Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: c1ccc([C@@H]2C[C@H]2NCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
Chloroform (50 mL) was added to a 200 mL round-bottomed flask containing tert-butyl 4-(2-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate (161 mg, 0.467 mmol). HCl/1,4-Dioxane (1 mL, 4.00 mmol) was added and the mixture stirred 18 hours at room temperature. Upon completion, the residue was adsorbed directly onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 4 g column) Fractions were collected, solvents removed and the resulting residue was taken up in MeOH (2 mL). Excess 2M HCl in Et2O was added and the solution stirred for 10 minutes. The solvent was removed to yield the 2HCl of the desired product (35 mg, 22% yield) as a brown solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, MeOH-d4) δ ppm 1.39 (br. s., 1H) 1.51 (br. s., 4H) 1.79 (br. s., 3H) 2.00 (br. s., 2H) 2.61 (br. s., 1H) 3.02 (br. s., 3H) 3.29 (br. s., 1H) 3.35-3.53 (m, 2H) 7.17-7.28 (m, 3H) 7.28-7.36 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:9][C:10]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:6][CH2:7][CH3:8]>C(Cl)(Cl)(Cl)Cl>[CH2:5]([O:9][C:10]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:3])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
On the other hand, 15 ml of carbon tetrachloride (solvent) and 3 ml of thionyl chloride were added to 2.16 g (0.0158 mol) of 4-n-butoxycarbonyloxy benzoic acid, and the mixture was heated and refluxed. After sufficiently reacting them, excess thionyl chloride and carbon tetrachloride (solvent) were distilled off under reduced pressure to obtain 4-butoxycarbonyloxy benzoic acid chloride (one having Formula 7 wherein R2 is a n-butyl group).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[N+:14]=[N-:15]>>[ClH:1].[S:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:18]1
Reactant: [N-]=[N+]=NCc1ccsc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccsc3)nn2)c[nH]1
Yield: 46.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g, 0.486 mmol) was reacted with 3-Azidomethyl-thiophene (0.081 g, 0.582 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Thiophen-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-imidazol-2-ylamine hydrochloride (0.0727 g, 46%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.61 (s, 1H), δ 7.24 (s, 1H), δ 7.23 (d, 1H), δ 6.87 (d, δ 6.29 (s, 1H), δ 2.54 (t, 2H), 2.33 (t, 2H), δ 1.75 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.6, 147.4, 147.3, 136.1, 127.9, 127.0, 126.9, 124.2, 122.2, 109.1, 53.1, 27.9, 24.3; HRMS (ESI) calcd for C13H16N6S (M+) 289.1229. found 289.1234.
Reaction SMILES: [Na+].[NH2:2][C:3]([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH:9]([S:12][C:13]2[CH:19]([CH3:20])[CH:18]3[N:15]([C:16](=[O:24])[CH:17]3[CH:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O-:27])=[O:26])[CH2:8]1)=[O:4].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)(O)[O-].[I-].[Na+]>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[O:34][CH2:35][O:26][C:25]([C:14]1[N:15]2[CH:18]([CH:19]([CH3:20])[C:13]=1[S:12][CH:9]1[CH2:8][CH:7]([CH2:6][O:5][C:3]([NH2:2])=[O:4])[O:11][CH2:10]1)[CH:17]([CH:21]([OH:23])[CH3:22])[C:16]2=[O:24])=[O:27]
Reactant: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(SC3COC(COC(N)=O)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 407 using 0.460 g of product from Example 21, 0.24 ml of chloromethyl pivalate, 0,189 g ofsodium bicarbonate and 0,252 g of sodium iodide to give after chromatograph0.32 g of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:32])[CH:20]4[NH:24][C:25]([O:27]C(C)(C)C)=O)[C:17]=3[C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CS(O)(=O)=O.[S:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[CH2:59]C(Cl)=O>C(#N)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:32])[CH:20]4[NH:24][C:25](=[O:27])[CH2:59][C:55]4[S:54][CH:58]=[CH:57][CH:56]=4)[C:17]=3[C:33]([O:35][CH:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:34])=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)OC(C)(C)C)C4SC3)s2)cc1
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)Cc5cccs5)C4SC3)s2)cc1

Procedure:
On treating 3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.4 g) with methanesulphonic acid (3.4 cc) in acetonitrile (15 cc), in accordance with the working method described in Example 15, crude 7-amino-3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.9 g) is obtained, and this is acylated with (thien-2-yl)-acetyl chloride (0.62 cc) in accordance with the working method described in Example 1. The crude product obtained is purified by crystallisation from acetonitrile (200 cc). 3-[2-(4-Acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-8-oxo-7-[(thien-2-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.33 g) is obtained in the form of a beige crystalline powder.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:24][CH:23]=1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 32.7 %

Procedure:
Following the procedure of Example 3, step 4, 0.202 g (1.08 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydro benz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.164 g (1.19 mmol) of anhydrous potassium carbonate and 0.183 g (1.14 mmol) of 4-chlorobenzyl chloride. Chromatography on flash silica, eluting with 30% ethyl acetate/petroleum ether, gave 0.110 g (33%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 257°-259° C. NMR δ(D2O/CD3CN) 1.51 (1H, m), 1.65 (1H, m), 1.78-1.82 (2H, m), 2.59-2.67 (2H, m), 2.80-2.89 (3H, m), 3.13 (1H, t of d), 3.41 (1H, m), 3.60 (1H, m), 4.29 (2H, d, J=3.7 Hz), 7.14-7.20 (3H, m), 7.25-7.28 (1H, m), 7.52 (4H, m). m/z (CI+, NH3) 312 (M+H)+, 186 (M-CH2C6H4Cl) +, 125. Analysis calcd. for C20H23Cl2N: C, 68.97; H, 6.66; N, 4.02%. Found: C, 68.59; H, 6.63; N, 3.98%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH:10](O)=O>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][CH:10]=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CO
Product: Brc1cnc2nc[nH]c2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of 2,3-diamino-5-bromopyridine (3.0 g, 16.00 mmol) in formic acid (30 mL) was heated to reflux for 3 hours. After cooling the reaction mixture to room temperature it was concentrated and the residue was taken into 50% ethyl acetate in toluene (100 mL) then concentrated and the process repeated once more to remove excess formic acid. The resulting solid was triturated with ethyl acetate and the solid residue collected by filtration to give 6-bromo-1H-imidazo[4,5-b]pyridine (3.7 g, 95%). GCMS (EI) for C6H4BrN3: 198 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH2:16]([S:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Br)=[CH:29][CH:30]=[N:31]2)=[CH:26][N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH2:16]([S:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=3[O:2][CH3:1])=[CH:29][CH:30]=[N:31]2)=[CH:26][N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1ccnc2cc(SCc3ccccc3)ncc12
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(SCc3ccccc3)ncc12
Temperature: 110 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A screw capped vial was charged with 2-methoxy-4-(trifluoromethyl)phenyl boronic acid (0.096 g, 0.438 mmol), 7-(benzylthio)-4-bromo-1,6-naphthyridine (0.145 g, 0.438 mmol), and potassium phosphate tribasic (0.279 ml, 1.313 mmol). Dioxane (1.756 ml) and water (0.585 ml) were added and the vial was purged with argon, followed by addition of Pd(AmPhos)2Cl2 (0.019 g, 0.026 mmol). The vial was capped and heated to 110° C. After 3 hours, the reaction was cooled to room temperature, diluted with water (30 mL), and washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were collected and the solvent was removed under reduced pressure to provide 0.129 g of 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine as an off white solid. m/z (ESI) 427.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([CH3:17])[C:8]=2[CH3:18])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.[CH3:24][C:25]([CH3:27])=O.CC(C)([O-])C.[K+]>CS(C)=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:17][C:9]1[C:8]([CH3:18])=[C:7]([O:6][C:5]2[C:4]([N+:21]([O-:23])=[O:22])=[C:3]3[C:2](=[CH:20][CH:19]=2)[NH:1][C:25]([CH3:27])=[CH:24]3)[CH:12]=[CH:11][C:10]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(C)=O
Reactant: Cc1c(CC(=O)O)ccc(Oc2ccc(N)cc2[N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere, 2-(4-(4-amino-2-nitrophenoxy)-2,3-dimethylphenyl)acetic acid (0.723 g, 2.29 mmol) was dissolved in DMSO (18 mL) and acetone (0.503 mL, 6.86 mmol) was added. The reaction was treated with potassium tert-butoxide (0.770 g, 6.86 mmol) and allowed to stir at room temperature for 1.5 h. The reaction was diluted with water and citric acid was added to pH 4. The mixture was extracted with ethyl acetate. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 9% methanol in dichloromethane, afforded the title compound. LC-MS ESI (neg.) m/z: 353.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][OH:19])=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboximidamide (10.0 mg, 0.0218 mmol) was stirred in MeOH (500 μL) and hydrogen chloride in 1,4-dioxane (500 μL, 4.0 M) was added. The mixture was stirred for 30 min at rt. Purification by preparative LCMS gave the desired product (2.8 mg, 42%). 1H NMR (400 MHz, d6-DMSO): δ□ 11.00 (s, 1H), 8.99 (s, 1H), 7.09 (m, 1H), 6.82 (m, 1H), 6.53 (m, 1H), 5.92 (s, 1H), 4.95 (s, 1H). MF=C10H8ClFN4O2S; LCMS calculated for C10H9ClFN4O2S (M+H)+: m/z=303.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN=[N+]=[N-])S(=O)(=O)O
Yield: 95 %

Procedure:
Methyl 4-bromo-2-sulfo-butyrate (1.07 g, 4.11 mmol) and sodium azide (0.70 g (10.7 mmol) in DMF (50 ml) was stirred overnight. The mixture was evaporated and purified by SiO2 chromatography and eluted with CH3OH/CH2Cl2/HAc and crystallized with CH3OH/Toluene/Hexane to afford 1.00 g (95%) of the title compound. m.p=267-272° C. (decomp). 1H NMR (DMF-d7): 12.06 (br, 1H), 3.65 (s, 3H), 3.59 (dd, 1H, J=5.4, 8.9 Hz), 3.47 (m, 2H), 2.24 (m, 2H). 13C NMR 171.10, 64.29, 52.24, 50.64, 21.35. ESI MS m/z+267.9 (M+2Na−H), m/z−222.0 (M−H). HRMS m/z−(C5H9N3O5S−H) calcd 222.0185, found 222.0179.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)c(-c2cccnc2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
5,6-Dimethyl-3-hydroxy-[2,3′]bipyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.80 g), and 4-dimethylaminopyridine (732 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 140° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (811 mg, yield 88%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:61])([CH3:60])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([N:37]2[CH2:43][CH:42]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)[CH:17]=1>CN(C=O)C.O>[CH3:59][Si:56]([CH3:58])([CH3:57])[CH2:55][CH2:54][O:53][CH2:52][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:60])[CH3:61])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([N:37]2[CH2:38][CH:39]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:42]([CH2:41][CH2:40]3)[CH2:43]2)[C:17]=1[Br:8]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NBS (64 mg, 0.36 mmol) was added to a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (249 mg, 0.33 mmol) in DMF (6 mL). After stirring at room temperature for 1 h, the mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.66 Min (5 min run, UV254nm). Mass calculated for M+H 836.3, observed m/z 836.06 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.[F:23][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C1COCC1.CC#N>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[C:6]([F:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1cc2[nH]c3c(C(N)=O)ccc(Br)c3c2cc1F

Procedure:
A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [SELECTFLUOR®] (0.100 g, 0.554 mmol) in THF (2 mL) and MeCN (2 mL) was heated at 60° C. overnight. The cooled mixture was filtered and the filtrate was concentrated. The residue was purified using reverse-phase preparative HPLC to give ethyl 5-bromo-8-carbamoyl-3-fluoro-9H-carbazole-2-carboxylate as a tan solid (0.035 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=2)[CH:24]=[N:23]1>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:28]3[CH:29]=[C:30]4[C:25]([CH:24]=[N:23][N:22]4[CH3:21])=[CH:26][CH:27]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: Cn1ncc2ccc(B(O)O)cc21
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccc3cnn(C)c3c2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (35 mg, 0.119 mmol) and 1-methyl-1H-indazol-6-ylboronic acid (23 mg, 0.131 mmol), (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-indazol-6-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.30 was isolated, following column chromatography.
Reaction SMILES: [F:1][C:2]1[C:25]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]2)=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1>[Ni].C(O)C.O1CCCC1>[F:1][C:2]1[C:25]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]2)=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCCN(c2cc3[nH]c(-c4cccc5c4-c4ccccc4C5=NO)nc3cc2F)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCCN(c2cc3[nH]c(-c4cccc5c4-c4ccccc4C5N)nc3cc2F)CC1
Yield: 76.1 %

Procedure:
The procedure used in Example 6 is followed, starting from 950 mg of 4-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 135 mg of Raney nickel in 20 ml of ethanol and 20 ml of tetrahydrofuran for 16 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, concentration to dryness under reduced pressure, and then purification by formation of a paste with diisopropyl ether, in this way we obtain 700 mg of 4-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-9H-fluoren-9(R,S)-ylamine, in the form of an orange powder which is used as it is in the following stage.
Reaction SMILES: [C:1]([S:5](/[N:7]=[C:8](/[C:10]1[N:11]=[N:12][N:13]([C:15]2[CH:16]=[C:17]([CH:30]=[C:31]([N:33]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36])[CH:32]=2)[C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH:14]=1)\[CH3:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH2:45]([Li])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:1]([S:5]([NH:7][C:8]([C:10]1[N:11]=[N:12][N:13]([C:15]2[CH:16]=[C:17]([CH:30]=[C:31]([N:33]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:34][CH2:35][CH3:36])[CH:32]=2)[C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH:14]=1)([CH3:9])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(/C(C)=N/S(=O)C(C)(C)C)nn2)c1)S(C)(=O)=O
Reactant: [Li]Cc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)(Cc3ccccc3)NS(=O)C(C)(C)C)nn2)c1)S(C)(=O)=O
Reaction time: 1 h
Yield: 23.4 %

Procedure:
To a 0° C. suspension of 0.03 g (0.05 mmol) 3-{4-[(1E)-N-(tert-butylsulfinyl)ethanimidoyl]-1H-1,2,3-triazol-1-yl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 5 mL toluene was added 0.1 mL (0.2 mmol, 2M solution in toluene) trimethylaluminum followed by 1 mL (approx. 0.2 mmol, 0.2 mM solution in ether) benzyllithium. The reaction mixture was stirred for 1 hr, then 0.4 mL more benzyllithium was added and the reaction mixture stirred for another hour at 0° C. The reaction was quenched by addition of 1 mL of saturated sodium sulfate solution and 50 mL EtOAc and stirred vigorously. To this was added MgSO4 and the resulting mixture was filtered through celite and concentrated. Purification by flash chromatography (1×8 cm silica gel, linear gradient 30-100% EtOAc/hexanes) afforded 8 mg 3-(4-{1-[(tert-butylsulfinyl)amino]-1-methyl-2-phenylethyl}-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide which was dissolved in 1 mL methanol. To this was added 0.7 mL 2M HCl in ether. After 30 minutes the mixture was concentrated and purified by preparative HPLC (5->95% CH3CN/H2O over 30 min, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford 3 mg 3-[4-(1-amino-1-methyl-2-phenylethyl)-1H-1,2,3-triazol-1-yl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide as its trifluoroacetate salt. 1H NMR (CD3OD, 500 MHz) δ 8.55 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.99 (m, 1H), 7.42 (m, 2H), 7.26 (m, 3H), 7.07 (m, 2H), 7.00 (m, 2H), 5.25 (m, 1H), 3.77 (t, J=6.83 Hz, 2H), 3.47 (d, J=13 Hz, 1H), 3.27 (d, J=13 Hz, 1H), 3.01 (s, 3H), 1.76 (s, 3H), 1.59 (d, J=7.18 Hz, 3H), 1.53 (m, 2H), 0.95 (t, J=7.33 Hz, 3H). High resolution mass spec (FT/ICR) calc M+H=579.2548 found 578.2560.