Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[C:11]=1[CH3:19].N([O-])=O.[Na+].Cl>O.O1CCCC1>[CH3:19][C:11]1[C:10]([Cl:9])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[C:17](=[O:18])[NH:7][N:6]=[N:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cl)cccc1N=C=O
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1-n1nn[nH]c1=O

Procedure:
A mixture of aluminium chloride 4.71 g, sodium azide 6.89 g and tetrahydrofuran 100 mL was stirred with heating under reflux for one hour. After the reaction mixtures were cooled under ice-cooling, thereto were added a mixture of the above-mentioned 1-chloro-3-isocyanato-2-methylbenzene and tetrahydrofuran 10 mL and the resulting mixtures were stirred with heating under reflux for five hours. After cooling the mixtures, to a mixture of sodium nitrite 10.59 g and water 300 mL was added the reaction mixtures with stirring. The mixtures were acidified with concentrated hydrochloric acid and were extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=3)[C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C2(O)CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Temperature: 25 °C

Procedure:
A flask equipped with a Dean-Stark trap was charged with 3.4 g of (9.85 mmol) of 1,2,3,4-tetrahydro-1-hydroxy-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound C) and 40 ml of benzene. A catalytic amount of p-toluenesulfonic acid monohydrate was added and the resulting solution heated to reflux for 2 hours. Upon cooling to room temperature, Et2O was added and the solution washed with H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure, and column chromatography (100% hexane/silica gel) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.32 (1H, dd, J=2.1, 8.2 Hz), 7.21 (5H, m), 7.15 (1H, d, J=2.1 Hz), 5.98 (1H, t, J=4.7 Hz), 2.40 (3H, s), 2.32 (2H, d, J=4.7 Hz), 1.30 (6H, s).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([NH:30][C:31]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=S)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:37]([O:36][C:34]([NH:33][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:11]2[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:17]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1cccc(N)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a suspension of 3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)aniline (364 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (385 mg) and diisopropylethylamine (0.465 ml) in dichloromethane (12 ml) was added 1-methyl-2-chloropyridinium iodide (385 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 35 g, 20% ethyl acetate in n-hexane) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)phenyl)guanidine (549 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:18]1C=C2C(=CC=1)N(C(OC(C)(C)C)=O)N=C2C.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(-c3cccnc3Cl)cc12
Yield: 43 %

Procedure:
5-(2-Chloropyridin-3-yl)-3-methyl-1H-indazole was synthesized in the similar manner to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of tert-butyl 5-bromo-3-methyl-1H-indazole-1-carboxylate (1.5 g, 4.8 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.3 g, 5.3 mmol), Pd(PPh3)4 (390 mg, 0.33 mmol) and 2M aq.Na2CO3 (7 mL, 14 mmol) in 1,4-dioxane (40 mL). Upon work-up and purification procedure used in the prepartion of 5-(2-chloropyridin-3-yl)-1H-indazole provided 5-(2-chloropyridin-3-yl)-3-methyl-1H-indazole (0.52, 43%) as a white crystalline solid. 1H NMR (DMSO-d6): δ 12.75 (s, 1H), 8.41 (dd, 1H, J=1.7 and 4.7 Hz), 7.91 (dd, 1H, J=1.7 and 7.6 Hz), 7.77 (s, 1H), 7.52 (d, 1H, J=8.5 Hz), 7.51 (dd, 1H, J=4.7 and 7.6 Hz), 7.41 (dd, 1H, J=1.4 and 8.5 Hz), 2.49 (s, 3H).LCMS: rt 6.28 min (A), purity 97%, MS (m/e) 244.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C([Li])CCC.C(NC(C)C)(C)C.[C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:46])[CH3:45].N1C=CN=C1>C1COCC1>[C:48]([O:47][C:44](=[O:46])[CH2:45][C:17](=[O:19])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of CBZ-L-tert-leucine (20.53 g, 77.4 mmol, 1 equiv) in THF (150 mL) was added 1,1′-carbonyldiimidazole (13.81 g, 85.14 mmol, 1.1 equiv) at 23° C. The resulting solution was stirred at 23° C. for 1 h. In a separate flask, n-butyllithium (101.59 mL of a 1.6 M solution in hexanes, 162.54 mmol, 2.1 equiv) was added to a solution of diisopropylamine (22.78 mL, 162.54 mmol, 2.1 equiv) in THF (100 mL) at −78° C. The reaction mixture was stirred for 15 min at −78° C., warmed to 0° C. for 5 min, then cooled back to −78° C. A solution of tert-butyl acetate (21.9 mL, 162.54 mmol, 2.1 equiv) in THF (10 mL) was added via cannula, and the resulting mixture was stirred at −78° C. for 10 min. The above imidazole solution was then added dropwise to the lithium enolate at −78° C. The resulting mixture was stirred at −78° C. for 1 h, quenched with 1 M HCl (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to afford 4-benzyloxycarbonylamino-5,5-dimethyl-3-oxo-hexanoic acid tert-butyl ester as a pale yellow oil (12.06 g, 44%): IR (cm−1) 1717, 1508, 1265, 739; 1H NMR (CDCl3) δ 1.09 (s, 9H), 1.44 (s, 9H), 3.50 (s, 2H 4.29 (d, 1H, J=9.3), 5.03 (s, 2H), 5.35-5.42 (m, 1H), 7.34 (s, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:34])[O:32][CH3:33].Cl>C(Cl)Cl.O>[CH3:33][O:32][C:31]([NH:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)=[O:34]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To 70 ml of methylene chloride was added 3.46 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Further, 870 mg of pyridine was added thereto. The mixture was ice-cooled. To this solution was dropwise added a solution of 1.04 g of methyl chlorocarbonate dissolved in 30 ml of methylene chloride, in 10 minutes. The mixture was then stirred for 30 minutes at 20°-25° C. 50 ml of water was added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 2.95 g (yield: 73%) of 3-methoxycarbonylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 233°-235° C.
Reaction SMILES: C(C1CCCN([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[NH:23][C:19]=3[CH:18]=2)=[O:16])C1)C1C=CC=CC=1.N1C2C=CC=CC=2NC1=O.[Cl:37]CC(Cl)=O>>[Cl:37][CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=C(CN1CCCC(Cc2ccccc2)C1)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(Cl)CCl
Agent: O=c1[nH]c2ccccc2[nH]1
Product: O=C(CCl)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
from 5-(2-(3-benzylpiperidino)-1-oxoethyl)-2,3-dihydrobenzimidazol-2-one ("K"; obtainable by reaction of 2,3-dihydrobenzimidazol-2-one with chloroacetyl chloride to give 5-chloroacetyl-2,3-dihydrobenzimidazol-2-one ("L"), then reaction with 3-benzylpiperidine):
Reaction SMILES: C1(C[O:8][C:9]2[NH:17][C:16]([NH:18]C(=O)C)=[N:15][C:14]3[C:10]=2[N:11]=[CH:12][N:13]=3)C=CC=CC=1.C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1NC(=O)C(F)(F)F)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>CC#N>[NH:17]1[C:9](=[O:8])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[N:15]=[C:16]1[NH2:18]
Reactant: CC(=O)Nc1nc2ncnc-2c(OCc2ccccc2)[nH]1
Agent: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To 5 g (17.65 mmol) of N-[6-(phenylmethoxy)-1H-purin-2-yl]-acetamide was added 150 mL of dry CH3CN and 9.60 mL (38.34 mmol) of BSA and this mixture was stirred at 80° C. for 3 h. At this time, 15.65 g (33.80 mmol) of 2-deoxy-2-[(trifluoroacetyl)amino]-β-D-glucopyranose-1,3,4,6-tetraacetate was added followed by 6.80 mL (35.30 mmol) of TMSOTf. This mixture was heated with stirring at 80° C. for 12 hours. At this time, the reaction mixture was poured into 200 mL of saturated, aqueous NaHCO3 and this mixture was extracted twice with EtOAc. The combined organic layers were washed once with H2O and brine before drying over MgSO4. The crude product was obtained by filtration and concentration of the filtrate in vacuo to a brownish foam. The glycosylation product was obtained by silica gel column chromatography eluted with 50% to 75% EtOAc / hexanes. Appropriate fractions were collected and further purified by normal phase preparative HPLC eluting prepacked silica cartridges with 50% EtOAc/hexanes. In this manner, 1.75 g (15% yield) of the desired product, N-[6-(phenylmethoxy)-9-[3,4,6-tris-O-acetyl-2-deoxy-2-[(trifluoroacetyl)amino]-β-D-glucopyranosyl]-1H-purin-2-yl]acetamide, was isolated. 1H NMR: (CDCl3): guanine H-8 8.42 (s, 1H), anomeric H-1 6.19 (d, 1H), benzyl methylene 5.62 (m, 2H), N-acetamide methyl 2.30 (s, 3H). FAB-MS: m/z 667 for (M+1))+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16](CC=C)[C:15]([Cl:23])=[N:14][C:13]=2[N:12]([CH2:24][CH2:25][CH2:26][CH3:27])[C:11]1=[O:28])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1([C:41]2[NH:45][N:44]=[N:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>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.CO.CN(C=O)C>[CH2:24]([N:12]1[C:13]2[N:14]=[C:15]([Cl:23])[NH:16][C:17]=2[C:18](=[O:19])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:43]2[N:44]=[N:45][C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:42]2)[C:11]1=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCOS(C)(=O)=O)c(=O)n2CCCC
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCCn2nnc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 60 h
Yield: 28.2 %

Procedure:
A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs2CO3 (45 mg, 0.14 mmol) and DMF (3 ml) was treated with 5-phenyl-1H-tetrazole (20 mg, 0.14 mmol) and stirred for 60 h at 50° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (20 mg, 0.017 mmol) was added and the mixture degassed once more. Morpholine (150 μl, 1.7 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an NH2-propyl column with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as an off-white solid (15 mg, 29%).
Reaction SMILES: [CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1>CO.[Pd]>[CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH2:15][CH2:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]ncc(n1)c23
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=C2CCC3=C2C(=N1)C=NNC3=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 59.8 %

Procedure:
A mixture of tricyclic nucleoside 6.6 (20 mg, 0.06 mmol) and 10% Pd/C (12.8 mg, 0.2 eq.) in 20 mL of MeOH under H2 pressure (32 psi) was shaken for 7 hr at room temperature. The mixture was filtered through 0.45 μm filter. The combined filtrates were evaporated and purified on a silica gel column with 5% MeOH in CH2Cl2. 12 mg of pure compound 8.1 was obtained (yield 60%). 1H NMR (300 MHz, DMSO-d6): δ 10.65 (br s, 1H, NH), 8.37 (s, 1H, H-4), 7.48 (s, 1H, H-1), 6.12 (s, 1H, H-1′), 5.05 (m, 3H, 3×OH), 3.89-3.12 (m, 4H, H-3′, H-4′, 2×H-5′), 2.86-2.74 (m, 4H, 2×H-8, 2×H-9), 0.64 (s, 3H, CH3); LCMS: ES-MS 393.6 (+CH3COO).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[O:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@@H:5]4[CH2:6]3)=[O:32])=[CH:34][CH:35]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: O=C1c2ccccc2NC[C@H]2CCCN12
Product: O=C(Nc1ccc(C(=O)N2C[C@H]3CCCN3C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 43 %

Procedure:
The same procedures used in Example 25 were repeated using (11aR)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 25 and 4-[(2-phenylbenzoyl)amino]benzoic acid to thus give the title compound. Yield 43.0%.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([Cl:48])=[C:17]([NH:23][C:24]3[N:29]=[C:28]([N:30]([CH:40]4[CH2:42][CH2:41]4)[CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:27]4=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]4[N:25]=3)[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:48][C:16]1[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)=[CH:20][C:19]([C:21]#[N:22])=[CH:18][C:17]=1[NH:23][C:24]1[N:29]=[C:28]([N:30]([CH:40]2[CH2:42][CH2:41]2)[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(O[Si](C)(C)C(C)(C)C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
(I13D): To a round bottom flask charged with 2-((3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (I13C) (1.446 g, 2.113 mmol) in tetrahydrofuran (21.13 ml) and cooled to 0° C. was added TBAF (4.23 ml, 4.23 mmol). The reaction mixture was stirred at room temperature 2 d. The reaction mixture was poured into a separatory funnel containing saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was taken up in dichloromethane. A white precipitate was isolated by filtration. The filtrate was purified by column chromatography on the ISCO system (40 g, 0-50% EtOAc/CH2Cl2). The precipitate was combined with the column isolate to provide 2-((2-chloro-5-cyano-3-(4-hydroxypiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.816 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CCN(C(C)C)C(C)C.[CH:22]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.O=P(Cl)(Cl)Cl.NCCNCCN.CCN(C(C1C=CC=C(C)C=1)=O)CC.[OH-]>ClCCCl.CC(N(C)C)=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:27]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:28])[CH:11]=1
Reactant: O=C(O)C1CCCC1
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: NCCNCCN
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=C(O)c1ccc(Cl)cc1NC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). Cyclopentanecarboxylic acid (13.7 mg, 120 μmol, 3 eq.) and POCl3 (18.2 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA, Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of 1M aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the final product (4.3 mg, 99% purity). MS (EI) for C13H14ClNO3: 268 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:38][CH:39]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (75 mg, 0.337 mmol). The final product was collected as a white solid (60 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 8.61 (t, J=4.93 Hz, 1H) 8.45 (d, J=2.27 Hz, 1H) 8.34 (s, 1H) 8.00 (s, 1H) 7.90 (dd, J=8.59, 2.53 Hz, 1H) 7.78 (s, 1H) 6.55 (d, J=8.59 Hz, 1H) 6.10-6.17 (m, 2H) 5.91 (s, 1H) 5.13 (quin, J=6.57 Hz, 1H) 4.42 (br. s., 1H) 4.41 (br. s., 1H) 2.52-2.56 (m, 2H) 2.13 (s, 3H) 1.51-1.57 (m, 2H) 1.50 (s, 3H) 1.48 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=459.2
Reaction SMILES: [CH2:1]([S:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([NH2:20])[C:12]=1[CH2:21][CH2:22][NH2:23])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.O.[Ni]>[CH2:1]([S:8]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:20])[C:12]=1[CH2:21][CH2:22][NH2:23])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: NCCc1c(N)cc([N+](=O)[O-])cc1S(=O)(=O)Cc1ccccc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: NCCc1c(N)cc(N)cc1S(=O)(=O)Cc1ccccc1

Procedure:
20.0 g of 2-(2-aminoethyl)-amino-5-nitrophenyl benzyl sulphone are suspended in 100 ml of ethanol and 100 ml of water. In an autoclave 1 g of Raney nickel is added, 40 bar of hydrogen are injected, and the temperature is raised to 60° C. until after a further injection of hydrogen there is no further consumption. After the reduction has ended the resultant solution is clarified hot from Raney nickel, the nickel residue is washed with 40 ml of hot water, and the resulting solution is reacted as per Example 16.