Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:13]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:13])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(Br)cn2nccc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Br)cn2ncc(I)c12
Reaction time: 1 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (50.0 mg, 0.220 mmol) was dissolved in acetonitrile (2 ml). N-iodosuccinimide (49.5 mg, 0.220 mmol) was added and the mixture was stirred for 1 h, at which time LCMS indicated about 60% conversion. Additional N-iodosuccinimide (9.9 mg, 0.044 mmol) was added and the mixture was stirred for 30 minutes, at which time LCMS indicated about 80% conversion. Additional N-iodosuccinimide (9.9 mg, 0.044 mmol) was added and the mixture was stirred for 30 minutes, at which time LCMS indicated about 80% conversion. Additional N-iodosuccinimide (14.9 mg, 0.066 mmol) was added and the mixture was stirred for 30 minutes, at which time LCMS indicated complete conversion. The reaction mixture was diluted in ethyl acetate, washed with 1N aqueous sodium hydroxide and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine as a colorless solid (faster eluting), along with recovered starting material 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (slower eluting). 1H NMR (600 MHz, CDCl3) δ 8.25 (d, 1H); 7.80 (s, 1H); 6.47 (s, 1H); 3.93 (s, 3H). LRMS (ESI) calculated for C8H779BrIN2O [M+H]+, 352.9; found 352.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: Nc1ccncc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C(Nc1ccncc1)c1cccc(Cl)c1
Yield: 52 %

Procedure:
Employing 0.18 g (1.9 mmol) of 4-amino-pyridine and 0.51 g, (2.9 mmol) of 3-chlorobenzoyl chloride in the procedure described above and elution with CHCl3/MeOH/Et3N (9.8:0.1:0.1) resulted in white crystals (52% yield).
Reaction SMILES: CC([N:5]([C@@:9]([CH3:31])([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[N:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@:9]([CH3:31])([CH2:10][CH3:11])[NH2:5])=[CH:20][CH:19]=2)=[CH:23][C:24]=1[O:29][CH3:30]
Reactant: CC[C@](C)(C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-methyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Reference Intermediate R7, 65 mg) in dry dichloromethane (3 mL) cooled to 0° C., TFA (0.700 mL, 9.08 mmol) was added dropwise. The reaction was stirred at that temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 (20 mL) added at 0° C., and extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a white solid (44 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])/[C:12](=[CH:11]/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:13]([NH2:15])=[O:14])[CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc(CCC(N)=O)cc1OC
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(OC)c(OC)c1)C(N)=O
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
3-(3,4-dimethoxyphenyl)propionic acid amide (20.5 mg, 0.1 mmol) prepared in the same manner as in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, and under cooling with ice, tetrakistriphenylphosphine palladium(0) (5 mg, 0.004 mmol) was added, and then a tetrahydrofuran solution (0.5 ml) of tri-n-butyltin hydride (35 μl, 0.13 mmol) was dropwise added. After stirring for 30 minutes, the solution was concentrated under reduced pressure, and the residue was purified by tin-layer silica gel column chromatography (hexane:ethyl acetate=1:1) to give (E)-2-(tributylstannyl)-3-(3,4-dimethoxyphenyl)acrylamide (14.8 mg, 30%) as a pale yellow oily substance.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([CH:29]2[CH2:34][NH:33][CH:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]2)[CH:11]=1>C(#N)C.CO>[NH2:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([CH:29]2[CH2:34][NH:33][CH:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]2)[C:11]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CN1
Solvent: CO
Solvent: CC#N
Product: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
N-bromosuccinimide (44 mg, 0.249 mmol) was added into a solution of methyl 5-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-2-carboxylate (100 mg, 0.249 mmol) in acetonitrile (1.5 mL) and methanol (0.5 ml). The resulting solution is stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified by prep-LC to afford the title compound (22.32 mg): LC/MS RT=2.56 min. Mass calculated for, M+H 481.09, observed 481.09.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1>>[CH2:24]([O:23][C:16]1[CH:15]=[C:14]([CH:13]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:19]=[CH:18][C:17]=1[N+:20]([O-:22])=[O:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-nitro-3-benzyloxybenzaldehyde dimethyl acetal in an analogous manner to that described in Example 1, gave 9-(3-benzyloxy-4-nitrophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from methanol/water gave a yellow crystalline solid of melting point 239-240° C.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]=[CH:21][N:22]=4)=[CH:14][CH:13]=3)=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:39](Cl)(Cl)=[O:40].Cl.[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)#[N:45]>ClCCl>[C:44]([CH:46]1[CH2:51][CH2:50][N:49]([C:39]([N:4]2[CH2:5][C:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:18]5[N:19]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]=[CH:21][N:22]=5)=[CH:16][CH:17]=4)[CH:9]=[CH:8][C:7]=3[O:1][CH2:2][CH2:3]2)=[O:40])[CH2:48][CH2:47]1)#[N:45]
Reactant: N#CC1CCNCC1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(C#N)CC2)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (361 mg, 0.92 mmol) was taken into dichloromethane (5 mL) followed by addition of DIPEA (0.32 mL, 1.84 mmol). The solution thus obtained was added slowly by syringe over several minutes to a solution of phosgene (20 W % in toluene, 0.49 mL, 0.93 mmol) diluted in dichloromethane (5 mL) and cooled to 0° C. The resulting mixture was stirred for 5 minutes then allowed to warm to room temperature and concentrated. The residue was taken back into dichloromethane (5 mL) followed by addition of DIPEA (0.48 mL, 2.76 mmol) and 4-cyanopiperidine hydrochloride salt (156 mg, 1.06 mmol) then stirred for 12 h. The mixture was concentrated then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography (100% ethyl acetate) to give 2-methylpropyl 2-(4-{4-[(4-cyanopiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}phenyl)-1H-imidazole-1-carboxylate (296 mg, 61% yield) as a crystalline solid. MS (EI) for C30H33N5O4: 529 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.Cl.[CH3:13][N:14]([CH2:16][C:17](Cl)=[O:18])[CH3:15]>CN1CCCC1=O.[OH-].[Na+]>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:17](=[O:18])[CH2:16][N:14]([CH3:15])[CH3:13])[N:10]=2)[N:7]=1
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1cn2nc(I)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
To a solution of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1040 mg, 4.0 mmol) in N-methylpyrrolidone (5.0 mL) was added dimethylaminoacetyl chloride hydrochloride (948 mg, 6.0 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30), and precipitated from diisopropyl ether to give the title compound (1019 mg, 74%) as a pale-yellow powder.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:8]1[CH:46]=[CH:45][C:11]([C:12]([NH:14][C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][CH:33]([O:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[CH2:32][CH2:31]2)=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C(C)(C)C)=[CH:19][CH:18]=2)=[O:13])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].FC(F)(F)C([O-])=O>O.CO>[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][CH:33]([O:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:31]2)=[O:29])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[O:13])=[CH:45][CH:46]=1)(=[NH:6])[NH2:7]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)c2ccc(C(=N)N)cc2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: CO
Product: N=C(N)c1ccc(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
From 2.5 g of the acetate of t-butyl [[1-[N-(p-amidinobenzoyl)-3-(p-t-butoxyphenyl)-L-alanyl]-4-piperidinyl]oxy]-acetate there is obtained in analogy to Example 1, after chromatography (silylated silica get RP-18, water/methanol gradient), 1.0 g of [[1-[N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]oxy]acetic acid as the trifluoroacetate. M.p. 125°-130° C. (ethyl acetate, decomposition). MS (FAB): 469 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12].N>>[F:19][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1cccc(F)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.51 (m, 1H), 7.60-7.82 (m, 4H), 7.84 (s, 1H), 8.42 (dt, J=8.1, 1.7 Hz, 1H), 8.80 (dd, J=5.0, 1.4 Hz, 1H), 9.17 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)[CH:11]=1)[C:3]([OH:5])=O.[CH:39]([N:42](C(C)C)[CH2:43]C)(C)C.[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50].CNC>ClCCl>[CH3:39][N:42]([CH3:43])[C:3]([CH:2]([O:1][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)[CH:11]=1)=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(C(O)C(=O)O)c3)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(C(OC(=O)C(C)(C)C)C(=O)N(C)C)c3)cc12
Reaction time: 0.17 h

Procedure:
Hydroxy-{5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-acetic acid (208 mg, 0.393 mmol) was dissolved in dichloromethane (3.0 mL) and cooled in an ice water bath. Di-iso-propylethylamine (137 μL, 0.786 mmol) and pivaloyl chloride (48.3 μL, 0.393 mmol) were added. After 10 minutes, dimethylamine solution (2 M tetrahydrofuran) was added (393 μL, 0.786 mmol) and the mixture was stirred for 15 h. The mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate (1×) and brine (1×), dried over sodium sulfate, filtered and concentrated to a foam (quantitative). The material was used as is in the next step. MS: m/z 641 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:31])=O>>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Yield: 76 %

Procedure:
A solution of 6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.5 g, 4.7 mmol) in thionyl chloride (15 ml) containing DMF (1.5 ml) was heated at reflux for 3 hours. After cooling, the volatiles were removed under vacuum. The residue was azeotroped with toluene. The solid was partitioned between methylene chloride and sodium hydrogen carbonate. The aqueous layer was adjusted to pH10 with 6M aqueous sodium hydroxide. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography to give 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.21 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:2]([C:26]4[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=4)=[N:3][CH:4]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-N-quinolin-7-yl-nicotinamide (D70) (40 mg, 0.14 mmol) in DME (0.9 ml) under an argon atmosphere was added 4-trifluoromethylphenylboronic acid (33 mg, 0.17 mmol), 2M sodium carbonate solution (0.17 ml) and tetrakis(triphenylphosphine)palladium (0) (8 mg, 0.007 mmol). The reaction was heated at reflux until complete by tlc, then cooled to room temperature and diluted with EtOAc and dried over MgSO4. The solvent was removed in vacuo and the resultant crude product was purified by SPE column chromatography. Elution with 75% EtOAc in 40-60° C. petroleum ether gave the title compound as an off-white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.31 (dd, 1H), 8.83 (dd, 1H), 8.46 (dd, 1H), 8.39 (dd, 1H), 8.20 (m, 3H), 8.07 (d, 1H), 7.94 (dd, 1H), 7.89 (d, 1H), 7.79 (d, 2H), 7.40 (dd, 1H).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]([CH3:29])[CH3:28].C(N(CC)CC)C>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), N-amino-2-(dimethylamino)acetamide (147.5 mg, 0.95 mmol), and molecular sieves in ethanol was added triethylamine (0.25 mL, 1.86 mmol). The reaction was allowed to stir under a nitrogen atmosphere at 75° C. overnight. The reaction was filtered using a fritted funnel and the filtrate was concentrated. This was purified by semi-preprative HPLC. The material was taken up in ethyl acetate and washed with aqueous sodium bicarbonate. This organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (192 mg, 23% yield). 1H NMR (CD3OD) δ 8.7 (s, 1H), 8.0–8.1 (m, 3H), 7.7 (d, 1H), 7.25 (t, 2H), 4.5 (s, 2H), 3.0 (s, 6H), ES-MS (m/z) 337 [M+1]+.
Reaction SMILES: O1CC[C@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@H:36]([N:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@H](CN(C(=O)O)[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (115 mg, 0.251 mmol) was suspended in 8 mL of anhydrous CH2Cl2 and gently heated until an homogenous solution was formed. After cooling to room temperature, a 2.0 M solution of HCl in Et2O (0.126 mL, 0.251 mmol) was added in one portion. The reaction mixture was diluted with 25 mL Et2O, and the product precipitated from the solution. The reaction was stirred for an additional 30 minutes before the solid was filtered and dried to obtain (S)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride (108 mg, 86%) as a light yellow solid. LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=6.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.73 (s, 1H), 7.44-7.51 (m, 2H), 7.00-7.07 (m, 2H), 5.06-5.09 (m, 1H), 4.52-4.62 (m, 2H), 3.62-3.74 (m, 4H), 3.23-3.29 (m, 1H), 3.00 (d, J=6.8 Hz, 2H), 2.52 (s, 3H), 2.02-2.11 (m, 1H), 1.61-2.01 (m, 4H), 1.24-1.43 (m, 2H), 0.84-0.89 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:19])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:4]>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:19])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)COc1ccc(N)cc1
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(4-Nitro-phenoxy)-acetic acid methoxycarbonylmethyl ester 95 (20 grams, 74.3 mmol) was dissolved in dimethyl formamide (100 mL) in a pressure vessel, palladium on carbon (5%, 8 grams) added, and the mixture stirred under an atmosphere of H (4 Kg) for 2 hours. The catalyst was removed by filtration and to the filtrate; ice water (400 mL) was added. Crude 96 was extracted into ethyl acetate, dried over Na2SO4 and distilled, crude 3 was recrystallized from chloroform:hexane (1:6) to get pure 96 (13 grams, 73%) as a light brown shining powder. M.p: 76.5-78.5° C. IH NMR (CDCl3) δ 3.32 (bs, 2H, NH2), 3.76 (s, 3H, Ester), 4.70 (s, 2H, OCH2), 4.74 (s, 2H, OCH2), 6.60 (d, 2H, Ar), 6.74 (d, 2H, Ar).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C(OC)=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:45][C:46]2[CH:64]=[CH:63][C:49]3[N:50]([CH3:62])[C:51]([NH:53][C:54]4[CH:59]=[CH:58][C:57]([Br:60])=[C:56]([CH3:61])[CH:55]=4)=[N:52][C:48]=3[CH:47]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)[C:67](O)=[O:68]>CO.C(Cl)Cl>[Br:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:51]2[N:50]([CH3:62])[C:49]3[CH:63]=[C:64]([O:68][CH3:67])[C:46]([O:45][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:47][C:48]=3[N:52]=2)=[CH:55][C:56]=1[CH3:61]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(Nc2nc3cc(Oc4ccnc(C(=O)OC(C)(C)C)c4)ccc3n2C)ccc1Br
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Agent: NC(N)=S
Solvent: ClCCl
Solvent: CI
Solvent: CO
Product: COc1cc2c(cc1OC1(C(=O)O)C=CC=CN1)nc(Nc1ccc(Br)c(C)c1)n2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-methylphenylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=482.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:21][N:20]([CH3:22])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: c1ccc(-n2cccc2)cc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1cccn1-c1ccccc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and benzylidene-dimethyl-ammonium chloride.