Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1O>C(Cl)Cl.N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1ccc(O)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Trifluoromethanesulfonic anhydride (2.14 g, 7.6 mmol) was dissolved in DCM (5 ml) and cooled to 5° C. To this was added 2-chloro-4-isopropyl-phenol (1.23 g, 7.2 mmol), in 10 ml DCM and 1.75 ml pyridine, dropwise. The reaction mixture was stirred at 110° C. for 2 hours. The resultant dark solution was washed with 1M HCl (20 ml), water (20 ml) and saturated aqueous NaHCO3 (20 ml). The DCM extract was dried and concentrated in vacuo to provide the title compound as a dark orange oil (1.71 g, 78%). 1H NMR (CDCl3) 1.22-1.29 (6H, d, J=6.87 Hz), 2.88-3.00 (1H, sept, J=6.89 Hz), 7.15-7.20 (1H, m), 7.24 (1H, d, J=8.36 Hz), 7.36 (1H, d, J=2.17 Hz).
Reaction SMILES: CO[NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[NH:5].[Cl-].[NH4+]>CCO.O>[CH3:12][C:8]1[N:7]=[C:6]([C:4]([NH2:5])=[NH:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CONC(=N)c1cccc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=N)N)n1
Temperature: 80 °C

Procedure:
To a solution of N-methoxy-6-methyl-pyridine-2-carboxamidine (1 eq, 32.9 mmol, 4.94 g) in EtOH (40 ml) and water (10 ml) at room temperature is added ammonium chloride (1 eq, 32.9 mmol, 1.76 g). The resulting mixture is heated to 80° C. for 4 hours and then allowed to cool to room temperature overnight. The solvent is removed in vacuo to afford the title compound which is used in subsequent steps without further purification [2M+H]+=271
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([O:16]C)=[O:15])[CH2:4][CH2:3]1.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]([C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 5-oxo-1-(phenylmethyl)-proline (0.182 g) as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH:20]4[CH:16]([CH2:17][NH:18][CH2:19]4)[CH2:15][CH2:14]3)[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[C:36]([C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH:35]=[C:34]([CH2:44][CH3:45])[CH:33]=2)C=CC=CC=1.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH2:44]([C:34]1[CH:33]=[C:32]([NH:31][C:30]([N:18]2[CH2:19][CH:20]3[CH:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=5)[CH2:8]4)[CH2:14][CH2:15][CH:16]3[CH2:17]2)=[O:29])[CH:37]=[C:36]([C:38]2[N:42]([CH3:43])[N:41]=[N:40][N:39]=2)[CH:35]=1)[CH3:45]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: Fc1ccc(C[C@@H]2CCCN(C3CCC4CNCC43)C2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(NC(=O)N2CC3CCC(N4CCC[C@@H](Cc5ccc(F)cc5)C4)C3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.2 %

Procedure:
A mixture of (3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]octahydrocyclopenta[c]pyrrole (53 mg, 175 μmol), [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (56 mg, 175 μmol), triethylamine (49 μL, 350 μmol) and acetonitrile (2 mL) was stirred at room temperature. After 18 hours, the mixture was concentrated to provide a residue. The residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, and was dried over sodium sulfate and concentrated to provide a residue. The residue was purified by flash column chromatography, eluting with 2% methanol/dichloromethane containing 0.2% aqueous ammonia, to provide a tan glass (56 mg, 75%). 1H NMR (300 MHz, CDCl3) δ7.83 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 7.09 (m, 2H), 6.96 (m, 2H), 6.52 (broad s, 1H), 4.22 (s, 3H), 3.61 (m, 2H), 3.5-3.2 (m, 2H), 3.0-2.6 (m, 6H), 2.6-2.4 (m, 3H), 2.0-1.5 (m, 10H), 1.27 (m, 3H), 0.93 (m, 1H). Mass spec (ES+) m/z 532.4 (M+H+, 100%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.Cl.[CH3:16]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:16])=[O:13])=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1c[nH]c2ccccc12
Reaction time: 8 h

Procedure:
3-Indolepropionic acid (5 g) was dissolved in MeOH (50 mL) and treated with conc. HCl (5 mL). The solution was stirred overnight before the solvent was removed under reduced pressure to provide methyl 3-indolepropionate in quantitative yield. Crude methyl 3-indolepropionate (4.70 g, 23.2 mmol) was dissolved in THF (50 mL), cooled to 0° C., and treated with DIBAL-H (69.5 mL, 69.5 mmol). The reaction mixture was stirred for 2 h at 0° C. and then quenched by the slow addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with 1:1 ethyl acetate/hexane, afforded the 3-(3-hydroxypropyl)indole as a yellow solid. 1H NMR (200 MHz, DMSO-d6) δ 7.48 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15–6.92 (m, 4H), 4.40 (t, J=6.0 Hz, 1H), 3.55 (t, J=6.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 1.92–1.76 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH2:20]([NH:23][C:24](=[O:27])[O:25][CH3:26])[C:21]#[CH:22]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CCNC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CCNC(=O)OC)nc21

Procedure:
A suspension of 0.8 g (2.85 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 22 ml of a DMF/Et3N (v/v; 2.2/1) mixture is placed in a 10 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 0.98 g of methyl (prop-2-yn-1-yl)carbamate (8.66 mmol), 0.076 g of CuI (0.40 mmol) and 0.139 g of bis(triphenylphosphine)palladium(II)dichloride (0.20 mmol) are successively added.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][O:16][CH3:17].[C:18]1([C:24](=O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:36][C:34](=[O:35])[NH:33]2)=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: NC(N)=O
Reactant: COCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COCCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 42.3 %

Procedure:
To a solution of 4-hydroxy-3-(2-methoxyethoxy)-5-nitrobenzaldehyde (Intermediate 80) (200 mg, 0.83 mmol), 1,2-diphenylethanone (196 mg, 1.0 mmol) and urea (150 mg, 2.5 mmol) in ethanol (3 mL) was added conc. HCl (0.2 mL), then the resulting mixture was refluxed for 2 days. The mixture was concentrated under reduced pressure and purified by prep-HPLC (0.1% TFA as additive) to give Compound 155 (162 mg, yield 42%) as yellow solid. 1H NMR (MeOD 400 MHz) δ 7.62 (d, J=1.6 Hz, 1H), 7.27-7.24 (m, 6H), 7.07-7.03 (m, 3H), 6.91-6.86 (m, 2H), 5.37 (s, 1H), 4.17-4.10 (m, 2H), 3.76 (t, J=4.4 Hz, 2H), 3.43 (s, 3H). MS (ESI): m/z 462.1 [M+1]+.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH2:14][CH2:15][N:16]3C(=O)C4=CC=CC=C4C3=O)[CH:9]=2)[CH:4]=1.O.NN>C(O)C>[Br-:1].[NH2:16][CH2:15][CH2:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[N+:3]([CH3:2])[CH:12]=[CH:11]2
Reactant: C[n+]1ccc2cc(OCCN3C(=O)c4ccccc4C3=O)ccc2c1
Agent: NN
Agent: [Br-]
Solvent: O
Solvent: CCO
Product: C[n+]1ccc2cc(OCCN)ccc2c1

Procedure:
2-Methyl-6(2-Phthalimidoethoxy)isoquinolinium bromide (900 mg.) and hydrazine hydrate (0.3 g.) in ethanol (50 ml) were heated under reflux for 2 hr. The mixture was cooled and the precipitated hydrazide filtered off. Addition of ether to the filtrate gave a solid which was recrystallised from acetonitrile and had m.p. 173°-176°.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC.O1CCOCC1.CN1C(=O)N(C)CCC1>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(-c3cccs3)cc2c1O
Reaction time: 0.08 h

Procedure:
A deoxygenated mixture of 0.75 g of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 40, 0.75 g of 2-(tributylstannyl)thiophene, 60 mg of bis(triphenylphosphine)palladium(II)dichloride, 7.5 mL of dioxane and 2.5 mL of DMPU is stirred for 2 h at 100° C. The cooled mixture is diluted with 20 mL of hexanes and 60 mL of distilled water. The mixture is stirred for 5 minutes and then filtered. The solid is washed with two 50 mL portions of distilled water and then with two 25 mL portions of methyl t-butyl ether. It is then dissolved in 20 mL of refluxing acetic acid, treated with 2 g of activated carbon and filtered through celite. The volume of the filtrate is reduced to 10 mL and the hot solution diluted with 10 mL of distilled water. Upon cooling, 0.3 g of the title compound precipitates and is collected by filtration.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.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.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:78])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[NH:74][CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:63][CH2:62][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:60][CH2:59]1>CN(C=O)C>[F:78][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:53]=[C:54]2[CH2:76][CH:75]([CH3:77])[N:74]([C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[CH2:73][C:55]2=[N:56][C:57]=1[N:58]1[CH2:59][CH2:60][CH:61]([O:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=2[F:72])[CH2:62][CH2:63]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: CO[C@H](C)C(=O)O
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)C(=O)N1Cc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CC1C
Reaction time: 2 h

Procedure:
A solution of (R)-2-methoxypropanoic acid (1.9 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (90 μL) was stirred for 10 min at room temperature then treated with N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) 6 ppm 1.17 (t, J=6.6 Hz, 1.4H), 1.27 (dd, J=6.7, 2.7 Hz, 1.6H), 1.33 (dd, J=11.6, 6.8 Hz, 1.4H), 1.38 (dd, J=6.7, 2.7 Hz, 1.6H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.53-2.68 (m, 1H), 2.94-3.05 (m, 2H), 3.08-3.10 (m, 0.5H), 3.12-3.14 (m, 0.5H), 3.35 (s, 3H), 3.37-3.42 (m, 2H), 3.78 (td, J=14.5, 4.2 Hz, 2H), 4.03 (t, J=18.8 Hz, 1H), 4.30-4.41 (m, 1H), 4.43-4.51 (m, 1H), 4.70-4.82 (m, 1H), 5.03-5.14 (m, 0.5H), 5.18-5.23 (m, 0.5H), 5.90-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J=11.3, 8.5, 2.9 Hz, 1H), 7.18 (td, J=9.2, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 525.9.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:27]([O:21][CH2:20][C@@H:19]([OH:22])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCCCCCOC[C@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of (R)-3-(hexadecyloxy)propane-1,2-diol (1 eq), TBDMSCl (1.4 eq), NEt3 (1.4 eq) and DMAP (0.05 eq) in DCM (0.5 M) was stirred at 25° C. over night. The reaction was diluted with DCM and was with H2O twice, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (S)-1-(tert-butyldimethylsilyloxy)-3-(hexadecyloxy)propan-2-ol as a colorless oil.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: COc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1OC

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 3,4-dimethoxyphenylboronic acid: MS (ESI) m/z 353 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:35])=[CH:25][CH:24]=1)#[N:18]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Yield: 95.7 %

Procedure:
4-(4-Aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (109 mg, 0.325 mmol) was dissolved in toluene (5 ml) while heating, and then 4-fluorophenyl isocyanate (0.057 ml, 0.488 mmol) was added and the mixture was heated to reflux for 1 hour. After cooling, the precipitated crystals were filtered out, washed with ethyl acetate and dried under reduced pressure to obtain the title compound (148 mg, 0.311 mmol, 96.4%) as white crystals.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:46]1([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3Br)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a suspension of tert-butyl (1-(4-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.213 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added phenyl boronic acid (0.07 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl (1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.084 g, 40%) as a yellow solid. 1H NMR (DMSO-d6) 400 MHz δ 8.55 (s, 1 H), 8.06 (dd, JA=4.8 Hz, JB=2.4 Hz, 1H), 7.95 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 7.78 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.58-7.50 (m, 1H), 7.44-7.36 (m, 4H), 7.35-7.31 (m, 2H), 7.30-7.18 (m, 4H), 7.14-7.09 (m, 1H), 6.89 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 6.73 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 2.45-2.28 (m, 4H), 2.04-1.92 (m, 1H), 1.83-1.70 (m, 1H), 1.33 (br. s, 9H); LCMS: 556 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>CC(N(C)C)=O>[N:9]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNC1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Brc1ccc(N2CCC2)nc1
Temperature: 170 °C

Procedure:
A mixture of 5-bromo-2-chloropyridine (Sigma-Aldrich, Buchs, Switzerland, 196 mg, 1.018 mmol), azetidine (Sigma-Aldrich, Buchs, Switzerland, 0.213 ml, 3.06 mmol) and pyridine (0.124 ml, 1.528 mmol) in DMA (2.5 ml) was heated under microwave irradiation at 150° C. for 10 min and 170° C. for 10 min. The reaction was not completed. Again azetidine (0.106 ml) was added and the RM was heated under microwave irradiation at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an off-white solid. (HPLC: tR 1.97 min (Method A); M+H=213, 215 (Br-pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.12 (s, 1H), 7.70-7.60 (m, 1H), 6.37-6.29 (m, 1H), 3.96-3.86 (m, 4H), 2.34-2.24 (m, 2H))
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([C@H:21]([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14]2.Br[CH2:27][CH2:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33]>CN(C=O)C>[Br:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([C@H:21]([CH3:25])[C:22]([O:24][CH2:27][CH2:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33])=[O:23])=[CH:14]2
Reactant: O=[N+]([O-])OCCCCBr
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCCCCO[N+](=O)[O-])ccc2c1Br

Procedure:
A mixture of triethylamine (5.25 g, 52 mmol), of 2-(S)-(5-bromo-6-methoxy-2-naphthyl)propanoic acid (Bromo-Naproxen) (13.3 g, 43 mmol); e.e.99%) and of 4-bromobutylnitrate (43 mmol) in DMF (120 ml) was stirred under nitrogen for 2 days at 25° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[C:11](=[S:13])=[S:12].Cl[CH2:15][C:16](=O)[CH3:17]>CS(C)=O.O>[CH3:17][C:16]1[N:4]([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[C:11](=[S:13])[S:12][CH:15]=1
Reactant: CC(=O)CCl
Reactant: S=C=S
Reactant: Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1-n1c(C)csc1=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-methyl aniline (10.71 g, 100 mmol) in DMSO (50 mL) was treated with 20N aqueous NaOH (5 mL, 100 mmol) at room temperature. The mixture was cooled to 0° C. and CS2 (7.61 g, 100 mmol) was added. Upon stirring for 1 hour at room temperature, a change of color from dark-red to orange was observed. The solution was then cooled to 0° C. and chloroacetone (9.25 g, 100 mmol) was added. After stirring for 3 hours at room temperature, water (100 mL) was added and the mixture was stirred for an additional 10 minutes at 0° C. The precipitate was filtered and successively washed with water and ethanol. The crude product was suspended in 95% ethanol (100 mL), and 36% HCl (50 mL) was added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, the precipitate was filtered to yield the desired product. (8.7 g, 38%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][NH:25][S:26]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)(=[O:28])=[O:27]>>[ClH:1].[CH3:24][NH:25][S:26]([CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:2]2[N:7]=[C:6]([N:8]([C:9]3[CH:22]=[CH:21][C:12]4[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH3:23])[CH:5]=[CH:4][N:3]=2)=[CH:35][CH:36]=1)(=[O:27])=[O:28]
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Product: CNS(=O)(=O)CCc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NC(C)C)n4C)n2)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (54 mg, 0.25 mmol) as a white solid (71 mg, 52%). 1H NMR (300 MHz, d6-DMSO) δ 9.05 (s, 1H), 7.68-7.76 (M, 3H), 7.19 (d, J=8.4 Hz, 1H), 7.08-7.13 (M, 3H), 6.96 (q, J=5.1 Hz, 1H), 6.81 (dd, J=8.1 and 1.8 Hz, 1H), 6.53 (d, J=6.9 Hz, 1H), 5.60 (d, J=5.7 Hz, 1H), 4.04 (m, 1H), 3.51 (s, 3H), 3.42 (s, 3H), 3.21-3.30 (m, 2H), 2.83-2.88 (m, 2H), 2.59 (d, J=5.1 Hz, 3H), 1.23 (d, J=6.6 Hz, 6H) ppm. MS (ESI) m/z=509 [M+H]+.