Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C[O:7][C:8](=O)[N:9]=[C:10](SC)[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[NH:38]([C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[NH2:39]>C(N(CC)CC)C>[CH2:33]([O:32][C:27]1[CH:26]=[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:7])[N:38]([C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[N:39]=2)[CH:30]=[C:29]([OH:31])[CH:28]=1)[CH3:34]
Reactant: NNc1ncccn1
Reactant: CCOc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(O)cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To 1 ml of a DMF solution containing 45 mg of {2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (78a)), 11 mg of 2-hydrazinopyrimidine and 0.014 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for one day under a nitrogen atmosphere and then concentrated. The residue was dissolved in 1 ml of methanol, 1 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 3 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 5-{(3-ethoxy-5-hydroxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: FC1C(N2CCNCC2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:49])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.[CH3:50][CH:51]1[O:56][CH:55]([CH3:57])[CH2:54][NH:53][CH2:52]1>>[CH3:57][CH:55]1[O:56][CH:51]([CH3:50])[CH2:52][N:53]([C:29]2[C:30]([F:49])=[CH:31][C:32]3[C:33]4[C:34]([C:39](=[O:48])[N:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:41]=4)=[CH:35][NH:36][C:37]=3[CH:38]=2)[CH2:54]1
Reactant: CC1CNCC(C)O1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Agent: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Product: CC1CN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)CC(C)O1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 2,6-dimethylmorpholine. 1H-NMR (DMSO-d6) δ (ppm): 1.15 (6H, d, J=6.73 Hz), 2.40 (2H, brm), 3.41 (2H, d, J=10.99 Hz), 3.76 (2H, brm), 7.13 (1H, m), 7.26 (1H, d, J=7.69 Hz), 7.41 (2H, t, J=7.42 Hz), 7.83 (2H, d, J=12.91 Hz), 8.19 (2H, m), 8.66 (1H, s). m/z 393.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]([O-])([CH3:21])[CH3:20].[K+].BrC[N:26]1[C:30](=[O:31])C2=CC=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>C1COCC1>[CH2:18]=[C:19]1[CH:21]=[CH:34][CH:35]=[C:28]2[C:27]([N:26]([N:14]3[C:15]4[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:17][CH:16]=4)[CH:12]=[CH:13]3)[C:30](=[O:31])[CH:20]12)=[O:36]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1C=CC=C2C(=O)N(n3ccc4cc(OCc5ccccc5)ccc43)C(=O)C12
Reaction time: 3 h
Yield: 76 %

Procedure:
5-Benzyloxyindole (500 mg, 2.24 mmol) was dissolved in THF (20 mL) and treated with 1M KOtBu in THF (2.24 mL, 2.24 mmol). After stirring for 3 hours, N-(bromomethyl) phthalimide (538 mg, 2.24 mmol) was added and the reaction mixture was stirred for an additional 24 hrs. Standard aqueous workup and purification by silica gel chromatography, eluting with 3:1 hexane/ethyl acetate, provided N-(methylenephthalimido)-5-benzyloxyindole (650 mg, 76%). 1H NMR (200 MHz, CDCl3) δ 7.83 (d, J=5.5 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.72–7.65 (m, 2H), 7.45 (m, 1H), 7.42 (d, 3.0 Hz, 2H), 7.40–25 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 7.00 (dd, J=2.2, 9.0 Hz, 1H), 6.49 (d, J=3.2 Hz, 1H), 5.91 (s, 2H), 5.07 (s, 2H). MS (EI. m/z) M+=382.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([C@@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][CH2:20][C@@H:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=5)[CH2:22]4)[CH2:15][CH2:14]3)[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([C@@H:13]3[CH2:14][CH2:15][C@H:16]([N:19]([CH2:20][C@@H:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=5)[CH2:22]4)[C:41](=[O:43])[CH3:42])[CH2:17][CH2:18]3)[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C[C@H]1Cc2ccc(C#N)cc2C1)[C@H]1CC[C@@H](n2c(C(C)(C)O)nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 55 %

Procedure:
To a solution of cis-(S)-2-({4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-cyclohexylamino}-methyl)-indan-5-carbonitrile (25 mg, 0.054 mmol) in methylene chloride (5 mL) was added triethylamine (11 mg, 0.108 mmol), acetyl chloride (5 mg, 0.063 mmol) and trace amount of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 65 hours. The reaction mixture was diluted with dichloromethane and the solution was washed with saturated aqueous sodium bicarbonate solution followed by brine. The organic extract was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with dichloromethane and ethyl acetate in the presence of 4% methanol to give cis-(S)—N-{4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-cyclohexyl}-N-(5-cyano-indan-2-ylmethyl)-acetamide (15 mg). LC-MS showed a single peak, C29H33ClN4O2 (m/e) calcd 504.2292, obsd 505.3. 1H-NMR (CD3OD) □ 7.67 (br, 1H) 7.59 (s, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.23 (d, 1H), 5.57 (m, 1H), 3.48 (br d, 2H), 3.15 (m, 2H), 2.97 (m, 1H), 2.84 (m, 2H), 2.59 (br, 2H), 2.32 (br, 1H), 2.11 (br s, 2H), 1.93 (m, 4H), 1.72 (s, 6H), 1.28 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.[OH-].[CH2:18]([N+:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([N+:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc([O-])cc1
Yield: 94.7 %

Procedure:
A mixture of 4-nitrophenol (13.9 g, 0.10 mol) and benzene (250 mL) was treated with tetraethylammonium hydroxide (14.7 g, 0.10 mol), added as a 20% aqueous solution. The mixture was heated under reflux until all water was removed by azeotropic distillation. The solution was allowed to cool with continued stirring. Upon standing, 25.4 g of a yellow solid was obtained; it was recrystallized from THF. 1H NMR (CDCl3) confirmed the title compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:5]([O:7][CH:8]([O:4][CH2:1][C:2]#[CH:3])[CH3:9])[CH3:6]
Reactant: C=COCC
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C#CCOC(C)OCC
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of 20 g (0.36 mol) of 2-propyn-1-ol 1n 637 ml (6.66 mol) of ethyl vinyl ether was treated at 0° under argon with 1.27 ml (16.7 mmol) of trifluoroacetic acid and subsequently stirred at room temperature for 65 hours. 1.3 g of sodium carbonate were added, the react ion mixture was stirred at room temperature for a further 30 minutes and concentrated on a rotary evaporator. Distillation of the residue under reduced pressure Yielded 1-(1-ethoxyethoxy)-2-propyne of boiling point 55°/30 mmHg. MS: 127 (M-H) m/e.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:12]1([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si](Cl)(C)C>ClCCCl>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([NH:21][C:19](=[O:20])[CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:21][C:19](=[O:20])[CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CN(C)c1ccc(C(NC(=O)Cc2ccccc2)NC(=O)Cc2ccccc2)cc1
Temperature: 70 °C
Yield: 34.9 %

Procedure:
To a suspension of 4-(dimethylamino)benzaldehyde (149 mg, 1 mmol) and 2-phenylacetamide (270 mg, 2 mmol) in 2 mL anhydrous DCE, TMSCl (216 mg, 2 mmol) was added. The mixture was heated at 70° C. for 12 h, then cooled to room temperature and the crude product precipitated from the solution. The crude product was recrystallized with methanol and hexane to give the final product (140 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=8.0 Hz, 2H), 7.59 (s, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.21-7.32 (m, 10H), 6.54 (t, J=8.0 Hz, 1H), 3.52 (dd, J=14.0, 15.6 Hz, 4H), 3.06 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=O)C.[OH-].[Na+].O>C(O)C>[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CC(=O)OCCCCCBr
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(SCCCCCO)[nH]c2c1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
2.46 g of 5-methyl-2-mercaptobenzimidazole and 3.4 g of 5-bromopentyl acetate were dissolved in 30 ml of ethanol and the mixture was refluxed with stirring under heating for 7 hours. After cooling to room temperature, the reaction mixture was added with was 22.5 ml of 2 N sodium hydroxide solution and stirred at room temperature for 1 hour, and then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to obtain 3.04 g of the title compound as pale yellow oil (yield: 81%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C@H:13]([C:16]1[O:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=1)[CH2:14][CH3:15])[CH3:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@@H:11]([C@H:13]([C:16]1[O:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=1)[CH2:14][CH3:15])[CH3:12])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC[C@@H](c1nc(C(=O)OC)co1)[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](c1nc(C(=O)O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
1N aqueous sodium hydroxide (5.69 ml, 5.69 mmol) was added in one portion to a solution of methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (711 mg, 2.28 mmol) in anhydrous THF (9.11 ml). The reaction was allowed to stir at room temperature for 3.5 hours before evaporating the organic in vacuo. The remaining aqueous was cooled to 0° C. and acidified to pH 4 using 1N HCl. The aqueous phase was then extracted with ethyl acetate (3×25 mL). The aqueous pH was re-checked and judged to be ˜pH 6-7. A small amount of 1N HCl was added to re-acidify the aqueous layer which was once again extracted with an additional portion of ethyl acetate (1×25 mL). The combined organics were dried (MgSO4) and evaporated in vacuo to give crude 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (679 mg, 2.28 mmol, 100% yield) as a white solid which was used immediately in the next reaction. EDC (545 mg, 2.84 mmol) was added in one portion to a mixture of 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (679 mg, 2.28 mmol) and HOBT (436 mg, 2.84 mmol) in anhydrous dichloromethane (23.0 ml) and the reaction allowed to stir at room temperature under a nitrogen atmosphere for 30 minutes. Ammonia was then bubbled through for approximately 5 minutes and the resulting white suspension allowed to stir at room temperature overnight. The reaction was then evaporated in vacuo and the residue partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give tert-butyl-((2R,3R)-3-(4-carbamoyloxazol-2-yl)pentan-2-yl)carbamate (677 mg, 2.28 mmol, 100% yield) which was used immediately in the next step. LC/MS: M+H+320.15, ret. time=1.89 min. Column: Phenomenex, 2.0×30 mm, 2.5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.05% TFA; Mobile Phase B: 90:10 methanol:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. HPLC: ret. time=2.73 min. Column: YMC CombiScreen ODS-A, 4.6×50 mm; Mobile Phase A: 10:90 methanol:water with 0.2% H3PO4; Mobile Phase B: 90:10 methanol:water with 0.2% H3PO4; Temperature: 50° C.; Gradient: 0-100% B over 4 minutes, then a 0.75-minute hold at 100% B; Flow: 4 mL/min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.[CH3:16][C:17]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:4]1[N:5]=[C:6]([Cl:8])[CH:7]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:17]=2[CH3:16])[N:3]=1)[CH3:15]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cccc(N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
A stirred mixture of 2.7 g of (4.6-dichloro-2-pyrimidinylthio)acetic acid, ethyl ester, 1.2 g of 2,3-dimethylaniline and 1.06 g of anhydrous sodium carbonate in 20 ml. of ethanol was heated under reflux for 4 hr. The mixture was filtered and water added to the filtrate until a precipitate appeared. The solid was recrystallized from 95% ethanol to a mp. of 88°-93°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([N:24]4[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.Cl.CC(O)C>CO.CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([N:24]4[CH2:25][CH2:26][CH:27]([NH2:30])[CH2:28][CH2:29]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)nc34)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)nc34)c2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (79 mg, 0.120 mmol, 88% pure) in THF (2 mL) was treated with NaOH 5M (0.048 mL, 0.239 mmol). The reaction mixture was heated to reflux (bath temperature 80° C.). After 1 h, NaOH 5M (0.45 mL, 0.96 mmol, 8.0 equiv) was further added. After 23 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-7% MeOH/DCM), affording tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (31 mg, 51%). MS (ESI, pos. ion) m/z: 506.2 (M+1). A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (31 mg, 0.061 mmol) in MeOH (0.5 mL) was treated with HCl, 5-6n in IPA (0.123 mL, 0.613 mmol). The reaction was heated to 50° C. under N2. After 2 h, the reaction was cooled to 23° C. and the product (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was slurried in MeOH/DCM and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine MS (ESI, pos. ion) m/z: 406.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([CH3:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cscc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: O
Solvent: COCCOC
Product: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 200 mg, 64%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8](CN)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:13]([N:15](CC)CC)C.[C:20]([O:24][C:25]([O:27]C(OC(C)(C)C)=O)=O)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([O:24][C:25]([NH:15][CH2:13][C:11]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:12]=1)=[O:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 4-nitrobenzylamine hydrochloride (10.3 g, 54.7 mmol) and triethylamine (11.1 g, 109 mmol) in dichloromethane (75 mL) was added a solution of di-tert-butyldicarbonate (15.5 g, 71.1 mmol) in dichloromethane (25 L). After stirring overnight at room temperature, the reaction was washed with 10k citric acid (2×250 mL), dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate/hexanes to afford the 13.80 g of the title compound. (100%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=2)=[C:42]([F:54])[CH:41]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]([C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])[CH2:28][CH2:27]2)[C:19](=[O:38])[C:18]=1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]2[NH:3][C:4](=[O:7])[O:5][N:53]=2)=[C:42]([F:54])[CH:41]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.46 g), sodium hydrogen carbonate (0.69 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-fluorobiphenyl-2-carbonitrile (0.31 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.14 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.11 g, 44%).
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: II
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CC(=O)O
Product: Ic1ccc(N2CCNCC2)cc1
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Over a period of 15 minutes samples of iodine (8.62 grams, 0.034 mol) and silver benzoate (7.78 grams, 0.034 mol) were added in portions to a magnetically stirred solution of 5 grams of 1-phenylpiperazine in 80 mL acetic acid. The mixture stirred for 1hour. The solvent was evaporated and the residue partioned between 150 mL diethyl ether and 150 mL 2N sodium hydroxide. The organic layer was washed with 100 mL water, 100 mL brine, then dried over potassium carbonate and concentrated in vacuo to yield 1.0 gram (11%) of 1-(4-iodophenyl)-piperzine (110°-115° C.). the material obtained was used without further purification. 1H NMR (CDCl3, dTMS) 7.51 (2H, d, 3JHH =9 Hz, m-ArH), 6.69 (2H, d, 3JHH =9 Hz, o-ArH), 3.17 (4H, m), 3.04 (4H, m), 13C NMR (CDCl3) 151.36, 137.73, 118.05, 81,35, 49.92, 45.95.