Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:26][CH:25]=1)[C:4]1[C:13]([C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2F)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([OH:23])=[CH:9]2.CC(C)([O-])C.[K+]>CN(C=O)C>[F:21][C:17]1[CH:16]=[C:15]2[C:14](=[C:19]([F:20])[CH:18]=1)[C:13]1[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:23])[CH:7]=[CH:6]3)[CH:3]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[CH:28][CH:29]=1)[O:2]2
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc2c3c(ccc2c1)-c1c(F)cc(F)cc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 50 °C
Yield: 77.9 %

Procedure:
Dissolve 5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-(2,4,6-trifluoro-phenyl)-naphthalen-2-ol hydrochloride (730 mg, 1.4 mmol) and potassium tert-butoxide (5.36 mg, 4.8 mmol) in dry DMF (25 mL) and heat at 50° C. for 10 minutes. Cool reaction and pour onto ice/ethyl acetate. Separate organic layer and wash with 10% aqueous lithium chloride. Dry, filter, and concentrate in vacuo. Purify by silica gel chromatography using a 1-6% gradient of methanol in dichloromethane to yield 532 mg (76%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:35]=[CH:36]\[CH2:37][N:38]1[CH2:42][CH2:41][C@@H:40]([O:43][C:44](=[O:46])[CH3:45])[CH2:39]1)CCC>O1CCOCC1.CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]3[C:16]([C:17]4[CH:29]=[CH:28][O:27][C:18]=4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:2](/[CH:35]=[CH:36]\[CH2:37][N:38]2[CH2:42][CH2:41][C@@H:40]([O:43][C:44](=[O:46])[CH3:45])[CH2:39]2)[CH:7]=1
Reactant: CCCC[Sn](/C=C\CN1CC[C@@H](OC(C)=O)C1)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](OC(C)=O)C2)ccc2c1OCc1occc1-2
Temperature: 50 °C
Yield: 86.4 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 0.09 g) and acetic acid (R)-1-((Z)-3-tributylstannylallyl)-pyrrolidin-3-yl ester (Intermediate 83, 0.170 g) in dioxane (4.5 mL) and DMSO (0.5 mL) was de-gassed and purged with argon for several minutes. tris-(Dibenzylideneacetone)dipalladium (0.017 g) and tri-tert-butylphosphonium tetrafluoroborate (0.011 g) were added and the solution was de-gassed, purged with argon and then heated at 50° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-{4-fluoro-2-[(Z)-3-((R)-3-acetoxypyrrolidin-1-yl)-prop-1-enyl]-benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (0.092 g) as a thick yellow oil which was used without further characterisation.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:25]12[CH:30]([NH:31][C:32](=[O:48])[O:33][CH2:34][CH:35]3[C:47]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:41]4[C:36]3=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:29]1[CH2:28][NH:27][CH2:26]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:27]3[CH2:26][CH:25]4[CH:29]([CH:30]4[NH:31][C:32](=[O:48])[O:33][CH2:34][CH:35]4[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=5[C:42]5[C:47]4=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:28]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(NC1C2CNCC21)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)CC21)OCC1c2ccccc2-c2ccccc21
Temperature: -60 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (1.0 g, 1.0 eq.) was dissolved in DCM (50 mL) and cooled to −60° C. where (9H-fluoren-9-yl)methyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate (1.09 g, 1.2 eq.), T3P (50% in EtOAc) (2.02 mL, 1.2 eq.) and DIPEA (0.95 mL, 2 eq.) was added. The clear reaction mixture was stirred at −60° C. for 1 h, quenched with water, and extracted with DCM. The organic layer was dried over sodium sulphate, concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (2% Methanol in DCM) to yield (Z)-(9H-fluoren-9-yl)methyl (3-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.26 g, 69% yield).
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[C:28]([O:34][CH3:35])[CH:27]=1.Br[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@@H:46]2[CH:51]3[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]3)[CH2:47]2)=[O:45])=[CH:39][CH:38]=1.[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@@H:46]3[CH:51]4[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]4)[CH2:47]3)=[O:45])=[CH:39][CH:38]=2)=[CH:27][C:28]=1[O:34][CH3:35]
Reactant: O=C(Nc1ccc(Br)cc1)[C@H]1CN2CCC1CC2
Reactant: COc1cc(Br)ccc1CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)ccc1CO
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
118 mg (0.47) of bis(pinacolato)diboron, 193 mg (1.4 mmol) of dry potassium carbonate, and (4-bromo-2-methoxyphenyl)methanol are dissolved in 1 ml of DMF. Argon is passed through the reaction mixture for 15 minutes, and then 14.2 mg (0.02 mmol) of PdCl2(dppf) are added, and the mixture is heated at 85° C. overnight. Then, 120 mg (0.39 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 1.94 ml of 1N sodium hydroxide solution and a further 14.2 mg (0.02 mmol) of PdCl2(dppf) are added. The mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 60:40:2). The solvent is stripped off under reduced pressure, and final residues of solvent are removed under high vacuum. 5 mg (4% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33].O>CC#N.CN(C)C1C=CN=CC=1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (50 mg) was dissolved in CH3CN (2 mL). To this solution was added 3-methoxy-4-methoxycarbonyl-phenylboronic acid pinacol ester (120 mg, [CAS Reg. No. 603122-40-3]), cupric(II)-acetate (74.5 mg) and 4-dimethylaminopyridine (66.7 mg). The rection mixture was stirred at 80° C. for 18 hours. The mixture was cooled, poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by amino phase chromatography (ethyl acetate:heptane=2:3) to give the desired compound as a colorless solid (24 mg, 33%). MS (neg. ion, m/e)=527.9 [(M−H)−].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([Cl:13])[N:5]=1.[CH3:14]I.O>O1CCCC1>[Cl:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH3:14])=[C:6]([Cl:13])[N:5]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
Sodium hydride (60% in mineral oil, 2.53 g, 63.5 mmol) was added to an ice-cooled solution of 2,6-dichloropurine (10.0 g, 52.9 mmol) in tetrahydrofuran (75 mL) and the mixture was stirred for 30 min. Methyl iodide (3.29 mL, 52.9 mmol) was added drop-wise and the reaction mixture was stirred over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. Dichloromethane was added and undissolved material was collected by filtration. The crystalline compound turned out to be 2,6-dichloro-7-methyl-7H-purine (1.19 g, 11%) The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hepatane) to give 2,6-dichloro-9-methyl-9H-purine (3.0 g, 28%).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:34])[CH:8]=1.[OH-].[Na+]>C1COCC1>[F:34][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[N:16]=2)[CH:2]=[O:1]
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CCCCC3)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CCCCC4)nc3s2)c(F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine (0.467 g, 0.984 mmol) in 5 mL 1:1 THF/5N HCl was sealed and heated to 80° C. The resulting yellow solution was allowed to stir 3 h, was cooled, and then was treated with ice and 10N NaOH until basic. The reaction mixture was partitioned between EA and water, washed with water, brine, dried over sodium sulfate, filter, concentrate in vacuo to give 3-fluoro-4-(5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as an oil/solid that contained some starting material. This material was carried on without further pyrification. MS (ESI) m/z: Calculated: 416.1; Observed: 417.1 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH:17]([NH:20][C:21]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=O)[CH2:18][CH3:19])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>>[CH:23]1([C:21]2[N:12]3[C:13]([C:14](=[O:16])[NH:15][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[N:11]3)=[C:17]([CH2:18][CH3:19])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 3.5 g (9.4 mmol) N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclopentanecarboxamide, 1.45 g (9.4 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[C:10]21[CH2:12][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:26]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[O:27][Si:28](Cl)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[C:10]2([CH2:12][CH2:11]2)[C@H:13]2[C@@H:14]([O:17][Si:26]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:30])[CH3:31])[O:19][CH2:18]2)[C@H:15]1[OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: OC[C@@H]1[C@@H](O)[C@@H](O)[C@@H](OCc2ccccc2)C12CC2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@@H](O)[C@@H](OCc1ccccc1)C21CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a stirred mixture of triol 24 (2.9 g, 10.9 mmol) and imidazole (5.2 g, 76.8 mmol) in DMF (80 mL) at 0° C. under argon was added dropwise 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (3.5 mL, 11.0 mmol). After the mixture was stirred at room temperature for 1 h, quenched with MeOH (15 mL) and water (100 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (40 mL) dried over Na2SO4. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc:Hexane 1:30 to 1:5) to give 25 (5.1 g, 92%) as an oil. [α]24D −105.94° (c 0.58, CHC13); 1H NMR (500 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 4.77 (d, J=12 Hz, 1H), 4.62 (d, J=12 Hz, 1H), 4.18-4.14 (m, 3H), 4.05 (dd, J=4.5, 12.0 Hz, 1H), 3.78 (dd, J=8, 12 Hz, 1 H), 2.89 (m, 1 H), 2.78 (d, J=2.0 Hz, 1H, OH) 1.08-0.97 (m, 28H), 0.61 (m, 1H), 0.43 (m, 1H), 0.32 (m, 1H), 0.24 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 154.0,147.3, 138.1, 128.4, 80.2, 74.2, 71.2, 71.1, 64.9, 50.1, 29.24 23.83, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.9, 16.8, 13.4, 12.9, 12.7, 12.5. 7.20; HR-MS Calcd. For (C27H46O5Si2+H)+ 507.2884, found 507.2798.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:36])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=1)=[O:19])=[CH:7]2.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:39][N:38]=[N:37][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:36])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:21]=1)=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccc2c(Br)c(OCC#N)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
A mixture of 1-benzyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.7725 g, 1.44 mmol), prepared in the previous step, sodium azide (0.28 g, 4.3 mmol) and ammonium chloride (0.23 g, 4.3 mmol) in 15 mL DMF was stirred under nitrogen for 4 h at 100° C. The reaction was diluted with water, made basic with 1N NaOH, and extracted five times with ethyl acetate. The ethyl acetate layer was acidified with 1N HCl and the solvent was removed under reduced pressure to give 0.133 g of the desired compound as an off-white solid. The aqueous layer was acidified with 1N HCl. The solution sat at room temperature for 18 h (overnight). A solid had precipitated from solution and was collected by filtration, rinsed with water, and dried under reduced pressure to give the title compound (0.4962 g, 60%) as an off white solid, mp 197-198° C.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18]>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 90 %

Procedure:
(S)-2-(oxiran-2-ylmethy)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in acetonitrile (70 mL) respectively, then heated to reflux. Tetra-n-butylammonium bromide (0.55 g, 1.71 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.57 g, yield: 90.0%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](NC2C([N+]([O-])=O)=CN=C(Br)C=2)C)C=CC=CC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:61](=O)([O-])[O-:62].[K+].[K+]>CN(C=O)C.O.C(OCC)(=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>[C:1]1([C@@H:7]([N:9]2[C:10]3[CH:11]=[C:12]([C:19]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:20]=4[CH:21]=[CH:22][CH:23]=[N:24]5)[N:13]=[CH:14][C:15]=3[NH:16][C:61]2=[O:62])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cc(-c2cccc3ncccc23)ncc1[N+](=O)[O-])c1ccccc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[C@H](Nc1cc(Br)ncc1[N+](=O)[O-])c1ccccc1
Agent: OB(O)c1cccc2ncccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Temperature: 85 °C
Yield: 77 %

Procedure:
((1S)-1-Phenylethyl)(5-nitro-2-(5-quinolyl)(4-pyridyl))amine. ((1S)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine (5.6 g, 1.75 mmol) and 5-quinolineboronic acid (393 mg, 2.27 mmole) were dissolved in DMF (25 ml). Nitrogen gas was bubbled into solution for 2 min. Potassium carbonate (970 mg, 7.00 mmol) in water (5 mL) was then added followed by tetrakis(triphenylphosphine)palladium (0) (0.175 mmol). The solution was then heated to 85° C. under nitrogen for 1 h. The solution was condensed under reduced pressure and the crude product was diluted with ethyl acetate and filtered through a plug of silica-gel. The resultant filtrate was condensed under reduced pressure to afford the title compound (500 mg, 77%). MS (ESI) m/z 371 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:10][CH:9]=1)=[O:6].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:5]([NH:7][S:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[O:2][CH3:1])=[CH:9][CH:10]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1)(=[O:28])[CH2:9][CH2:8][CH3:17]
Reactant: COc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3OC)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-methoxy-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyric chloride and triethylamine for 2-isocyanato-propane. LC/MS m/z 508 (M−H)−, 510 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:12][NH2:13]>>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([NH:13][CH3:12])[NH:6][C:5]=2[CH:7]=1
Reactant: CN
Reactant: Fc1ccc2nc(Cl)[nH]c2c1
Product: CNc1nc2ccc(F)cc2[nH]1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.Cl.F[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>C(O)C>[ClH:1].[ClH:1].[N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1
Reactant: Fc1ccccn1
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4ccccn4)CC3)C[C@H]1CO2

Procedure:
A mixture of 0.482 g of the compound of Example 1 (1.48 mmol) and 0.245 ml of diisopropylethylamine in 5 ml of 2-fluoropyridine is heated at reflux for 24 hours. After evaporating off the solvents and then diluting with water, the mixture is extracted with ethyl acetate, dried (MgSO4) and evaporated. The residue obtained is purified by chromatography on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (97/3/0.3) as eluant to yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.