Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:4][C:5]([CH2:7][N:8]([S:34]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2)(=[O:36])=[O:35])[C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([CH2:16][C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH2:28])=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=3)=[N:15][C:11]=2[CH:10]=1)=[O:6])C.[OH-].[Na+]>C(O)C.O>[C:5]([CH2:7][N:8]([S:34]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2)(=[O:36])=[O:35])[C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:28])=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=3)=[N:15][C:11]=2[CH:10]=1)([OH:6])=[O:4]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCC)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N=C(N)c1ccc(Cc2nc3cc(N(CC(=O)O)S(=O)(=O)c4cccc5cccnc45)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-ethyloxycarbonyl-benzamidine-hydrochloride and sodium hydroxide in ethanol/water.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.4 %

Procedure:
A mixture of ethyl 2-[1-benzyl-6-(4-trifluoromethoxyphenyl)-1H-indol-3-yl]-2-oxoacetate (1.27 g, 2.72 mmol), potassium hydroxide (0.539 g, 9.61 mmol) in THF (12 mL) and water (12 mL) was stirred at room temperature for 3.5 hours. The mixture was poured into excess water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was dried under vacuum at 92° C. for 15 hours to yield the title compound (0.985 g, 82%) as a yellow solid. A sample crystallized from isopropanol gave a solid, mp: 202-204° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (t, 1H, J=0.73 Hz), 7.8-7.85 (m, 2H), 7.65 (dd, 1H, J=8.3 Hz and 1.5 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25-7.4 (m, 5H), and 5.65 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.59; H, 3.54; N, 3.18.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:42][O:41][C:31]1[N:30]=[C:29]([O:28][CH:23]2[CH2:22][CH:21]3[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]4[C:18]([C:44]([NH:46][S:47]([CH:50]5[CH2:51][CH2:52]5)(=[O:48])=[O:49])=[O:45])([NH:19][C:20]3=[O:43])[CH2:17]4)[CH2:24]2)[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:32]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCNC(=O)N3C2)cc(-c2ccccc2)n1
Yield: 16 %

Procedure:
Compound 2e was dissolved in a 1:2 mixture of TFA:DCM (12 ml) and stirred at RT for 1 h. NaHCO3 was added and the organic layer was separated, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (32 mg, 16% over two steps). MS (M+H)+639.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([CH3:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [4-(benzyloxy)-2-methylphenyl]acetate (1.05 g, 3.36 mmol) in DCM (8 ml) was treated with TFA (7.77 ml, 101 mmol) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 257 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.[Na]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][CH:36]1[CH2:37][CH2:38][O:33][CH2:34][CH2:35]1
Reactant: COC(=O)c1ccncc1N
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccncc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3-amino-isonicotinic acid methyl ester (500 mg, 3.29 mmol), dry N,N-dimethylformamide (10 mL), trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 eq) was added tetrahydro-pyran-4-one (0.5 mL, 4.94 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 24 hours then poured into saturated sodium hydrogenocarbonate (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and evaporated to dryness affording the crude title compound as yellow syrup that was used as such for the next step.
Reaction SMILES: [C:1]([C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][C:12]=1[CH2:22][CH3:23])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[Na]>CN(C)C=O>[CH2:22]([C:12]1[O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[C:11]=1[C:1](=[O:10])[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1)[CH3:23]
Reactant: CCc1oc2cc(OC)ccc2c1C(=O)c1ccc(OC)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCc1oc2cc(OC)ccc2c1C(=O)c1ccc(O)cc1
Yield: 100 %

Procedure:
Dimethyl formamide solution of 3-(p-anisoyl)-2-ethyl -6-methoxybenzofuran (2.39 g, 7.7 mmol) and ethanethiolic sodium salt (971 mg, 11.5 mmol) was stirred at 80° C. for 4 hours. This reaction was completed using NH4Cl solution and extraction was performed with chloroform. The extract was washed with water and saline solution, dried over Ma2SO4, and concentrated under reduced pressure. The residue was purified by HPLC (silica gel, ethyl acetate:hexane=2:8) and a target product (2.28 g, 7.70 mmol, 100%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][N:25]([CH3:31])[C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][N:25]([CH3:31])[C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:27]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and (S)-N,N-dimethylpyrrolidin-3-amine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 10-35% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (60 mg, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 2.20-2.37 (m, 1 H) 2.61-2.71 (m, 1 H) 2.90 (d, J=3.79 Hz, 6 H) 3.79-3.91 (m, 1 H) 4.02-4.19 (m, 2 H) 4.35 (d, J=6.57 Hz, 2 H) 6.26 (d, J=2.27 Hz, 1 H) 7.15 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 7.99 (d, J=8.59 Hz, 2 H) 8.04 (d, J=2.02 Hz, 1 H) 9.87 (br. s., 1 H) 10.77 (s, 1 H). ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: [SH:1][CH:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](SC)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].CS[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[SH:1][CH:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]([NH:5][C:6]1([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:41]4[C:42]5[C:43](=[CH:3][CH:2]=[CH:33][CH:34]=5)[CH:44]=[CH:39][CH:40]=4)=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CSc1ccc(-c2ccc(CC(NC(=O)C3(NC(=O)C(S)CC(C)C)CCCC3)C(=O)O)cc2)cc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CC(C)CC(S)C(=O)NC1(C(=O)NC(Cc2ccc(-c3ccc(-c4cccc5ccccc45)cc3)cc2)C(=O)O)CCCC1

Procedure:
2-{[1-(2-mercapto4-methyl-pentanoylamino)-cyclopentanecarbonyl]-amino}-3-(4′-methylthio-biphenyl-4-yl)-propionic acid (from 4-methylthiophenyl-boronic acid; mp 187-189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].N1C=CC=CC=1.C1COCC1.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O.CCOC(C)=O.C(Cl)Cl>[CH:16]1([C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:3]([CH3:21])[CH:4]=3)[CH:8]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Add N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (Intermediate A1, 500 mg, 1.76 mmol), pyridine (280 mg, 3.52 mmol) to a mixed solvent of THF (5 mL) and DCM (5 mL). Cool to 0° C.; add slowly phenyl chloroformate (330 mg, 2.11 mmol). Stir the reaction at room temperature for 2 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete. Dilute with water, extract with DCM. Combine the organic layers, wash with 1M diluted HCl, brine sequentially, and dry over anhydrous Na2SO4. Concentration under reduced pressure affords the title compound (700 mg, 98.3%). MS: (M+1) 273.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([C:14]1[N:21]2[C:17]([S:18][CH:19]=[CH:20]2)=[CH:16][N:15]=1)[NH:7][C:8](=[O:13])C(F)(F)F)(=O)C.[OH-].[Na+].N[C@H](C1N2C(SC=C2)=CN=1)CO.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(O)=O.C(Cl)Cl>[CH:8]([NH:7][C@@H:6]([C:14]1[N:21]2[C:17]([S:18][CH:19]=[CH:20]2)=[CH:16][N:15]=1)[CH2:5][OH:4])=[O:13]
Reactant: CC(=O)OC[C@@H](NC(=O)C(F)(F)F)c1ncc2sccn12
Agent: N[C@@H](CO)c1ncc2sccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN[C@H](CO)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
To the solution of 0.747 g of 5-[(S)-2-acetoxy-1-(trifluoroacetylamino)-ethyl]imidazo[5,1-b]thiazole in 10 ml of methanol was added 5 ml of an aqueous solution of 0.233 g of sodium hydroxide, and the mixture was then stirred at room temperature for 14 hours. The reaction mixture was concentrated to dryness under reduced pressure to give solid product containing 5-[(R)-1-amino-2-hydroxyethyl]imidazo[5,1-b]thiazole. To this product was added 50 ml of methylene chloride, and the mixture was stirred well. The mixture of 1.2 g of acetic anhydride and 2.7 g of formic acid which had been preliminarily heated to 50° C. for 10 minutes and cooled to room temperature was added to the suspension. After mixing at room temperature for 30 minutes, the mixture was cooled to room temperature. Water (5 ml) and potassium carbonate (5 g) were added, and the resulting mixture was stirred at room temperature for 30 minutes. Methanol (20 ml) was added, and the mixture was further stirred for i hour. The organic layer was separated by decantation. The aqueous layer containing crystalline products was washed five times with 20 ml of methylene chloride, and the methylene chloride layers were combined with the organic layer separated previously. The combined organic layer was dried with anhydrous potassium carbonate and concentrated to dryness, and the residue was purified on Sephadex LH20 (eluent: chloroform-methanol=1:1) to give 0.440 g of 5-((S)-1-formylamino-2-hydroxyethyl)imidazo[5,1-b]thiazole. Quantitative yield. NMR (CDCl3) δ: 3.90 (1H, dd, J=11.6 Hz, 3.6 Hz), 4.42 (1H, dd, J=11.6 Hz, 2.0 Hz), 5.45 (1H, ddd, J=9.0 Hz, 3.6 Hz, 2.0 Hz), 6.8-6.9 (1H, br), 6.83 (1H, d, J=4.3 Hz), 6.97 (1H, s), 7.76 (1H, d, J=4.3 Hz), 8.26 (1H, s). MS (EI, DMSO, 200° C.): 211 (M+).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4].C(O)(=O)C.[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41](=[O:47])[NH:42][CH2:43][CH2:44][CH:45]=O)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O1CCOCC1>[CH:35]1[C:36]2[CH:37]([CH2:39][O:40][C:41](=[O:47])[NH:42][CH2:43][CH2:44][CH2:45][NH:1][CH:2]([C:5]3[N:10]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:9](=[O:18])[C:8]4=[CH:19][CH:20]=[CH:21][N:7]4[N:6]=3)[CH2:3][CH3:4])[C:38]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=CCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCC(NCCCNC(=O)OCC1c2ccccc2-c2ccccc21)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A mixture of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (180 mg, 0.64 mmol), acetic acid (Example 26, 65 μl, 0.95 mmol), 3-oxo-propyl-carbamic acid 9H-fluoren-9-ylmethyl ester (Org. Lett. 2002, 4, 3001–3003), 1,4-dioxane (5 mL), and 4 Å molecular sieves was stirred at room temperature for 15 min then treated with sodium triacetoxyborohydride (112 mg, 0.53 mmol). After 45 min, the reaction was diluted with methylene chloride (25 mL), filtered, washed with saturated sodium bicarbonate, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/hexanes to give the desired compound (170 mg, 32%): MS (ESI+) 562.2 (M++H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](C=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].FC1C=CC(CS(C2C=C3C(=CC=2)NC(=O)C3)(=O)=O)=CC=1.N1CCCCC1>C(O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][CH:14]=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:21]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Agent: O=C1Cc2cc(S(=O)(=O)Cc3ccc(F)cc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCCc2[nH]cc(C)c2C1=O
Temperature: 25 °C
Yield: 132 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(4-fluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 65a (58 mg, 0.19 mmol) were dissolved in 2 ml of ethanol, and added with 34 μl of piperidine the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-(5-(4-fluorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 71 (73 mg, yield 66%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33][N:34]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.NN>>[NH2:34][CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:28][CH2:29]1
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Product: NC[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ethanolic solution of trans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione (265 mg, 0.46 mmol) was charged with an excess of hydrazine (0.14 mL, 4.6 mmol) and allowed to stir at rt for 16 h. The solution was filtered through a fritted glass funnel and the solids were washed with EtOH (4×). The filtrate was concentrated and the crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with 2%˜7N NH3 in MeOH/CH2Cl2 to 4%˜7N NH3 in MeOH/CH2Cl2]. The purified material was recrystallized from CH2Cl2/hexanes to afford the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.16-1.26 (m, 2H), 1.58-1.65 (m, 1H), 1.87-1.99 (m, 2H), 2.02-2.09 (m, 2H), 2.13-2.22 (m, 2H), 2.72 (d, 2H, J=6.4 Hz), 2.92-3.01 (m, 1H), 7.10 (d, 1H, J=5.2 Hz), 7.25-7.28 (m, 1H), 7.42-7.55 (m, 3H), 7.89-7.94 (m, 3H), 8.18-8.20 (m, 2H), 8.24 (d, 1H, J=8.8 Hz), 8.39-8.41 (m, 1H); MS (ES+): m/z 449.0 [MH+]; HPLC: tR=2.0 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: [S:1](=[O:38])(=[O:37])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH3:28])[N:14]=[CH:13][N:12]=2)[CH2:7][C@@H:6]1[O:29][Si](C(C)(C)C)(C)C)[NH2:2].F.N1C=CC=CC=1>N1C=CC=CC=1.C1COCC1>[S:1](=[O:38])(=[O:37])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH3:28])[N:14]=[CH:13][N:12]=2)[CH2:7][C@@H:6]1[OH:29])[NH2:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)ncn1
Yield: 52.5 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl sulfamate (0.239 g, 0.000423 mol) in pyridine (3.44 mL) and THF (3.44 mL) was added pyridine hydrofluoride (0.953 mL, 0.0106 mol) dropwise. After stirring the reaction for 2 hours, an additional amount of pyridine hydrofluoride (0.50 mL, 0.0055 mol) was added. After 2.75 hours the reaction was quenched by slow dropwise addition of saturated aqueous NaHCO3 and extracted with EtOAc (4×). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) and then by preparative plate chromatography (EtOAc) to obtain 100 mg (52%) of the title compound. 1H NMR (CD3OD, 400 MHz) δ: 8.15 (s, 1H), 7.24-7.15 (m, 4H), 5.98 (s, 1H), 5.34 (bs, 1H), 4.41-4.38 (m, 1H), 4.32 (dd, 1H, J=7.5, 9.7 Hz), 4.24-4.20 (m, 1H), 4.17 (dd, 1H, J=7.3, 9.8 Hz), 3.35 (s, 3H), 3.13-3.00 (m, 3H), 2.57-2.48 (m, 1H), 2.31-2.25 (m, 1H) 2.12-1.93 (m, 4H) ppm. LC/MS: Rt=1.33 min, ES+ 451 (FA standard).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([C:15]([OH:16])([CH3:17])[CH3:14])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 3,5-dibromopyridine (264 g, 1.12 mol) in toluene (3000 mL). The solution was cooled to −78° C., and a solution of n-butyllithium in hexanes (2.6 M, 475 mL, 1.24 mol) was then added, giving a solution that was stirred for 2 hours at −78° C. Acetone (108 g, 1.86 mol) was then added. After 1 hour, the reaction mixture was quenched by addition of 350 mL saturated aqueous ammonium chloride solution. The resulting solution was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (ethyl acetate/petroleum ether 1:10-1:5) provided the title compound: 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.56 (s, 1H), 8.01 (s, 1H), 1.61 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:37][CH:38]=1)[CH3:23]
Reactant: CN(C)Cc1ccccc1-c1ccc(N)cc1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)Cc1ccccc1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (60 mg, 0.19 mmol) and 4-(2-dimethylaminomethyl-phenyl)phenylamine (50 mg, 0.22 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.034 mL, 0.37 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (8 mg). MS 531.1 and 533.1 (M+H, Cl pattern).