Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:33])[NH:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[C:22]([F:31])=[CH:21][C:20]=1[CH3:32])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:27]1[C:28]([CH3:30])=[CH:29][CH:25]([C:23]2[CH:24]=[C:19]([NH:18][C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:33])[C:20]([CH3:32])=[CH:21][C:22]=2[F:31])[NH:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)n[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=CC(c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)NN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzylchloroformate (104 mg) was added dropwise to a room temperature solution of [4-fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester and DIPEA in CH2Cl2 (2 ml). The mixture was stirred at room temperature for one hour, and then 10% aqueous citric acid solution was added. The organic layer was separated dried (Na2SO4), filtered and concentrated under reduced pressure. “Flash chromatography” of the residue (0 to 20% EtOAc in hexanes) gave 210 mg of 3-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[S:10][C:5]=2[C:4](=[O:17])[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>O1CCCC1>[Cl:28][C:29]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:7]1[C:6]2[N:8]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[S:10][C:5]=2[C:4](=[O:17])[N:3]=[C:2]1[CH3:1]
Reactant: Cc1nc(=O)c2sc(N3CCOCC3)nc2[nH]1
Reactant: Clc1cccc(CBr)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (75 mg, 0.297 mmol) in Tetrahydrofuran (THF) (1.5 mL) was stirred at 0° C. for 15 min, then lithium bis(trimethylsilyl)amide (446 μl, 0.446 mmol, 1.0 M in THF) was added and stirring was continued for 30 min. 2,3-Dichlorobenzyl bromide (86 mg, 0.357 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. Additional stirring at 65° C. for 2 h completed the reaction resulting in a mixture of the desired product and the regio-isomer. The reaction was concentrated and the residue was purified by reversed-phase HPLC to provide the product, 4-[(2,3-dichlorophenyl)methyl]-5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (28 mg, 23%). LC/MS: MS (ES+) m/e 411 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 3.52 (m, 4H) 3.64-3.72 (m, 4H) 5.60 (s, 2H) 6.90 (d, J=7.3 Hz, 1H) 7.33 (m, 1H) 7.64 (d, J=8.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:29][C:30]3([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]3)[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), 1-amino-cyclopropanecarboxylic acid (135 mg, 1.3 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-{3-[4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl]-phenylamino}-cyclopropanecarboxylic acid (128 mg, 80%) as a white solid: MS (ESI) M+1=486.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[N:22]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Reactant: C1CCNC1
Solvent: CCO
Product: COC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.4 %

Procedure:
Methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (70 mg, 0.2 mmol) and pyrrolidine (56.8 mg, 0.8 mmol) were added to ethanol (30 mL) and the mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated under reduced pressure to obtain methyl 2-(3-(pyrrolidin-1ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (81 mg, yield 88%). LC-MS (ESI) m/z 337 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])([CH3:10])[CH3:9].[Br:19]NC(=O)CCC(N)=O>S(=O)(=O)(O)O>[Br:19][C:16]1[CH:17]=[CH:18][C:11]([CH:8]([CH3:10])[CH3:9])=[C:12]([CH:15]=1)[CH:13]=[O:14]
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(C)c1ccccc1C=O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of trifluoroacetic acid (50 ml) and 2-isopropylbenzaldehyde (2.0 g, 13.5 mmol) was added conc. sulphuric acid (98%) (10 ml) at room temperature, followed by N-bromosuccinamide (NBS, 3.6 g 20.2 mmol) in portions. After 2 hrs, the mixture was poured into ice water and extracted with dichloromethane (3×30 mL). The organic layers were combined and neutralized with saturated aqueous sodium bicarbonate, washed with brine (30 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography to furnish 5-bromo-2-isopropylbenzaldehyde (1.80 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH:5]=[CH:4][C:3]=1[OH:24].[CH2:25](OC(OCC)OCC)C>>[CH:19]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=3[C:9](=[CH:8][C:6]3[CH:5]=[CH:4][C:3]4[O:24][CH:25]=[N:1][C:2]=4[CH:7]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1O
Reactant: CCOC(OCC)OCC
Product: C(=C1c2ccccc2CCc2ccccc21)c1ccc2ocnc2c1
Temperature: 25 °C
Yield: 84 %

Procedure:
Dissolve 2-amino-4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (see Example 63) (60 mg, 0.191 mmol) in triethylorthoformate (3 mL) and heat to reflux for 4.5 h. Cool to room temperature and concentrate in-vacuo to a brown oil. Chromatograph on 10 g silica gel eluting with 5% to 25% ethyl acetate/hexanes to afford 52 mg (84%) of the title compound as a colorless oil; MS (ES) 324 (M+H), 322 (M−H), HPLC shows 94% purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
3-Amino-1-propanol (6.92 mL, 90.5 mmol) was added dropwise to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (20.0 g, 90.5 mmol) and triethylamine (18.9 mL, 136 mmol) in DMF (300 mL) at room temperature. After 16 hours, the solvent was removed under reduced pressure and the resulting oil was partitioned between ethyl acetate (450 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL). The combined aqueous layers were back-extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was triturated with hexanes/ethyl acetate (2:1) and was isolated by filtration to yield 12.43 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:11]([C@@H:12](O)[C:13](=[O:36])[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:10]1)(C(C)(C)C)(C)C.C(N(S(F)(F)[F:44])CC)C>C(Cl)Cl>[OH:8][C@@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:11]([C@@H:12]([F:44])[C:13](=[O:36])[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:10]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](O)[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](F)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 31.6 %

Procedure:
A solution of methyl 3α-tert-butyldimethylsilyloxy-6α-hydroxy-7-keto-5β-cholanoate (2.4 g, 4.49 mmoles) in methylene chloride (50 ml) was added dropwise in one hour to a solution of diethylamino-sulfur-trifluoride (2.72 ml, 20.0 mmoles) in methylene chloride (50 ml) and the mixture was left to react overnight under argon atmosphere, with magnetic stirring. The reaction mixture was washed with water (1×30 ml), subsequently with a sodium bicarbonate saturated solution (2×20 ml), finally with brine (1×30 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue (2.0 g) was subjected to flash chromatography on silica, eluting with methylene chloride, to obtain 0.6 g of a pure product (32%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1.[OH-].[Na+].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([S:20]([CH3:19])(=[O:22])=[O:21])[C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)S(C)(=O)=O
Yield: 41.1 %

Procedure:
To a solution of 1-(2-chloro-5-thiazolylmethyl)-3,3- dimethyl-2-nitroguanidine (0.300 g) in an aqueous NaOH solution (NaOH (0.319 g) and water (10 ml)) were added CH2Cl2 (10 ml) and 4-dimethylaminopyridine (0.013 g). To the mixture was added methanesulphonyl chloride (0.391 g) dropwise at room temperature under stirring. After stirring for 30 minutes, the mixture was partitioned. The organic layer was dried over MgSO, and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (1:1) to afford 0.160 g of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-l-methanesulphonyl-2-nitroguanidine (Compound No. 28) as a pale yellow crystal, m.p. 82°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]=[N:16][OH:17])[N:12]=[C:11]([CH3:18])[N:10]=1)=[O:8].[CH3:23][N:24]1[CH:29]=[C:28]([CH:30]=[CH2:31])[CH:27]=[CH:26][C:25]1=[O:32].Cl[O-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([C:15]2[CH2:31][CH:30]([C:28]3[CH:27]=[CH:26][C:25](=[O:32])[N:24]([CH3:23])[CH:29]=3)[O:17][N:16]=2)[N:12]=[C:11]([CH3:18])[N:10]=1)=[O:8]
Reactant: C=Cc1ccc(=O)n(C)c1
Reactant: Cc1nc(C=NO)cc(C(=O)NCc2ccc(F)c(F)c2)n1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C(=O)NCc2ccc(F)c(F)c2)cc(C2=NOC(c3ccc(=O)n(C)c3)C2)n1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
To a solution of N-(3,4-difluorobenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (13.60 g, 44.4 mmol, Preparation #A.1.2) and 1-methyl-5-vinylpyridin-2(1H)-one (6 g, 44.4 mmol, Preparation #F.1.13) in DCM (150 mL) was added 9% aqueous sodium hypochlorite solution (80 mL, 1296 mmol, Avra labs) drop wise at 10-15° C. for about 30 min. Reaction mixture was allowed to stir for another 15-30 min, diluted the reaction mixture with water (100 mL) and the product extracted with DCM (2×100 mL). The combined organic layers was dried over sodiumsulphate and evaporated to dryness. The resulting crude material was purified by silica gel column chromatography by eluting with 2% methanol in DCM. Relevant fractions containing product were combined and evaporated under reduced pressure to afford N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 3 g (15.38%) as pale yellow solid; 1H NMR (400 MHz, DMSO): δ 9.606-9.574 (m, 1H), 8.179 (s, 1H), 7.872-7.866 (d, J=2.4 Hz, 1H), 7.527-7.497 (dd, J=9.6 Hz, 1H), 7.421-7.353 (m, 2H), 7.205-7.173 (m, 1H), 6.436-6.412 (d, J=9.6 Hz, 1H), 5.688-5.637 (m, 1H), 4.504-4.488 (d, J=6.4 Hz, 2H), 3.836-3.764 (m, 1H), 3.463-3.440 (m, 1H), 3.425 (s, 3H), 2.767 (s, 3H); MS m/z: 440.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[NH:13][C:12](=[S:24])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:25]([S:24][C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C#CCOc1ccc2[nH]c(=S)nc(-c3ccc(C(C)C)cc3)c2c1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCOc1ccc2nc(SCc3ccccc3)nc(-c3ccc(C(C)C)cc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg (299 μmol) 4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione in 2 ml THF are added 35.5 μl (299 μmol) benzyl bromide and 76 μl (448 μmol) DIEA. After stirring for 18 h at r.t. the reaction mixture is extracted with dichloromethane and water. After evaporation of the organic layers the crude product is purified by flash chromatography using hexanes/ethyl acetate 20:1 as eluent.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:40])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[CH:15]=1>C(O)C>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[C:16]3[CH:15]=[C:14]([C:13](=[O:40])[NH:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=4)[CH:19]=[CH:18][C:17]=3[N:20]=[C:21]2[CH3:22])=[CH:27][CH:28]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 89.8 %

Procedure:
Four milliliters of acetic acid and 8 ml of ethanol were added to 0.434 g of N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide, and the mixture was stirred at 90° C. for 7 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and ether were added to the residue for crystallization. The crystals were separated through filtration, and were dried to give 0.375 g of 1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-benzimidazole (242).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]=23)=[CH:13][CH:14]=1)[CH3:23]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc3c2CCC3)cc1
Yield: 21.4 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.110 g, 0.33 mmol) was reacted with tert-butyl piperazine-1-carboxylate (0.073 g, 0.40 mmol) to afford the title compound (0.034 g, 21%) as an orange foam. MW=480.59. 1H NMR (CDCl3, 500 MHz) δ 7.27 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.17 (s, 1H), 5.59 (s, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.60 (s, 2H), 3.54-3.48 (m, 4H), 3.40-3.34 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.12 (quin, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.27 (t, J=7.0 Hz, 3H); APCI MS m/z 481 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:34][CH2:35][CH3:36])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:34][CH2:35][CH3:36])[CH:16]2[CH2:17][C:18]3[CH:19]=[C:20]([O:26][S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH:21]=[CH:22][C:23]=3[CH2:24][CH2:25]2)[CH2:10][CH2:9]1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-{[propyl-(7-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, (220 mg, 0.41 mmol) in methylene chloride (5.0 mL) under an inert atmosphere was added trifluoroacetic acid (1.0 ml). The reaction was stirred at room temperature for 1h. The reaction was concentrated in-vacuo and partitioned between 1N NaOH (20 ml) and EtOAc (30 ml). The organic layer was separated, dried (MgSO4), and concentrated to afford trifluoro-methanesulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (114 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:23]#[N:24])[C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([S:27]P([O-])(OCC)=S)C>O>[NH2:24][C:23](=[S:27])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:11]
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@@H](C#N)O[Si](C)(C)C(C)(C)C
Reactant: CCOP([O-])(=S)SCC
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl ((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate (115.6 mg, 0.287 mmol), diethyldithiophosphate (1 mL) and water (3 drops) was stirred overnight at room temperature. The reaction mixture was partitioned between saturated NaHCO3 (40 mL) and EtOAc (40 mL). The aqueous layer was separated and extracted with EtOAc (2×40 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl ((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxopropyl)carbamate as a colorless oil. Rf=0.30 (20% EtOAc in hexanes). LCMS calc.=383.2; found=383.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.37-7.29 (m, 5H), 5.13 (m, 2H), 4.85 (d, J=8.2 Hz, 1H), 4.72 (s, 1H), 4.47 (m, 1H), 1.05 (d, J=6.7 Hz, 3H), 0.96 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=3)[S:61][C:51]=2[C:52]([N:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3cccc(N4CCOCC4)c3)nc12

Procedure:
From 3-morpholin-4-yl-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[CH3:15][S:16]([C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:24](=[O:25])[C:22]1[S:23][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)s1
Agent: CN(C)c1ccncc1
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)s1
Yield: 70 %

Procedure:
The title compound was prepared according to the procedure of Example 32. A 2.06 g (10.0 mmoles) sample of 5-methylsulfonyl-2-thiophenecarboxylic acid (prepared according to Cymerman-Craig, J., et al., J. Chem. Soc.:237 (1954)) reacted with 10 ml of thionyl chloride to give 2.14 g of crude acid chloride as a solid. The reaction of 1.75 g (8.33 mmoles) of 5-chloro-2-oxindole-1-carboxamide with 5-methylsulfonyl-2-thiophenecarbonyl chloride in the presence of 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine gave 3.17 g of crude product after acidic workup. A single recrystallization from acetic acid gave 2.31 g (5.80 mmoles, 70% yield) of pure 5-chloro-3-(5-methylsulfonyl-2-thenoyl)-2-oxindole -1-carboxamide as a deep-orange solid, m.p. 212°-14° C.