, 2H), 1.42 (s, 9H), and 1.41 (m, 2H), 2 —NH proton signals were not observed.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: Cc1ccc(-c2nc3c(O)cccc3s2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc2sc(-c3ccc(C)cc3)nc12

Procedure:
The 4-hydroxy-2-(4-methylphenyl)benzothiazole (5.8 g) obtained in Example 1 was added to 58 ml of acetic anhydride and refluxed for 3 hours. After the reaction, the reaction mixture was dried under reduced pressure. The residue was washed with a small amount of cyclohexane, and recrystallized from cyclohexane to give 4.8 g of 4-acetoxy-2-(4-methylphenyl)benzothiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].Cl.C(OCC)(=O)C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH3:20])=[O:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C=CC(=O)OC
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(-c2ccc(O)cc2)cc1
Yield: 83.3 %

Procedure:
A mixture of 2 g (8.03 mmol) of 4-(4-bromophenyl)phenol, 1.1 g (12.8 mmol) of methyl acrylate, 18 mg (0.08 mmol) of Palladium acetate, and 94 mg (0.31 mmol) of tri-(o-tolyl)phosphine in 3.7 ml of triethylamine was refluxed for 6 hours. A further 6 mg of Palladium acetate and 30 mg of tri-(o-tolyl)phosphine were added and heated for an hour, then a further 30 mg of Palladium acetate and 94 mg di tri-(o-toluyl)phosphine were added and heated for 3.5 hours. Then the reaction was acidified with 6M HCl, ethyl acetate was added, and stirred for a time to dissolve the precipitate, the phases were separated, the organic phase dried over Na2SO4 and the solvent evaporated. The crude product (934 mg) was purified by taking up in hexane/ethyl ether and filtered off to give 1.7 g of the title product.
Reaction SMILES: [C:1]([O-:4])(=O)C.[Na+].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9]>C(O)=O>[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH:9][CH:1]=[O:4]
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(C)c1N
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc(C)c1NC=O
Yield: 79 %

Procedure:
4.1 10.0 g of sodium acetate are dissolved in 120 ml of formic acid. 50.0 g of 2,6-dimethylaniline 11 are then introduced, and the mixture is stirred under reflux for 24 h. The mixture is subsequently subjected to conventional work-up, giving 48.9 g (79%) of N-(2,6-dimethylphenyl)formamide 12; MS-EI (M+)=149.
Reaction SMILES: O.[C:2]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[CH:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O>[C:10]1([NH:9][C:2](=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: O=C(O)/C=C\C(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a 300 ml flask equipped with a water separator, reflux condenser, stirrer and a thermometer, 15.44 g of maleic anhydride (hereinafter abbreviated as MAN), 70 ml of xylene (hereinafter abbreviated as Xy) and 10 ml of dimethylformamide (hereinafter abbreviated as DMF) were charged. A mixture of 13.97 g of aniline (hereinafter abbreviated as AN) and 20 ml of xylene was added with stirring at 80° C. at a constant rate over 15 minutes and further aged for 15 minutes to obtain N-phenylmaleamic acid as a white slurry. To the slurry, 2.04 g (2.5% by mole per mole of MAN) of zinc N-phenylmaleamate/dimethylformamide adduct (hereinafter abbreviated as Zn(PMA)2.DMF) was added and the mixture was heated to reflux with stirring. Water generated by the reaction was removed by azeotropic distillation and the reaction was carried out at about 140° C. for 3.5 hours. The white slurry of PMA gradually dissolved as the dehydration reaction progressed and an orange yellow solution was obtained from which the catalyst component precipitated.