Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:37]=[CH:36][C:22]([C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)Cl.[Cu]I>[O:17]=[C:9]1[N:8]([C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:35]=3[N:34]=[CH:33][CH:32]=[CH:31]4)=[O:24])=[CH:21][CH:20]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10]1
Reactant: O=C1NC(c2ccccc2)C2(CCCCC2)O1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2cccnc12)c1ccc(N2C(=O)OC3(CCCCC3)C2c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 11 %

Procedure:
To a 50 mL dried round bottom flask containing a degassed solution of 4-phenyl-1-oxa-3-azaspiro[4.5]decan-2-one (1 eq., 1.73 mmol) and 4-iodo-N-(quinolin-8-yl)benzamide (1.2 eq.) in DMF (15 mL), potassium carbonate (2.5 eq.) and trans (N,N)-dimethyl cyclohexanediamine (0.5 eq.), was added CuI (0.1 eq). The resulting mixture was then stirred at 120° C. for 15 hours. Reaction progress was monitored by TLC (TLC eluent: 10% MeOH in DCM). The reaction mixture was cooled and poured into crushed ice (5 g). The solid thus obtained was filtered, washed with water (25 mL) and dissolved in DCM. The DCM solution was then washed with water (100 mL), brine (50 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography using silica gel and DCM as eluting solvent to yield (R+S) 4-(2-oxo-4-phenyl-1-oxa-3-azaspiro[4.5]decan-3-yl)-N-(quinolin-8-yl)benzamide (90 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.46 (s, 1H), 8.95 (dd, J=4.4, 1.6 Hz, 1H), 8.66 (d, J=6.4 Hz, 1H), 8.44 (dd, J=8.4, 1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.75-7.72 (m, 3H), 7.68-7.61 (m, 3H), 7.32-7.39 (m, 4H), 5.52 (s, 1H), 2.08-2.11 (m, 1H), 1.83-1.89 (m, 1H), 1.74-1.53 (m, 3H), 1.35-1.42 (m, 2H), 1.20-1.23 (m, 3H). m/z (ESI) 478.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:24](O)=[O:25])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl.O>[C:28]([NH:31][C:24]([C:21]1[C:19]2=[N:20][C:15]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:12])[F:14])[CH:6]=4)[N:2]([CH3:1])[N:3]=3)=[CH:16][N:17]=[C:18]2[NH:23][CH:22]=1)=[O:25])([CH3:30])([CH3:29])[CH3:27]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.4 %

Procedure:
A mixture of 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (100 mg, 0.28 mmol), 2-methylpropan-2-amine (20 mg, 0.28 mmol), HOBt (149 mg, 1.12 mmol), EDCI (211 mg, 1.12 mmol) and triethylamine (133 mg, 1.12 mmol) in dichloromethane (15 mL) was stirred at room temperature for 15 hours, then water (30 mL) was added, product extracted with dichloromethane (3×30 mL), the combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/ethyl acetate=10:1) to give N-tert-butyl-2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (18 mg, 15.6%) as an orange solid. LCMS: (M+H)+=417; 1H NMR (300 MHz, DMSO): δ 12.89 (s, 1H), 9.06 (s, 1H), 8.71 (s, 1H), 8.44 (s, 1H), 8.05 (d, 1H, J=9.0 Hz), 7.93 (s, 1H), 7.84 (d, 1H, J=9.0 Hz), 4.28 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]([NH:23]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:7]=1>CO.O1CCCC1.[H][H].[C].[Pd]>[CH3:1][O:2][C:3](=[O:34])[CH:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(N)Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1

Procedure:
4.09 g of 2-{([(benzyloxy)carbonyl]amino}-3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxyphenyl)-2-propenoic acid methyl ester was dissolved in 50 ml of methanol and 20 ml of tetrahydrofuran. 0.41 g of 10% palladium carbon was added, followed by stirring for 64 hours at room temperature in hydrogen atmosphere. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was evaporated, to give 2.92 g of (2-amino)-3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxyphenyl)propionic acid methyl ester as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C1CCCCC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1N
Temperature: 70 °C
Yield: 86.9 %

Procedure:
3-Nitro-2-(Boc-piperazine)pyridine 6 (1.765 g, 5.72 mmol) was dissolved in methanol (15 mL) at room temperature. Then Pd(OH)2 (1.234 g) and cyclohexene (2.0 mL, 19.52 mmol) were added. The resulting mixture was heated at 70° C. for 2 h. The mixture was concentrated to remove the solvent. DCM was added and then it was filtered through a pad of silica gel, washed with DCM and 10% MeOH/DCM. The collected solution was concentrated and dried under high vacuum to afford a slight pink solid as the product (1.384 g, 87% yield). 1H-NMR (CDCl3): 7.794 (dd, J=5.0 Hz and 1.5 Hz, 1H, Ar—H), 6.956 (dd, J=7.5 Hz and 1.5 Hz, 1H, Ar—H), 6.854 (dd, J=7.5 Hz and 5.0 Hz, 1H, Ar—H), 3.783 (br, 2H, NH2), 3.571 (t, J=4.5-5.0 Hz, 4H, 2 CH2), 3.059 (t, J=4.5-5.0 Hz, 4H, 2 CH2), 1.482 (s, 9H, 3 CH3). LC-MS: 279.2 (MH+). (ref. Romero D. L. et al. J. Med. Chem. 37, 999-1014, 1994.)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)(=[O:12])[CH3:11]
Reactant: O=C(O)C1CCCNC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCCC(C(=O)O)C1
Yield: 97.4 %

Procedure:
Nipecotic acid (3.87 grams) (30.0 mmoles) was reacted with acetic anhydride (9.17 grams) (90 mmoles) as described in Preparative Example 13A to give the title compound (Yield: 5.0 grams, 97%, MH+ 172).
Reaction SMILES: C(OC([C:6]1[C:7](=[O:24])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=O)C.[OH-].[K+].Cl>>[F:23][C:19]1[CH:18]=[C:17]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][N:10]=3)[C:15]([OH:16])=[CH:6][C:7]2=[O:24])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(O)c2cccnc2n(-c2cccc(F)c2)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=c1cc(O)c2cccnc2n1-c1cccc(F)c1
Yield: 6.9 %

Procedure:
To 3-ethoxycarbonyl-1-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2 (1H)-one (328 mg, 11.0 mmol) was added an aqueous solution (7 ml) of potassium hydroxide (560 mg, 10.0 mmol), and the mixture was heated under reflux overnight, acidified to pH1 with conc. hydrochloric acid, refluxed for 1 hour, filtered off to give precipitates which were washed with water and dried to afford 1-(3-fluorophenyl)-4-hydroxy-1,8-naphthyridin-2 (1H)-one (194.5 mg, 76%) as crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([OH:5])=O.O=S(Cl)Cl.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][CH:2]1[C:3](=[O:5])[C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[CH2:6]1)[CH:13]=[CH:12][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10]3
Reactant: CC(Cc1ccc2ccc(-c3ccccc3)cc2c1)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1Cc2ccc3ccc(-c4ccccc4)cc3c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-3-(7-phenyl-2-naphthyl)propanoic acid (6.25 g, 21.5 mmole) was suspended in CH2Cl2 (20 ml), and SOCl2 (2.9 ml, 40 mmole) and 0.05 ml of DMF were added. The resulting mixture was stirred for 2 h at room temperature, refluxed for additional 1 h, evaporated and dried in vacuo. AlCl3 (4.3 g, 33 mmol) was suspended in CH2Cl2 (40 ml), and solution of obtained chloroanhydride in CH2Cl2 (20 ml) was added at 0° C. within 0.5 h. The resulting mixture was allowed to warm to room temperature, stirred for additional 2 h, and poured into ice/HCl (˜200 g+40 ml). The resulting mixture was extracted by CH2Cl2 (4×50 ml). Combined organic phase was washed by aq. KHCO3, dried over MgSO4, evaporated and dried in vacuo giving practically pure solid product. The yield 5.45 g (92%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][OH:6]
Reactant: Cc1c(Cl)cccc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of 1.70 g of 3-chloro-2-methylbenzoic acid in 20 mL of THF was added dropwise 20 mL of a borane/THF complex under ice-cooling, followed by stirring at room temperature for 2 hours. After completion of the reaction, 1 N hydrochloric acid was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.52 g (yield 97%) of a title compound as a white crystal.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[C:19]([O:20][CH2:21][C@@H:22]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15].Cl.O1CCOCC1>CO>[NH2:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:21][O:20][C:19]1[C:3]([CH:2]([F:1])[F:35])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(C(F)F)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-(difluoromethyl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (500 mg, 0.480 mmol) in MeOH (10 mL) at 0° C. was added 4N HCl in 1,4-dioxane (20 mL, 80 mmol). The solution was warmed to room temperature and stirred for 2 h. The mixture was then was concentrated under reduced pressure. The residue was taken up in EtOAc and the EtOAc layer was washed with saturated aqueous NaHCO3 then H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep. HPLC to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-(difluoromethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (60 mg, 0.149 mmol, 31% yield) as pale yellow solid. LC/MS (ESI) m/e 390.2 [(M+H)+, calcd for C21H26F2N3O2, 390.2]; LC/MS retention time (method A): tR=2.09 min; HPLC retention time (method A): tR=10.1 min; HPLC retention time (method B): tR=9.18 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.73 (s, 1H), 8.66 (s, 2H), 7.07-7.41 (m, 2H), 4.66-4.53 (m, 1H), 4.52-4.49 (m, 1H), 3.78-3.89 (m, 4H), 3.22 (s, 3H), 1.74-1.88 (m, 2H), 1.63-1.71 (m, 1H), 1.04 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[N:13]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: c1cnc2nn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1-n1nnc2ncccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
4-Chloro-2-fluoro-1-nitrobenzene (25 g, 142 mmol) and 1H-[1,2,3]triazolo[4,5-b]pyridine (18.8 g, 157 mmol) were slurried in DMF (50 mL) in a 200 mL round-bottom flask fitted with a magnetic stir bar. Potassium carbonate (29.5 g, 214 mmol) was added to the mixture and it was then heates while stirring in a 60°C. oil bath under N2. LCMS analysis after two hours indicated complete consumption of the nitrobenzene and two different isomeric forms of the desired product. Water (250 mL) was subsequently added in a steady stream to the rapidly stirring mixture to precipitate the crude product. The resultant precipitate was collected by vacuum filtration and washed twice with 100 mL water. The resultant damp filter was slurried with 50 mL toluene and the solids collected by vacuum filtration. This action was repeated three additional times and then the resultant solid was dried in vacuo to afford 21.6 g (55% yield) 1-(5-chloro-2-nitrophenyl)-1 H-[1,2,3]triazolo[4,5-b]pyridine as an off-white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[N:66]1([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][N:74]=2)[CH2:71][CH2:70][CH:69]([NH2:72])[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:72][CH:69]5[CH2:70][CH2:71][N:66]([C:73]6[CH:78]=[CH:77][CH:76]=[CH:75][N:74]=6)[CH2:67][CH2:68]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(c3ccccn3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.021 g (0.12 mmole) 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.046 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-benzamide (I-108) as a white solid.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[NH:9][N:8]=1.Br.Br[CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:23]([N:22]([CH2:25][CH3:26])[CH2:21][CH2:20][CH2:19][NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[NH:9][N:8]=1)[CH3:24]
Reactant: CCN(CC)CCCBr
Reactant: Nc1n[nH]c2ccc(I)cc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1n[nH]c2ccc(I)cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
To 80 ml of anhydrous N,N-dimethylformamide were added 9.7 g of 3-amino-5-iodoindazole as prepared in accordance with the method described in C. E. Kwartler et el., J. Am. Chem. Soc., 65 1804(1943), 8.3 g of 3-bromopropyldiethylamine hydrobromide and 8.3 g of anhydrous potassium carbonate. The mixture was stirred for 24 hours at 80° C. and condensed under reduced pressure. The condensed residue was added with 100 ml of chloroform and 50 ml of water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 7.15 g of 3-(3-diethylaminopropylamino)-5-iodoindazole having the following analytical values in a yield of 51%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:18][C:9]2=[N:10][C:11]([Br:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[N:18]([C@H:35]([CH3:37])[CH2:36][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:9]2=[N:10][C:11]([Br:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(OCC)c(Br)nc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCC)c(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate j) from 6-bromo-5-ethoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(C1Cc2ccc(OCCCBr)cc21)N1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCCCOc1ccc2c(c1)C(C(=O)N1CCCCC1)C2

Procedure:
Sodium azide (2.4 g) is added to a stirred solution of 5-(3-bromopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (12.8 g) in ethanol/water (13 ml/130 ml). The reaction mixture is refluxed overnight, poured into water, washed with methylene chloride and the organic extract washed, dried, filtered and evaporated in vacuo affording the desired azide product as an oil, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH:9]([OH:11])[CH2:10][CH:3]1[CH:4]1[CH:6]2[O:5]1.C[O:13][C:14](=O)[C:15]([OH:26])([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.[H-].[Na+].O>ClCCl>[CH3:1][N:2]1[CH:7]2[CH2:8][CH:9]([O:11][C:14](=[O:13])[C:15]([OH:26])([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH:3]1[CH:4]1[CH:6]2[O:5]1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN1C2CC(O)CC1C1OC12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1C2CC(OC(=O)C(O)(c3cccs3)c3cccs3)CC1C1OC12
Temperature: 70 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
The product of step (b) (2.00 g, 12.9 mmol) and the product of step (a) (3.61 g, 14.2 mmol) were melted together at 70° C., under a vacuum of 210 Torr for 1 h. Sodium hydride (60% suspension in oil, 620 mg, 15.5 mmol) was added and the reaction mixture was stirred at 70° C. under 210 Torr for 3 h. The reaction mixture was allowed to cool to ambient temperature and then water (30 mL) and dichloromethane (30 mL) were added. The organic layer was separated and washed with water (2×20 mL), dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography (5% MeOH/DCM) to give the title compound as a solid (2.03 g, 5.4 mmol, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: O=C1CC(c2ccncc2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2ccncc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 6-bromo-2-(pyridin-4-yl)chroman-4-one (1 g, 3.3 mmol) in anhydrous DCM (25 mL) was added TiCl4 (1 M solution in DCM, 6.6 mL, 6.6 mmol) dropwise within 15 min at room temperature. After the addition, the reaction mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (1.35 g, 7.26 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-2-(pyridin-4-yl)chroman-4-ylidene)cyanamide (1 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:3](=[O:4])[CH2:2][Cl:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccccc1
Product: O=C(CCl)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of chloroacetyl chloride (11.4 mL) was added drop-wise over 1 hour to a stirred solution of benzylamine (15 mL) and TEA (23 mL) in dry TFP (200 mL) previously cooled at 0–3° C. under a Nitrogen atmosphere. The dark suspension was allowed to warm gradually to r.t. and then stirred at r.t. for 3 hours. The inorganic salts were filtered and washed with AcOEt (300 mL). The filtrate was washed with 2N hydrochloric acid solution (2×250 mL), sodium hydrogen carbonate (2×200 mL) and water (200 mL). The organic layer was dried and concentrated in vacuo to give a dark solid, which was crystallized from Et2O/CH (1:1, 700 mL) to give N-benzyl-2-chloroacetamide (17.8 g) as a grey solid (T.l.c.: AcOEt 100%, Rf=0.47).