Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH2:2][CH3:3].[H-].[Na+].[C:15]1([C:21]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:22]2[C:26]([C:27]3[C:32]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:24]=[N:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:1]([C:4]1[N:12]([CH2:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[N:22]([C:21]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:23]=[N:24][N:25]=3)=[CH:38][CH:37]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc2cccnc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a stirred mixture of 2-propyl-1H-pyrrolo-[2,3-b]pyridine (29 mg, 0.18 mmol) in DMF (1 mL) was added NaH (6.7 mg of an 80% dispersion in oil, 0.271 mmol). After 20 min, N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (111 mg, 0.19 mmol) was added and the mixture was stirred for 30 min. Water was added and the mixture was extracted with EtOAc. Purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gave 2-propyl-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)[1,1']-biphenyl-4-yl]methyl]-1H-pyrrolo[2,3-b]pyridine as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2(50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3(sat.). The aqueous phase was extracted three times with CH2Cl2 then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94% yield) as a off-white foam. MH+=284.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19].Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>ClCCl>[CH2:24]([N:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:31])[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](CC(=O)OC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 255B (31.28 g, 126.6 mmol) in dichloromethane (500 mL) was added N-benzylglycine ethyl ester (24.46 g, 126.6 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (24.3 g, 126.6 mmol), and pyridine (70 mL). After addition of the reagents, the reaction was allowed to warm to ambient temperature and stirred for 16 hours. The solution was concentrated and then partitioned between ethyl acetate and HCl (1 M, aqueous). The organic solvent was collected, and the aqueous again washed with ethyl acetate. The organic solvent was combined, washed with K2CO3 (2 M aqueous), washed with brine, and dried with MgSO4. Concentration of the dried solution afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][CH:13]1[CH2:15][CH:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:11].[C:38]([O:43][CH2:44]Cl)(=[O:42])[CH:39]([CH3:41])[CH3:40]>C(Cl)(Cl)Cl>[C:38]([O:43][CH2:44][S:11]/[C:10](=[N:9]\[C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])/[NH:12][CH:13]1[CH2:15][CH:14]1[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)(=[O:42])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)C(=O)OCCl
Reactant: Cc1cccc(C)c1NC(=S)NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1/N=C(/NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)SCOC(=O)C(C)C
Temperature: 100 °C
Yield: 19.4 %

Procedure:
To a solution of 1-(2,6-dimethylphenyl)-3-(2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclopropyl)thiourea (75 mg, 0.143 mmol) in chloroform (CHCl3; 0.72 mL) was added chloromethyl isobutyrate (31.1 mg, 0.172 mmol). The mixture was heated at 100° C. for 1 h. The mixture was cooled to 25° C., and the residue was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound (17.3 mg, 19%) as a yellow oil: IR νmax 3332 (br), 3124, 2976, 2939, 1739, 1631, 1590, 1518, 1264, 1171, 986 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.2 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H), 5.65 (br s, 2H), 2.88 (br s, 1H), 2.68-2.52 (m, 1H), 2.10 (s, 6H), 1.82-1.46 (m, 2H), 1.46-1.22 (m, 2H), 1.22-1.18 (m, 6H); ESIMS m/z 624 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:29][C:28](=[O:30])[NH:27][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[CH:33]=[CH:34][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:39])[N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:31]=[C:32]([C:35]([F:37])([F:36])[F:38])[CH:33]=[CH:34][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)oc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-1,3,4-oxadiazol-2(3H)-one (Example 441, 10 mg, 0.0183 mmol) in DMF (0.10 mL) was added cesium carbonate (6 mg, 0.0183 mmol) and iodomethane (0.0011 mL, 0.0183 mmol). After stirring at rt for 1.5 h, the reaction mixture was quenched with water, and the product was extracted with EtOAc (3×). The combined extracts were washed with water and brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 chromatography, to provide the title compound. LC/MS: m/e 560.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.09 (1H, d, J=2.0 Hz), 7,69 (1H, dd, J=8.5, 2.1 Hz), 7.61 (1H, d, J=7.5 Hz), 7.10-7.20 (3H, m), 6.94-6.98 (3H, m), 6.83 (1H, d, J=8.7 Hz), 4.65-4.95 (2H, br), 3.53 (3H, s), 1.25 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCOCC1>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([C:24]([F:27])([F:25])[F:26])=[C:15]([CH:20]=1)[O:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(N)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 42 h

Procedure:
(R)-2-(5-Nitro-2-trifluoromethyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.19 g, 5.60 mmol) was dissolved in 40 mL MeOH and 10 mL dioxane. To the nitrogen-degassed solution was added 10% Pd/C (0.3 g). The reaction was stirred vigorously at RT under 1 atm H2 gas for 42 h. The reaction was filtered through Celite® and concentrated in vacuo to yield the title compound as a white foam. MS (MNa+)=383.3; Calc'd 360.38 for C17H23F3N2O3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[C:12]=3[CH:31]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([OH:53])C.O>C(OCC)(=O)C.C(O[Pd]OC(=O)C)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH2:28])=[O:53])=[CH:29][CH:30]=4)[C:12]=3[CH:31]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C#N)cc1)CC2C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C(N)=O)cc1)CC2C
Temperature: 60 °C
Yield: 50.8 %

Procedure:
A mixture of 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (150 mg, 0.37 mmol), triphenylphosphine (194 mg, 0.74 mmol) and diacetoxypalladium (8.3 mg, 0.037 mmol) in mixed solution of ethanol (6 mL) and water (2 mL) was heated at 60° C. for 30 minutes under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL*3). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to afford 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzamide as a white solid (80 mg, 50.8%).
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:19]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:24])[N:18]1[CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1
Reactant: COc1nc(CO)cc(C)c1C#N
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(CN2C(=O)c3ccccc3C2=O)cc(C)c1C#N
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (1.50 g, 8.42 mmol), phthalimide (1.3 g, 8.84 mmol) and triphenylphosphine (2.3 g, 8.77 mmol) in Tetrahydrofuran (THF) (50 mL) at 0° C. in an ice bath was added dropwise DIAD (1.8 mL, 9.26 mmol). Within minutes a white suspension formed. Additional THF (˜50 mL) was added to allow stirring. The reaction was allowed to warm to RT and stirred for 3 h. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. The remaining solid was triturated with a small volume of EtOAc, filtered, washed with a small volume of EtOAc, then dried under vacuum to give the product 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile (2.12 g, 6.90 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00-7.92 (m, 2H), 7.92-7.87 (m, 2H), 7.15 (s, 1H), 4.86 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H). MS(ES)+m/e 308.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]4[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]4)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Temperature: 95 °C
Reaction time: 120 h
Yield: 112 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (100 mg, 0.31 mmol) in 1.6 ml of NMP was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (200 mg, 1 mmol) and DIPEA (70 μL, 0.4 mmol). The reaction solution was stirred at 95° C. for 5 days. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl 3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (160 mg) as TFA salt. ES/MS m/z 461.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:25][O:26][C:27](=[NH:29])[NH2:28].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[NH:29][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:28]=1
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.62 g, 10.0 mmole), O-methylpseudourea hydrogen sulfate (1.72 g, 10.0 mmole), and sodium bicarbonate (2.52 g, 30.0 mmole) in dimethylformamide (7 ml) was heated at 65°-70° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed with water and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a yellow oil which was purified by flash chromatography (5% ethyl acetate in dichloromethane). The resulting foam was crystallized from isopropyl ether/hexanes to provide 2.41 g of 1, 4-dihydro-2-methoxy-6-methyl -4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as a colorless crystalline product; melting point 103.5°-105° C. Analysis Calc'd. for C15H17N3O5 :
Reaction SMILES: [Na].[OH:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(O)C.[I-].[Na+]>[CH2:19]([O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCC)cc2)cc1
Yield: 84.9 %

Procedure:
Sodium metal (0.46 g, 20 mmol) was dissolved in ethanol (50 mL) and 4,4'-dihydroxybenzophenone (1.0 g, 4.67 mmol) was added followed by 1-bromooctadecane (7.8 g, 23.4 mmol) and a catalytic amount of sodium iodide (approximately 30 mg) and the reaction mixture was refluxed for 48 hours. The resulting suspension was cooled and filtered. The solid was washed with dichloromethane followed by hexane and the white solid was dried to afford compound 22 (2.85 g, 84.8% yield). 1H NMR (300 MHz, pyridine-d5) δ7.95 (d, J=8.7 Hz, 4H, aryl), 7.09 (d, J=8.7 Hz, 4H, aryl), 4.05 (t, J=6.6 Hz, 4H, 2×OCH2), 1.80 (tt, J=6.6 and 7.5 Hz, 4H), 1.48 (m, 4H), 1.33 (brS, 60H), 0.87 (t, J=6.6 Hz, 6H, 2×CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]1[C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[NH:16][C:26]1=[O:28])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 204.9 %

Procedure:
To a chilled solution of (2-amino-4-cyanophenyl)-carbamic acid tert-butyl ester (2.1 g, 8.8 mmol) in CH2Cl2 (50 mL) and triethylamine (1.22 mL, 8.8 mmol) was added a solution of triphosgene (0.94 g, 3.2 mmol) in CH2Cl2 (50 mL) slowly. The reaction was stirred at room temperature for 3 hours, diluted with CH2Cl2, washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using a gradient from 30% to 60% ethyl acetate in n-heptane as eluent to afford 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (1.7 g, 75%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-methylpiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.87 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]4(C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:32][C:33]1([CH:38]=O)[O:37][CH2:36][CH2:35][O:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:32][C:33]3([CH3:38])[O:37][CH2:36][CH2:35][O:34]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: CC1(CNc2nc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)ccc2F)CCOCC1
Reactant: CC1(C=O)OCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(CN[C@H]2CC[C@H](Nc3cc(-c4ccc(F)c(NCC5CCOCC5)n4)c(Cl)cn3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (21 mg, 0.048 mmol) in DCM (1.0 ml) was added 2-methyl-1,3-dioxolane-2-carbaldehyde (synthesized following the procedure reported in Org. Lett., 2009, 11, 3542-3545), sodium triacetoxyborohydride (20.51 mg, 0.097 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC and lyophilized to give 12 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 534.1 (MH+), retention time=0.62 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc(CCN2CCOCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CN(C)C(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
2-[(2,5-dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (300 mg, 0.96 mmol), 3-[2-(4-morpholinyl)ethyl]aniline (198 mg, 0.96 mmol) were combined in a vessel with 10 mL of isopropanol and TFA (74 μL, 0.96 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction mixture was concentrated to dryness. The crude product was purified via semi-preparative HPLC to afford the title compound as a white solid (83 mg, 18%): Mass (M+H)+=481, 483.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[S:15][C:16]([C:18]([N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH3:21])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:9]=2[CH:29]=1.O>CCO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18]([C:16]1[S:15][C:14]2[C:8]3[CH:7]=[CH:6][C:5]([CH2:4][NH:2][CH3:1])=[CH:29][C:9]=3[O:10][CH2:11][CH2:12][C:13]=2[CH:17]=1)=[O:19]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a solution of CH3NH2 in EtOH (0.25 mL) was added TEA (0.5 mL) and 8-(bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (250 mg). The reaction mixture was stirred for 2 h at 60° C. before added water. The mixture was extracted with EtOAc (20 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC(CH2Cl2: MeOH=10:1) to afford 243 as a light yellow solid (95.6 mg, 42.8%). MS: (ESI+) 412.9