Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[C:14](I)=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:23]1([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>CN(C=O)C.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.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[C:14]([C:33]3[CH:32]=[C:31]4[C:36]([CH:37]=[CH:38][C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[N:30]4)=[CH:35][CH:34]=3)=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(N)ncnc32)CC1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)CC1
Temperature: 80 °C

Procedure:
A solution of cis-4-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester (16.2 mg 0.0391 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (15.6 mg, 1.2 eq.), Pd(PPh3)4 (2.7 mg, 0.06 eq.) and Na2CO3 (10.4 mg, 2.5 eq.) in DMF (2.5 mL)/H2O (0.5 mL) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under nitrogen. After that time, the reaction mixture was treated with H2O and extracted with EtOAc (3×10 mL). The combined extracts were washed with H2O (2×5 mL) and brine (5 mL), and dried over MgSO4. The drying agent was filtered off, the filtrate was concentrated in vacuo, and the crude yellow oil was purified by HPLC to obtain the title compound as yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.29-1.36 (t, 3 H, J=7.2 Hz), 1.74-2.09 (m, 6 H), 2.34-2.41 (m, 2 H), 2.75 (m, 1 H), 4.19-4.25 (q, 2 H, J=7.2 Hz), 4.77-4.85 (m, 1 H), 5.22 (brs, 2 H), 7.22 (s, 1 H), 7.46-7.57 (m, 3 H), 7.68-7.70 (dd, 1 H, J=1.6 & 8.0 Hz), 7.89-7.93 (m, 2 H), 8.18-8.20 (dd, 2 H, J=0.8 & 8.0 Hz), 8.25-8.27 (m, 2 H), 8.37 (s, 1 H). MS (ES+): 492.1 [MH+]. HPLC: tR=3.1 min (polar—5 min).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[NH:4][C:5]1[S:9][N:8]=[C:7]([OH:10])[C:6]=1[C:11]([NH2:13])=[O:12].CC([O-])(C)C.[K+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C.CCCCCC.C(OCC)(=O)C.CO.C(O)(=O)C>[CH3:1][N:2]([CH3:15])[C:3](=[O:14])[NH:4][C:5]1[S:9][N:8]=[C:7]([O:10][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]=1[C:11]([NH2:13])=[O:12]
Reactant: CCCCCCCI
Reactant: CN(C)C(=O)Nc1snc(O)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCOc1nsc(NC(=O)N(C)C)c1C(N)=O
Temperature: 25 °C

Procedure:
A suspension of 5-(3,3-Dimethyl-ureido)-3-hydroxy-isothiazole-4-carboxylic acid amide (200 mg, 0.87 mmol) in DMF (5 mL) was treated with KOtBu (107 mg, 0.96 mmol) at ambient temperature causing complete dissolution. Next was added 1-iodoheptane (1 mL) and the reaction stirred at ambient temperature until complete dissappearance of starting materials as measured by TLC using hexane/ethyl acetate/methanol/acetic acid (48/48/2/2) as eluent. The reaction mixture was then concentrated by rotary evaporation under high vacuum, the residue dissolved in ethyl acetate and methanol, and was then purified via radial chromatography (2 mm plate) using the same eluent as for TLC affording two components. The more polar material was identified as the N-alkyated adduct (102 mg, 0.311 mmol, 36%). 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=6.7 Hz, 3H), 1.25-1.31 (m, 8H), 1.64-1.70 (m, 2H), 3.07 (s, 6H), 3.68 (t, J=7.2 Hz, 2H), 5.40 (s, 1H), 8.86 (s, 1H), 12.1 (s, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 13.94, 22.45, 26.48, 28.74, 29.52, 31.52, 36.11, 42.54, 166.99 ppm; MS (APCl, m/z): 329 [M+H]+. The less polar material was the O-alkyated adduct (134 mg, 0.408 mmol, 48%). 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 1.24-1.50 (m, 8H), 1.75-1.88 (m, 2H), 3.07 (s, 6H), 4.43 (t, J=6.7 Hz, 2H), 5.42 (s, 1H), 7.25 (s, 1H appears to be superimposed on CDCl3 peak), 11.6 (s, 1H) ppm; 13C NMR (101 MHz, CDCl3 ) δ 13.94, 22.45, 25.86, 28.83, 31.60, 36.11, 68.69, 97.69, 154.15, 162.27, 166.20, 169.45 ppm; MS (APCl, mlz): 329 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[I:13]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]([NH2:8])=[C:6]([I:13])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Product: Nc1c(I)cc(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 76 step A from 4-chloro-2-trifluoromethyl-phenylamine (1 g, 5.11 mmol) and N-iodo succinimide (1.73 g, 7.67 mmol). Off white solid. (1.64 g, 88%). GC-MS: 321 (M).
Reaction SMILES: C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[O:34]1[CH2:38][CH2:37][O:36][CH:35]1[CH2:39][CH2:40][C:41]1[S:45][C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[N:43][C:42]=1[C:52]([OH:54])=O.CCN(C(C)C)C(C)C.[N:64]1[C:72]2[C:67](=[N:68][CH:69]=[CH:70][CH:71]=2)[S:66][C:65]=1[C:73]1[CH:79]=[CH:78][CH:77]=[CH:76][C:74]=1[NH2:75].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:36]1[CH2:37][CH2:38][O:34][CH:35]1[CH2:39][CH2:40][C:41]1[S:45][C:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[N:43][C:42]=1[C:52]([NH:75][C:74]1[CH:76]=[CH:77][CH:78]=[CH:79][C:73]=1[C:65]1[S:66][C:67]2[C:72]([N:64]=1)=[CH:71][CH:70]=[CH:69][N:68]=2)=[O:54]
Reactant: Nc1ccccc1-c1nc2cccnc2s1
Reactant: O=C(O)c1nc(-c2ccccc2)sc1CCC1OCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCC1OCCO1
Reaction time: 16 h
Yield: 66 %

Procedure:
2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (669 mg, 1.8 mmol) was added to a solution of 5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenylthiazole-4-carboxylic acid (504 mg, 1.7 mmol), DIPEA (613 μL, 3.5 mmol), and 2-(thiazolo[5,4-b]pyridin-2-yl)aniline b (250 mg, 1.1 mmol) in DMF (7 mL). The reaction mixture was stirred for 16 h, poured into sat aq NaHCO3 and extracted with EtOAc. The organic fractions were washed with brine, dried and concentrated. The crude product was crystallized from EtOH to give 5-(2-(1,3-dioxolan-2-yl)ethyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (372 mg, 66% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][N:7]=1.C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][C:5]1[O:1][C:2]([C:6]2[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][N:7]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1onc(-c2ccco2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(Br)o2)c1C
Yield: 21.6 %

Procedure:
Ethyl 3-(furan-2-yl)-4-methylisoxazole-5-carboxylate (5.8 g, 26.2 mmol), NBS (5.6 g, 31.5 mmol), and benzoyl peroxide (0.64 g, 2.62 mmol) were added to 150 mL of carbon tetrachloride and the mixture was refluxed for 16 h. Reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc/hexanes) to give 1.7 g of the title compound. MS: (+) m/z 300.31, 322.28 (M+1, 79Br/81Br).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][CH:21]=[C:22]([C:24]([NH2:26])=[O:25])[N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: NC(=O)c1csc(Br)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C(N)=O)cs3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole-4-carboxamide (J. Am. Chem. Soc. 1952, 74, 5799).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[O:27][CH3:28])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][C:20]=3[O:27][CH3:28])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1OC)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Yield: 67 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 67% of theory, C28H31N7O4 (529.6) Rf value: 0.16 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =530
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3](=[O:20])[CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.[NH2:23][C@H:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])[CH2:25][C:26]([OH:28])=[O:27]>>[CH3:21][C:2]([CH3:1])([CH3:22])[C:3](=[O:20])[CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:17]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([OH:28])=[O:27])=[O:19])[CH:7]=1
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: CC(C)(C)C(=O)CNc1cc(C(=O)O)nn1-c1ccccc1
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(NCC(=O)C(C)(C)C)n(-c2ccccc2)n1

Procedure:
This synthesis is carried out by combination of 5-(3,3-Dimethyl-2-oxo-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid and (S)-3-Amino-3-o-tolyl-propionic acid applying General Procedure A.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.ClCCl>[C:7]1([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
19 g (53 mmol) of methyltriphenylphosphonium bromide [1779-49-3] are suspended in dried THF under protective gas, and 6 g (53 mmol) of potassium tert-butoxide are added in portions at 0° C.; an immediate colour change to orange occurs. 14 g (51.2 mmol) of N,N-diphenyl-p-aminobenzaldehyde [4181-05-9] are added to the reaction solution at 0° C. The mixture is warmed to room temperature and stirred for a further 20 h. The solvent is stripped off in vacuo, the residue is taken up in dichloromethane, the solution is extracted with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo. The yellow oil obtained is chromatographed over silica gel, giving 12 g (44 mmol) (86%) of a white solid having a purity of 99.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1)[NH2:5].Cl[C:15]1[N:20]=[C:19]([C:21]2[N:22]=[N:23][N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:25]=2)[CH:18]=[CH:17][N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:24]2[CH:25]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:5][C:4]4[CH:6]=[C:7]([C:9]5[S:13][CH:12]=[N:11][CH:10]=5)[CH:8]=[C:2]([CH3:1])[CH:3]=4)[N:20]=3)[N:22]=[N:23]2)=[CH:32][CH:31]=1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Cl)n3)nn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(Nc4cc(C)cc(-c5cncs5)c4)n3)nn2)cc1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
To a solution of 3-methyl-5-(1,3-thiazol-5-yl)aniline (63 mg, 0.33 mmol) and the product of Step 1 (100 mg, 0.33 mmol) in degassed 1,4-dioxane (1.3 mL) were added Pd(OAc)2 (7.4 mg, 0.033 mmol), Xantphos (29 mg, 0.050 mmol) and Cs2CO3 (216 mg, 0.66 mmol) and the reaction was heated to 100° C. for 30 minutes. After cooling, the reaction was partitioned between EtOAc (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (10 mL). The combined organic phases were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. Purification on silica (30-70% ethyl acetate in hexanes) afforded 4-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (50 mg, 33%) as a colorless foam. MS ESI: [M+H]+ m/z 456.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[CH:10]([CH2:12][C:13]([O:15]CC)=[O:14])[O:9][B:8]([OH:18])[C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:1][CH2:2][C:3]1[C:11]2[CH:10]([CH2:12][C:13]([OH:15])=[O:14])[O:9][B:8]([OH:18])[C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(CN)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CN)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
The mixture of ethyl 2-(4-(aminomethyl)-1-hydroxy-6-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (20 mg), LiOH (24 mg, 1 mmol) in THF/MeOH/H2O (1.5 ml/1.5 ml/1.5 ml) was stirred at room temperature for 2 hrs. The solvent was removed in reduced pressure to dryness. The crude product was purified by Prep-HPLC to give desired product 5 mg as white powder (TFA salt). 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.22 (brs, 3H), 7.19 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 5.60 (dd, J=9.4, 2.2 Hz, 1H), 4.04 (q, J=4.5 Hz, 2H), 3.78 (s, 3H), 2.99 (dd, J=15.8, 2.4 Hz, 1H), and 2.11 (dd, J=9.4, 15.8 Hz, 1H). MS (ESI) m/z=252 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[O:28][CH3:29])[C:21]([O:23]C)=[O:22])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:30][C:31]([NH2:33])=[NH:32])=[N:6][CH:5]=1.Cl>O1CCOCC1>[ClH:3].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[O:28][CH3:29])[C:21]([OH:23])=[O:22])(=[O:15])=[O:16])=[CH:11][CH:12]=2)[C:7]([NH:30][C:31]([NH2:33])=[NH:32])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
An aqueous solution of NaOH (0.7 mL, 1.0 M, 0.7 mmol) was added slowly to a stirred solution of methyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoate (52.2 mg, 0.113 mmol) in dioxane (2.5 mL) and the mixture stirred at room temperature for 1.5 h, and then at 70° C. for 3 h. The mixture was cooled to room temperature, dilute HCl (2 mL, 2 N) was added, the solvents were evaporated in vacuo and the residue was dried by azeotroping with i-PrOH (×3). The solid was extracted with hot i-PrOH (×4), the combined organic extracts were filtered, and the solvents were evaporated in vacuo. The residue was triturated with Et2O to give 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoic acid hydrochloride (29 mg, 0.055 mmol) as a solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.[Pd]>[OH:32][CH:29]([CH2:30][OH:31])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OCC(O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OCC(O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(RS)-(2,3-dihydroxypropyl)oxy]quinazoline (930 mg) in methanol (10 ml) is added 10% palladium/carbon (280 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 15 hours. To the reaction mixture is added chloroform (30 ml), and the mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in methanol-chloroform, and the solution is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in acetone, and the solution is allowed to stand at room temperature, and the precipitated crystals are separated by filtration to give 4-[(RS)-(2,3-dihydroxypropyl)oxy]-2-(1-piperazinyl)quinazoline (355 mg) as crystals.
Reaction SMILES: C1(C)C=CC(S([CH:10]([N+:18]#[C-:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=O)=O)=CC=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[N:28][CH:29]2[CH2:37][CH:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[CH2:31][CH2:30]2)=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:18]=[CH:19][N:28]([CH:29]3[CH2:37][CH:36]4[N:32]([CH2:33][CH2:34][CH2:35]4)[CH2:31][CH2:30]3)[C:27]=2[C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: C(=NC1CCN2CCCC2C1)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Fc1ccc(-c2ncn(C3CCN4CCCC4C3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
α-(p-Toluenesulfonyl)-4-fluorobenzylisocyanide (10.1 g, 34.9 mmol) and (±)-7-(4-pyridylmethyleneamino)-1,2,3,5,6,7,8,8a-octahydroindolizine (8.0 g (34.9 mmol), prepared as described in 2)) were dissolved in dichloromethane (150 ml). To the solution was added 1,8-diazabicyclo[5.4.0]-7-undecene (5.22 ml, 34.9 mmol), and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=20:1:1), to give the title compound (1.87 g) as a pale yellow powder (yield 14%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
To a stirring solution of 8 (0.116 g, 0.45 mmol) in dry THF and Pyridine (10 ml/0.300 ml), cyclohexanecarbonyl chloride (0.100 ml, 0.68 mmol) was added and stirred at room temperature for 4 h. The reaction was quenched by the addition of water and the yellow solid was filtered, air-dried and dissolved in EtOAc and passed through a bed of SiO2 gel. Elution with EtOAc afforded the desired product 9 (0.095 g, 58%). 1H NMR (DMSO-d6, 500 MHz): δ 13.49 (1H, s), 10.38 (1H, s, NH), 8.76 (1H, s), 8.41 (4H, dd, J=15 and 5 Hz); 8.34 (1H, s), 2.53 (1H, m), 1.80-1.20 (10, m); MS m/z: 366 (M+1), 364 (M−1). The product was used for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH3:39])[CH:33]=1>>[CH3:39][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][NH:29][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]4[CH3:28])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:37]=[CH:36][C:35]=1[OH:38]
Reactant: Cc1cc(CCN)ccc1O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: Cc1cc(CCNc2nccc(-c3cccc(CN4CCNC[C@@H]4C)c3)n2)ccc1O

Procedure:
Intermediate 68 was coupled with 4-(2-amino-ethyl)-2-methyl-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (s, 1H), 8.26 (d, 1H), 7.78 (d, 1H), 7.64 (t, 1H), 7.45 (d, 1H), 7.13 (d, 1H), 6.98 (s, 1H), 6.88 (d, 1H), 6.60 (d, 1H), 4.71 (d, 1H), 3.99 (d, 1H), 3.84 (s, 2H), 3.45 (m, 3H), 3.23 (m, 3H), 3.02 (t, 1H), 2.86 (t, 2H), 2.07 (s, 3H), 1.54 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:19]3[CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21][C:20]=3[NH:8][C:4]=2[CH:3]=1
Reactant: NNc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reaction time: 18 h
Yield: 41.7 %

Procedure:
3-Bromophenylhydrazine (40.0 g, 0.179 mol) and N-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and cone. HCl (72 mL) was added. The reaction mixture was then heated to reflux for 18 h, concentrated and basified using 10% NH4OH in methanol (10%, 100 mL). The solvent was removed, and the residue was suspended in CH2Cl2 (1.2 L). Boc2O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) and triethylamine (46.4 mL, 0.358 mol) were then added, and the reaction progressed at room temperature for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na2SO4, filtered and concentrated to dryness. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) to give the more polar title compound (26.2 g, 42%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.1 Hz, 1H, partially masked by solvent), 7.18 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 3.80 (t, J=5.5 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.51 (s, 9H).