Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH2:33][NH:32][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)NCCO)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminoethanol (8 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration in vacuo, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(2-hydroxyethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (6 mg, 10%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 8.18 (dd, 1H, J1=6.6 Hz, J2=1.8 Hz), 8.08 (d, 1H, J=2.1 Hz), 8.04-8.01 (m, 1H), 7.67 (t, 1H, J=7.8 Hz), 7.60-7.55 (m, 1H), 6.39 (d, 1H, J=7.5 Hz), 6.29 (d, 1H, J=8.7 Hz), 4.30-4.26 (m, 1H), 3.78-3.69 (m, 3H), 3.58-3.49 (m, 3H), 2.21-2.08 (m, 3H), 1.81-1.78 (m, 1H), 1.19 (d, 3H, J=5.1 Hz). LC-MS: [M+H]+, 458, tR=1.52 min, HPLC: 96.29% at 214 nm, 96.47% at 254 nm, tR=5.332 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[O:27])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([F:34])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)N3CCOCC3)c2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2cccc(C(=O)N3CCOCC3)c2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(3-(morpholine-4-carbonyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 7% of the corresponding Z isomer, MS (ESI+): m/z=498.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 47.4 %

Procedure:
A solution of 4-pyridyl piperazine (9.78 g), 4-fluorobenzonitrile(7.26 g) and powdered potassium carbonate(10 g) was stirred and heated in DMSO(100 ml) at 100° C. for 18 hours. The solution was poured into water (500 ml) to give a precipitate which was filtered and washed with water. The crude solid was dried in a vacuum oven for 18 hours. The residue was dissolved in dichloromethane and purified by flash chromatography on alumina (ICN Alumina N 32-63) using an increasing concentration of ethyl acetate in dichloromethane (up to 100% ethyl acetate) as eluant to give a solid which was recrystallised from ethyl acetate/isohexane to give 1-(4-cyanophenyl)-4-(4-pyridyl)piperazine (7.5 g) as a solid. m.p. 157-158° C.; microanalysis. found: C, 72.7; H, 6.1; N, 21.0%; C16H16N4 requires: C, 72.7; H, 6.1; N, 21.2%. NMR (dmso-d6):3.45-3.55(8H,bs),6.8-6.9(2H,d);7.0-7.1(2H,d); 7.55-7.65(2H,d);8.1-8.2(2H,d); MS m/Z 265 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[N:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:12])[N:18]=2)(=[O:21])=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1cccc(S(=O)(=O)Cl)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(S(=O)(=O)Nc2cccc3cccnc23)n1
Yield: 22.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (250 mg, 1.73 mmol), 6-methyl-pyridine-2-sulfonyl chloride 441 (530 mg, 2.77 mmol), DMAP (cat.), pyridine (3 ml) and DCM (2 ml) gave the title compound (115 mg, 22%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([F:20])=[CH:18][C:17]([Br:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([F:20])=[CH:18][C:17]([Br:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)cc(F)c3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)cc(F)c2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-bromo-7-fluorobenzoxazole (284 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[Cl:18][C:19]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]([NH:29][S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 45.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Intermediate 461) (1.24 g, 4.29 mmol), 5-chloro-quinolin-8-ylamine (Intermediate 27) (0.64 g, 3.58 mmol), DMAP (cat.), pyridine (0.86 ml, 10.7 mmol) and DCM (5 ml) gave the title compound (700 mg, 45%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@@H:20]4[O:21]C(C)(C)[O:23][C@@H:19]4[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17]3)=[C:9]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:8]=2)[CH2:3]1.[CH:46]1[N:50]=[CH:49][N:48]([C:51](N2C=NC=C2)=[O:52])[CH:47]=1>C(Cl)Cl>[OH:21][C@@H:20]1[C@H:19]([OH:23])[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:51]([N:48]3[CH:47]=[CH:46][N:50]=[CH:49]3)=[O:52])[CH2:3]1)=[N:8][C:9]=2[NH:31][CH2:32][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)n5ccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising N-{(3aR,4S,6R,6aS)-6-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-yl}-propionamide (Intermediate M) (0.24 g, 394 μmol) and CDI (0.275 g, 1.7 mmol) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by chromatography on silica eluting with 100% DCM changing to 5% MeOH in DCM to afford the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[NH:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[N:19]([CH2:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2
Reactant: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2CCCc1ccccc1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 790 mg (2.42 mmol) of cesium carbonate in 10 mL of DMF is heated at 90° C. for 10 minutes. After addition of 600 μl (1.21 mmol) of (3-bromopropyl)benzene, the reaction is continued for 2 hours at 90° C. The solvent is evaporated off. The residue is purified by RP18 reverse-phase chromatography (eluent: H2O 100% to CH3CN 100%) to give 100 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:15][CH:14]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(C(=O)Cc2ccncc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC(C(=O)c1ccc(OC)cc1)c1ccncc1
Reaction time: 0.5 h

Procedure:
Under an argon, 2-(4-pyridyl)-4′-methoxyacetophenone (J. Am. Chem. Soc., 112, 2163-3168, 1990: Dimitrios Stefanidis and John W. Bunting; 9.6 g, 42.3 mmol) was suspended in tetrahydrofuran (200 ml), and under ice cooling, lithium diisopropylamide (2.0 M solution; 25 ml, 50.0 mmol) was added. At the same temperature, the mixture was stirred for 30 minutes. Methyl bromoacetate (6.0 ml, 63.4 mmol) was then added dropwise, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 2 hours. The reaction mixture was diluted with toluene. The mixture was washed successively with 2 N hydrochloric acid, water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated and purified by chromatography on a silica gel column [silica gel: 100 g, hexane/ethyl acetate (1/2)], whereby the title compound (10.63 g, 84.1%) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([CH:12]1[NH:16][C:15](=[O:17])[NH:14][C:13]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1COCC1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([CH:12]1[CH2:13][NH:14][C:15](=[O:17])[NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC1NC(=O)NC1=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC1CNC(=O)N1
Yield: 78.1 %

Procedure:
A dry 250 ml round bottom flask equipped with a nitrogen inlet, reflux condenser and stirring bar was charged with 2.44 g of 5-undecylhydantoin and 100 ml of THF. To this was added dropwise 10 ml of 3.5M Vitride in toluene. After the initial foaming had ceased the reaction mixture was refluxed for 30 hours. The reaction was quenched with saturated sodium sulfate solution and extracted with 3×50 ml of ether. The combined ether extracts were dried, filtered and concentrated. Recrystallization from ether gave 1.8 g (78%) of white crystals, m.p. 97°-99° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Li]C(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1.O>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]1[CH2:5][CH2:4][CH:3]=[CH:2][O:1]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=COCCC1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1CCC=CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of 2,3-dihydropyran (2.0 g, 23.8 mmol) in dry THF (50 mL) was added tert-BuLi (26.2 mmol) at -78° C. and the resulting solution was stirred at 0° C. for 1 hour. The mixture was cooled to -78° C. and tributylstannyl chloride (5.53 g, 17.0 mmol) was added and stirring was continued for fifteen minutes at which time the reaction mixture was diluted with water and extracted 3× with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was filtered through a plug of silica gel to yield 5.23 g (59%) of the title compound as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:3]2[CH:4]=[N:5][N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[CH3:1])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1CCc1ccccc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1CCc1ccccc1
Yield: 30.8 %

Procedure:
The reaction and treatment in the same manner as in Example 64 were conducted using 5-methyl-1-(2-phenylethyl)pyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.75 g) and the resulting product was recrystallized from ethyl acetate to give the title compound (0.4 g), melting point: 195° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C)c(Br)c1
Product: CCCN(CCC)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-methyl-N,N-dipropyl-benzenesulfonamide (Intermediate 148), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[CH3:11][O:10][C:3]1([CH2:2][NH:1][C:19](=[O:21])[CH3:20])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1
Reactant: COC1CCC(CN)(OC)O1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CCC(CNC(C)=O)(OC)O1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
11.5 [lacuna] (71.3 mmol) of 2-aminomethyl-2,5-dimethoxytetrahydrofuran and 20 ml (143 mmol) of triethylamine were dissolved in 150 ml of anhydrous tetrahydrofuran. At 0° C., a solution of 5 ml (71.3 mmol) of acetyl chloride in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 1 h. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. 12 g of crude product were obtained and were reacted further without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:27]=[C:26]4[O:28][CH2:29][C:23]5[C:24]6[C:25]4=[C:16]([CH2:17][O:18][C:19]=6[CH:20]=[C:21]([C:30]4[NH:34][C:33]([C@@H:35]6[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]6[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[N:32][CH:31]=4)[CH:22]=5)[CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:55][O:56][C@H:57]([CH3:67])[C@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:59](O)=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:66][O:65][C:63]([NH:62][C@@H:58]([C@H:57]([O:56][CH3:55])[CH3:67])[C:59]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:27]=[C:26]3[O:28][CH2:29][C:23]4[C:24]5[C:25]3=[C:16]([CH2:17][O:18][C:19]=5[CH:20]=[C:21]([C:30]3[NH:34][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]5[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[N:32][CH:31]=3)[CH:22]=4)[CH:15]=2)=[CH:12][N:13]=1)=[O:60])=[O:64]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Reaction time: 1 h

Procedure:
A mixture of methyl (R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (90 mg, >0.123 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (26 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1 hour. An additional 0.135 mmol of (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid and HATU were added and stirring continued for 3 hours. The crude product was purified by reverse phase HPLC to product (22 mg) as a trifluoroacetate salt.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][O:68][C:69]1[N:74]=[CH:73][C:72]([CH:75]=O)=[CH:71][CH:70]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:75]([C:72]3[CH:73]=[N:74][C:69]([O:68][CH3:67])=[CH:70][CH:71]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cn1
Reaction time: 6 h
Yield: 34 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 6-methoxy-3-pyridinecarboxaldehyde (1.1 eq, 0.21 mmol, 29 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (31 mg, 34%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2Ar), 3.68 (br s, 4H, piperazine N(CH2)2), 3.95 (s, 3H, OCH3), 7.00 (d, J=8.7 Hz, 1H, methoxypyridine H-5), 7.40 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.79 (d, br, J=7.8 Hz, 1H, pyridine H-4), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.43 (dd, J=8.7, 2.3 Hz, 1H, methoxypyridine H-4), 8.50 (d, br, J=3.5 Hz, 1H, pyridine H-6), 8.57 (s, 1H, pyridine H-2), 8.96 (d, J=2.3 Hz, 1H, methoxypyridine H-2), 13.53 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][C@@H:30]([CH2:49][CH3:50])[C@H:31]([N:35]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[C:36]1=[O:48])[C:32](O)=[O:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:32](=[O:33])[C@@H:31]([N:35]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[C:36]1=[O:48])[C@@H:30]([CH3:29])[CH2:49][CH3:50])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
A solution of the product from Example 6A (0.046 g, 0.119 mmol) in THF (0.9 mL) was treated with the product from Example 7B (0.050 g, 0.119 mmol), EDAC (0.035 g, 0.183 mmol), HOBT (0.025 g, 0.185 mmol), and NMM (0.040 mL, 0.364 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, dilute sodium bicarbonate solution, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.080 g, 100% yield).