Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:25][OH:26].[CH2:27]([O:29][CH2:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37](O)=[CH:36][C:34]=2[CH:35]=1)[CH3:28].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:29][CH2:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37]([O:26][CH2:25][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=6)[CH2:14][CH2:13]5)[C:6]=4[C:2]=3[CH3:1])=[CH:36][C:34]=2[CH:35]=1)[CH3:28]
Reactant: CCOCc1cc2cc(O)ccc2o1
Reactant: Cc1c(CO)oc2cccc(OC3CCN(Cc4cccnc4)CC3)c12
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCc1cc2cc(OCc3oc4cccc(OC5CCN(Cc6cccnc6)CC5)c4c3C)ccc2o1
Temperature: -30 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a cooled (−30° C.) solution of [3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-benzofuran-2-yl]-methanol (30 mg), 2-ethoxymethyl-benzofuran-5-ol (16 mg) and 1,1′-azobis(N,N-dimethylformamide) (37 mg) in THF (1 ml) was added tributylphosphine (53 μl) and the resulting solution was stirred overnight at −30° C. The resulting suspension was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH=20:1 as a developing solvent) to give 3-[4-[2-(2-ethoxymethyl-benzofuran-5-yloxymethyl)-3-methyl-benzofuran-4-yloxy]-piperidin-1-ylmethyl]-pyridine (27 mg) as a colorless oil. FAB-MS: m/z 527 (MH+); 1H-NMR (CDCl3): δ 1.26 (3H, t, J=7 Hz), 1.99 (4H, m), 2.41 (3H, s), 2.42 (2H, m), 2.70 (2H, m), 3.55 (2H, s), 3.61(2H, q, J=7 Hz), 4.52 (1H, m), 4.58 (2H, s), 5.10 (2H, s), 6.60 (1H, d, J=8 Hz), 6.63 (1H, s), 6.97 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.03 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.15 (1H, d, J=2.5 Hz), 7.26 (1H, dd, J1=8 Hz, J2=5 Hz), 7.37 (1H, d, J=9 Hz), 7.68 (1H, dt, J1=8 Hz, J2=2 Hz),8.51 (1H, dd, J1=5 Hz, J2=2 Hz), 8.56 (1H, d, J=2 Hz).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:26]3[S:27][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Reactant: O=Cc1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3c(F)cccc23)s1
Yield: 77.3 %

Procedure:
A solution of 1-benzenesulfonyl-3-bromo-7-fluoroindole (0.5 g, 1.41 mmol), 5-formyl-2-thiophene boronic acid (0.24 g, 1.55 mmol), bis(triphenylphosphine) palladium (II) dichloride (0.06 g, 0.08 mmol) and triethylamine (0.39 ml, 2.82 mmol) in ethanol (4 ml) was subjected to microwave irradiation at 150° C. for 420 s. The resulting suspension was concentrated under reduced pressure and the residue passed through a silica pad eluting with dichloromethane to afford crude 5-(1-benzenesulfonyl-7-fluoroindol-3-yl)-thiophene-2-carboxaldehyde as a brown solid (0.42 g) which was used in the next step with no further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](N(CC)CC)=[O:7])=[C:4]([CH2:15][C@H:16]([OH:18])[CH3:17])[CH:3]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:13][CH:14]=1)[C:6](=[O:7])[O:18][C@H:16]([CH3:17])[CH2:15]2
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C[C@@H](C)O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Temperature: 25 °C

Procedure:
A solution of 4-bromo-N,N-diethyl-2-[(2R)-2-hydroxypropyl]benzamide (12.2 g, 38.8 mmol) dissolved in 4N HCl in dioxane (200 mL) was stirred at room temperature and monitored by TLC. After 3 days the reaction was partitioned between EtOAc (300 mL) and water (300 mL). The aqueous phase was further extracted with EtOAc (2×250 mL). The combined organic layers were then washed with water (200 mL), brine (200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was then purified via MPLC (15-30% EtOAc/Hexane) to afford (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one: 1H NMR (500 MHz; CDCl3): 7.98 (d, J=8.2 Hz, 1H), 7.56 (dd, J=1.5, 8.2 Hz, 1H), 7.45 (s, 1H), 4.71 (m, 1H), 2.94 (m, 2H), 1.55 (d, J=6.3 Hz, 3H); LC-MS: (M+1)+241.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[H-].[Na+].[C:14](=[S:16])=[S:15].Cl[CH2:18][C:19]#[N:20]>C(OCC)C>[C:14](=[S:1])([SH:16])[SH:15].[C:14](=[S:16])([S:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[S:15][CH2:18][C:19]#[N:20]
Reactant: S=C=S
Reactant: CO[Si](CCCS)(OC)OC
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CO[Si](CCCSC(=S)SCC#N)(OC)OC
Product: S=C(S)S
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
(3-Mercaptopropyl)trimethoxysilane (1.97 g, 0.01 mol) was added within 10 minutes to a stirred suspension of sodium hydride (60% w/w, 0.42 g, 0.0175 mol) in dry diethyl ether (20 mL) whilst maintaining the reaction temperature between 5-10° C. The reaction mixture was then cooled to ˜0° C. when carbon disulfide (1.34 g, 0.012 mol) was added and the resulting mixture was kept at this temperature for one hour. Then α-Chloroacetonitrile (1.30 g, 0.017 mol) was added and the mixture was stirred at ambient temperature for a one hour. The reaction mixture was the filtered and the filtrate concentrated on rotary evaporator. Purification by chromatography on a short silica gel column (ethyl acetate: n-hexane 1:4) gave the title compound as a yellow liquid (2.25 g, 72%). 1H-nmr (CDCl3) δ 0.75 (m, 2H), 1.86 (m, 2H), 3.46 (t, 2H), 3.58 (s, 9H), 4.15 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[NH:5][C:6](=[O:29])[N:7]([CH:28]=1)[C@@H:8]1[O:27][C@H:12]([CH2:13][NH:14][C:15](=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]([NH:14][CH2:13][C@H:12]1[O:27][C@@H:8]([N:7]2[CH:28]=[C:3]([CH2:1][CH3:2])[C:4](=[O:30])[NH:5][C:6]2=[O:29])[CH2:9][C@@H:10]1[OH:11])=[O:26]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3N)O2)c(=O)[nH]c1=O
Yield: 53.9 %

Procedure:
A solution of 0.2 g of 2',5'-dideoxy-5-ethyl-5'-[2-(2-nitrophenyl)acetamido]uridine in 100 ml of ethanol was hydrogenated over 0.1 g of 10% palladium-on-carbon catalyst at room temperature and under atmospheric pressure until the uptake of hydrogen was complete. The mixture was filtered and the filtrate was evaporated to yield an oil which crystallized from ethanol to give 0.1 g of 5'-[2-(2-aminophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 195°-196° C.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]2[C:16]([N:17]=1)=[CH:15][C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=1[CH:7]=2)[CH2:2][CH3:3].[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:18].[CH3:39][N:24]1[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=[C:23]1[S:22][CH2:21][CH2:20][CH2:19][N:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[C:16]3[N:17]=[C:4]([CH2:1][CH2:2][CH3:3])[O:5][C:6]3=[CH:7][C:8]=2[CH2:14][CH2:13]1
Reactant: CCCc1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: CCCc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-propyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (87 μmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a colourless solid (55 μmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N2CCN(C)CC2)c1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in Example 15, N-[2-methyl-5-(2-morpholinopyrid-4ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give the title compound; NMR Spectrum: (DMSOd6) 2.84-2.89 (m, 4H), 2.92-3.08 (m, 4H), 3.58-3.61 (m, 4H), 3.81-3.84 (m, 4H), 6.95 (d, 1H), 7.09 (s, 1H), 7.10 (d, 1H), 7.41-7.44 (m, 2H), 7.53 (d, 1H), 7.76 (d, 1H), 7.96 (s, 1H), 8.04 (s, 1H), 8.3 (d, 1H); Mass Spectrum: M+H+ 560.
Reaction SMILES: [Cl:1][C:2]1[C:12]([OH:13])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:14]1([S:20]([CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:12]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:21])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=S(CCCCCl)c1ccccc1
Reactant: O=C1Nc2cc(Cl)c(O)cc2CO1
Product: O=C1Nc2cc(Cl)c(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylchloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.C([Cl:23])(=O)C>CO>[ClH:23].[CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[O:4][N:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1noc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: CO
Product: Cc1noc(C2CCNCC2)n1
Product: Cl
Temperature: 60 °C
Yield: 45.6 %

Procedure:
Crude tert-butyl 4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (5.73 g, 21.3 mmol) was dissolved in MeOH (100 mL) and a premixed solution of acetyl chloride (1.53 mL, 42.8 mmol) in MeOH (10 mL) was added and the mixture heated to 60° C. for 1 hour, then the solvents were evaporated and the resultant gum triturated with dichloromethane/diethyl ether (1:1) to give a cream solid which was filtered, washed with diethyl ether and dried, to give the title compound as a solid (1.98 g, 55% yield); MS: 168 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:16]1[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)=O>CCOCC>[C:8]([C:16]1[N:20]=[C:19]([CH2:21][S:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:18][N:17]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: O=C(c1ccccc1)c1noc(CCl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1noc(CSc2ccccc2)n1
Reaction time: 1 h

Procedure:
A solution of 11.4 ml of triethylamine in 30 ml Et2O was added dropwise to a solution consisting of 9.0 g of 3-benzoyl-5-chloromethyl-1,2,4-oxadiazole, 4.2 ml of thiophenol, 20 ml of acetone and 80 ml of Et2O at room temperature. The resulting mixture was stirred for one hour. The reaction mixture was diluted with Et2O, washed with 5% HCl (2×), water (2×) and brine, and dried over MgSO4. Concentration gave 11.5 g of an oil. Purification by high pressure liquid chromatography with 70% CH2Cl2 /hexane as an eluent yielded 10.3 g (84%) of an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:11]=[C:12]=[S:13])=[C:6]([F:14])[CH:5]=1)[CH3:2].[CH3:17][NH:18][NH2:19]>C(O)C>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[C:9]([F:10])=[CH:8][C:7]([NH:11][C:12](=[S:13])[N:18]([CH3:17])[NH2:19])=[C:6]([F:14])[CH:5]=1)[CH3:16]
Reactant: CNN
Reactant: CCN(CC)c1cc(F)c(N=C=S)cc1F
Solvent: CCO
Product: CCN(CC)c1cc(F)c(NC(=S)N(C)N)cc1F
Yield: 98.3 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.9 g (0.012 mole) of 4-diethylamino-2,5-difluorophenyl isothiocyanate with 0.55 g (0.012 mole) of methylhydrazine in 75 ml of ethanol yielded 3.4 g of 4-(4-diethylamino-2,5-difluorophenyl)-2-methyl-3-thiosemicarbazide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]([F:16])=[N:10][C:11]([F:15])=[N:12][C:13]=1F.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:7][C:8]1[C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][C:11]([F:15])=[N:10][C:9]=1[F:16]
Reactant: C1COCCN1
Reactant: Fc1nc(F)c(Cl)c(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1nc(F)c(Cl)c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Morpholine (0.774 mg) was added to a solution of 5-chloro-2,4,6-trifluoropyrimidine (1.5 g), N,N-diisopropylethylamine (1.15 g) in 1,4-dioxane (30 ml) and stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water, the organic layer dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 8% ethyl acetate in isohexane. Yield 0.88 g
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([C:14](=O)[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2].CO[C:22]([N:26](C)C)(OC)[CH3:23].C[N:30](C=O)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:22]([CH3:23])[NH:26][N:30]=2)[C:11]([F:17])=[CH:10][C:9]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CN(C)C=O
Reactant: CC(=O)c1cc(NC(=O)OC(C)(C)C)c(C)cc1F
Product: Cc1cc(-c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (5-Acetyl-4-fluoro-2-methyl-phenyl)-carbamic acid tert-butyl ester (425 mg) and (1,1-dimethoxy-ethyl)-dimethyl-amine (653 mg) in DMF (2 ml) was heated at 90° C. for 3 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0° C., and hydrazine hydrate (5 ml) at 0° C. was added. The mixture was stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue was purified by“flash chromatography” (0 to 30% EtOAc in hexanes) to give 370 mg of [4-fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16])[CH2:2][CH3:3].[CH2:18]([C:21]1C([N+]([O-])=O)=CC2NC(=O)COC=2C=1)[CH2:19]C.C([Mg]Br)CC>>[CH2:1]([C:4]1[C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=[C:6]([CH2:19][CH2:18][CH3:21])[C:5]=1[N+:15]([O-:17])=[O:16])[CH2:2][CH3:3]
Reactant: CCCc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Reactant: CCCc1c([N+](=O)[O-])ccc2c1NC(=O)CO2
Agent: CCC[Mg]Br
Product: CCCc1cc2c(c(CCC)c1[N+](=O)[O-])NC(=O)CO2

Procedure:
The title compound is synthesized from either 5-propyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine or 7-propyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and propyl magnesium bromide using the method illustrated in Example 37.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1.CCN(CC)CC>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([O:38][CH3:37])[CH:44]=2)=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: COc1cc(N)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C#N)cc2F)ccn1
Yield: 66.3 %

Procedure:
A solution of 4-cyano-2-fluoro-benzoic acid (6.7 g, 40.58 mmol), HATU (15.4 g, 40.58 mmol), 2-methoxypyridin-4-amine (5.0 g, 40.58 mmol) and Et3N (22.62 mL, 162.3 mmol) in dichloromethane (60.3 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-50%) to yield 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 66%) as a white solid. ESI-MS m/z calc. 271.07. found 272.1 (M+1)+; Retention time: 1.17 minutes (3 minutes run).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)[CH:6]=[N:7][CH:8]=1.[C:21]1([O:27]C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:21][O:27][N:9]1[C:5]2[C:6](=[N:7][CH:8]=[CH:3][CH:4]=2)[C:16](=[O:17])[CH:11]=[CH:10]1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: COc1cncc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Solvent: CCCCCC
Product: COn1ccc(=O)c2ncccc21
Temperature: 245 °C

Procedure:
A two-necked RBF equipped with an air condenser was charged with 5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (18 g) and diphenyl ether (180 mL). The reaction mixture was heated at 240-250° C. for 5 min under N2 atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtain product as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[OH-].[K+].C1C(=O)N([Br:27])C(=O)C1.O>CN(C=O)C>[Br:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:10]=2)[NH:14][N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-1H-indazole (1 g, 4.35 mmol) in DMF (13 ml) were added KOH (488 mg, 8.7 mmol) and NBS (1.15 g, 6.48 mmol) at RT. The reaction mixture was stirred for 2 h at RT. Water was added to the reaction mixture and extracted with EtOAc (2×20 ml). Combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-15 EtOAc-hexane to provide 3-bromo-5-(2,6-difluoro-phenyl)-1H-indazole (600 mg, 45% yield). MS (ESI, pos. ion) m/z: 306.9 (M−1).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[F:19][C:16]([F:17])([F:18])[C:11]1[N:10]=[C:9]([NH2:8])[C:14]([NH2:15])=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2nc(C(F)(F)F)ccc2N)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(F)(F)F)nc1N

Procedure:
A solution of N2-(4-methoxy-benzyl)-6-trifluoromethyl-pyridine-2,3-diamine from step (a) above (220 mg, 0.7 mmol) in 1:1 TFA/DCM (4 mL) was stirred at room temperature for 90 min. The reaction mixture was concentrated to yield a gummy residue, which was dissolved in MeOH (2 mL) and purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 178 (M+1).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[C:24]([F:35])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:9])=C.Cl.[OH-].[Na+]>C(O)C.O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[C:24]([F:35])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NOCCO)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 11s (0.039 g, 0.068 mmol) is dissolved in ethanol (2 mL) and aqueous 2 M HCl (200 uL) is added. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with water and then neutralized with aqueous 2 M NaOH (˜200 uL) until pH 7 and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and brine in a separatory funnel and the layers separated. The ethyl acetate layer is dried (Na2SO4) and concentrated under reduced pressure to yield 0.034 g (91%) of the pure desired product as an off-white solid. MS ESI (+) m/z 541, 543 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.75 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.40 (dd, A of ABX pattern, 1H), 4.28 (dd, B of ABX pattern, 1H), 3.92 (m, X of ABX pattern, 1H), 3.66 (t, 2H), 3.35 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H), 2.28 (s, 3H), 1.54 (m, 3H), 1.30 (m, 1H). 19F NMR (376 MHz, CD3OD) −134.87 (s).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:4][N:3]=1.P(Cl)(Cl)[Cl:21].Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([OH:34])=O>N1C=CC=CC=1>[Cl:21][CH:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)[C:32]([NH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:4][N:3]=1)=[O:34]
Reactant: Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: ClP(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)C(Cl)c1ccccc1
Yield: 42.1 %

Procedure:
150 mg of 3-amino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole was dispersed in 6 ml of pyridine. While this dispersion was being cooled on a salt-ice bath, 122 mg of phosphorus trichloride was added thereto with stirring. After the resulting mixture was stirred at the same temperature for 25 minutes, 335 mg of 2-chlorophenylacetic acid was added thereto, followed by stirring at room temperature for 20 hours. After the pyridine was distilled off under reduced pressure, the residue was extracted with methanol and chloroform. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 80 g of silica gel [with an elution solvent comprising chloroform-methanol (30:1)]. Thus, 101 mg (42% yield) of the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:18][CH2:19][CH3:20])(=O)C.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:18])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: O=C1c2ccccc2CN1C1CCN(Cc2ccccc2)CC1

Procedure:
Following the procedure outlined in Example 6 and substituting commercially available 1 phenylmethyl 4-aminopiperidine (2.29 g), 0.60 g of product was isolated as a white crystalline solid from ethyl acetate/skellysolve B: mp 116-118° C. Anal. calcd for C20H22N2O 0.25 H20: C, 77.26; H, 7.29; N, 9.01. Found: C, 77.65; H, 7.38; N, 9.08.