Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[C:18]([CH3:21])[N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1csc2nc([C@H](C)Nc3nc(N)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A solution of 7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.33 mmol) and 2-amino-6-bromopurine (0.11 g, 0.49 mmol) in 1-butanol (0.66 mL) was treated with N,N-diisopropylethylamine (86 μL, 0.49 mmol), degassed with nitrogen for 5 min and heated at 100° C. for 18 hours. The reaction was not complete and was, therefore, heated at 115° C. for an additional 5 hours. The reaction mixture was diluted with methanol (10 mL), stirred, and filtered. The filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (27 mg, 19%) as a white solid. LCMS for C20H18FN8OS (M+H)+: m/z=437.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.10 g, 0.25 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.25 mmol), DIEA (0.064 g, 0.50 mmol), DMAP (0.033 g, 0.27 mmol), and THY (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give (0.82 g, 67%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.41 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.02-6.97 (m, 2H), 5.26 (s, 1H), 5.01-4.99 (m, 1H), 4.56-4.53 (m, 1H), 4.16-4.08 (m, 1H), 3.01 (s, 3H), 1.52 (d, J=7.0 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 480. Found: [M+H]+ 481.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[O:23][NH:22][C:21](=O)[CH:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccn2)c1CO
Reactant: COC(=O)c1cc(=O)[nH]o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (465 mg, 2.44 mmol) in THF (10 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (350 mg, 2.45 mmol) and triphenylphosphine (769 mg, 2.93 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.23 mL, 2.68 mmol) was added and the reaction mixture was stirred for 1 h at 0° C. and then overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4) afforded the title compound (443 mg, 57%) as a white solid. MS: m/e=316.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:15])[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:39])=O)C=CC=CC=1>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH:13]([C:14]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[NH2:39])=[O:15])[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:1])[CH3:3]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)N(N)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 18A (308 mg, 0.8 mmol, 1 eq) was dissolved in 15 mL of tetrahydrofuran. Sodium hydride (60% in oil, 38 mg, 0.96 mmol, 1.2 eq) was added, and the mixture was stirred at rt for 15 min. O-Diphenylphosphinylhydroxylamine (224 mg, 0.96 mmol, 1.2 eq) was then added, and the reaction was stirred at rt for 1 h. LC analysis indicated that the starting material had been consumed. Water was added, and the reaction was extracted with CH2Cl2. The combined organic extracts were dried and concentrated in vacuo to provide Compound 18B as a semi-solid in quantitative yield. The compound was used without further purification. LC: R.T.=3.39 min (retention time) (YMC Combiscreen ODS-A S5 column eluting with 10-90% aqueous methanol over a 4 minute gradient.)
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[C:34]([O:35][CH3:36])=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:41]([OH:43])=[O:42])=[CH:31][N:32]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:27][CH:26]=1>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[C:34]([O:35][CH3:36])=[C:33]4[C:28]([C:29](=[O:44])[C:30]([C:41]([OH:43])=[O:42])=[CH:31][N:32]4[C@@H:37]4[CH2:39][C@@H:38]4[F:40])=[CH:27][CH:26]=3)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
After adding 3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (165 mg, 731 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 609 μmol) was added thereto and it was heated under reflux for 13 hours under a nitrogen atmosphere. After concentrating the reaction solution under reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, stirring was performed at room temperature for 30 minutes. 1 mol/l Hydrochloric acid (5 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution and the insolubles were removed by filtration. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by preparative chromatography (development at the lower layer of a 7:3:1 mixture of chloroform methanol:water), recrystallized in isopropyl alcohol, and dried under a reduced pressure. 146 mg (60%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Si:20]([O:27][C:28]1[CH:33]=[C:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:31]=[CH:30][C:29]=1[C@H:42]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][N:9]([CH3:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:48][C@H:45]2[CH2:46][CH2:47][C@H:42]([C:29]3[CH:30]=[CH:31][C:32]([O:34][Si:35]([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36])=[CH:33][C:28]=3[O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH2:43][CH2:44]2)=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)O[C@H]2CC[C@H](c3ccc(O[Si](C)(C)C(C)(C)C)cc3O[Si](C)(C)C(C)(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
Triethylamine (20 μl), 4-dimethylaminopyridine (catalytic amount) and 4-dimethylaminobenzoyl chloride (26 mg) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (30 mg) in dry dichloromethane (2 ml) at room temperature under argon. After 24 hr, the solvent was removed under reduced pressure and the residue was partitioned between water (10 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:24 v/v) to give the title compound as a white solid (18 mg, 45%); m/z (ES+) 585 (M+H)+.
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][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50]>>[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][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:37][CH2:38][CH2:39][N:40]3[C:44](=[O:45])[C:43]4=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]4[C:41]3=[O:50])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CCCN5C(=O)c6ccccc6C5=O)c4=O)CC3)c2cc1OC
Yield: 42 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 478.0 mg (1.00 mol) of Compound 24 was used and N-(3-bromopropyl)phthalimide was used in place of methyl iodide. As a result, 280 mg (yield: 42%) of Compound 34 was obtained as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH2:22][CH:21]=2)[N:17]=[C:16]2[N:39]([CH:42]([CH3:44])[CH3:43])[N:40]=[CH:41][C:15]=12)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:41]=[N:40][N:39]([CH:42]([CH3:44])[CH3:43])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH2:22][CH:21]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate (0.5 g, 0.829 mmol) was taken in DCM (6 mL), TFA (2 mL) was added and stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure, neutralized with saturated NaHCO3 solution. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with acetonitrile followed by diethyl ether to provide the desired compound. LCMS: 504.35 (M+1)+; HPLC: 99.26% (@ 254 nm) (Rt; 4.223); 1H NMR (DMSO-d6, 400 MHz) δ 11.56 (bs, 1H), 10.25 (bs, 1H), 8.87 (t, 1H, J=4.8 Hz), 8.80 (bs, 1H), 8.55 (bs, 1H), 8.34 (s, 1H), 7.89 (s, 1H), 6.93 (bs, 1H), 5.90 (s, 1H), 5.21 (m, 1H), 4.39 (d, 2H, J=4.8 Hz), 4.08 (bs, 2H), 3.75 (bs, 2H), 3.30 (m, 3H), 3.16-3.12 (m, 1H), 2.96 (m, 3H), 2.32 (m, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 1.86 (m, 2H), 1.52 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:13])(=[O:3])[CH3:2].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1C=CC=CC=1>C(O)C>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1C
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1ccc(C=CC(=O)O)cc1C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A mixture of 4-acetamido-3-methylbenzaldehyde (1.23 g), malonic acid (795 mg), pyridine (549 mg) and ethanol (1.7 ml) was refluxed for 3 hours under nitrogen atmosphere. To the mixture was added ethanol (1.7 ml), and the mixture was stirred for 30 minutes under ice-bath cooling. The resulting precipitate was collected by filtration and washed with ethanol to give 4-acetamido-3-methylcinnamic acid (1.08 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][C:26](N4C=CN=C4)=[O:27])=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1>ClCCl>[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(CCCOc1ccc2c(c1)CCN(C1CCC1)CC2)n1ccnc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(CCCOc1ccc2c(c1)CCN(C1CCC1)CC2)N1CCCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Piperidine (0.1 ml, 1.1 mmol) was added to a stirred solution of 3-cyclobutyl-7-{[4-(1H-imidazol-1-yl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine (E167, Step 1) (150 mg, 0.42 mmol) in dichloromethane (5 ml). After stirring at room temperature for 5 days the reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E167); MS (ES+) m/e 371 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:20][C:19]2[CH:22]=[CH:23][C:16]([I:15])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCc1ccc(I)cc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2ccc(I)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-iodobenzyl chloride
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC[O-].[Na+]>[C:5]1([S:11][CH2:2][C:3]#[N:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCl
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: N#CCSc1ccccc1
Temperature: 20 °C

Procedure:
Chloroacetonitrile (11.4 cc) is added at a temperature in the region of 5° C., in the course of 45 minutes, to a stirred solution of thiophenol (20 g) and a 2M ethanolic solution of sodium ethylate (90 cc). Stirring is maintained for 5 hours at a temperature in the region of 20° C. The reaction mixture is filtered, and the filtrate is evaporated to dryness at 50° C. under vacuum (20 mm Hg; 2.7 kPa). The residue is dissolved in a mixture (30 cc) of cyclohexane and ethyl acetate (70:30 by volume) and the solution is poured onto silica (1,000 g) contained in a column 6.5 cm in diameter. Elution is performed with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent. Phenylthioacetonitrile (14.5 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10]N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]2[C:5]=1[C:13]1[CH2:12][CH2:19][CH2:17][C:15](=[O:16])[C:14]=1[NH:10]2
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CO
Product: O=C1CCCc2c1[nH]c1c(Cl)ccc(Cl)c21
Temperature: 60 °C
Yield: 98.4 %

Procedure:
(2,5-Dichlorophenyl)hydrazine hydrochloride (0.3 g, 1.40 mmol) was dissolved in MeOH (3 mL) and 1,2-cyclo hexadione (0.15 g, 1.40 mmol) was added and the mixture heated to 60° C. for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was diluted with water, neutralized with NaHCO3 solution and extracted with EtOAc (3×15 mL). The combined organic extracts were concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to provide the title compound (0.35 g, 11.8%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.92 (bs, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 3.36 (t, J=6.2 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of crude (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g) in dichloromethane (10 mL) was added diisopropylethyl amine (0.337 g, 2.61 mmol) followed by a solution of ethyl chloroformate (0.119 g, 1.09 mmol) in dichloromethane (1 mL) dropwise over 30 minutes at 0° C. and the mixture stirred at this temperature for 2 h. The mixture was then quenched by ice and diluted with dichloromethane and aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by preparative LC/MS (high pH) to provide the title compound as an off white solid (60 mg, 18%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88 (s, 3H), 1.07-1.21 (m, 1H), 1.23 (t, J=7.03 Hz, 3H), 1.29-1.43 (m, 3H), 1.45-1.92 (m, 13H), 2.02-2.24 (m, 2H), 2.81-3.01 (m, 2H), 3.23-3.40 (m, 2H), 3.41-3.69 (m, 5H), 4.10 (q, J=7.29 Hz, 2H).
Reaction SMILES: C([O:8][P:9]([O:19][C@H:20]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([CH:42]([NH:44]C(=O)OCC3C=CC=CC=3)[CH3:43])=[N:40][CH:41]=2)=[CH:32][CH:31]=1)[C@H:21]([NH:24][C:25](=[O:29])[CH:26]([F:28])[F:27])[CH2:22][F:23])([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C.O>[P:9]([OH:11])([OH:10])([O:19][C@H:20]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[N:40][C:39]([CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)[C@H:21]([NH:24][C:25](=[O:29])[CH:26]([F:28])[F:27])[CH2:22][F:23])=[O:8]
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@@H](OP(=O)(OCc3ccccc3)OCc3ccccc3)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(N)c1ccc(-c2ccc([C@@H](OP(=O)(O)O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reaction time: 5 h
Yield: 91.4 %

Procedure:
Palladium on carbon (1:9, 23 mg, 0.022 mmol) is added to the product of step 4, Example 95A (235 mg, 0.308 mmol) in ethanol (5 mL) and water (1 mL). The mixture is evacuated with nitrogen three times and stirred under hydrogen for 5 hours. The reaction mixture is filtered through a 4 mL pad of solka flok and rinsed with alternating 4 mL rinses of ethanol and water ten times. The solvent is removed under reduced pressure to give the crude product, which is taken up in water (5 mL) and filtered through a 0.45 um filter disk, rinsing with water (2 mL). The filtrate is freeze dried to give the title product (126 mg): 1H NMR δ 8.75 (1H, s), 8.07 (1H, d), 7.63 (2H, d), 7.52-7.48 (4H, m), 6.00 (1H, t), 5.42 (1H, d), 4.82 (1H, dd), 4.64-4.43 (4H, m), 1.62 (3H, d); m/z: 447.12.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a mixture of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (653 mg, 1.38 mmol), K2CO3 (406 mg, 2.94 mmol) in DMF (10 mL) was added MeI (519 mg, 3.66 mmol), then the mixture was stirred at 80° C. After 3 hours, the solvent was removed by vacuum, the mixture was washed with H2O (20 mL) and extract with DCM (50 mL×3), dried over Na2SO4 and concentrated to give the desired product of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, yield: 89%). 1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 7.69˜7.75 (m, 2H), 7.05˜7.10 (m, 1H), 6.98˜7.03 (m, 1H), 5.64 (d, J=3.0 Hz, 1H), 3.09 (s, 3H), 2.97 (s, 3H), 2.95 (d, J=3.6 Hz, 3H). MS (M+H)+: 473/475.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[C:21]([CH3:30])[C:20]=1[CH3:31]>>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22](/[CH:23]=[CH:24]/[C:25]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[C:21]([CH3:30])[C:20]=1[CH3:31]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(C)c1C
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3C)nc2n(CCC)c1=O
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.31 g (10.24 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.42 g (15.4 mmol) of 4-methoxy-2,3-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.96 g (yield 48%) of Compound 12 as a white powder.