Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:49]=[CH:48][CH:47]=[CH:46][C:6]=1[C:7]([NH:9][C:10]1[CH:43]=[CH:42][C:13]([C:14]([N:16]([CH3:41])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]2)=[O:31])=[O:15])=[CH:12][C:11]=1[O:44][CH3:45])=[O:8])(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:49]=[CH:48][CH:47]=[CH:46][C:6]=1[C:7]([NH:9][C:10]1[CH:43]=[CH:42][C:13]([C:14]([N:16]([CH3:41])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]2)=[O:31])=[O:15])=[CH:12][C:11]=1[O:44][CH3:45])=[O:8]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1O
Reaction time: 6 h
Yield: 77.3 %

Procedure:
A solution of 4-[2-(acetyloxy)benzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-dimethylaminopiperidin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]benzamide (400 mg) in methanol (10 ml) was treated with 1N sodium hydroxide solution (3 ml) at ambient temperature. After 6 hours, the reaction mixture was concentrated in vacuo and extracted with the mixture of dichloromethane and diluted hydrochloric acid. The organic phase was washed with brine and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (SiO2 30 g, 5% methanol in chloroform) to give 4-[2-(hydroxy)benzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-dimethylaminopiperidin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]benzamide (290 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH:7]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:5][CH2:4]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:38][N:3]1[CH2:4][CH:5]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:24]=3)[CH:18]=2)=[O:12])[CH2:7][CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(C(=O)NCC2=CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1nnc(C(=O)NCC2=CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide dihydrochloride (30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.47 mmol, 0.1 g) was added and stirred at room temperature for 2 h. The reaction was diluted with DCM (5 mL), and the DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM -6% (NH3 in MeOH, 2M) in DCM to provide 6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1-methyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide, which was converted to dihydrochloride salt by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, and the salt was washed with anhydrous ether and solid was dried under high vacuum (38 mg). LCMS: m/z 464.1 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.38 (1H, s), 7.46 (2H, d), 7.12 (2H, d), 5.71 (1H, s), 4.40-4.50 (1H, m), 4.11 (2H, s) 3.88 (1H, d), 3.55-3.70 (2H, m), 3.17-3.28 (3H, m), 2.94 (3H, s), 2.52-2.66 (1H, m), 2.44 (1H, d), 1.97-2.10 (2H, m),1.75-1.88 (2H, m), 1.25-1.70 (10H, m), 0.84 (3H, t).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:20]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])=[O:21])[CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C.Br>CCOCC>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:20]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])=[O:21])[CH3:19])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.50 g of Z-Leu-Leu-Ala-Gln-OH was added 20 ml of acetic acid containing 25% of hydrogen bromide, then the mixture was stirred at a room temperature for 1 hour. To the reaction mixture was added dried ether, and solid material precipitated was collected by filtration to obtain H-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)/[CH:10]=[N:25]/[S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)[Si](C)(C)OC(C=O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 3.0 g (10.6 mmol) of {[tert-butyl (dimethyl)silyl]oxy}(3-chlorophenyl)acetaldehyde (from Step C) and 1.3 g (10.6 mmol) of (R or S)-2-methyl-2-propanesulfinamide in 50 mL anhydrous dichloromethane was added copper(II) sulfate (3.4 g, 21.2 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. Wash reaction with water and extract with dichloromethane. Dry the organics with magnesium sulfate, filter and concentrate under vacuum. The residue was purified by Horizon MPLC, with a 40M+ silica gel column, eluting with a gradient eluent system of 0-25% ethyl acetate in hexane to afford the title compound (3.26 g, 80%). %). m/z (ES) 387, 390 (M, M+2)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])=[CH:5][CH:4]=1.P([CH:29]([CH2:35][CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])(O)(O)=O>>[CH2:35]([C:29](=[CH:18][C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[C:12]([CH2:11][C:10](=[O:22])[NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:4][CH:5]=2)[CH:17]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:36]
Reactant: CCOC(=O)C(CC)P(=O)(O)O
Reactant: COc1ccc(C=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(=Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)CC
Yield: 88.5 %

Procedure:
0.7 g of N-[4-(trifluoromethyl)phenyl]-2-(5-formyl-2-methoxyphenyl)acetamide and 1.6 g of ethyl 2-phosphonobutanoate were treated in the same manner as in Production Example 1a), to give 0.8 g of ethyl 2-ethyl-3-(4-methoxy-3-{2-oxo-2-[4-(trifluoromethyl)anilino]ethyl}phenyl)-2-propenoate as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=[N:3]1.[F:9][C:10]1[CH:38]=[CH:37][CH:36]=[CH:35][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]([C:22]2[N:23]=[C:24](I)[C:25]3[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:26]=3[N:27]=2)=[N:14]1>CN1CCCC1=O>[F:9][C:10]1[CH:38]=[CH:37][CH:36]=[CH:35][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:25]3[C:30]([CH3:31])([CH3:32])[C:29](=[O:33])[NH:28][C:26]=3[N:27]=2)=[N:14]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: Cn1nccc1CN
Solvent: CN1CCCC1=O
Product: Cn1nccc1CNc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C(C)(C)C(=O)N2

Procedure:
111.1 mg (1.0 mmol) of 1-(1-methyl-1H-pyrazol-5-yl)methanamine was put in a vial of a microwave reactor block and a solution of 51.4 mg (100 μmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) in 0.6 ml of 1-methyl-2-pyrrolidinone was added. Then the reactor block was sealed and was irradiated for 6 h with microwaves, in order to reach and maintain a temperature of the mixture of 170° C. After cooling, it was purified by preparative LC-MS (method 6). The product-containing fractions were concentrated by evaporation by means of a centrifugal dryer under vacuum. The residue of the individual fractions was in each case dissolved in 0.6 ml DMSO and combined. Then the solvent was evaporated completely in the centrifugal dryer. 32.7 mg (61% of theor.) of the target product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][S:11][CH:12]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[NH2:14][CH2:13][CH:12]([S:11][CH2:10][C@@H:9]([C:22]([OH:24])=[O:23])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(C[N+](=O)[O-])c1ccsc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)OC(=O)N[C@@H](CSC(CN)c1ccsc1)C(=O)O
Yield: 73.2 %

Procedure:
74.8 g of N-t-butoxycarbonyl-S-[2-nitro-1-(3-thienyl)ethyl]-L-cysteine were reduced with hydrogen in the presence of 10% w/w palladium-on-carbon, as described in Example 63(b), to give 50.4 g of the title compound as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20]Cl>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: ClCCCl
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCCl
Temperature: 67.5 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (14) (10.0 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. After cooling, 1,2-dichloroethane was removed under reduced pressure, the remaining slurry was poured onto ice and the mixture was extracted with Et2O (3×250 mL) and EtOAc (4×250 mL). The combined organic layers were washed with water (4×400 mL) and brine (2×400 mL), dried (MgSO4), and the solvent was removed in vacuo. Crystallization from EtOAc/hexane provided 15 (11.9 g, 84%) as colorless needles. 1H NMR (200 MHz, CDCl3): δ=3.88 (t, J=6.1 Hz, 2 H, 2′-H2), 3.97 (s, 3 H, OMe), 4.35 (t, J=6.1 Hz, 2 H, 1′-H2), 7.01 (d, J=8.1 Hz, 1 H, 5-H), 7.43 (d, J=1.8 Hz, 1 H, 2-H), 7.51 (dd, J=8.1, 1.8 Hz, 1 H, 6-H), 9.86 (s, 1 H, CHO) ppm; 13C NMR (50.3 MHz, CDCl3): δ=41.5 (C-2′), 56.2 (OMe), 68.9 (C-1′), 111.0, 111.3 (C-2, C-5), 127.4 (C-6), 129.9 (C-1), 148.1 (C-3), 154.9 (C-4), 190.7 (CHO) ppm; MS (70 eV, EI): m/z (%)=214 (100) [M]+, 151 (57) [M-CH2)2Cl]+; C10H11ClO3 (214.65): calcd. C, 55.96; H, 5.17; found C, 56.04; H, 4.97.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][C@@H:23]5[CH3:29])=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][C@H:23]1[CH2:24][CH2:25][CH2:26][C@@H:27]([CH3:28])[N:22]1[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cc1
Temperature: 130 °C
Yield: 31.1 %

Procedure:
A degassed mixture of 6-bromo-3-[4-((2S,6R)-2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (223 mg, 0.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.0 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05 mmol) in 2N aqueous sodium carbonate solution (6 mL) and acetonitrile (6 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 25 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (70 mg, 31%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.82-8.77 (m, 2H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.71-7.65 (m, 2H), 7.56-7.51 (m, 2H), 4.00 (d, J=1.9 Hz, 5H), 2.65-2.52 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.30 (m, 3H), 1.25 (d, J=6.2 Hz, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.C(O)(=O)C>[OH-].[Pd+2].[OH-].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(O)c2[nH]1
Yield: 18 %

Procedure:
A slurry of the product of step (e) (105 mg) and palladium hydroxide (100 mg) in a solution of 1:1 acetic acid:tetrahydrofuran (10 mL) was stirred under an atmosphere of hydrogen for 24 h. The catalyst was filtered off, the filtrate evaporated and the residue purified by reverse phase HPLC to afford the title compound (16 mg) in the form of a white solid as a trifluoroacetate salt. m/z: [M+H+] calcd for C31H28N2O4, 493.2; found 493.5. 1H NMR (300 MHz, DMSO-d6): 10.40 (d, 1H, J=20 Hz), 8.60 (br s, 1H), 8.01 (d, 1H, J=8.8 Hz), 7.49 (d, 2H, J=8.2 Hz), 7.14-7.34 (m, 7H), 7.03 (d, 1H, J=7.4 Hz), 6.93 (d, 2H, J=7.4 Hz), 6.86-6.82 (m, 2H), 6.46 (d, 1H, J=9.9 Hz), 6.07 (s, 1H), 5.18 (m, 1H), 3.19-2.82 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:33])[CH3:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 3.18 mmol) in 15 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was chilled in an ice water bath and treated first with triethylamine (0.89 mL, 6.7 mmol) and then slowly with acetyl chloride (0.89 mL, 3.3 mmol). After 2 h, the reaction was warmed to ambient temperature, quenched with 15 mL of saturated NaHCO3 solution and diluted with 30 mL of CHCl3. The phases were separated and the organic portion was washed with H2O (15 mL) and brine (15 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow foam. The foam was crystallized from MeCN to give light yellow crystals. The crystals were pulverized and then triturated with Et2O for 18 h and filtered off to yield N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)acetamide (0.728 g) as a white solid. mp 178–181° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J=8.1 Hz, 1H), 7.82 (t, J=5.1 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.45–7.42 (m, 1H), 7.26–7.22 (m, 1H), 6.96 (t, J=5.6 Hz, 1H), 6.59 (s, 2H), 4.75 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.20–3.14 (m, 4H), 1.77 (s, 3H), 1.71 (p, J=7.0 Hz, 2H), 1.17 (t, J=7.0Hz, 3H);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][N:10]=2.[Se](=O)=[O:13]>O1CCOCC1>[N:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:11]=[C:2]([CH:1]=[O:13])[CH:3]=[CH:4][C:5]=12
Reactant: O=[Se]=O
Reactant: Cc1ccc2nccnc2n1
Solvent: C1COCCO1
Product: O=Cc1ccc2nccnc2n1
Temperature: 110 °C
Yield: 50.1 %

Procedure:
6-Methyl-pyrido[2,3-b]pyrazine (100 mg, 0.69 mmol) was dissolved in dioxane. Selenium dioxide (269 mg, 2.4 mmol) was added, and the suspension was refluxed at 110° C. for 3 minutes. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried using magnesium sulfate, and concentrated to yield the title product (55 mg, 50%) as a pink solid. 1H NMR (DMSO-d6): δ=8 s, 1H), 9.31 (d, 1H,J=1.6 Hz), 9.21 (d, 1H, J=1.6 Hz), 8.81 (d, 1H, J=8.5 Hz), 8.42 (d, 1H, J=8.5 Hz). Calculated mass=159, [M+H]+=160.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=[O:6].[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:43])[C:22]([NH:24][CH2:25][C:26]1[S:30][CH:29]=[C:28]([N:31]2[C:35]([C:36](O)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)[CH:27]=1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH:8][C:36]([C:35]1[N:31]([C:28]2[CH:27]=[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:43])[S:30][CH:29]=2)[N:32]=[C:33]([C:39]([F:40])([F:42])[F:41])[CH:34]=1)=[O:37])=[O:6]
Reactant: COc1ccccc1C(=O)NN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccccc1C(=O)NNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxybenzhydrazide (0.040 g, 0.238 mmol) and compound 7 (preparation described in scheme 2 example 1c, step 7) (0.11 g, 0.238 mmol) in dichloromethane (2 mL) under nitrogen was added EDC (0.046 g, 0.238 mmol) followed by DMAP (5.81 mg, 0.048 mmol). The reaction was left to stir for 16 hours at room temperature. Another portion of EDC (20 mg, 0.104 mmol) was added and the reaction continued for 4 hours. The solvent was then removed on the rotary evaporator and the crude purified by silica gel column chromatography with a Biotage 12M column and a gradient of 0-5% methanol in dichloromethane to give compound 16 as a yellow crust (73.7 mg, 51%). LRMS (ESI): calc. 610.2; found 511.2 (MH-Boc)+, 633.3 (MNa)+.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[CH3:26][C@H:27]1[CH2:31][CH2:30][C@H:29]([CH3:32])[NH:28]1>>[CH3:26][C@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9]
Reactant: C[C@H]1CC[C@H](C)N1
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Product: C[C@@H]1CC[C@H](C)N1CC1CCCN1C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and mixture of cis and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:25])=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH3:25])=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(COc3cccc([N+](=O)[O-])c3)c(C)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(COc3cccc(N)c3)c(C)o2)cc1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A solution of 6.0 g (0.18 mol) of 2-(4-methoxyphenyl)-5-methyl-4-[(3-nitrophenoxy)methyl]oxazole and 20.0 g (0.09 mol) of stannous chloride dihydrate in 150 ml of ethanol is heated to 70° C. for 20 hours. The solution is allowed to cool to room temperature and poured into 2 L of ice water. The mixture is made alkaline by the addition of solid sodium bicarbonate and extracted twice with 500 ml of ethyl acetate. The combined ethyl acetate solution is washed with 500 ml of brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Recrystallization from ether/hexane gives 3.8 g (69%) of crystals, m.p. 132°-134° C. The product is used without further purification in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[C:14]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH2:15][C:16]([O-])=[O:17].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:21]([O:20][C:14](=[O:19])[CH2:15][C:16]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: FC(F)(F)CNc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(=O)N(CC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
(4-Chlorophenyl) (2,2,2-trifluoroethyl)amine (1.84 g, 8.8 mmol) and mono-t-butyl malonate (1.37 mL, 8.9 mmol) were dissolved in DCM (50 mL) and the solution cooled in an ice bath prior to portion wise addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g, 8.9 mmol). After one hour the reaction was complete by TLC and was diluted with ethyl acetate and sequentially washed with 1 N NaOH, 1N HCl, and brine. The organic layer was dried with MgSO4 and concentrated under reduced pressure to give a white solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (9H, s), 3.13 (2H, s), 4.34 (2H, q, J=8.7 Hz), 7.22 (2H, m), 7.41 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH:23]([F:25])[F:24])[N:3]=1.[N+:26]([O-])([OH:28])=[O:27]>OS(O)(=O)=O>[Cl:1][C:2]1[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH:23]([F:24])[F:25])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCC(F)F
Agent: O=S(=O)(O)O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (7.2 g, 18.6 mmol) and fuming HNO3 (20 mL) in conc. H2SO4 (40 mL) in analogy with example 1c.