Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([NH2:26])=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1.[CH:27](=O)[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([NH:26][CH2:27][CH3:28])=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1
Reactant: CC=O
Reactant: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Solvent: ClCCl
Product: CCNc1nn(C)c2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-methyl-1H-indazol-3-amine (Example 120, 140 mg, 0.40 mmol) in dry DCM (Aldrich, 4.0 mL) at RT were added acetaldehyde (Aldrich, 21.1 mg, 0.48 mmol) followed by NaHB(OAc)3 (Aldrich, 102 mg, 0.48 mmol). After being stirred for 4 h at RT, the reaction was quenched by addition of water. The aqueous layer was extracted with DCM. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (DCM/acetone: 100/0 to 60/40) afforded the title compound. MS (ESI, pos. ion) m/z: 379.3 (M+1). Mass Calc'd for C21H22N4O3: 378.43.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[CH3:31][C:32]([CH3:34])=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:29][CH2:28][N:27]([CH:32]([CH3:34])[CH3:31])[CH2:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: CC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C(C)C)CC1)C3
Temperature: 25 °C
Reaction time: 60 h
Yield: 41.8 %

Procedure:
To a solution of Example 3 (100 mg; 0.23 mmol; 1 eq.) in DCM (3 mL) was added acetone (52 μL; 0.70 mmol; 3 eq.) and AcOH (16 μL; 0.28 mmol; 1.2 eq.) and then after few minutes sodium triacetoxyborohydride (149 mg; 0.70 mmol; 3 eq.). The reaction mixture was stirred at room temperature for 60 hours and acetone (104 μL; 1.41 mmol; 6 eq.) and sodium triacetoxyborohydride (50 mg; 0.23 mmol; 1 eq.). The reaction mixture was stirred for 5 hours then diluted with DCM. The organic phase was washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (45 mg, 41%). 1H NMR (CDCl3) δ 7.41-7.33 (m, 2H), 7.08-6.96 (m, 2H), 4.99 (s, 0.8H), 4.98 (s, 1.2H), 4.66-4.49 (m, 3H), 2.98-2.14 (m, 5H), 2.91 (s, 2H), 2.86 (s, 1H), 2.70 (s, 1H), 2.62 (s, 2H), 1.89-1.61 (m, 4H), 1.09 (s, 6H). HPLC (max plot) 93.8%; Rt 2.80 min. UPLC/MS: (MS+) 468.5 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=3)[S:29][C:20]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[CH:32][CH:31]=3)[S:29][C:20]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCC(O)CC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
4-Hydroxypiperidine (100 mg, 0.99 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (165 mg, 0.36 mmol) in 5 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (0.55 g, 2.60 mmol) is added. After stirring at 0° C. for 4 hours, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 5% methanol in ethyl acetate to provide 98 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 149-150° C.; 1H NMR (DMSO-d6) δ 1.35-1.45 (m, 2H), 1.65-1.75 (m, 2H), 2.00-2.10 (m, 2H), 2.62-2.70 (m, 2H), 3.47 (s, 3H), 3.85 (s, 3H), 4.54 (d, J=4 Hz, 1H), 7.37 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.59 (s, 1H), 9.72 (s, 1H); MS 536.9 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])=[O:8])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-hydroxyhex-2-enamido)phenylcarbamate (398 mg, 1 mmol) and triethylamine (151.5 mg, 1.5 mmol) in DCM (10 mL) was added methanesulfonyl chloride (127.6 mg, 1.1 mmol) at 0° C. and stirred for 0.5 hour, then the reaction was stirred at room temperature for 1 hr, then water (10 mL) was added, the mixture was extracted with DCM (3×20 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-6-(2-(tert-butoxycarbonyl amino)phenylamino)-6-oxohex-3-enyl methanesulfonate (358 mg, yield 90%) as oil after purification by column chromatography (eluent: PE:EA=10:1). LC-MS found 399 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7]O.[N:17]1C=CC=C[CH:18]=1.S(Cl)(Cl)=O.FC(F)OC1C=C(C=CC=1OC(F)F)CCl.[C-]#N.[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:18]#[N:17])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: OCc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: c1ccncc1
Agent: FC(F)Oc1ccc(CCl)cc1OC(F)F
Agent: [C-]#N
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#CCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 45 °C
Yield: 98.5 %

Procedure:
A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 mL, 120 mmol) in chloroform (200 mL) under an argon atmosphere was treated with thionyl chloride (9.62 mL, 130 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a purple oil. To a solution of this 3,4-bisdifluoromethoxybenzyl chloride in dimethylformamide (200 mL) under an argon atmosphere was added sodium cyanide (11.86 g, 240 mmol). The resulting mixture was stirred and gently heated at 45° C. for 3 h, was cooled and was concentrated. The mixture was partitioned between ether and 5% aqueous sodium carbonate and was extracted five times with ether. The organic extract was washed once with brine, was dried (sodium carbonate) and the solvent was removed in vacuo to provide an oil (27 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.N[C:20](N)=[O:21]>>[Cl:8][C:5]1[N:4]=[C:3]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]4[O:16][CH2:17][O:18][C:12]=4[CH:11]=3)[C:20](=[O:21])[NH:1][C:2]2=[CH:7][CH:6]=1
Reactant: NC(N)=O
Reactant: Nc1ccc(Cl)nc1Nc1ccc2c(c1)OCO2
Product: O=c1[nH]c2ccc(Cl)nc2n1-c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A mixture of 7.9 g. of the aminopyridine product of Step B and 25 g. of urea was heated in an oil bath at 185°-190° C. The reaction was kept at this temperature for 10 minutes then cooled and extracted with water. The crude product was extracted with 75 ml. of 2.5 N sodium hydroxide. The alkaline solution was treated with charcoal and excess acetic acid then was added to precipitate the product. The precipitate was purified by crystallization from dimethylformamide-ether.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.Cl[CH2:13]CCl.S(Cl)(Cl)=O.CN(C=O)C>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: ClCCCl
Solvent: CN(C)C=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorobenzoic acid (10 g, 0.04 mol) was suspended in 1,2-dichloroethane (60 mL, 0.8 mol) to which was added thionyl chloride (10 mL, 0.1 mol) followed by a drop of DMF. The mixture was heated to reflux for 1 hour. Excess thionyl chloride and 1,2-dichloroethane were stripped off and the crude product was treated with methanol (50 mL) and heated to reflux for an hour. The mixture was concentrated to dryness, dissolved in dichloromethane, treated with cold sat. sodium bicarbonate solution. The organic layer was dried, then concentrated under vacuum to obtain the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH3:10][Si:11]([CH3:27])([CH3:26])[CH2:12][CH2:13][O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC>[CH3:26][Si:11]([CH3:10])([CH3:27])[CH2:12][CH2:13][O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[NH:5][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[C:7]([I:9])[CH:6]=1
Reactant: Nc1cc(I)cc(I)c1
Reactant: C[Si](C)(C)CCOC(=O)NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOC(=O)NCCCCCC(=O)Nc1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
3,5-Diiodoaniline [Dininno, F.; Guthikonda, R. N.; Schmitt, S. M. 1994 U.S. Pat. No. 5,292,879 A] (1 g, 2.90 mmol), 6-(2-Trimethylsilanyl-ethoxycarbonylamino)-hexanoic acid (1 g, 3.77 mmol) in DMF (12 ml) were added DIPEA (0.9 ml, 5.8 mmol) and HATU (1.65 g, 4.35 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with Et2O. To the mixture was added sat.NaHCO3 and then separated. The aqueous phase was extracted with Et2O (3×40 ml). The combined extraction were washed with 5% HCl (30 ml), H2O (50 ml), sat.NaHCO3 (30 ml), and Brine (30 ml), and finally dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by silica gel column with (Hexane:EtOAc=6:4) to afford 21 (1 g, 59%) as a colorless powder. 1H NMR (300 MHz, (CD3)2SO): δ 0.09 (S, 9H), 0.84 (t, J=2.1 Hz, 2H), 1.34 (m, 2H), 1.40 (m, 2H), 1.50 (m, 2H), 2.41 (t, J=1.8 Hz, 2H), 2.47 (m, 2H), 2.89 (m, 2H), 4.01 (t, 2H), 6.92 (bt, 1H), 7.68 (m, 1H), 7.99 (m, 2H); 13C NMR (75 MHz, (CD3)2SO): δ −0.72, 18.0, 25.2, 26.4, 29.9, 36.9, 61.9, 96.4, 127.0, 139.0, 142.3, 156.9, 172.2; IR (film): 3326, 2853, 2361, 1687, 1541, 1450, 1249, 837 cm−1; MS: (ESI)) [M+Na]+ 624.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24]C(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])[NH:12][CH:13]=1.Cl.CO.[C:32](O)(=O)[CH:33]=C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH:32]=[CH2:33])[CH2:20][CH2:21]2)=[O:15])[NH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Reactant: C=CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C=CC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Reaction time: 1 h
Yield: 16.5 %

Procedure:
The mixture of tert-butyl 4-(4-(2,4-dichlorophenyl)-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (270 mg, 0.64 mmol) in HCl/MeOH (20 mL, 57.2 mmol) was stirred for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in DMF (5 mL). To this mixture, acrylic acid (50 mg, 0.7 mmol), BOP (437 mg, 0.72 mmol) and DIEA (248 mg, 1.92 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (40 mg, 27% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 11.88 (s, 1H), 7.66-7.63 (m, 2H), 7.43 (m, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 6.85-6.78 (m, 1H), 6.18-6.13 (dd, J=2.4, 12.4 Hz, 1H), 5.74-5.71 (dd, J=2.4, 10.4 Hz, 1H), 3.76 (s, 4H), 3.68-3.63 (m, 4H). ESI-MS m/z: 377.3 [M−H]−.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]1([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH2:19]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+].O>CO>[C:10]1([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH2:19][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CC(=O)OC
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Solutions of dimethyl malonate (1.32 g) in dry methanol (5 ml) and 3-phenylbenzyl bromide (2.47 g) in dry methanol (5 ml, hot solution) were added successively to a stirred solution of sodium methoxide [from sodium (0.23 g) and dry methanol (20 ml)]. The resulting mixture was stirred for 2 hours at room temperature and for 2 hours under reflux, then poured into water and extracted with ether. The extracts were washed with water, dried, concentrated and purified by column chromatography using a 1:1 mixture of dichloromethane and 40°-60° C. petrol as eluant to give dimethyl (m-phenylbenzyl)malonate (1.77 g, 59%) as a yellow oil, lR (film) : 1 755 and 1 740 cm-1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(OC(N([N+]([O-])=O)[C@H](C(O)=O)CCCNC(=N)N)=O)(C)(C)C.C(Cl)(=O)OCC(C)C.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46]>CN(C)C=O.O1CCCC1.C(N(CC)CC)C>[NH2:1][C@H:2]([C:10]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: NCC(N)=O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)O)[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H](N)C(=O)NCC(N)=O
Temperature: 25 °C

Procedure:
Protected arginine, i.e., tert-butyloxycarbonylnitro-arginine is dissolved in a suitable solvent such as dimethylformamide and tetrahydrofuran. The dissolved protected amino acid is then cooled to a temperature slightly below the freezing point (0° C), whereupon isobutyl chlorocarbonate and triethylamine is added with stirring. After a short period, glycinamide dissolved in dimethylformamide is added. The mixture is then permitted to warm to room temperature and stirred for a period of several hours and then filtered. The filtrate is recovered and evaporated to dryness and then extracted with dimethylformamide. The dimethylformamide solution is precipitated with ethylacetate to yield the dipeptide, i.e., protected arginyl-glycinamide.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[CH3:10][C:11]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH:12]=[N:13][OH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][C:11]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH:12]=[N:13][OH:14].[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](=[O:14])[O-:7])=[O:4]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: CC(C)(C=NO)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=O)[O-])C(=O)CCl
Reaction time: 72 h

Procedure:
To a solution of 5.0 g (0.029 m) of N-chloroacetyl-N-methylcarbamoyl chloride dissolved in 40 ml of toluene was added 4.74 g (0.029 m) of 2-methyl-2-methylsulfonylpropionaldoxime dissolved in 35 ml. of toluene followed by a slow addition of 2.9 g (0.029 m) of triethylamine. The reaction mixture was stirred at ambient temperatures over a period of 3 days. The solid product was filtered. The filter cake was washed with water and hexane and air dried to afford 5.7 g of a white solid with a melting point of 120°-121° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10]2.[C:31](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:31])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[CH:15]=1)[NH:12][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(OCCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 5-(3-methoxypropoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (3.97 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (30 mL) was added methyl iodide (1.56 g) at room temperature, and the reaction mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was crystallized from ethyl acetate-hexane, and the crystals were washed with hexane to give the title compound (3.63 g, yield 88%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 98-99° C.
Reaction SMILES: C[O:2][C:3](=[O:11])[CH2:4][N:5]1[CH:9]=[C:8](I)[CH:7]=[N:6]1.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.[F-].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[NH2:36][C:22]1[N:23]=[CH:24][C:25]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][C:3]([OH:2])=[O:11])[CH:9]=2)=[CH:26][C:21]=1[C:13]1[S:12][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: COC(=O)Cn1cc(I)cn1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn(CC(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 85 °C

Procedure:
A mixture of (4-iodopyrazol-1-yl)-acetic acid methyl ester (124 mg, 0.467 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (150.0 mg, 0.4246 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), potassium fluoride (74.0 mg, 1.27 mmol) and 4:1 dioxane:water (4:1, 1,4-dioxane:H2O, 6 mL) was heated in the microwave reactor at 85° C. for 30 min. The solution was concentrated in vacuo and dry-loaded onto silica gel for column chromatography. The material was eluted with 2% MeOH/DCM. The fractions containing the product were concentrated in vacuo. The material was redissolved in 1,4-dioxane (5 mL), and 4M HCl in 1,4-dioxane (1 mL) was added. The solution was heated to 50° C. in a sealed tube for 3 h. The solvent was removed in the corrosive pump to afford the title compound as an orange solid. MS (ES+): m/z=352.08 (100) [MH+]. HPLC: tR=2.78 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=3)[CH2:8][CH2:7][N:6]2[C:21]=1[C:22]([OH:24])=[O:23])=O.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[Na]>CO.C1COCC1.C(O)(=O)C>[C:30]([NH:34][CH2:1][C:3]1[C:4]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=3)[CH2:8][CH2:7][N:6]2[C:21]=1[C:22]([OH:24])=[O:23])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(C=O)c(C(=O)O)n1CC2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CNC(C)(C)C)c(C(=O)O)n1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a solution of 500 mg of 15d and 110 mg of tert-butyl amine in 20 ml of methanol and 5 ml of THF was added 140 mg of sodium cyanoborohydride and 90 mg of acetic acid. The mixture was stirred for 3 hr at RT, then 140 mg of sodium cycanoborohydride was added additionally and stirring was prolonged for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography over silica gel, using a gradient of dichloromethane and methanol, to provide 520 mg of 15e; MS-ESI: [M+1] 469.23.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=O.[N:18]1[C:23](C)=[CH:22][CH:21]=[CH:20][C:19]=1C>CN1CCN(C)C1=O.CCOC(C)=O>[CH2:15]([O:14][C:13](=[O:17])[NH:12][C:10]1[N:1]=[C:2]2[CH:7]=[C:6]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[CH:5]=[CH:4][N:3]2[CH:9]=1)[CH3:16]
Reactant: Nc1ccccn1
Reactant: Cc1cccc(C)n1
Reactant: CCOC(=O)NC(=O)CCl
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cn2ccc(-c3cccnc3)cc2n1

Procedure:
A solution of aminopyridine (3) (0.94 g, 5.49 mmol), ethyl chloroacetylcarbamate (1.09 g, 6.58 mmol) and 2,6-lutidine (0.76 mL, 6.58 mmol) in 1,3-dimethyl-2-imidazolidinone (6 mL) was warmed under nitrogen at 110° C. for 4.5 hours. The mixture was diluted with EtOAc and washed with water (6 times), then adsorbed onto silica by removal of solvent in vacuo. The product was chromatographed on silica. Elution with EtOAc gave foreruns, while MeOH/EtOAc (2:23) eluted product (79 mg, 5%) as a solid, mp 248-252° C. (decomposed).