Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([C@H:7]([NH:11][C@H:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O)=[O:6])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:47]=[C:48]1[C:56]2[CH:55]=[C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]3=[CH:52][C:51]=2[C:50](=[O:61])[NH:49]1>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([C@H:7]([NH:11][C@H:12]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:9][N:49]1[C:50](=[O:61])[C:51]2[CH:52]=[C:53]3[CH:60]=[CH:59][CH:58]=[CH:57][C:54]3=[CH:55][C:56]=2[C:48]1=[O:47])=[O:6])[CH3:27]
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Reactant: CC(C)C[C@H](N[C@H](CCO)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
2.5 g of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-hydroxypropyl]-L-leucine, phenylmethyl ester, prepared as in Example J, 1.85 g triphenylphosphine, and 1.4 g 1,3-dihydro-1,3-dioxo-2H-Benz[f]isoindole in 100 mL dry tetrahydrofuran was cooled to 0° C. and treated with 1.1 mL diethylazidodicarboxylate. The resulting mixture was allowed to warm up to 23° C. over 24 h and the solvent removed by evaporation. The residue was purified by silica chromatography using methylene chloride as eluent to give a light yellow solid. Trituration with 20 mL methanol and filtration gave the title compound as a white solid which crystallized from methanol; 1.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=2[N:29]=1>C(O)CCC>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH3:18])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:26][C:27]=2[CH:33]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CCCCO
Product: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC)cc4s3)cc2)cc1

Procedure:
As shown in Reaction Scheme 12, a mixture of methyl N-[(4′-aminobiphenyl-4-yl)carbonyl]-2-methylalaninate (100 mg, 0.32 mmol), 2-chloro-6-methoxybenzothiazole (83 mg, 0.42 mmol, commercially available), and 1-butanol (4.0 mL) was heated at 90° C. overnight. The solvent was evaporated under reduced pressure to afford crude methyl N-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalaninate; LC-MS m/z 476.2 (MH+), retention time 3.25 minutes.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:25][CH2:26][CH3:27])[CH2:5][CH2:6][NH:7][C:8]([NH:19][C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)=[C:9]1[C:14](=[O:15])OC(C)(C)[O:11][C:10]1=[O:18])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.CO>C(OCC)C>[CH2:26]([O:25][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[NH:19][C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:14](=[O:15])[C:9]=1[C:10]([OH:11])=[O:18])[CH3:27]
Reactant: CCOC(CCNC(Nc1ccsc1)=C1C(=O)OC(C)(C)OC1=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: CCOCC
Product: CCOC(CCNc1[nH]c2ccsc2c(=O)c1C(=O)O)OCC
Temperature: 25 °C
Yield: 78.4 %

Procedure:
5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.62 mol) was suspended in a solution of hexamethyldisilazane (1.08 L, 5.18 mol) in xylenes (2.4 L) and was heated at reflux for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford a dark oil. The dark oil was carefully treated with methanol (0.5 L) to form brown solids, followed by addition of ethyl ether (1.6 L). The resultant solids were filtered and washed with MeOH/Ether (1:3) (0.8 L). The solids were dried under vacuum to afford 432.2 g (78%) of the desired intermediate 5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid as a beige solid. 1H NMR (400 MHz, DMSO d6) δ 1.09 (m, 6H), 1.91 (m, 2H), 3.40 (m, 2H), 3.58 (m, 2H), 4.06 (s, 1H), 4.60 (t, 1H, J=5.2 Hz), 7.28 (d, 1H, J=4.8 Hz), 8.05 (d, 1H, J=4.8 Hz), 9.94 (m, 1H), 11.8 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:31])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28].CO.NCCNCCN>C(Cl)Cl.N1C=CC=CC=1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:31])=[C:26]([CH:30]=1)[C:27]([NH:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: NCCNCCN
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
(2S,3R)-2-Methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine (92 mg, 0.34 mmol) was dissolved in DCM (4 mL) and pyridine (1 mL). The solution was cooled in an ice-water bath. To this solution was added a solution of 5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar, 0.48 g, 2.77 mmol, 1.6 equiv.) in DCM (2 mL). The solution was stirred at r.t. for 2 h. The reaction was judged to be complete when TLC (10% MeOH in DCM) and LC/MS did not detect the SM at 274, but detected only the product peak at 410.2 and at retention time of 3.02 min. Polymer bounded diethylenetriamine (4 mmol/g, 0.12 g) was added and stirred at r.t. for 30 min., then filtered and rinsed with DCM. The solvent was evaporated to dryness, re-dissolved in DCM and NaHCO3 aqueous solution. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were successively washed with sodium bicarbonate (5 mL) and brine (5 mL×2), dried (anhydrous potassium carbonate), passed through a silica gel pad (self packed, ˜10 g), rinsed with DCM (no product) and then with 10% MeOH in DCM (contain product). The solution was concentrated in vacuo to obtain a crude product, which was purified on a silica gel column by eluting with 0 to 10% MeOH in DCM to obtain 48 mg (34% yield) of the title compound as a semi-solid. LC/MS: t=3.020 min, MS: 410.2. 1H NMR (300 MHz, CDCl3), δ (ppm): 7.49 (m, 1H), 7.23 (m, 1H), 7.11 (m, 2H), 6.41 (m, 1H), 3.70 (m, 2H), 3.57 (t, 6.2 Hz, 1H), 3.39 (m, 2H), 3.32 (m, 1H), 3.16 (m, 1H), 3.06 (m, 1H), 2.95 (m, 2H), 2.65 (m, 1H), 2.62 (s, 1H), 2.61 (s, 3H), 2.49 (m, 1H), 2.38 (s, 3H), 2.05 (m, 2H), 1.90 (m, 2H), 1.80 (m, 1H), 1.40 (d, 6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[O:11])=[C:4]([F:36])[C:3]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[O:11])=[C:4]([F:36])[C:3]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c[nH]cn3)c2F)c1
Reaction time: 2.5 h
Yield: 60 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-(triphenylmethyl)-1H-imidazole-4-carboxamide (0.145 g, 0.22 mmol) was dissolved in CH2Cl2 (3 mL) and TFA (3 mL) added. The solution was stirred for 2.5 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.070 g, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.01 (br. s., 1H), 8.53 (br. s., 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.45-7.54 (m, 4H), 7.38 (t, 1H), 4.54 (d, 2H). MS: m/z 405.0 (M+1).
Reaction SMILES: [Br-:1].[Li+].C[Si](Cl)(C)C.[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18]O)[C:11]=2[O:10]1>C(#N)C.C(OCC)C>[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][Br:1])[C:11]=2[O:10]1
Reactant: [Br-]
Reactant: CC1(C)Cc2cccc(CO)c2O1
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)Cc2cccc(CBr)c2O1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 8.7 grams (0.1 mole) of lithium bromide in 100 mL of acetonitrile is stirred, and 13.5 grams (0.125 mole) of trimethylsilyl chloride is added. Upon completion of addition, a solution of 8.9 grams (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol in 50 mL of acetonitrile is added. Upon completion of addition, the reaction mixture is warmed to reflux, where it is stirred for about 18 hours. After this time the reaction mixture is cooled to ambient temperature and then is taken up in 200 mL of diethyl ether. The mixture is then washed with 25 mL of water and then with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue, yielding 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl bromide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@:8]1([CH2:15][N+:16]([O-])=O)[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@:8]1([CH2:15][NH2:16])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CC=C[C@H]21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@]1(CN)C[C@H]2CC=C[C@H]21
Reaction time: 6.5 h

Procedure:
Tert-butyl[(1R,5S,6S)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (peak 2, 20.7 g, 77.4 mmol) was dissolved in ethanol (200 mL) and water (100 mL). To the solution, iron powder (34.69 g, 619.5 mmol) and ammonium chloride (2.09 g, 38.72 mmol) were added, and the mixture was stirred for 6.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a mixture of the compound of interest and the starting material at almost 1:1 ratio (20.18 g, estimated by 1H-NMR). This mixture was dissolved again in ethanol (200 mL) and water (100 mL). To the solution, iron powder (40.36 g, 720.7 mmol) and ammonium chloride (4.18 g, 78.1 mmol) were added, and the mixture was stirred for 9 hours under heating to reflux while iron powder (32.73 g, 584.5 mmol) was further added thereto in three portions. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (17.53 g, 95%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:32])C.C1COCC1.CO.[OH-].[Na+]>CCOC(C)=O.Cl>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[C:8]([CH3:32])[CH:9]=3)=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A 1 L round-bottomed flask was charged with compound 7.4 (40.9 g, 85.8 mmol), THF (100 mL) and MeOH (100 mL). Next, 2 N NaOH (86 mL, 172 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 h. The solution was neutralized with 2 N HCl (86 mL) and the organic solvent was evaporated to give an aqueous solution and an insoluble oil. The residue was diluted with AcOEt (300 mL) and 1N HCl (300 mL), and partitioned. The organic phase was successively washed with water (400 mL) and brine (400 mL), dried over MgSO4, and concentrated to give white crystals. Recrystallization from 520 mL of AcOEt/hexane (3/10) gave compound 7 (33.4 g) as white crystals. MS APSI m/e: 447 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 13.0 (1H, brs); 7.64 (2H, d, J=8.8 Hz); 7.38 (2H, d, J=8.3 Hz); 7.30-7.20 (2H, m); 7.16 (4H, d, J=8.3 Hz); 6.89 (1H, d, J=8.5 Hz); 5.14 (2H, s); 4.74 (2H, s); 2.19 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])C=N1.[NH:24]1C=C(N)N=[CH:25]1>>[NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[N:24]=[CH:25]1
Reactant: Nc1c[nH]cn1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cn(CCN)cn2)c1

Procedure:
The title compound was synthesized according to above mentioned procedure for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide, starting from 1H-imidazol-4-amine. LC-MS conditions B: tR=0.47 min, [M+H]+=312.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[CH3:23][C:24]1([CH3:40])[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=1)=[O:31].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>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:28]3[CH2:27][CH2:26][N:25]([C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=4)=[O:31])[C:24]([CH3:40])([CH3:23])[CH2:29]3)=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: COc1cccc(C(=O)N2CCNCC2(C)C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)CC2(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 50 mg (0.22 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 80 mg (0.22 mmol) (2,2-dimethyl-piperazin-1-yl)-(6-methoxy-pyridin-2-yl)-methanone trifluoroacetate, 77 mg (0.24 mmol) TBTU and 0.10 mL (0.58 mmol) DIPEA in 1.5 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])C.[N+:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:20])=[O:19]>C1(C)C(C)=CC=CC=1>[CH3:17][O:16][C:14]([C:6]1[NH:7][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][CH:21]([N+:18]([O-:20])=[O:19])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15]
Reactant: COC(=O)c1[nH]c2cnccc2c1CN(C)C
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(Cc1c(C(=O)OC)[nH]c2cnccc12)[N+](=O)[O-]
Temperature: 156 °C
Reaction time: 3 h

Procedure:
Ethyl 3-[2-(methoxycarbonyl)pyrrolo[2,3-c]pyridine-3-yl]-2-nitropropanoate (32) was synthesized according to a procedure previously published (Synthetic Commun. 1997, 27, 3201-3211). A 1 L single-necked round-bottomed flask was equipped with a magnetic bead and a reflux condenser and placed into an oil bath. The flask was charged with methyl 3-[(dimethyl amino)methyl]pyrrolo[2,3-c]pyridine-2-carboxylate (31, 8 g) and xylene (200 mL), and stirring was initiated. The solid did not dissolve in xylene and remained as a slurry. The resulting solution was degassed with nitrogen for 10 minutes. Ethyl nitroacetate (12, ˜11.4 mL) was added as a single portion to the slurry. The solution was continued to be degassed with nitrogen for a minimum of 1 h while stirring. At this stage a slight change in the nature of the slurry was observed, probably due to the formation of the gramine salt of ethyl nitroacetate. The reaction mixture was heated to reflux (˜156° C.) for 4 h. During reflux, the solid went into solution and simultaneously a white/light yellowish solid precipitated. The reaction mixture was continued to be stirred at reflux until the reaction was deemed complete, i.e., when no starting material peaks were observed on NMR. Indeed, the NMR matched with the NMR of pure product. If reaction was not complete, stirring was continued at 156° C. for another 3 h until the reaction was deemed to be complete, with additional ethyl nitroacetate added as required. This reaction was typically complete in 3-4 h. The reaction was monitored by NMR by taking an aliquot of reaction mixture (˜1 mL), cooling to room temperature, filtering through a polypad, washing with diethyl ether (˜2 mL), and submitting the solid for NMR analysis. Materials used to synthesize ethyl 3-[2-(methoxycarbonyl)pyrrolo[2,3-c]pyridine-3-yl]-2-nitropropanoate (32) are shown in Table 19.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(C)ON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1
Yield: 83.5 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhydride (7.6 g. ) and formic acid (3.4 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 3.75 g.), mp. 168° to 169° C. (dec.).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[C:5]([OH:10])[C:6]([CH3:9])=[N:7][CH:8]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[ClH:18].[Cl:18][CH2:2][C:3]1[C:4]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[C:5]([OH:10])[C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ncc(CO)c(-c2ncc[nH]2)c1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc(CCl)c(-c2ncc[nH]2)c1O
Product: Cl
Temperature: 0 °C

Procedure:
5-(hydroxymethyl)-4-(1H-imidazol-2-yl)-2-methylpyridin-3-ol (5.1 g, 25 mmol) was suspended in toluene (100 mL) and thionyl chloride (25 mL) was added. The suspension was heated to reflux for 2 h, cooled to 0° C. and filtered. The title compound was obtained as brown solid (Purity by NMR: 70-80%) and was used without further purification in the next step.
Reaction SMILES: BrC(CCCCCC)CCC[C:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:25]([Li])[CH2:26][CH2:27][CH3:28].[B:30]([O:35]C)(OC)[O:31]C.Cl>O.C1COCC1>[CH2:28]([N:17]1[C:18]2[CH:6]=[CH:7][CH:8]=[C:9]([B:30]([OH:35])[OH:31])[C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:27][CH2:26][CH2:25][CH2:10][CH2:18][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: CCCCCCC(Br)CCCc1cccc2c1[nH]c1ccccc12
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCn1c2ccccc2c2c(B(O)O)cccc21
Temperature: -30 °C
Reaction time: 1 h

Procedure:
By using the standard procedure, to a dry 100 mL two-neck round-bottom flask containing 4-bromodecylcarbazole 16 (3.86 g, 10 mmol) and dry THF (50 mL) was dropwise added 1.6 M of n-butyl lithium (10 mL, 15 mmol) under N2 at −78° C. while maintaining a good stirring. After stirring for 1 h, trimethyl borate (2.0 mL, 18 mmol) was added in one portion, and then the mixture was stirred for 1 h at −78° C. Water and HCl (3M) were in turn added when the mixture was naturally warmed to −30° C. Then the reaction mixture was poured into water wad extracted with ethyl acetate (3×50 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and evaporated to dryness under 35° C. The crude product was then loaded on silica gel column and eluted with dichloromethane and petroleum ether/ethyl acetate affording a pale-white solid (3.6 g, 68%). 1H NMR (400 MHz, DMSO-d6, δ) 8.59 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.93-7.88 (m, 3H), 7.59-7.52 (m, 2H), 7.45-7.41 (m, 1H), 7.22-7.18 (m, 1H), 4.39-4.37 (m, 2H), 1.76-1.74 (m, 2H), 1.25-1.16 (m, 14H), 0.84 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, DMSO-d6, δ) 141.6, 140.1, 131.8, 125.5, 122.3, 121.5, 119.9, 118.9, 109.3, 108.3, 42.2, 31.3, 28.9, 28.8, 28.7, 28.6, 28.5, 26.5, 22.1, 13.9. MS (FAB): m/z (M+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[O:54]1[C:58]([C:59](Cl)=[O:60])=[CH:57][CH:56]=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:58]2[O:54][N:55]=[CH:56][CH:57]=2)=[O:60])[CH2:48]1
Reactant: O=C(Cl)c1ccno1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2ccno2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 81 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 81% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z=545.0.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: Cn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
To a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 56.6 mol) in dichloromethane (1 mL) was added trifluoroacetic acid (129 mg, 87.2 μL, 1.13 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1 mL), methanol (0.5 mL) and ammonium hydroxide (0.15 mL) and stirred at room temperature for 2 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (12 mg, 36.4 mol, 64%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.19 (s, 1H), 9.16 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=3.0, 1 H), 7.86 (s, 1H), 7.70 (s, 1H), 7.49 (s, 1H), 5.15 (t, J=5.7, 1 H), 3.82 (s, 3H), 3.57 (d, J=5.9, 2 H), 1.37 (s, 9H); MS (EI/CI) m/z: 330.2 [M+H].