Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][N:37]([CH3:43])[S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:42][CH2:41][S:38]([N:37]([CH3:43])[CH3:36])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: C=CS(=O)(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(=O)(=O)N(C)C)CC3)cc1OCC2

Procedure:
2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with N,N-dimethylethenesulfonamide to give 249 as a white solid. 1H NMR δ (ppm)(DMSO-d6): 8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.37, 1.77 Hz), 6.85 (1 H, d, J=1.72 Hz), 5.88-5.80 (1 H, m), 4.48-4.42 (4 H, m), 3.23-3.15 (2 H, m), 2.95 (2 H, d, J=11.09 Hz), 2.74 (6 H, s), 2.68-2.60 (2 H, m), 2.09-1.98 (2 H, m), 1.73 (2 H, d, J=12.61 Hz), 1.64-1.55 (2 H, m), 1.43 (6 H, d, J=6.61 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.90 M+H+=513
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br-:1].[C:5]1([CH2:4][CH2:3][CH2:2][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Product: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Yield: 96 %

Procedure:
A magnetically stirred suspension of 1bromo-3-phenylpropane (Aldrich, 13.7 ml, 90 mmol) and triphenylphosphine (47.2 g, 180 mmole) was heated at 100° C. (Oil bath) for 2.0 hours. The resulting while solid was then cooled and triturated with ether (5X) to remove most of the unreacted triphenylphosphine, to give Part A(1) compound in 96% yield (wt. 40.0 g).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:2][CH2:3]1)=[O:28]
Reactant: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
Synthesized from compound 26. To a solution of compound 26 (0.2 g, 0.6 mmol) in 5 mL of CH2Cl2 was added 1 mmol of TEA and 0.8 mmol of 3-chloro-benzoyl chloride. The reaction was stirred overnight at room temperature. After the solvents were evaporated, the residue was purified with semi-preparative HPLC to afford a solid (16% yield). MP: 147-149° C.; MS (ES−): 436; 1H NMR (400 MHz, CDCl3): 1.88-2.08 (m, 2H), 2.86-3.07 (m, 4H), 3.52-3.71 (m, 4H), 3.81-3.89 (m, 2H), 7.33-7.43 (m, 4H), 7.62 (d, 1H), 7.81 (t, 1H), 7.90 (t, 1H). Anal. Calcd. for C22H21ClN6O2.0.7H2O: C, 54.89; H, 4.39; N, 16.70; Found: C, 54.93; H, 4.43; N, 16.34.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O.[O-:27][CH2:28][CH3:29].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]1[C:28](=[O:27])[C:29]2[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=2[NH:8][CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Reactant: CC[O-]
Reactant: Cn1ccnc1C=O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 18 %

Procedure:
A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (500 mg, 2.1 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (255 mg, 2.3 mmol) in ethyl propionate (20 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol [sodium (194 mg, 8.4 mmol) in ethanol (10 mL)] was added drop-wise. After the addition, the mixture was stirred at room temperature for 2.5 hr. The mixture was quenched with water (20 mL) and solvent was removed in vacuum. The residue was dissolved in water, and filtered; the cake was washed by water, then ethyl acetate to obtain ethyl 3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate as a yellow solid. The solid was dried in vacuum at 50° C. (140 mg, yield 18%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 1.18-1.21 (t, J=7.2 Hz, 3H), 3.31 (s, 3H), 4.16-4.19 (m, 2H), 4.56-4.59 (d, J=13.2 Hz, 1H), 5.14-5.17 (d, J=13.2 Hz, 1H), 6.54-6.56 (d, J=7.2 Hz, 1H), 6.72 (s, 1H), 6.86 (s, 1H), 6.98-6.99 (d, J=4.8 Hz, 1H), 7.24-7.29 (m, 3H), 7.34-7.38 (t, J=8.0 Hz, 1H), 7.42-7.44 (d, J=7.2 Hz, 2H), 7.49 (s, 1H); LC-MS (ESI) m/z: 376 (M+1)+.
Reaction SMILES: [NH4+].[Cl-].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[CH:6][C:5]=1[F:14]>O.[Fe]>[Br:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([CH3:13])=[C:8]([CH:9]=1)[NH2:10]
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(F)c(Br)cc1N
Temperature: 25 °C
Yield: 72.1 %

Procedure:
The mixture of iron powder (17.8 g, 318 mmol) and NH4Cl (5.10 g, 95.4 mmol) in water (100 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-3-fluoro-6-nitrotoluene (18.6 g, 79.5 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3×200 mL). The organic solution was washed with H2O (3×300 mL) and brine (300 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 11.7 g (72%) of title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 6.82 (m, 2H), 3.49 (bs, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=[O:18])=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N>C(O)C>[OH2:18].[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:16][C:13]1[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]2[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:15][N:14]=1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cnc1C
Product: O

Procedure:
A mixture of 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone and 1.1 molar equivalents of 2-(5-methyl-4-imidazolylmethylthio)ethylamine was heated at 130° for 5 hours and heated under reflux in ethanol for 12 hours, evaporated to dryness and the product isolated as 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone monohydrate, m.p. 115° (softening at 98°).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)cc1F
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)c(F)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.23-7.36 (m, 2H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1H), 8.35 (td, J=8.5, 6.4 Hz, 1H), 8.56 (dt, J=7.8, 1.9 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[CH3:32]N(C)C=O.[H-].[Na+]>O>[CH3:32][C:26]1[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[C:24]([O:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:20][CH:19]=2)[N:25]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C#N)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (4.28 g), 2-chloro-3-cyanopyridine (2.10 g) and N,N-dimethylformamide (5.0 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.90 g, 33%) of 6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 116-117° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][SH:25])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25][C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.6 g, 0.088 mol) was added to a cold solution of 2-chloro-5-nitrobenzoic acid (16.1 g, 0.08 mol) in dimethylformamide (200 mL) and the mixture was stirred for 5 min. The cold mixture was treated dropwise with a solution of 4-methoxy-α-toluenethiol (13.2 g, 0.08 mol) in dimethylformamide (80 mL) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was diluted with water and acidified with dilute hydrochloric acid to pH 1. The resulting precipitate was filtered, washed with water and azeotroped to dryness from a mixture of methylene chloridetoluene. The residue was suspended in ethyl ether, filtered and washed with ethyl ether to give the title compound as a yellow solid (16 g, 63%), which was used without further purification. Mp 200-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:10][S:11](O)(=[O:13])=[O:12]>S(=O)(=O)(O)N>[N+:1]([C:4]1[CH:9]=[C:8]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Agent: NS(=O)(=O)O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 105 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
123.1 g (1.0 mol) of nitrobenzene are allowed to run rapidly into 582.5 g (5.0 mol) of chlorosulfonic acid and 1 g of sulfamic acid at room temperature. The mixture is then heated to 105° C. and stirred at this temperature for 6 hours. For working up, the reaction mixture is dripped into ice water. The precipitated crystals are filtered off with suction and washed with water. 194.6 g of dry 3-nitrobenzenesulfonyl chloride having a melting point of 59°-61° C., corresponding to a yield of 87.8% of theory, are obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:21](/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1)=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 66.8 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.249 mmol), styrene (37 uL, 0.324 mmol), diisopropylethylamine (87 uL, 0.324 mmol) and DMF (2.5 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (2.8 mg, 0.0125 mmol) and P(o-tol)3 (11 mg, 0.0374 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted 3× with EtOAc and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give the title compound (63 mg, 67%) which was used without further purification. MS ESI 379.2 [M+H]+, calcd for [C22H26N2O2Si+H]+ 379.18.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8].C(N[C@H:27]([C:29]([OH:31])=O)[CH3:28])(OC(C)(C)C)=O.CO[C:34](=O)[C@H:35]([CH2:37][C:38]1C=C[CH:41]=[CH:40][CH:39]=1)N>>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][C:29](=[O:31])[CH2:27][CH2:28][CH:34]=[CH:35][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Product: CCCCCC=CCCC(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) using General Procedure A, followed by removal of the BOC-group using General Procedure Y) and dec-4-enoic acid prepare from ethyl dec-4enoate (ICM) using General Procedure N), the title compound was prepared as a solid (mp =115.5-117.5° C.). The reaction was monitored by tlc (Rf=0.52 in 50% EtOAc/hexanes; 0.60 in 10% CH3OH/CH2Cl2) and the product was purified by flash chromatography using 10% CH3OH/CH2Cl2 as the eluent.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36].[CH2:37](O)[C:38]#[CH:39].C1(C)C=CC=CC=1.CCOCC>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][C:28]([CH3:33])([CH3:32])[C:29]([O:31][CH2:39][C:38]#[CH:37])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36]
Reactant: C#CCO
Reactant: Cc1ccc(OC(C)(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CCOC(=O)C(C)(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
A mixture of 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}-2-methylpropionic acid (0.500 g, 0.000960 mol), p-toluenesulfonic acid (0.0100 g), propargyl alcohol (0.0538 g, 0.000960 mol) and toluene is stirred one day at 50° C., cooled to room temperature and concentrated in vacuo to obtain a residue. Chromatography of the residue on silica gel with ether:methylene chloride affords the title compound (0.360 g, 67.2%) which is identified by NMR spectral analysis.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1)=O.O.[OH-].[K+]>C(O)C.[C].[Pd]>[C:25]([CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][CH:19]([CH:17]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:29][CH:28]=1)([OH:27])=[O:26]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC1=CCC(C=CC(=O)c2c(O)cccc2OCC(=O)O)C=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a suspension of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (1 g) and 4-formylcinnamic acid (0.79 g) in ethanol (10 mL) were added water (2 mL) and potassium hydroxide (3 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure. To the residue was added 2 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-(2-carboxyethyl)-2′-(carboxymethoxy)-6′-hydroxydihydrochalcone (1.55 g). This material was dissolved in acetic acid (12 mL). To the solution were added sodium acetate (8.6 g) and acetic anhydride (8.6 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice. To the extract was added 1 mol/L aqueous sodium hydroxide solution, and the aqueous layer was separated. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.29 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(Br)cc2nccc(Cl)c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(SCc2ccccc2)cc2nccc(Cl)c12
Temperature: 60 °C
Yield: 62 %

Procedure:
To a vial charged with 7-bromo-4-chloro-5-methylquinoline (0.048 g, 0.187 mmol) was added Xantphos (0.022 g, 0.037 mmol), Pd2(dba)3 (0.017 g, 0.019 mmol), dioxane (0.748 ml), DIEA (0.065 ml, 0.374 mmol) and benzyl mercaptan. The mixture was purged with argon and heated to 60° C. overnight. The mixture was directly loaded onto a 25 HP silicycle column and purified by ramping EtOAc in heptane (0 to 50%, 10% DCM throughout) to provide product as a light yellow solid (35 mg, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.97 (s, 3H) 4.31 (s, 2H) 7.22-7.26 (m, 1H) 7.27-7.31 (m, 1H) 7.31-7.39 (m, 3H) 7.44 (d, J=6.94 Hz, 2H) 7.82 (d, J=1.96 Hz, 1H) 8.61 (d, J=4.70 Hz, 1H). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[CH:9][C:10]2[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].O>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[C:15]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Nc1cccc(C)c1C=Nc1cccnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cccc(C)c1CNc1cccnc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.1 %

Procedure:
To a solution of 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylideneamino)pyridine (229 mg) in methanol (4.6 ml) and chloroform (4.6 ml) was added sodium borohydride (200 mg) and the mixture was stirred for 3.5 hours at room temperature. After water was added, organic layer was separated and dried over magnesium chloride. The solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylamino)pyridine (217 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:19]2[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=2)[N:3]=1.[CH3:29][C:30](OC(C)=O)=[O:31].C(Cl)Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:19]2[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:31])[CH3:29]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCNC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC[C@@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Prepared according to Example 50, using TEA (39.9 μl, 0.287 mmol), 2-(2-methyl-3-((3R)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Ex. 75, 90 mg, 0.239 mmol), Ac2O (45.1 μl, 0.478 mmol), and DCM (2.4 mL) and stirring at 25° C. for 1 h. Isolation of the free base from the mixture by addition of saturated aq. NaHCO3 and extraction with 10% MeOH/DCM, followed by drying of the organic extract over Na2SO4, filtration, and concentration under reduced pressure afforded 2-(3-(((3R)-1-acetyl-3-piperidinyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (34 mg, 30%). 1H NMR (DMSO-d6) δ: 7.85-7.91 (m, 1H), 7.77-7.83 (m, 1H), 7.54-7.63 (m, 2H), 7.30-7.40 (m, 2H), 7.05-7.11 (m, 1H), 4.45-4.55 (m, 1H), 4.27-4.39 (m, 1H), 4.13-4.27 (m, 1H), 3.96-4.10 (m, 1H), 3.86-3.95 (m, 1H), 3.76-3.86 (m, 1H), 3.39-3.46 (m, 3H), 2.87-2.97 (m, 1H), 2.07 (s, 3H), 1.59 (s, 3H), 1.10-1.22 (m, 3H). m/z (ESI, +ve) 419.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:12])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O>C(O)CCC>[ClH:13].[C:1]1([C:7]2[N:8]3[C:9]([S:12][C:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=43)=[N:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nc(-c2ccccc2)c[nH]1
Reactant: O=C1CCCCC1Cl
Solvent: CCCCO
Product: Cl
Product: c1ccc(-c2cnc3sc4c(n23)CCCC4)cc1
Yield: 75 %

Procedure:
A solution of 4-Phenyl-1H-imidazole-2-thiol 24 (Maeda et al., Chem. Pharm. Bull. 1984, 32, 2536-2543) and 2-chlorocyclohexanone was refluxed in butanol for 3 hours. After cooling, the resulting precipitate was filtered to give 25 in 75% yield: mp 274-278° C.; 1H-NMR (DMSO-d6) 1.89 (m, 4H), 2.76 (m, 4H), 7.38 (t, 1H), 7.49 (t, 2H), 7.88 (d, 2H), 8.51 (s, 1H); HR-MS (EI) m/z 254.0874 (M+).