Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>COCCOC.[Cu]I.[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>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:23])[CH3:22]
Reactant: COC(=O)Cc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
To a solution of ester 318 (7.50 g, 27.2 mmol) in dry DME (125 mL) at 0° C. was added triethylamine (6.0 mL, 4.3 g, 43 mmol), copper (I) iodide (1.00 g, 5.25 mmol), and bis(triphenylphosphine) palladium (II) chloride (0.65 g, 0.93 mmol). The mixture was degassed with a stream of N2 for 5 min, then trimethylsilylacetylene (5.8 mL, 4.1 g, 41 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 24 h. It was concentrated under reduced pressure, partitioned between ethyl acetate and water, washed with brine, dried (anhydrous MgSO4), filtered and concentrated. Flash chromatography of the residue (eluent 4% ethyl acetate/hexanes) afforded title compound 319 (4.65 g, 69% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.22 (dd, J=7.4, 0.8 Hz, 1H); 7.07-6.95 (m, 3H); 3.58 (s, 2H); 3.45 (s, 3H); 0.00 (s, 9H). LCMS: (M+H) 247.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[SH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1ncccc1NC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80512.2 %

Procedure:
To a DMF (2 ml) solution of this amide (159 mg, 0.5 mmol) and 2-mercaptobenzoxazole (83 mg, 0.55 mmol) were added 18-crown-6 (13 mg, 0.05 mmol) and potassium carbonate (83 mg, 0.6 mmol). and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent-hexane:ethyl acetate=5:2→2:1) to obtain 156 g (yield 81%) of a desired compound as a colorless needle crystal.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:3][C:4]1[N:5]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1ncc[nH]1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(C=O)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a suspension of NaH (0.612 g, 15.3 mmol : 60% suspension of mineral oil) of in dry DMF (10 ml) cooled to 10° C. was added a DMF (8 ml) solution of 2-methylimidazole (1.23 g, 15 mmol) under a nitrogen atmosphere, and the mixture was stirred for 30 min at room temperature. 4-Fluorobenzaldehyde (1.90 g, 15.3 mmol) was added to the reaction mixture, and the resulting solution was stirred for 14 h. The reaction mixture was poured into an ice-cold saturated aqueous NH4Cl solution (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (100 ml) and brine (80 ml), dried over MgSO4 and the solvent removed under reduced pressure. The resultant residue was purified by column chromatography (SiO2 ; hexane:ethyl acetate=1:1 then ethyl acetate) to give crude 4-(2-methylimidazol-1-yl)-benzaldehyde (1.0 g), which was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:41]C(=O)OC(C)(C)C)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[C:23](/[N:25]=[C:26]1\[S:27][C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:29][N:30]\1[CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:24])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:41][C@H:10]([CH2:9][OH:8])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=1[C:23](/[N:25]=[C:26]1\[S:27][C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:29][N:30]\1[CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](N)CO)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of Example 69A (500 mg, 0.7 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with trifluoroacetic acid (0.27 mL, 3.5 mmol). The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure, diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, eluted with CH2Cl2-MeOH: 6:1) afforded 260 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H), 1.58-1.73 (m, 1H), 1.75-2.04 (m, 3 H), 2.25-2.43 (m, 1 H), 3.08 (q, J=5.6 Hz, 1 H), 3.36-3.53 (m, 3 H), 3.59-3.69 (m, 1 H), 3.74-3.86 (m, 1 H), 3.94-4.01 (m, 1 H), 4.05-4.12 (m, 1 H), 4.19-4.36 (m, 3 H), 4.68 (t, J=5.2 Hz, 1 H), 7.24-7.34 (m, 2 H), 7.76 (dd, J=8.9, 2.2 Hz, 1 H), 8.07 (d, J=2.4 Hz, 1 H); MS (DCI/NH3) m/z 502 (M+H)+. Anal calculated for C23H30F3N3O4S.0.75H2O: C, 53.63; H, 6.16; N, 8.16. Found: C, 53.40; H, 6.06; N, 8.16.
Reaction SMILES: [NH2:1][C:2]([O:9][CH2:10][CH3:11])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([O:9][CH2:10][CH3:11])[C:3]=1[C:7]#[N:8]
Reactant: CCOC(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CCOc1nsc(N)c1C#N
Yield: 69.2 %

Procedure:
A mixture of 38 g of 3-amino-2-cyano-3-ethoxypropenethioamide (above) and 400 ml of ethanol was heated to the reflux temperature. To the hot mixture was added 26.0 ml of 30% hydrogen peroxide at a rate sufficient to maintain reflux. After addition was complete the reaction mixture was heated under reflux during one half hour. To the mixture was added 100 ml of ethanol, and reflux was continued during an additional one half hour, at which time thin-layer chromatography indicated that the reaction was complete. The reaction mixture was filtered hot. The filtrate was allowed to cool slowly overnight to give 26.0 g of 5-amino-4-cyano-3-ethoxyisothiazole; m.p. 216°-217°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cc(Br)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Yield: 94.1 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-bromoaniline, 3.0 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2), whereby 3.6 g of 2-fluoromethyl-3-(2-methyl-4-bromophenyl)-6-nitro-4(3H)-quinazolinone are obtained as pale yellow prisms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(O)c1cc(F)cc(Br)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of 1-(3-bromo-5-fluoro-phenyl)-ethanol (2.9 g, 13.2 mmol) in methylene chloride (150 ml) was added at room temperature pyridinium dichromate (3.98 g). The reaction mixture was stirred for 4 hours at room temperature and the solvent was removed in the presence of silica gel. The crude product was purified by chromatography over silica gel to provide 1-(3-bromo-5-fluoro-phenyl)-ethanone (1.39 g, 45%) as a light yellow solid, MS: m/e=216.1 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:29][OH:30].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:30][NH:29][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 12g (125 mg, 0.303 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (210 mg, 3.03 mmol) and a freshly prepared solution of sodium methoxide in methanol (104 mg, 4.50 mmol of sodium dissolved in 1 mL of methanol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13g
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=1)[N:9]=2.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl.CO>[CH:30]1([CH2:29][N:7]2[C:6]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CC4)c3n2)cn1
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (103.3 mg, 0.21 mmol) and morpholine (74.3 mg, 0.85 mmol) was heated at 140° C. and stirred for 3 hours. Morpholine (74.3 mg, 0.85 mmol) was added, the resulting mixture was further stirred for 3 hours, left standing to cool followed by the addition of dichloromethane-methanol (10:1), and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (87.1 mg, 91%) as a pale yellow solid.
Reaction SMILES: [I:1]I.[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[N:5]1.[OH-].[K+].S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[I:1][C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH3:3])[CH:8]=3)[CH:10]=2)[NH:15][CH:16]=1
Reactant: II
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3[nH]cc(I)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.2 A solution of 1.125 g (4.4 mmol) of iodine in 16 ml of DMF is slowly added dropwise at RT to a suspension of 901 mg (4.4 mmol) of 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine and 620 mg (11.1 mmol) of KOH in 12 ml of DMF. When the addition is complete, the mixture is stirred at RT for a further 30 min. The reaction mixture is subsequently poured into 300 ml of an ice-cold, saturated sodium sulfite solution. The yellow precipitate is filtered off with suction and washed with 10 ml of ice-cold water. The filter residue is dried, giving 3-iodo-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as beige crystals, ESI 325
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C(N=C=NC(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:24](=[O:26])[CH2:23][CH2:22][N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]2=3)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCC(=O)O)c3ccccc23)CC1
Reactant: COc1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CCn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 29 h
Yield: 83.5 %

Procedure:
3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoic acid (0.105 g, 0.292 mmol), p-anisidine (0.0377 g, 0.306 mmol, 1.05 equiv.) and dimethylaminopyridine (0.0357 g, 0.292 mmol, 1.00 equiv.) were dissolved in THF at rt under N2. Diisopropylcarbodiimide (0.0503 mL, 0.0405 g, 0.321 mmol, 1.00 equiv.) was added, then the reaction mixture was stirred for 29 h. The reaction mixture was taken up in EtOAc and washed with 10% aq. citric acid (2×), saturated aq. NaHCO3 (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.1686 g) was chromatographed (SiO2 25 g, eluted with 9:1 toluene: acetone) to give tert-butyl 6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4, 5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.113 g) in 84% yield. 1H NMR (300 MHz, CDCl3) δ 1.47, 2.68-2.76, 2.95-3.08, 3.56-3.70, 3.79, 4.53, 6.83, 7.12-7.54; MS (ESI+) for C27H33N3O4 m/z 464.0 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.NCC(N[C@H](C(NCC(OCC1C=CC=CC=1)=O)=O)C(C)C)=O.[NH:65]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C:67]([OH:69])=O>>[NH:65]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C:67]([NH:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:69]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: CC(C)[C@H](NC(=O)CN)C(=O)NCC(=O)OCc1ccccc1
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Yield: 98.6 %

Procedure:
III (8.0 g, 14 mmol) was deblocked as described for II and coupled with Boc-Gly-OH by the excess mixed anhydride method and worked up as described under III to obtain the title compound in 98.6% yield, Rf2 0.75. Anal. Calcd. for C32H43N5O8 : C 61.42, H 6.92, N 11.19%. Found: C 61.12, H 7.21, N 11.19%.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:7])[N:9]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Reactant: NCC(=O)O
Product: COc1ccc(Oc2ccc3c(C#N)nc(C(=O)NCC(=O)O)c(O)c3c2)cc1

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=391.9.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[C:15]3[C:16]([NH2:20])=[N:17][CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30]([N:6]1[C:7]2[C:3](=[C:2]([F:1])[C:10]([C:11]3[C:15]4[C:16]([NH2:20])=[N:17][CH:18]=[CH:19][C:14]=4[O:13][CH:12]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:31]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Nc1nccc2occ(-c3ccc4c(c3F)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 3-(4-fluoro-2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (190 mg, 0.555 mmol), 2,5-difluorophenylacetic acid (100 mg, 0.583 mmol), HATU (232 mg, 0.611 mmol), and Hunig's base (0.388 mL, 2.221 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was stirred at room temperature for 2 hours. HPLC indicated complete consumption of starting material, so the mixture was poured into water (30 mL), the suspension was stirred for a few minutes, and the precipitate was collected by vacuum filtration and dried in the vacuum oven overnight to give 3-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (209 mg, 0.469 mmol, 84% yield) as a light tan solid. LC/MS (ES) m/z=424 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.26-3.31 (d, J=8.34 Hz, 2H), 3.97 (s, 3H), 4.38 (t, J=8.46 Hz, 2H), 5.48 (s, 2H), 6.95 (d, J=5.81 Hz, 1H), 7.14-7.35 (m, 4H), 7.87 (d, J=6.06 Hz, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.96 (s, 1H).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[CH:20][CH:21]=3)[CH2:11][CH:10]([C:22]3[O:24][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(=NO)c1ccccn1
Product: CCc1ccc(C2CC(c3nc(-c4ccccn4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 27 mg (30% of theory)
Reaction SMILES: [I-:1].[K+].N([O-])=O.[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[N:17]([N:21]=[C:22](N)[N:23]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(#N)C.C(OCC)(=O)C>[I:1][C:22]1[N:23]=[C:16]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=3)=[CH:20][CH:19]=[CH:18][N:17]2[N:21]=1
Reactant: COc1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cccn3nc(I)nc23)cc1
Reaction time: 19 h
Yield: 65.4 %

Procedure:
A solution of potassium iodide (5.4 g, 32 mmol, 3.9 equiv) and sodium nitrite (1.73 g, 25.1 mmol, 3.00 equiv) in water (10 mL) was added over 5 min to a solution of 8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.01 g, 8.36 mmol, 1 equiv) and p-toluenesulfonic acid (7.3 g, 38 mmol, 4.6 equiv) in acetonitrile at 24° C. After 19 h, the reaction mixture was diluted with ethyl acetate (250 mL), and the resulting solution was washed sequentially with water (2×120 mL) and saturated aqueous sodium choride solution (120 mL). The collected organic was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (20→30% ethyl acetate in heptane) provided product as a light yellow solid (1.92 g, 65% yield). 1H NMR (400 MHz, CDCl3), δ: 8.46 (dd, J=6.8, 1.0 Hz, 1H), 7.96 (m, 2H), 7.59 (dd, J=7.4, 1.1 Hz, 1H), 7.01-7.06 (m, 3H), 3.86 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.Cl>C(O)C>[CH:3]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=2)[CH2:5][CH2:4]1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of NaBH4 (15 g) in ethanol (180 mL) was added the crude 4-cyclopropylbenzaldehyde prepared in (1) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 6 N hydrochloric acid (90 mL) at 0° C. The reaction mixture was stirred for 30 min and then concentrated in vacuo. Water was added to the residue and the mixture was extracted with toluene. The solvent was removed under reduced pressure. The resulting residue was distilled under reduced pressure to give the title compound (60 g, 79%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:14])[CH:13]=1)[C:7]([O:9]C)=[O:8])(=O)[CH3:2].[OH-].[K+].O.NN.Cl>C(O)CO.O>[Br:14][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([CH2:1][CH3:2])[CH:13]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C(C)=O)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCc1cc(Br)cc(C(=O)O)c1
Temperature: 200 °C
Yield: 86.4 %

Procedure:
The compound methyl 3-acetyl-5-bromobenzoate (1.2 g, 4.8 mmol) was dissolved in ethylene glycol (10 mL) and KOH (0.41 g, 7.3 mmol) followed by hydrazine hydrate (0.44 mL, 7.3 mmol) were added. The reaction mixture was heated to 200° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The pH of the aqueous layer was adjusted to 2-3 using 1.5N HCl. The product was extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 50% EtOAc in petroleum ether) to yield 3-bromo-5-ethylbenzoic acid (0.95 g, yield 89%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.07 (m, 1H), 7.88 (m, 1H), 7.59 (m, 1H), 2.73 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H). MS (ESI) m/z: Calculated for C9H9BrO2: 227.98. found: 229.0 (M+H)+.