Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.NO.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.C1CC[N:33]2[C:28](=NCCC2)[CH2:27]C1.COC(=O)C[Cl:40]>C(Cl)Cl>[Cl:40][CH2:27][C:28]1[N:9]=[C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]2[N:33]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccc(C)c(N)n1
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: NO
Solvent: ClCCl
Product: Cc1ccc(C)n2nc(CCl)nc12
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of 3,6-Dimethyl-2-pyridinamine (2.00 g, 16.4 mmol) in 50 mL of DCM was added dropwise a solution of hydroxylamine-2,4,6-Trimethyl-benzenesulfonate (4.22 g, 19.6 mmol) in 50 mL of CH2Cl2 at 0° C., and the mixture was stirred and allowed to warm to room temperature. The solvents were evaporated and the residue dissolved in 80 mL of MeOH then treated with DBU (3.43 mL, 22.9 mmol) and the solution stirred for 5 mins. After chloroacetic acid methyl ester (1.44 mL, 16.4 mmol) was added, the resultant mixture was stirred at room temperature for 48 h. After being concentrated under reduce pressure, the residue was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=2/1) to give 2.65 g of 2-Chloromethyl-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine in 82% yield. LC-MS (MH+): m/z=195.9, tR (minutes)=1.14
Reaction SMILES: O=[C:2]=[N:3]S(Cl)(=O)=O.[C:8]12([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][N:10]1[CH:19]=[CH:20][CH:21]=[C:9]21.CN(C)C=O>C1COCC1>[C:2]([C:19]1[N:10]2[CH2:11][CH2:12][N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]3([CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23][CH2:22]3)[C:9]2=[CH:21][CH:20]=1)#[N:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)N1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of N-(oxomethylene)sulfamoyl chloride (23.9 μL, 0.27 mmol) in THF (200.0 μL) was slowly added to a solution of 1-tert-butyl 2′-ethyl 3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate (100 mg, 0.27 mmol) in THF (1.0 mL) at −78° C. under nitrogen. The reaction mixture was stirred for 1 hour at −78° C. N,N-dimethylformamide (39.9 μL, 0.51 mmol) was then slowly added to the cold reaction mixture. The reaction mixture was then allowed to slowly warm to room temperature. The reaction was filtered and purified by reverse phase preparatory-LC-MS (10-99% CH3CN/H2O) using HCl modifier to give 1-tert-butyl 2′-ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate. ESI-MS m/z calc. 388.2, found 389.3 (M+1)+; Retention time: 1.82 minutes (3 minute run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C(O[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)(C)C.[Li]C(C)(C)C.[O:27]1[CH2:30][C:29](=[O:31])[CH2:28]1.[NH4+].[Cl-]>C1COCC1.O>[CH3:19][C:16]1([CH3:18])[C:15]([CH3:20])([CH3:21])[O:14][B:13]([C:2]2[CH:7]=[CH:6][C:5]([C:29]3([OH:31])[CH2:30][O:27][CH2:28]3)=[CH:4][CH:3]=2)[O:17]1
Reactant: O=C1COC1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(C3(O)COC3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
1,4-Dibromobenzene (3.3 g, 13.99 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.91 mL, 14.27 mmol) were taken up in THF (60 mL) and cooled to −78° C. before adding t-BuLi (16.46 mL, 28.0 mmol) dropwise. After stirring at −78° C. for 40 minutes, additional t-BuLi (16.46 mL, 28.0 mmol) was added. After 30 minutes oxetan-3-one (1.01 g, 13.99 mmol) was added and the reaction mixture was allowed to room temperature over 90 minutes. Water was added followed by saturated NH4Cl and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (6-50% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:69][N:70]1[CH2:75][CH2:74][S:73](=[O:77])(=[O:76])[CH2:72][CH2:71]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[O:77]=[S:73]1(=[O:76])[CH2:72][CH2:71][N:70]([CH2:69][CH:44]2[S:43][C:47]([C:49]3[NH:50][C:51]4[C:56]([CH:57]=3)=[CH:55][CH:54]=[CH:53][C:52]=4[N:58]([CH3:68])[S:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)(=[O:60])=[O:61])=[N:46][CH2:45]2)[CH2:75][CH2:74]1
Reactant: CN(c1cccc2cc(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of triphenylphosphine oxide (0.50 g) in dichloromethane (5 mL) was slowly added trifluoromethanesulfonic anhydride (0.25 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3-(1,1-dioxidothiomorpholino)propyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.37 g) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred for 30 min under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-10:0). The obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (87 mg, yield: 28%) as colorless prism crystals. MS: 520 (MH+). melting point 188-189° C.
Reaction SMILES: [Cu:1].O.OO.O=O.[CH3:7][S:8]([OH:11])(=[O:10])=[O:9]>>[CH3:7][S:8]([O-:11])(=[O:10])=[O:9].[Cu+2:1].[CH3:7][S:8]([O-:11])(=[O:10])=[O:9].[Cu:1]
Reactant: CS(=O)(=O)O
Agent: [Cu]
Agent: O=O
Agent: OO
Solvent: O
Product: CS(=O)(=O)[O-]
Product: [Cu+2]
Temperature: 80 °C

Procedure:
100 g copper wire scrap was introduced into an aqueous solution that contained 300 g methanesulfonic acid; this was brought to approximately 0.7 L by the addition of ion-exchanged water; and, while heating to 80° C., 30% aqueous hydrogen peroxide was intermittently added in 10 mL portions while monitoring the status of the reaction. Once a certain amount had been added, decomposition of the hydrogen peroxide began and oxygen gas was generated and this caused oxidation of the copper and its gradual dissolution in the methanesulfonic acid. Aqueous hydrogen peroxide was further added when the reaction had calmed. After several hours the copper wire was finally completely dissolved and an aqueous copper methanesulfonate solution with a copper concentration of 100 g/L was produced. The pH of the obtained aqueous copper methanesulfonate solution was 2.5.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[F:28][CH:29]1[CH2:32][N:31]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:36]3[CH2:37][CH2:38][CH:33]([N:31]4[CH2:30][CH:29]([F:28])[CH2:32]4)[CH2:34][CH2:35]3)=[CH:8][C:6]=2[N:7]=1
Reactant: FC1CN(C2CCNCC2)C1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: FC1CN(C2CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 4-(3-fluoro-azetidin-1-yl)-piperidine in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (201 mg, 47%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCCO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 4-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-pentan-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([NH2:49])=[CH:41][CH:40]=2)[CH:34]=[CH:33][N:32]=1>C(Cl)Cl>[NH2:30][C:31]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([NH:49][C:6]([NH:22][C:20]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[N:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:21]=3)=[O:7])=[CH:41][CH:40]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Nc1cc(COc2ccc(N)c3ccccc23)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL) was added dropwise under nitrogen a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (5.91 g, 25.8 mmol) in DCM (15 mL) over 40 min. The resulting solution was stirred at RT for 1 hr then added dropwise under nitrogen to a solution of 2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine (3) (3.80 g, 12.9 mmol). The mixture was stirred overnight and the volatiles were removed in vacuo. The crude material was purified by column chromatography (120 g); eluting with 0 to 6% MeOH in DCM to give 1-(4-((2-aminopyridin-4-yl)methoxy) naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) as an off white solid (4.27 g, 63%): m/z 521 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4].F[C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:23]2[C:24]([C:25]#[N:26])=[CH:27][CH:28]=[CH:29][N:30]=2)[CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCNC1
Reactant: N#Cc1cccnc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(c2ncccc2C#N)C1
Temperature: 60 °C
Yield: 75.8 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 104B (54.2 mg, 0.175 mmol), the 2-fluoronicotin-onitrile (Aldrich, 32.1 mg, 0.263 mmol), and anhydrous acetonitrile (2 mL). Neat triethylamine (53.1 mg, 0.525 mmol) was added. The reaction mixture was heated to 60° C. in a heated shaker block and mixed for 24 hours. After cooling to room temperature, the volatiles were removed by rotary evaporator. The product was purified by flash chromatography (silica gel: 20-65% ethyl acetate in hexanes) to give 54.6 mg (76%) of the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, J=7.3 Hz, 3H), 1.21-1.34 (m, 3H), 1.52-1.62 (m, 1H), 1.57 (s, 9H), 2.20-2.27 (m, 2H), 2.59-2.64 (m, 2H), 3.35-3.43 (m, 1H), 3.69-3.78 (m, 2H), 3.88-3.95 (m, 1H), 4.04-4.09 (m, 1H), 6.69 (dd, J=7.5, 4.8 Hz, 1H), 7.93 (dd, J=7.9, 2.0 Hz, 1H), 8.31 (dd, J=4.8, 2.0 Hz, 1H), 8.57 (s, 1H). MS (ESI+) m/z 412 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38].CCN(C(C)C)C(C)C>C1COCC1.CO>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:2]=4[NH2:1])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 5-[3-amino-2-(2-fluorobenzyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.1 g, 0.22 mmol) in THF (2 mL) was added 2-chloro-N,N-dimethylacetamide (0.024 g, 0.2 mmol) and DIEA (0.11 g, 0.88 mmol). The mixture was stirred at room temperature for 18 h, diluted with methanol, and concentrated. The crude product was purified by HPLC (10 to 90% CH3CN). 1H NMR (400 MHz, CD2Cl2) δ 7.87 (s, 1 H) 7.58 (d, 1 H) 7.11-7.35 (m, 5 H) 7.01 (d, 1 H) 6.55 (s, 1 H) 5.50-5.55 (m, 4 H) 4.25 (s, 2 H) 2.90-3.30 (m, 11 H) 2.30 (dt, 2 H) 2.10 (d, 2 H) 1.83 (dt, 2 H). LC-MS [M+H]+=542.3, RT=0.31 min.
Reaction SMILES: COC(=O)C([C:10]([C:12]1[C:29]2=[C:30]3[C:19](C4C5C(=[CH:25][CH:26]=[CH:27][C:28]2=5)C=CC=4)=[CH:18][CH:17]=[CH:16][C:15]3=[CH:14][CH:13]=1)=[O:11])CCCCC.[CH3:33][O:34][C:35](=[O:60])[CH:36]([C:38]([C:40]1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=C[C:43]3=[CH:42][CH:41]=1)=O)C.[Cl-].COC(=O)CCC[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][C:73](O)=O.C1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=CC3=CC=1>>[CH3:33][O:34][C:35](=[O:60])[CH2:36][CH2:38][CH2:40][CH2:41][CH2:42][CH2:43][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:68]4[C:69]=3[C:70]([C:25]3[C:30]=2[C:29]=1[CH:28]=[CH:27][CH:26]=3)=[CH:71][CH:72]=[CH:73]4)=[O:11]
Reactant: COC(=O)C(C)C(=O)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Reactant: COC(=O)CCCCCCCCC(=O)O
Reactant: CCCCCC(C(=O)OC)C(=O)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Agent: [Cl-]
Agent: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Product: COC(=O)CCCCCCC(=O)c1ccc2c3cccc4cccc(c5cccc1c52)c43
Yield: 73.7 %

Procedure:
The synthesis and purification of perylenoylheptanoic acid methyl ester was achieved as described for perylenoyl propanoic acid methyl ester starting from sebacic acid monomethyl ester chloride and perylene. Yield 73.7%. Rf 0.23 (system 1). 1H-NMR (CDCl3) (δ, ppm): 1.43 (m, 4H, 4-CH2, 5-CH2), 1.67 (m, 2H, 3-CH2), 1.82 (m, 2H, 6-CH2), 2.32 (t, 2H, Ja,b=J2,3 7.42 Hz, 2-CH2), 3.05 (t, 2H, Ja,b=J6,7 7.35 Hz, 7-CH2), 3.69 (s, 3H, CH3), 7.43-7.64 (m, 3H, Ar), 7.74 (t, 2H, J 8.26 Hz, Ar), 7.84 (d, 1H, J 7.92 Hz, Ar), 8.13-8.30 (m, 4H, Ar), 8.48 (d, 1H, J 7.54 Hz, Ar).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=CC(S(OCC(C)CC)(=O)=O)=[CH:3][CH:2]=1.[C:17]1([CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1)[OH:18].[OH-].[Na+]>O.C(O)CCC>[CH3:6][CH:1]([CH2:2][CH3:3])[CH2:16][O:18][C:17]1[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCC(C)COc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a n-butanol suspension containing 37 mmol (9.0 g) of 2-methylbutyl p-toluenesulfonate prepared by tosylating S-(-)-2-methylbutanol and 74 mmol (8.2 g) of hydroquinone, added dropwise was a solution of 50 mmol (2.1 g) of sodium hydroxide dissolved in a solvent mixture comprising 3 ml of water and 10 ml of n-butanol, and the obtained mixture was then stirred for 8 hours at 120° C. After addition of water, the reaction solution was extracted with ether, and the extracted solution was dried and concentrated. The resulting concentrate was purified by column chromatography to obtain 4.8 g of the objective ether compound (Yield: 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[OH2:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[CH2:11][C:10]([OH:12])=[O:19]
Reactant: O
Reactant: CC(=O)Cl
Reactant: COc1cccc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(CC(=O)O)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
14.3 g (0.11 mol) of 3-chloroanisole are added at 0° C. to a mixture of 9.3 ml (0.13 mol) of acetyl chloride and 350 ml of methylene chloride. The mixture is stirred for 1 hour and then, with the temperature maintained at 0° C., 24 g (0.18 mol) of aluminum chloride are added and the reaction is allowed to proceed at this temperature for 2 hours. 20 ml of 1 N hydrochloric acid solution and 20 ml of water are then added. The two phases are separated, the organic phase is washed with water, dried over sodium sulfate and filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a silica gel column using an 8/2 cyclohexane/ethyl acetate mixture as the eluent to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:33]=1[CH3:42]>>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:34][C:33]=1[CH3:42]
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: Cc1cc(S(=O)(=O)Cl)cnc1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cnc1Cl

Procedure:
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 6-chloro-5-methylpyridine-3-sulfonyl chloride (270 mg), the title compound was obtained as a solid (yield 244 mg, 68%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](N)C(=O)O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Boc-Ile-AMP (0.32 g, 1.0 mmole) is stirred in 10 ml of TFA-CH2Cl2 (1:1, v/v) for 30 minutes. TFA and CH2Cl2 are removed in vacuo and the residue is held under vacuum overnight. The residue is extracted with EtOAc and 5 ml of saturated aqueous NaHCO3. The organic layers are filtered through Na2SO4 and concentrated. The crude product is chromatographed on silica gel using 4% MeOH-CH2Cl2 (NH4OH sat'd) to give 0.194 g (88%) of Ile-AMP.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH2:32])=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:7]3[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:8]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc3c(c2)OCO3)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1,3-benzodioxol-5-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.04 (s, 3H), 2.32 (s, 3H), 4.69 (d, J=4.2 Hz, 2H), 5.76 (bs, 1H), 5.95 (s, 2H), 6.22 (s, 1H), 6.67-7.75 (m, 2H), 7.14 (t, J=6.4 Hz, 1H), 7.21 (s, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 8.56 (d, J=3.6 Hz, 1H); MS (ESI) m/z 350.7 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1COc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 2-chloro-4-nitrophenol (3.5 g) and 2-(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (3.7 g), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration. The residue was washed with diisopropyl ether, and dried to give the title compound (5.04 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26](=[O:29])[NH:27][CH3:28])[C:15]=3[CH:30]=2)=[C:9]([CH3:31])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:4](=[O:5])[NH:41][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)=[CH:7][CH:8]=[C:9]([CH3:31])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:16]([C:26]([NH:27][CH3:28])=[O:29])[C:15]=2[CH:30]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3c(C)ccc(C(=O)O)c3F)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3c(C)ccc(C(=O)NC4(c5ccccn5)CC4)c3F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.273 mmol, 1.0 eq) in DMF (5.0 ml), 1-(pyridin-2-yl)cyclopropanamine (0.038 g, 0.285 mmol, 1.2 eq), TBTU (0.130 g, 0.403 mmol, 1.7 eq) and DIPEA (0.154 g, 1.187 mmol, 5.0 eq) were added. Mixture was stirred at ambient temperature for 12 h under nitrogen atmosphere. DMF was concentrated and to this residue water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate and ethyl acetate was evaporated. The crude was purified by preparative TLC eluted with hexane/EtOAc (5:5). The product was further purified by recrystallization with DCM and hexane. Yield: 0.045 g (39%). 1H NMR (400 MHz, DMSO-d6): δ 1.23-1.25 (m, 2H), 1.51-1.54 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (d, 3H, J=4.0 Hz), 7.13-7.15 (t, 1H, J=3.78 Hz), 7.27-7.29 (d, 1H, J=8.00 Hz), 7.33-7.35 (d, 1H, J=4.26 Hz), 7.39-7.44 (m, 3H, J=5.26 Hz), 7.56-7.60 (t, 2H, J=7.56 Hz), 7.68-7.72 (m, 1H), 7.80-7.82 (d, 1H, J=8.44 Hz), 7.96-8.00 (m, 2H), 8.43-8.49 (m, 2H), 9.12 (s, 1H). LCMS: (ES+) m/z=538.0 (M+H). Method: Column: Chromolith SpeedRod C18 (4.6×30) mm, 5 micron Mphase A: 10% MeOH-90% H2O-0.1% TFA Mphase B: 90% MeOH-10% H2O-0.1% TFA Flow: 5 ml/min