Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28]([O:30]CC)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7].[Li+].[OH-]>CCO.C1COCC1>[Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28]([OH:30])=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)OCC)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of ethyl 7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-2-naphthoate (Example 16, 84 mg, 0.10 mmol) in EtOH (0.5 mL) and THF (0.5 mL) was added 2N LiOH (0.5 mL, 1.03 mmol). The reaction mixture was stirred for 2 h at 40° C., concentrated to remove volatiles, diluted with water and quenched with 1N HCl. The solution was concentrated in vacuo and purified by preparative HPLC to afford the title compound (57 mg, 68%) as a white solid. 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.41 (s, 1H), 8.36 (s, 1H), 8.07 (t, J=7.3 Hz, 2H), 7.99 (d, J=1.3 Hz, 1H), 7.88 (s, 2H), 7.79 (d, J=8.8 Hz, 1H), 7.55-7.51 (m, 1H), 7.20-7.07 (m, 3.5H), 6.97 (d, J=7.5 Hz, 0.5H), 4.10 (br s, 6H), 2.97 (br s, 1.5H), 2.74 (br s, 1.5H), 2.19 (s, 2H), 2.14 (s, 1H), 1.38 (br s, 1H), 1.29-1.12 (m, 6H), 1.01-0.91 (m, 2H), 0.88-0.82 (m, 3H), 0.68-0.61 (m, 3H); MS(ESI+) m/z 784.2 (M+H)+.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])(C)(C)C.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[OH2:36]>CN1CCCC1=O>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:6]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[N:33]4[CH2:34][CH2:35][CH:30]([OH:36])[CH2:31][CH2:32]4)(=[O:21])=[O:20])=[CH:17][C:11]=3[N:10]=2)=[O:7])[CH2:32][CH2:31]1
Reactant: O
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2cc(OS(=O)(=O)c3ccccc3N3CCC(O)CC3)ccc2[nH]1)N1CCC(O)CC1

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester (200 mg, example 55 (Step 3) and 4-hydroxypiperidine (554 mg) in N-methylpyrrolidinone (6 ml) was heated at 110° C. for 24 hours. The reaction mixture was then poured into water (120 ml) and extracted three times with ethyl acetate (50 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95 C: 5, v/v) to give (4-hydroxy-piperidin-1-yl)-benzenesulfonic acid 2-[(4-hydroxy-piperidine-1-carbonyl)-amino]-1H-benzoimidazol-5-yl ester (125 mg) as a beige solid. Mass Spectrum: 516 [M+H]+, retention time=6.51 minutes.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.N1C=CC(NC(=O)C(C)=C)=CC=1>>[CH3:12][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc2cnccc2nc1O
Agent: C=C(C)C(=O)Nc1ccncc1
Agent: Cc1cc2cnccc2[nH]c1=O
Product: CC1Cc2cnccc2NC1=O

Procedure:
2-Hydroxy-3-methyl-1,6-naphthyridine, the tautomeric form of 3-methyl-1,6-naphthyridin-2(1H)-one, was reportedly prepared by Ogata et al. [Chem. Pharm. Bull. 20, 2264 (1972)] in two steps by first photocylization of N-(4-pyridinyl)methacrylamide to produce 1,2,3,4-tetrahydro-3-methyl-2-oxo-1,6-naphthyridine and then dehydrogenating said tetrahydro compound by heating it in acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[O:19]1[C:23](B(O)O)=[CH:22][C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:20]2[O:19][C:23]3=[CH:22][CH:21]=[CH:27][C:28]3=[CH:29][CH:30]=2)[C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3cccc-3o2)c1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and benzo[b]furan-2-boronic acid according to the general procedure B. Obtained as an orange solid (711 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([N:15]([CH3:23])[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.C(OC(=O)[NH:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)(C)(C)C.Cl>CS(C)=O>[NH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:5]2[CH:4]=[C:3]([C:9]3[N:14]=[C:13]([N:15]([CH3:23])[CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=[N:11][CH:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reactant: CN(CC1CCOCC1)c1cncc(-c2cc(F)ncc2Cl)n1
Agent: Cl
Solvent: CS(C)=O
Product: CN(CC1CCOCC1)c1cncc(-c2cc(N[C@H]3CC[C@H](CN)CC3)ncc2Cl)n1
Temperature: 102.5 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (15 mg, 0.045 mmol), DMSO (0.4 ml), and tert-butyl(trans-4-aminocyclohexyl)methylcarbamate (92 mg, 0.401 mmol) was stirred at 100-105° C. for 18 hours, and the reaction progress was followed by LCMS. To the crude intermediate was added 6 M aq.HCl (120 μl, 0.720 mmol) and heated at 80° C. for 40 minutes, and the reaction progress was followed by LCMS. The reaction mixture was let cool, added 0.5 ml of DMSO, filtered and purified by prep LC. After lypohilization, 15.6 mg of the title compound, as a TFA salt was obtained. LCMS (m/z): 445.2 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.12-1.47 (m, 6H) 1.59 (d, J=12.60 Hz, 2H) 1.67 (ddd, J=7.18, 3.81, 3.66 Hz, 1H) 1.92 (d, J=12.31 Hz, 2H) 2.01-2.11 (m, 1H) 2.16 (d, J=11.43 Hz, 2H) 2.83 (d, J=7.03 Hz, 2H) 3.17 (s, 3H) 3.33-3.45 (m, 2H) 3.56 (d, J=7.33 Hz, 2H) 3.60-3.72 (m, 1H) 3.93 (dd, J=11.14, 2.93 Hz, 2H) 6.92 (s, 1H) 8.02 (d, J=2.64 Hz, 2H) 8.11 (s, 1H).
Reaction SMILES: C([Cl:4])(=O)C.O[N:6]=[C:7]([C:13](=[O:17])[CH:14]1[CH2:16][CH2:15]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C.[Pt]>[ClH:4].[NH2:6][CH:7]([C:13](=[O:17])[CH:14]1[CH2:16][CH2:15]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(=NO)C(=O)C1CC1
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)C1CC1
Product: Cl
Reaction time: 5 h
Yield: 64.7 %

Procedure:
Acetyl chloride (15.35 ml, 16.88 g) was added to a cooled solution of ethyl α-(hydroxyimino)-β-oxocyclopropanepropanoate (20 g) in absolute ethanol (250 ml) before being added to a suspension of 5% platinum on carbon (1.85 g) in absolute ethanol (150 ml). The stirred mixture was then hydrogenated at room temperature and pressure for 5 h. The catalyst was filtered off through a pad of hyflo and the filtrate concentrated in vacuo to give, after azeotroping with toluene (2×80 ml), an off-white solid. This was triturated with ether (500 ml) to give the title compound (14.5 g) as a white solid. m.p. 196°-197° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:9][CH3:10])[C:5]([F:8])=[N:6][CH:7]=1.[CH2:11]([CH2:14][O:15]C)OC.B(F)(F)F.CC[O:23]CC.C(ON=O)(C)(C)C>CCCCC.C(Cl)Cl>[C:14]([O:15][C:2]1[CH:3]=[C:4]([CH2:9][CH3:10])[C:5]([F:8])=[N:6][CH:7]=1)(=[O:23])[CH3:11]
Reactant: CCOCC
Reactant: CCc1cc(N)cnc1F
Reactant: COCCOC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCCCC
Product: CCc1cc(OC(C)=O)cnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a stirred solution of the 5-amino-3-ethyl-2-fluoropyridine from Step 126d above (2.30 g, 16.4 mmol) in 3:1 dimethoxyethane:CH2Cl2 (50 mL) at −10° C. was slowly added borontrifluoride etherate (Aldrich, 4.23 mL, 34.5 mmol). t-Butylnitrite (Aldrich, 2.34 mL, 19.7 mmol) was added over the course of 15 min., keeping the reaction temperature below −5° C. The reaction mixture was warmed to 0° C. and stirred for 30 minutes. Pentane (500 mL) was added and the solid tetrafluoroborate diazonium salt was collected by filtration. The diazonium salt was dissolved in acetic anhydride (40 mL) and heated at 95° C. for 2 h (N2 evolution was noted at 85° C.). The solvent was evaporated, the residue was dissolved in Et2O (250 mL), and washed with saturated aqueous NaHCO3 (2×150 mL). The combined aqueous phases were extracted with Et2O (2×150 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the title compound as a yellow oil (2.22 g, 74%): 1H NMR (CDCl3, 300 MHz) δ1.26 (t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.67 (q, J=7.0 Hz, 2H), 7.35 (dd, J=2.5, 8.0 Hz, 1H), 7.84 (m, 1H); MS (CI/NH3) m/z 184 (M+H)+, 201 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:3]1[C:2]([CH3:1])=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=[N:4]1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])cnn1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (4.01 g, 31.6 mmol) in DMF (60 mL) were added CH3I (8.93 g, 63.0 mmol) and K2CO3 (8.73 g, 63.2 mmol). The reaction mixture was stirred at 60° C. in a sealed tube overnight and concentrated in vacuo. The residue was diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a beige solid (1.01 g, 22.7%).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[N:17]=[CH:18][N:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][N:22]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=[N:12]2)=[CH:7][CH:6]=1>O.C1COCC1.CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[N:17]=[CH:18][N:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A solution of lithium hydroxide monohydrate (62 mg, 1.46 mmol) in water (2.8 mL) was added dropwise to a suspension of methyl 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinate (277 mg, 0.732 mmol) in THF (4.8 mL) and methanol (1 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (245 mg, 92%) as a light brown solid. MS: m/e=363.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([Br:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:20][CH3:21])=[CH:9][CH:10]=2)[N:5]=[C:4]([Br:13])[CH:3]=1
Reactant: Oc1ccc2c(Cl)cc(Br)nc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc2c(Cl)cc(Br)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
4-Chloro(bromo)-7-hydroxyquinoline (200 mg) dissolved in N,N-dimethylformamide (DMF; 30 ml) was added with potassium carbonate (203 mg) and ethyl iodide (232 mg) and stirred at room temperature for 8 hours. The reaction mixture was added with water (50 ml) and methylene chloride (30 ml) and shaken to separate the organic layer. Further, the water layer was extracted three times with methylene chloride (30 ml). This extract solution was combined with the above-mentioned organic layer, washed with saturated saline solution and dried over magnesium sulfate. This extract solution was detected by thin-layer chromatography (TLC; MERCK, Art. 5554, methylene chloride : methanol=9 : 1) to find UV (254 nm) absorptive spots at Rf values of 0.7 and 0.4. After drying, the solvent was removed under reduced pressure from the extract solution. The residue was chromatographed by silica gel column chromatography (Wako Gel™ C-200, methylene chloride : methanol=9 : 1). Fractions corresponding to Rf value of 0.7 were collected and evaporated to obtain the aimed 4-chloro(bromo)-7-ethoxy-quinoline (185 mg). MS m/z: 207 (M+, 4-Cl derivative) and 251(M+, 4-Br derivative)
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13]C(=O)C(C)(C)C.C(O)C.[ClH:24]>O>[Cl-:24].[OH:1][C@H:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH3+:13]
Reactant: COc1ccc(NC(=O)C(C)(C)C)c(CCC(C)O)c1
Reactant: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc([NH3+])c(CC[C@@H](C)O)c1
Product: [Cl-]
Yield: 68 %

Procedure:
A mixture of the the product from Step B (7.31 g, 2.29 mmol), ethanol (100 mL), concentrated HCl (50 mL) and water (30 mL) was heated at reflux for three days. The volatile material was removed by evaporation and the residue was dried overnight. The residue was triturated with ethyl acetate, filtered and dried under a vacuum to give an amorphous powder (4.11 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:3]2[C:2]([NH:1][S:22]([CH:19]3[CH2:21][CH2:20]3)(=[O:24])=[O:23])=[CH:7][N:6]([CH3:8])[C:5](=[O:9])[CH:4]=2)=[C:12]([F:18])[CH:13]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cn1cc(N)c(Nc2ccc(Br)cc2F)cc1=O
Product: Cn1cc(NS(=O)(=O)C2CC2)c(Nc2ccc(Br)cc2F)cc1=O

Procedure:
5-Amino-4-(2-fluoro-4-bromophenylamino)-1-methylpyridin-2(1H)-one was reacted with cyclopropanesulfonyl chloride using the same procedure as described in step f of example 1 above, and purified by HPLC.
Reaction SMILES: [H-].[Na+].[F:3][CH:4](P(=O)(OCC)OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:6]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>CCCCC.C1COCC1>[F:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)[CH:6]=1)=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CCOP(=O)(OCC)C(F)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (166 mg, 6.92 mmol) under a N2 atmosphere was washed with n-pentane and dried blowing N2 gas. THF (5 mL) was added and the mixture was cooled to 0° C. Diethyl fluoro(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylphosphonate (940 mg, 2.3 mmol) was added as a solution in THF dropwise and the mixture was stirred for 30 min. tert-Butyl 4-oxopiperidine-1-carboxylate as a solution in THF was added dropwise and the reaction was stirred for 1 h. Excess NaH was quenched with water at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified by column chromatography to give the pure title compound (600 mg). 1H NMR (500 MHz, CDCl3): δ 1.4 (s, 9H), 2.0 (m, 2H), 2.4 (m, 2H), 3.4 (m, 2H), 3.5 (m, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.2 (m, 4H), 7.4 (t, 1H, J=8 Hz), 7.9 (d, 1H, J=8.5 Hz), 8.4 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCI
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (5.00 g, 52.58 mmol) in N,N-dimethylformamide (DMF) (55 mL) was slowly added to a cold (0-5° C.), stirring slurry of sodium hydride (2.52 g of an 80% dispersion in mineral oil, 84.0 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added 1-choro-3-iodopropane (12.90 g, 63.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water was added and the mixture was extracted with chloroform (4×100 mL). The combined chloroform extracts were washed with water (2×50 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation. Water (150 mL) was added, and the mixture was basified with 20% NaOH solution (5.0 mL). The alkaline solution was extracted with methyl t-butyl ether (MTBE) (5×100 mL). The combined MTBE extracts were washed with water (4×100 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 4.90 g (54.3%) of an oil. 1H NMR (CDCl3, 300 MHz): δ 8.34 (s, 1H), 8.24 (s, 1H), 7.22 (t, 2H, J=2.13 Hz), 4.18 (t, 2H, J=5.85 Hz), 3.77 (t, 2H, J=6.19 Hz), 2.27 (p, 2H, J=6.03 Hz). 13C NMR (CDCl3, 75 MHz): δ 154.99, 142.38, 138.07, 123.93, 121.09, 64.60, 41.22, 32.11. EI-MS: m/z (relative intensity) 171 (M+, 27.25%), 136 (4.66%), 95 (100.00%), 78 (17.98%), 41 (37.74%), 39 (34.23%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=2[F:1])=[C:6]([C:14]2[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH:7]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c(F)cc1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c(F)cc1=O
Temperature: 50 °C
Yield: 90.2 %

Procedure:
A mixture of 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one (90 mg, 0.24 mmol), ammonium chloride (26 mg, 0.48 mmol), iron powder (67 mg, 1.2 mmol) suspended in THF (500 μL), water (180 μL) and ethanol (500 μL) was heated to 100° C. using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with heated (50° C.) MeOH (˜10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (20 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, 5-[5-amino-2-(2,4-difluorophenoxyl)phenyl]-4-fluoro-1-methylpyridin-2-one (75 mg, 90%). LCMS (M+H)+=347. The material was carried forward without any further purification.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH3:29][O:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][O:30][CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:22][CH2:21][C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([C:11]3[N:12]4[C:4](=[CH:3][CH:2]=[N:1]4)[N:5]=[C:6]4[C:10]=3[CH2:9][CH2:8][CH2:7]4)=[CH:28][C:17]=2[CH:18]=1
Reactant: COC[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H]1CCCN1CCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 2-(R)-methoxymethylpyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give the desired 8-{2-[2-(2-(R)-Methoxymethyl-pyrrol idin-1-yl)-ethyl]-benzofuran-5-yl}-6,7-dihydro-5H-1,4,8a-triaza-s-indacene.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][NH:22][C:23]2[C:24]([CH3:40])=[N:25][C:26]([N:29]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@@H:35]4[CH3:39])[CH2:30]3)=[CH:27][CH:28]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C>CO.C(Cl)Cl>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:22]([C:23]3[C:24]([CH3:40])=[N:25][C:26]([N:29]4[CH2:33][CH2:32][C@@H:31]([N:34]5[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:39])[CH2:30]4)=[CH:27][CH:28]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=[O:13])([CH3:17])([CH3:16])[CH3:18].[NH3:9]
Reactant: CCOC(=O)C1(CCCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Product: N
Yield: 5 %

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 2 of Example 1, by cyclizing 4-{3-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-propyl}-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (113 mg, 0.20 mmol) to obtain 20 mg (20% yield over two steps) of the title compound after flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][S:15][CH:14](CO)[CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.SC[CH2:22][OH:23].C[O-:25].[Na+]>CO>[OH:23][CH2:22][SH:15]1[CH2:14][CH2:13][O:12][CH:11]([N:8]2[CH:7]=[N:6][C:5]3[C:4](=[O:25])[NH:3][C:2]([NH2:1])=[N:10][C:9]2=3)[CH2:16]1
Reactant: Nc1nc(Cl)c2ncn(C3CSC(CO)CO3)c2n1
Reactant: OCCS
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(ncn2C2C[SH](CO)CCO2)c(=O)[nH]1

Procedure:
2-Amino-6-chloro-9-(5-hydroxymethyl-1,4-oxathian-2-yl)purine (0.03 g) was dissolved in methanol (10 ml), and 2-mercaptoethanol (0.03 ml) and 1M, sodium methoxide solution (0.01 ml) were added thereto. The resultant mixture was stirred under reflux for three days. After concentrating the reaction mixture under reduced pressure, water was added thereto, and the aqueous layer was washed several times with ethyl ether. Acetic acid was added thereto to adjust pH of the aqueous layer to 7, and the solvent was distilled off under reduced pressure. The residue was purified on a silica gel column (eluent: chloroform/methanol=5/1) to obtain the desired product (0.02 g) as pale yellow solid.