Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)([O-:18])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)([O-:18])=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NCc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (25 g, 117 mmol, 1.0 eq) and 3-nitrobenzaldehyde (18 g, 117 mmol, 1.0 eq) in MeOH (500 mL) was added NaBH(OAc)3 (50 g, 234 mmol, 2.0 eq) by portions. Then the resulting mixture was stirred overnight at 30° C. LC-MS indicated complete conversion. The solvent was removed under vacuum and the residue was purified by column chromatography (DCM:MeOH=15:1) to provide tert-butyl N-(4-[(3-nitrobenzyl)amino]cyclohexyl)carbamate (33 g, 83%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:30])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:39]O>>[F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[O:30][CH2:39][C:38]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCOC(=O)CO
Reactant: COc1cc(O)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1
Product: CCOC(=O)COc1cc(OC)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 90E and ethyl glycolate were processed as described in Example 62A to provide the title compound. MS (ESI+) m/z 593 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCSC(N(CC(C)C)CC(C)C)=O.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:60](=[NH:73])([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C1(C)C=CC=CC=1.[Na]>[C:60](=[N:73][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)([C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC1(c2cccc(N=C(c3ccccc3)c3ccccc3)c2)COCC(=O)N1
Temperature: 105 °C
Yield: 102 %

Procedure:
A dried pressure tube was charged consecutively under an argon atmosphere with a solution of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (4.17 g, 15 mmol) in toluene (100 ml), sodium tent-butylate (4.586 g, 46 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-butyl-x-phos) (0.675 g, 1.6 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (0.494 g, 0.5 mmol), and benzophenone imine (5.88 g, 31 mmol). The sealed pressure tube was heated at 105° C. for 2.5 days. After cooling, the reaction mixture was evaporated to dryness and directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 33/66 as the eluent. There were obtained 5.67 g (99% of theory) of (RS)-5-[3-(benzhydrylidene-amino)-phenyl]-5-methyl-morpholin-3-one as a yellow foam. Mass (calculated) C24H22N2O2 [370.455]; (found) [M+H]+=371.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:44][CH2:45][C:46](O)=[O:47])=[CH:36]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]([NH:14][C:12]2[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:37]4[C:38]5[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=5)[NH:35][CH:36]=4)[CH2:10][CH2:9][C:8]=3[C:11]=2[C:25]([NH2:27])=[O:26])=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: NCCCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(CCCNC(=O)CCc1c[nH]c3ccccc13)C2
Yield: 38.2 %

Procedure:
To a stirred solution of 6-(3-aminopropyl)-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide (0.14 mmol) in anhydrous THF (1.5) were added triethyl amine (93 μL, 0.66 mmol), 3-indolepropionic acid (31 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (25 mg, 0.16 mmol) and the resultant mixture was stirred at room temperature for 8 h. Upon completion, the solvent was removed in vacuo and the oil was taken up in DCM. The organics were washed with water (×2) and dried (anhydrous Na2SO4) and evaporated to afford the crude product which was purified by flash chromatography Isolera system (SiO2 gel as stationary phase, 12 g HP column, dry loading) using DCM-DCM/MeOH (0%-12% MeOH in DCM) to afford the title compound as a brown solid (31 mg, 37% yield). 1H NMR (300 MHz, MeOH-d4) δ 7.55 (d, J=15.5 Hz, 1H), 7.50-7.43 (m, 2H), 7.34-7.24 (m, 3H), 7.12-6.95 (m, 3H), 3.38 (bs, 2H), 3.17 (t, J=6.7 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H), 2.82-2.74 (m, 2H), 2.68-2.61 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.36-2.27 (m, 2H), 1.67-1.54 (m, 2H). LRMS [M+H]579.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1OCC[N:14]=1.O.[ClH:16]>>[ClH:16].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH2:14])=[CH:4][CH:3]=1
Reactant: CC1=NCCO1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Solvent: O
Product: NCCSc1ccc(O)cc1
Yield: 11 %

Procedure:
A mixture of 4-hydroxythiophenol (2.48 g, 19.7 mmol) and 2-methyl-2-oxazoline (1.67 g, 1.69 mL, 19.7 mmol) were refluxed (neat) under argon for two hours. Upon cooling, the crude sticky solid was re-suspended in concentrated hydrochloric acid (aq) and refluxed for 12 hours. The mixture was then poured into water (20 mL) and extracted with diethyl ether (2×20 mL). The aqueous liquors were concentrated to dryness and twice re-dissolved in water and re-concentrated. Re-crystallisation of the resultant solid (ethanolidiethyl ether) gave the product as a cream solid (0.45 g, 11%); m.p. 130–31 ° C. (lit.11 128–29° C.); 1H (400 MHz, D2O) δ 3.07 (4H, br s, 2×CH2), 6.87 (2H, d, J 11.9 Hz, Ar), 7.41 (2H, d, J 11.9 Hz, Ar)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-Amino-N-methyl-benzamide (1.5 g, 10 mmol) and 2,4,5-Trichloro-pyrimidine (1.31 ew) were combined in DMF (30 mL). Potassium carbonate (1.3 eq) was added the mixture heated to 75° C. for 4.5 h and stirred at room temperature overnight. The mixture was poured into water and the white precipitate that ensued was filtered and dried to give 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2.7 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.86 (s, 1H), 8.54-8.48 (m, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.61 (t, J=8.7 Hz, 1H), 7.23 (t, J=8.9 Hz, 1H), 2.50 (d, J=1.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCNCC2CC2)ccc1OCc1ccccc1
Reactant: CNC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CN(CCc1ccc(OCc2ccccc2)c(OC)c1)CC1CC1
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of [2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)-amine, 0.27 ml (1.92 mmol) of triethylamine, 0.207 g (1.92 mmol) of 2-chloro-N-methyl-acetamide in 4 ml of dimethylformamide was heated with microwaves to 120° C. for 2 hours. The solvent was removed under vacuum and the crude was purified by flash chromatography (ethyl acetate/hexane 0:10→9:1 gradient). 0.52 g (84% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-bromophenol was dissolved in dichloromethane. Triethylamine (1 eq) and acetic anhydride (2 eq) were added and the mixture was stirred at room temperature for 5 hours. The solvent was eliminated by vacuum evaporation.
Reaction SMILES: [F-].[K+].P(C(C(F)(F)F)(F)F)(C(C(F)(F)F)(F)F)C(C(F)(F)F)(F)F.[CH2:25]([O:28][CH2:29][CH2:30][OH:31])[CH:26]=[CH2:27].[F:32][C:33]([P:39](=[O:54])(C(F)(F)C(F)(F)F)[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])([F:38])[C:34]([F:37])([F:36])[F:35]>>[F:38][C:33]([P:39]([C:40]([F:45])([F:46])[C:41]([F:43])([F:44])[F:42])(=[O:54])[O:31][CH2:30][CH2:29][O:28][CH2:25][CH:26]=[CH2:27])([F:32])[C:34]([F:37])([F:36])[F:35]
Reactant: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: C=CCOCCO
Agent: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Product: C=CCOCCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
Potassium fluoride (0.277 g; 4.8 mmol) is suspended in tris(pentafluoro-ethyl)phosphine oxide, (C2F5)3P═O, (16.783 g; 41.5 mmol) in a 100 ml glass flask, cooled (0° C.), and 2-allyloxyethanol (4.188 g; 41.0 mmol) is added. The two-phase reaction suspension is stirred at 0° C. for 3 h and at room temperature for 20 h. After recondensation in vacuo (10−3 mbar) at 50° C. (decomposition is observed from 40° C.) and subsequent fractional distillation under reduced pressure (b.p.: 40 to 42° C. at 3.8·10−3 mbar), 2-(allyloxy)-ethyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH2CH2OCH2—CH═CH2, can be isolated as clear and colourless liquid (7.083 g; 18.3 mmol) in a yield of 45% and a purity of 96%. The product is stored at −20° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[C:27]12([CH2:37][NH2:38])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=[C:2]([NH:38][CH2:37][C:27]23[CH2:36][CH:31]4[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]4)[CH2:34]2)[CH2:28]3)[N:7]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(NCC34CC5CC(CC(C5)C3)C4)n2)cc1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-(1-adamantyl)-methanamine (7.2 mg, 0.072 mmol). The mixture can be microwaved at 120 degrees for 20 minutes. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[C@@H:10]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:43]1([C:49](Cl)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][C:23]([NH:22][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:49]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:35])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:34])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate and triethylamine (1.52 g) in chloroform (100 ml) was added triphenylmethyl chloride (4.20 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl (4S)-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (7.20 g) as an oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([CH3:18])[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CCO.[Pd]>[CH2:19]([C:10]1[C:9](=[O:8])[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[N:12]([OH:34])[C:11]=1[CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCc1c(C)nc(C)c(OC)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCc1c(C)n(O)c(C)c(OC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 (19 mg, 0.66 mmol) and mCPBA (125 mg, 0.72 mmol) in anhydrous CH2Cl2 (2 mL) was stirred at 0° C. for 1 hr under argon atmosphere, the solution was washed with aqueous NaHCO3 dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was dissolved in EtOH, Pd/C was added and after applying an H2 atmosphere (1 bar), the solution was stirred at room temp for 30 min, After filtration through celite, which was thoroughly washed with EtOH, the filtrate was concentrated under diminished pressure and purified by chromatography on a silica gel column. Elution with 20:1 ethyl acetate/methanol gave 3-heptyl-1-hydroxy-5-methoxy-2,6-dimethylpyridin-4(1H)-one (CPD-5) as a light yellow oil; yield 9 mg (61%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.84-0.89 (m, 3H), 1.24-1.35 (m, 10H), 2.45 (s, 3H), 2.50 (s, 3H) 2.63-2.67 (m, 2H) and 3.74 (s, 3H).
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[OH:41][CH:42]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]1>>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][C:4]2[CH:3]=[C:2]([N:44]3[CH2:45][CH2:46][CH2:47][CH:42]([OH:41])[CH2:43]3)[CH:26]=[CH:25][C:5]=2[C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC(O)C3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 34 %

Procedure:
Using methods substantially equivalent to those described in Example 4-F, except that the reaction was quenched with water and the resulting precipitate was collected, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(3-hydroxypiperidin-1-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide (166 mg, 0.26 mmol, 34%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and 3-hydroxypiperidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:26]([C:23]3[CH:22]=[C:21]([CH3:20])[O:25][N:24]=3)=[O:27])[N:5]=2)=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])#[N:14]
Reactant: Cc1cc(C(=O)O)no1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Product: Cc1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)no1

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (150 mg) and 5-methylisoxazole-3-carboxylic acid (89 mg) using the method of Example 34(d). Yield 9 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.44 (s, 3H), 3.70 (q, 2H), 4.40 (t, 2H), 6.48 (d, 1H), 7.05 (d, 1H), 7.88 (d, 1H), 8.18 (d, 1H), 8.32 (dd, 1H), 8.67 (d, 1H), 8.79 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)[CH2:16][CH2:15]1)=[O:19]
Reactant: NCc1ccccc1F
Reactant: O=C(O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ncccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid (Compound AAB) (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 367 [(M+H)+; calcd for C21H24N4OF: 366].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([CH2:28][CH2:29][C:30]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCCSc1cccc2nccn12
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)OCCCSc1cccc2nccn12
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 4.80 mmoles) and triethylamine (0.80 ml, 5.74 mmoles) in methylene chloride (25 ml) was added 3-phenylpropionyl chloride (1.01 g, 5.99 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 1.37 g of the desired product (84.2%, yellow oily product).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[CH:17]=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(-c2ccccc2F)c2ccsc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 9.49 g of 4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 200 ml of dimethylformamide is added 1.76 g of 63% sodium hydride. The mixture is stirred at 60°C for 1 hour. The mixture is cooled to room temperature and 10.93 g of methyl iodide in 33 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-fluorophenyl)-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 175° - 176.5°C (after recrystallization from ethanol). From the second fraction, 1-methyl-4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 222° - 223°C (after recrystallization from ethanol). From the third fraction, 3-methyl-4-(o-fluorophenyl)-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 191° - 192.5°C (after recrystallization from ethanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.FC1C=CC(C([O-])=O)=CC=1>O>[CH2:15]([O:14][C:12](=[O:13])[C:11]1[CH:17]=[CH:18][C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])c1ccc(F)cc1
Solvent: O
Product: CCOC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 97.8 %

Procedure:
A mixture of morpholine (12 g, 0.14 mol) and ethyl 4-fluorobenzoate (8 g, 0.04 mol) is heated at 120° C. The conversion of the 4-fluorobenzoate is complete after 24 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 9.2 g of pure 4-(4-morpholinyl) benzoic acid ethyl ester after recrystallisation from aqueous ethanol (50%, v/v). Yield: 89%. m.p. 82-83° C.; MS 235 (100, M+); H1 NMR (CDCl3): δ 7.93 (d, 21H), 6.86 (dd, 2H), 4.33 (q, 2H), 3.85 (t, 4H), 3.28 (t, 4H), 1.37 (t, 311); C13 NMR (CDCl3): δ 166.57, 154.14, 131.14, 120.70, 113.46, 66.60, 60.39, 47.75, 14.40.