Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH:23]1([CH2:22][O:21][C:17]2[N:16]=[CH:15][C:14]([CH:12]([N:9]3[C:10](=[O:11])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:27])[C:7]=4[CH2:8]3)[CH3:13])=[CH:19][C:18]=2[CH3:20])[CH2:25][CH2:24]1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC1CC1
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC1CC1
Yield: 45 %

Procedure:
The title compound is prepared in 45% yield (275 mg, white solid) from 4-chloro-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (492 mg, 1.37 mmol, Intermediate-124, single enantiomer) and phenyl formate (336 mg, 1.37 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C[N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=O)OC(C)(C)C.O[CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[CH:32][N:33]2[C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>>[C:40]([C:39]1[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=1[N:33]1[C:34]2[C:30](=[C:29]([CH2:28][N:15]3[C:14](=[O:24])[C@@H:13]([NH:12][C:11](=[O:25])[C@@H:10]([NH:2][CH3:3])[CH3:26])[CH2:19][O:18][C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]3=4)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32]1)#[N:41]
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1-n1ccc2c(CO)cccc21
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2cccc3c2ccn3-c2ccccc2C#N)C1=O
Temperature: 60 °C
Yield: 10.3 %

Procedure:
In a similar manner to that described for Example 57 except in Step 1 the mixture was heated at 60° C. for 2.5 d and in Step 2 the material was purified by silica gel chromatography, tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino) propan-2-yl)carbamate (250 mg, 688 μmol, Eq: 1.00), 2-(4-(hydroxymethyl)-1H-indol-1-yl)benzonitrile (440 mg, 1.77 mmol, Eq: 2.58) was converted to the title compound (35 mg) as a white solid. MS m/z 494 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([OH:10])=[C:4]([Cl:11])[CH:3]=1.[H-].[Na+].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([O:10][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:4]([Cl:11])[CH:3]=1
Reactant: CCc1cc(Br)cc(Cl)c1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc(Cl)c1OCOCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of 4-Bromo-2-chloro-6-ethyl-phenol dissolved in THF (10 mL) was added to a cooled 0° C. suspension of NaH (0.43 g, 10.8 mmol, 60% dispersion in mineral oil) in THF (20 ml). After the addition was complete the reaction mixture was warmed up to room temperature and stirred for 30 mins. 2-Methoxyethoxymethyl chloride (1.34 mL, 11.7 mmol) was added and the reaction was stirred for 15 hours. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave the title compound as a clear oil (2.4 g, 76%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.3 Hz, 3 H), 2.70 (q, J=7.6 Hz, 2 H), 3.40 (s, 3 H), 3.61 (m, 2 H), 3.98 (m, 2 H), 5.15 (s, 2 H), 7.24 (s, 1 H), 7.37 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][NH:23][CH2:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[Si]([N:31]=[C:32]=[O:33])(C)(C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][N:23]([C:32]([NH2:31])=[O:33])[CH2:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCCNC3)cc12
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCCN(C(N)=O)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (0.0030 g, 0.0077 mmol) in DCM (0.5 mL) was added a drop of TMS isocyanate. The reaction was stirred at 0° C. for 30 min. The solution was directly loaded onto Prep TLC (20×20 cm, silica gel, 5% MeOH in DCM) to afford the desired product. 1H-NMR (CD3OD, 400 MHz): δ=1.87 (d, J=7.1 Hz, 3 H), 2.22-2.44 (m, 2 H), 3.46-3.57 (m, 2H), 4.11-4.20 (m, 2 H), 5.27 (d, J=7.3 Hz, 1 H), 6.00 (t, J=2.0 Hz, 1 H), 7.11-7.24 (m, 1 H), 7.34 (dd, J=16.2, 1.8 Hz, 2 H), 8.19 (s, 1 H). MS (ES+): m/z 433.04/434.96 [MH+]. HPLC: tR=3.23 min (ZQ3, polar—5 min).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:49]([C:46]2[CH:47]=[N:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=2)(=[O:50])=[O:51])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (129 μL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 6-methoxypyridine-3-sulfonyl chloride (129 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:6) to give the title compound as a pale-yellow oil (yield 247 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[C:39]=2[CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[C:39]=2[CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) and (RS)-3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionic acid tert.-butyl ester (Example K13) according to the general procedure M. Obtained as a red oil (424 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:45]=4[N+:53]([O-:55])=[O:54])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:45]=4[N+:53]([O-:55])=[O:54])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-[(2,4-dinitrophenyl)amino]hexanamide (20, 121 mg, 0.124 mmol) and K2CO3 (137 mg, 0.991 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (4 mL) was added thiophenol (100 μL, 0.971 mmol). After stirring at 23° C. for 18 h, the mixture was filtered and solvent removed in vacuo. Flash column chromatography (MeOH/triethylamine/CH2Cl2, 3:5:100) afforded 3 (50 mg, 51%) mp 157-158° C.; 1H NMR (360 MHz, CDCl3) δ 9.12 (d, J=2.6 Hz, 1H), 8.55 (t, J=5.0 Hz, 1H), 8.26 (dd, J=2.6 Hz, J=9.5 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H), 6.62 (t, J=5.5 Hz, 1H), 5.30 (d, J=4.7 Hz, 1H), 3.51 (dt, J=5.8 Hz, J=5.7 Hz, 2H), 3.41 (dt, J=7.0 Hz, J=5.5 Hz, 2H), 3.33 (dt, J=5.9 Hz, J=5.7 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.38-2.31 (m, 3H), 2.21-2.14 (m, 3H), 2.01-1.00 (m, 37H), 0.97 (s, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.86 (d, J=1.4 Hz, 3H), 0.84 (d, J=1.4 Hz, 3H), 0.66 (s, 3H); 13C NMR (125.8 MHz, CDCl3) δ 172.6, 171.8, 148.5, 141.6, 136.2, 130.6, 130.5, 124.6, 121.2, 114.1, 58.4, 57.0, 56.3, 50.5, 45.7, 43.5, 42.5, 40.4, 40.0, 39.7, 39.5, 38.2, 37.2, 36.5, 36.4, 36.0, 35.7, 35.5, 32.1 (×2), 29.9, 29.1, 28.6, 28.4, 28.2, 26.7, 25.2, 24.5, 24.0, 23.0, 22.7, 21.2, 19.6, 18.9, 12.0; IR (film) νmax 3354, 3299, 2933, 2868, 1647, 1620, 1335 cm−1; CI m/z 793.5584 (MH+, C45H73N6O6 requires 793.5592).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)c2ccccc2)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5 g, 32.02 mmol), 4-dimethylaminopyridine (4.74 g, 38.79 mmol) in dry CH2Cl2 (75 ml) was cooled to 0° C. and benzoyl chloride (4.95 g, 35.22 mmol) added dropwise in 15 min. The reaction mixture was stirred for 3 h at room temperature, diluted with CH2Cl2 (150 ml) and washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from diisopropylether then recrystallised from MeOH, giving 5-benzoyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 3 (5.32 g, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[O:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1>C1COCC1>[O:29]1[CH2:34][CH2:33][CH:32]([CH:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[OH:36])[CH2:31][CH2:30]1
Reactant: O=CC1CCOCC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A round bottom flask at −78° C. was charged with 4-bromo-4′-(trifluoromethyl)-1,1′-biphenyl (192 mg, 0.638 mmol) and THF (2.1 mL). nBuLi 2.5M in Hexane (281 μL, 702 mmol) was then added dropwise. The mixture stirred for one hour at −78° C. after which time, tetrahydro-2H-pyran-4-carbaldehyde (86 μL, 0.83 mmol) was added in one portion and mixture stirred for 30 minutes. Reaction mixture warmed up to 0° C. and stirred for an additional hour. Reaction quenched with ammonium chloride solution (aq. sat.) and extracted twice with ethyl acetate. Combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to provide the crude oil. Purification by silica gel flash chromatography (MeOH/DCM) to give the title compound as a colorless oil (118 mg, 55.0%). MS (M): 336.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.FC(F)(F)C(O)=O.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([SiH](CC)CC)C>C(Cl)(Cl)Cl>[CH2:17]([NH:16][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:3][C:4]2=[O:24])=[N:12][C:11]=1[CH3:13])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1nc(-n2ccc(NCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
To a solution of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.30 g, 0.88 mmol) and trifluoroacetic acid (15 mL) in chloroform (20 mL) was added benzaldehyde (0.10 mL, 0.98 mmol). The reaction mixture was stirred for 15 minutes at ambient temperature, then triethylsilane (0.15 mL, 1.00 mmol) was added. The reaction mixture was kept stirring for 2 hours at ambient temperature, then another portion of benzaldehyde (0.10 mL, 0.98 mmol) and triethylsilane (0.15 mL, 1.00 mmol) was added. The reaction mixture was kept stirring for another 2 hours at ambient temperature. The solvent was removed in vacuo, and the residue was washed with saturated aqueous sodium bicarbonate solution, water and t-butylmethyl ether to afford the title compound (0.30 g, 79%): mp 253-255° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.7 Hz, 1H), 8.39 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.44-7.21 (m, 10H), 6.21 (d, J=7.8 Hz, 1H), 5.31 (s, 1H), 4.36 (d, J=5.7 Hz, 2H), 4.31 (d, J=4.5 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 160.9, 155.9, 154.5, 150.2, 140.0, 138.3, 130.6, 128.9, 128.7, 127.7, 127.6, 127.1, 122.8, 103.6, 88.6, 46.0, 43.0, 17.5; MS (ES+) m/z 431.2 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([CH:11]([F:13])[F:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[F:12][CH:11]([F:13])[C:8]1[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]([CH2:4][NH:3][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:10][N:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Cool a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate dihydrochloride (29.8 g, 111.8 mmol, 1.0 equiv), DCM (510 mL), and triethylamine (59.2 mL, 424.6 mmol, 3.8 equiv) to 0° C., then add a solution of isobutyryl chloride (15.3 mL, 145.3 mmol, 1.3 equiv) in DCM (23 mL) drop wise over 20 min. Stir overnight while allowing the mixture to warm to room temperature. Remove the solid precipitate by filtration, and rinse the filter with EtOAc (500 mL). Concentrate the filtrate under reduced pressure; filter the concentrate to remove the solids; and rinse the solids with EtOAc. Concentrate the filtrate under reduced pressure to give a yellow oil. Subject this crude material to silica gel chromatography eluting with a gradient of 40-90% EtOAc/hexanes gradient, to give the title compound as a light yellow crystalline solid (25.8 g, 77% yield). ES/MS (m/z) 301 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 g of ethyl 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 5A; 158 mmol, 1 equivalent) were dissolved in 600 ml of 1,4-dioxane, 790 ml of 2 N aqueous sodium hydroxide solution (1.58 mol, 10 equivalents) were added and the mixture was stirred at RT for 16 h. 316 ml of 6 N hydrochloric acid were added, and the mixture was reduced to about ⅕ of the total volume. The resulting solid was filtered off, washed with water and tert-butyl methyl ether and dried under reduced pressure. This gave 35 g (74% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:29])[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:36](O)(=[O:39])[CH:37]=[CH2:38]>>[C:36]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([F:29])[CH:12]=2)[N:9]=1)(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)O
Reactant: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2F)c1
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(CCC)ccn3)c(F)c2)c2c(N)nccn12
Yield: 28.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-(4-propylpyridin-2-yl)benzamide (intermediate 39) and acrylic acid, to afford the title compound (5.9 mg, 28.9%). Data: UPLC(C) Rt: 2.41 min; m/z 528.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([C:17]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)(O)[CH3:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([C:17]([F:43])([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH3:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(O)(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(1RS)-1-(3-fluoropyridin-2-yl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (156 mg, 0.31 mmol) in CH2Cl2 (10.0 mL) at −40° C. under a nitrogen atmosphere was added DAST (0.08 mL, 0.22 mmol), and the resulting solution was stirred at this temperature for 1 hour. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3 (5 mL) and extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the resulting residue on a silica gel column (0 to 100% ethyl acetate/hexanes) afforded 4-(5-chloropyridin-3-yl)-2-[(1RS)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS APCI calcd. for C27H25ClF2N6 [M+H]+ 507. found 507. The two enantiomers were separated on a chiralpak-AD column (15% IPA/heptane) to afford faster eluting Enantiomer A and slower eluting Enantiomer B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CCCCCCC(N)c1nc(-c2ccc(F)cc2)c[nH]1
Product: CCCCCCC(NC1CCCCC1)c1nc(-c2ccc(F)cc2)c[nH]1
Yield: 15 %

Procedure:
This compound is obtained according to an operating method similar to that of Stage 35.3 of Example 35 using as starting amine, 1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-1-heptanamine (0.5 g; 0.0014 mol) and as ketone, cyclohexanone (0.17 ml; 0.0014 mol). A white-coloured powder is obtained with a yield of 15%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([OH:17])C>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([OH:17])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccc(C=O)s2)c1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: Cc1cccc(-c2ccc(C(=O)O)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 5-(3-methylphenyl)-2-thiophenecarboxaldehyde (prepared immediately above, 4.7 g, 23.3 mmol) was dissolved in 100 mL of ethanol and sequentially treated with a solution of silver nitrate (7.9 g, 116.5 mmol) in 15 mL of water. The suspension was stirred at room temperature for 1 hour, then filtered, and the filter cake was washed with water and ether. The flitrate was separated, and the aqueous layer was acidified with conc. HCl to pH 4. This solution was twice extracted with ether. The extract was dried over MgSO4 and concentrated to give 4.6 g (96% yield) of 5-(3-methylphenyl)-2-thiophenecarboxylic acid. MS: 236 (M+NH4)+. NMR (CDCl3) d: 7.86 (d, 1H, J=5 Hz), 7.5-7.4 (m, 2H), 7.35-7.10 (m, 3H), 2.4 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[N:11][C:10]=1[C:29]([NH:31][CH3:32])=[O:30])C1C=CC=CC=1.CO>[Pd].C(OCC)(=O)C>[CH3:32][NH:31][C:29]([C:10]1[N:11]=[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:20])=[O:19])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[OH:8])=[O:30]
Reactant: CNC(=O)c1nc(NS(=O)(=O)Cc2ccc(C)cc2)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2ccc(C)cc2)n(C)c(=O)c1O
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
A mixture of 5-(benzyloxy)-N, 1-dimethyl-6-oxo-2-(p-tolylmethylsulfonamido)-1,6-dihydro-pyrimidine-4-carboxamide (80 mg, 175 μmol), palladium on carbon (186 mg, 87.6 μmol), MeOH (5 ml) and ethyl acetate (5 ml) was placed under an atmosphere of hydrogen. After stirring for 1.5 hour, the reaction mixture was filtered and evaporated to dryness. Crystallization from MeOH provided the title product as an off-white solid (0.045 g; 70%). LCMS: m/z=367 (MH+).