Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:30])[NH:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:21][C@@H:22]([OH:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C1COCC1>O>[OH:29][C@@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][NH:20][C:19]1[CH:18]=[CH:17][NH:16][C:15](=[O:30])[C:14]=1[C:11]1[NH:12][C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: COC(=O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
In a 200 mL round-bottomed flask, 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester (0.87 g, 2.15 mmol) and LiOH (258 mg, 10.8 mmol) were combined with THF (20 mLl) and Water (5 mL) to give a purple suspension. The reaction was stirred at room temperature overnight. The next day the reaction was heated in dry block at 50° C. for 3.5 hr and cooled to room temperature. The reaction was dilute with water, concentrated, dilute with more water, and acidify with 1M HCl, and filtered. The resulting solid was washed with water and hexanes, and dried over house vacuum yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid (0.86 g, 102% yield) as a purple solid. LC/MS calcd for C21H18N4O4 (m/e) 390.0, obsd 391.2 (M+H); 1H NMR; (DMSO-d6): 13.35 (s, 1H), 11.19 (d, J=6.0 Hz, 1H), 10.97 (t, J=4.9 Hz, 1H), 7.75 (dd, J=7.7, 3.9 Hz, 2H), 7.56 (d, J=7.3 Hz, 2H), 7.22-7.44 (m, 5H), 6.20 (d, J=7.5 Hz, 1H), 5.80 (br. s., 1H), 4.92 (t, J=5.5 Hz, 1H), 3.54-3.74 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:41](Cl)=[O:42])=[N:29][N:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([O:39][CH3:40])[CH:33]=3)[N:29]=2)=[O:42])=[CH:18][C:17]=1[F:23]
Reactant: CCOc1cn(-c2ccc(F)c(OC)c2)nc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Product: CCOc1cn(-c2ccc(F)c(OC)c2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X9 was prepared from A2 and 4-ethoxy-1-(4-fluoro-3-methoxyphenyl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d5-DMSO, 300K) δ 1.39 (t, J=7.0 Hz, 3H), 3.94 (s, 6H), 3.96 (s, 3H), 4.10 (q, J=7.0 Hz, 2H), 6.48 (d, J=5.2 Hz, 1H), 7.40 (m, 2H), 7.46 (t, J=9.0 Hz, 1H), 7.52 (m, 2H), 7.70 (m, 2H), 8.03 (dd, J=2.4 Hz, J=13.2 Hz, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.52 (s, 1H), 10.19 (s, 1H). MS (ES) C30H26F2N4O6 requires: 576. Found: 577 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31].C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[O:31])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Reactant: O=C(O)c1ccccn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccccn4)cc3)ccc2n1
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 7 mg (0.1 mmol) 2-pyridinecarboxylic acid, and 0.028 ml (0.2 mmol) triethylamine in 2 ml DMF was added 36 mg (0.75 mmol) PyBrop and stirred at room temparature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 7.4 mg (23%) of the title compound. MS 412.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.33 (d, 2H), 7.60 (m, 1H), 7.70 (d, 2H), 7.86 (d, 1H), 8.00 (t, 1H), 8.04 (t, 1H), 8.35 (d, 1H), 8.65 (m, 1H), 8.94 (s, 1H), 8.98 (br. 2H), 9.32 (t, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(O)C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(C(=O)O)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and piperidine-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH2:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH3:14]
Reactant: [H][H]
Reactant: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Tert-butyl-(2R)-2-vinylpyrrolidine-1-carboxylate (0.21 g, 1.07 mmol) was dissolved in methanol (10 mL) with palladium on carbon, 10% catalyst (0.046 g, 20% by wt.) and subjected to a hydrogen atmosphere via balloon. The reaction was run overnight and filtered through Celite and concentrated in vacuo to yield tert-butyl (2S)-2-ethylpyrrolidine-1-carboxylate (0.18 g, HPLC RT=3.00 min.). LC-MS m/z (minus t-butyl+CH3CN+1)=185. 1H NMR (CD3OD, 400 Mhz) 3.67-3.63 ppm (m, 1H), 3.36-3.30 (m, 2H), 1.92-1.71 (m, 4H), 1.45 (s, 9H), 1.43-1.29 (m, 2H), 0.90-0.85 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH3:31])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][CH:25]5[CH2:27][O:26]5)=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:34]([C:37]1[NH:38][C:39]([SH:42])=[N:40][N:41]=1)([CH3:36])[CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH3:31])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][S:42][C:39]5[NH:38][C:37]([CH:34]([CH3:36])[CH3:35])=[N:41][N:40]=5)=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4CO4)c(C)c3)nc12
Reactant: CC(C)c1nnc(S)[nH]1
Solvent: CN(C)C=O
Product: CCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CSc4nnc(C(C)C)[nH]4)c(C)c3)nc12
Yield: 22.7 %

Procedure:
A solution of 300 mg of 5-(4-chloro-benzyl)-2-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-7-ethoxy-oxazolo[5,4-d]pyrimidine (prepared analogously as described in example 20, step (a)) and 92 mg of 5-isopropyl-4H-[1,2,4]triazole-3-thiol in 3 ml of dimethylformamide was heated for 2 h to 130° C. in a microwave reactor. After removal of the solvent the product was isolated by preparative HPLC (method HPLC1) to yield 89 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[F-].[Cs+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OB(O)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccccc3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.3 %

Procedure:
4-Chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (100 mg, 0.159 mmol) was dissolved in dimethoxyethane (5.0 mL), and the solution was added with phenylboronic acid (58.2 mg, 0.478 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (10.4 mg, 0.0130 mmol) and cesium fluoride (145 mg, 0.954 mmol), followed by stirring at 90° C. for 6.0 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to obtain 4-chloro-5-phenyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (44.5 mg, yield 50%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[CH3:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][S:25]4(=[O:30])=[O:29])[O:12][C:11]3=[O:31])[CH3:9])=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCS2(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@@](CCN4CCCS4(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:31]([O:30][C:29](=[O:38])[NH:28][CH2:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:22]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NCC1CCCNC1)OCc1ccccc1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCCC(CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)phenol (1.5 g, 5.54 mmol) was suspended in anhydrous CH2Cl2 (15 mL) and cooled to 0° C. under an N2 atmosphere. A mixture of benzyl (piperidin-3-yl)methylcarbamate hydrochloride (1.73 g, 6.09 mmol) in CH2Cl2 (20 mL), and triethylamine (23 mL, 16.67 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and the reaction was complete after one hour. It was then partitioned between CH2Cl2/H2O, and separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to an orange solid. Purification by silica gel chromatography using 98% CH2Cl2/2% EtOAc gave benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as a bright yellow solid (1.75 g, 66%). LC/MS: m/z 483.5 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:35][C:34]3[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(CN[C@@H](CC(C)C)C(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 3,4,5-trimethoxybenzaldehyde (0.244 g, 1.25 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 15 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.46 and 0.15. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.15) was isolated by flash chromatography (50% EtOAc in hexanes). Eighty-four percent (0.61 g) of the pure titled compound was obtained as a white foam: mp 58-62° C. APCI-MS m/z 582.4 (MH+).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]1[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39]([N:6]1[CH2:7][CH2:8][C@@H:3]([CH3:2])[C@@H:4]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[CH2:5]1)=[O:40]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCN(C(=O)Nc2ccc(F)cc2F)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.1 %

Procedure:
A round bottom flask was charged with 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.05 g, 0.17 mmol, Example #5 Step J) and DIEA (0.03 mL, 0.17 mmol) in DCM (1.6 mL). The reaction mixture was stirred for about 5 min at ambient temperature then 2,4-difluoro-1-isocyanatobenzene (0.02 mL, 0.17 mmol) was added and the reaction mixture was stirred at ambient temperature for about 18 h. The reaction mixture was diluted with DCM (5 mL) and washed with water (2 mL). The aqueous layer was back extracted with DCM (2 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by RP-HPLC (Table 1, Method e) to afford (3R,4R)-N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide (0.014 g, 20%): LC/MS (Table 1, Method j) Rt=1.77 min; MS m/z 411 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26](=[O:29])[NH:27][CH3:28])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)C(=O)OC(C)(C)C)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26]([NH:27][CH3:28])=[O:29])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cn2cc(-c3cnc(NC(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A solution of tert-butyl isopropyl(5-(2-(methylcarbamoyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl)carbamate (30 mg) in methylenechloride (2 ml) was treated with TFA (4 ml) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue chromatographed on silica gel using ethyl acetate as eluent to give 15 mg of 6-(2-(isopropylamino)thiazol-5-yl)-N-methyl-8-phenylimidazo[1,2-a]pyridine-2-carboxamide as a tan solid. LCMS (Conditions C): 2.62 min (RT); (M+H)+=392.14 (100%). 1H NMR, 500 MHz, CDCl3/CD3OD: δ 8.20 (s, 1 H), 8.19 (d, J=1.65 Hz, 1 H), 7.89 (d, J=1.37 Hz, 1 H), 7.88 (s, 1 H), 7.42-7.53 (m, 3 H), 7.36 (d, J=1.92 Hz, 1H), 7.34 (s, 1 H), 3.55-3.64 (m, 1 H), 1.34 (d, J=6.32 Hz, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])[OH:10])=[CH:5][CH:4]=1.[OH-].[CH2:21]([N+:25]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].CC(O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([P:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:10])[O-:11])=[CH:7][CH:8]=1.[CH2:34]([N+:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:35][CH2:36][CH3:37]
Reactant: COc1ccc(P(=O)(O)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(P(=O)([O-])c2ccc(OC)cc2)cc1

Procedure:
To a flask were added 2.0 g bis(4-methoxyphenyl)phosphinic acid, 3.0 g of a 55-60% solution of tetrabutylammonium hydroxide in water, 2.0 g of water and 18 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. A waxy solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.IC>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 53 %

Procedure:
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 195 mg (53%) of the title compound and 110 mg (30%) of the compound of Preparative Example 13.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH3:15][C:16]1([CH3:23])[NH:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].[OH-].[K+]>CS(C)=O>[F:12][C:11]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([N:18]2[C:17](=[O:22])[C:16]([CH3:23])([CH3:15])[NH:20][C:19]2=[O:21])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 110 °C

Procedure:
30 ml of dimethylsulfoxide and 24.8 grams of 2-nitro-5-chloro trifluoromethylbenzene were introduced at 20° C. with stirring into 100 ml of dimethylsulfoxide, 12.80 grams of 5,5-dimethyl-hydantoin and 6.28 grams of potassium hydroxide in the form of flakes. The mixture was heated to 110° C. for a period of time variable between 3 and 18 hours. The product was characterized and determined by thin layer chromatography.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][C:5]1[NH:9][CH:8]=[N:7][C:6]=1[CH2:10][S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=NC=[CH:28][CH:29]=2)=[CH:18][N:17]=1.[N:30]1C=CC=C(CC2C(=O)NC(SC)=NC=2)[CH:31]=1>>[ClH:1].[ClH:1].[ClH:1].[CH3:4][C:5]1[NH:9][CH:8]=[N:7][C:6]=1[CH2:10][S:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:30]=[CH:31][CH:25]=2)=[CH:18][N:17]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCCNc1ncc(Cc2cccnc2)c(=O)[nH]1
Agent: Cl
Product: Cc1[nH]cnc1CSCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1

Procedure:
In a similar manner 2-[3-(5-methyl-4-imidazolylmethylthio)propylamino]-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 184°-189° was prepared from 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37]Br>>[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37][N:25]([S:26]([CH3:29])(=[O:28])=[O:27])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][OH:7])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: Clc1cccc(Cl)c1CBr
Product: CC(C)C[C@@H](C(=O)NN(Cc1c(Cl)cccc1Cl)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2,6-dichlorobenzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[CH:24][S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCc1ccc(F)cc1
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.