Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH2:45][C:46]5[CH2:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][C:47]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:41][CH2:40]4)[CH:36]=[CH:35][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:61][C:62]([CH3:64])=O.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([C:47]2[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH2:51][C:46]=2[CH2:45][N:42]2[CH2:41][CH2:40][N:39]([C:37]3[CH:36]=[CH:35][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH:62]([CH3:64])[CH3:61])[CH2:28][CH2:27]5)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:38]=3)[CH2:44][CH2:43]2)=[CH:59][CH:58]=1
Reactant: CC(C)=O
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cnc4[nH]ccc4c3)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 226B (79 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added acetone (54 mg) and MP-cyanoborohydride (150 mg, 2.25 mmol/g). The mixture was stirred overnight. The mixture was filtered. The filtrate was concentrated and the residue was loaded on a silica gel cartridge and eluted with 5 to 10% 7N NH3 in methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12.09 (s, 1H), 8.34 (m, 1H), 7.93 (m, 2H), 7.66 (m, 4H), 7.35 (d, 2H), 7.06 (d, 2H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.59 (dd, 1H), 6.50 (d, 1H), 3.11 (m, 6H), 2.73 (m, 4H), 2.26 (m, 9H), 1.97 (s, 3H), 1.40 (t, 2H), 1.23 (s, 8H), 0.94 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:22][CH3:23])=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:31][C:32]#[N:33])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:22][CH3:23])=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c3c(O)cccc3n(Cc3ccccc3)c2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(OCC#N)cccc3n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a mixture of 9-benzyl-7-methoxy-9H-carbazol-4-ol (0.86 g, 2.8 mmol) in DMF (30 mL) is added potassium carbonate (1.17 g, 8.5 mmol) and bromoacetonitrile (0.56 mL, 8.0 mmol). The mixture is stirred at room temperature for 18 h. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (100 mL) silica gel using CH2Cl2 as eluent gave 0.9 g (94%) of the title compound; 1H NMR (CDCl3) δ3.86, 5.04, 5.46, 6.73, 6.82, 6.87, 7.05, 7.14, 7.28, 8.15; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 76.00; H, 5.32; N, 8.43.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:62]([NH:64][C:65]3([CH3:68])[CH2:67][CH2:66]3)=[O:63])=[CH:41][N:42]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])[N:8]=[C:7]2[C:34]1[N:39]=[C:38]2[C:40]([C:62]([NH:64][C:65]3([CH3:68])[CH2:67][CH2:66]3)=[O:63])=[CH:41][N:42]([C:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:37]2=[N:36][CH:35]=1
Reactant: CC1(NC(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Br)nc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC2(C)CC2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 80 °C
Yield: 76.5 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (200 mg, 0.36 mmol) and 2-bromo-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (250 mg, 0.43 mmol) in DMF (10 mL) were added CuI (18 mg, 0.08 mmol) and Pd(PPh3)4 (14 mg, 0.014 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4 concentrated under reduced pressure to afford 2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (200 mg, 47%), material used in the next step without further purification. LCMS: (M+H)+=726; (M+Na)+=748.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][N:16]=[C:17]=[O:18]>>[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][NH:16][C:17]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:18]
Reactant: Cc1cccc(CN=C=O)c1
Reactant: O=c1[nH]sc2ccccc12
Product: Cc1cccc(CNC(=O)n2sc3ccccc3c2=O)c1

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6k (37% yield) was synthesized from benzo[d]isothiazol-3-one and 3-methylbenzyl isocyanate as a white solid. mp 153-155° C.; IR(CHCl3) 3281, 1711, 1650,1534 cm−1; 1H-NMR (DMSO-d6) δ2.28 (s, 3H), 4.49 (d, J=5.9 Hz, 2H), 7.07 (d, J=7.5 Hz, 1H), 7.12-7.16 (m, 2H), 7.22 (t, J=7.5 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.78 (t, J=8.2 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 9.25 (br t, J=5.9 Hz, 1H); ESIMS m/e 299 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[OH:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C(O)c3ccccc3)cc2)c(C)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C(=O)c3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanol, prepared as described in Example 53, (60 mg, 0.127 mmol) was dissolved in CHCl3 (2 mL) and Des-Martin periodinane (59 mg, 0.140 mmol) was added. The reaction was stirred at 25° C. for 1.5 h, dissolved in EtOAc (100 mL), and the EtOAc was washed with sat. sodium thiosulfate solution (20 mL), water (20 mL) and brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes eluent to give {4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanone (59 mg, 99% yield) as a solid, mp 222–225° C. mass spec. (AP+): m/z 471 (M+1).
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20].I>C(OC(=O)C)(=O)C>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:21][C:19](=[O:20])[CH2:18][CH2:17]2
Reactant: COc1c(CCC(=O)O)cccc1Oc1ccccc1C
Agent: I
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1Oc1cccc2c1OC(=O)CC2
Yield: 85.6 %

Procedure:
A solution of 3-[2-methoxy-3-(o-tolyloxy)phenyl]propionic acid (15 g) in acetic anhydride (40 ml) was added dropwise to 48% hydriodic acid (80 ml) with stirring under ice-cooling in 5 minutes, and after removing methyl iodide, the mixture was refluxed under heating for 20 minutes. After cooling, the reaction mixture was evaporated, and water was added to the residue and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was added to a mixture of benzene (50 ml) and acetic anhydride (30 ml) and refluxed under heating for an hour. After cooling, the mixture was evaporated, and the residue was dissolved in diethyl ether, washed with water, aqueous sodium hydroxide and water successively, dried and then evaporated. The oily residue (13.8 g) was pulverized with n-hexane to give 8-(o-tolyloxy)chroman-2-one (11.4 g). This substance was purified by recrystallization from a mixture of ethanol and n-hexane. mp 80°-82° C.
Reaction SMILES: Cl[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[C:9](OC)(=[O:13])C(C)=C>>[CH3:9][O:13][CH2:7][CH:2]([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=C(C)C(=O)OC
Reactant: COC(=O)C(C)(C)Cl
Product: COCC(C)C(=O)OC
Yield: 18 %

Procedure:
An analysis of the obtained crude reaction solution by gas chromatography revealed that the conversion of methyl 2-chloro-2-methylpropanoate was 68.8% and the yield of methyl methacrylate was 13.6%. As to another product, methyl 3-methoxy-2-methylpropanoate was obtained in an 18.0% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[N:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[N:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(c2csc(Sc3ccc(C(C)=O)cc3)n2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2csc(Sc3ccc(/C(C)=N/O)cc3)n2)CCOCC1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[4-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[4-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone oxime in 90% yield, m.p. 146° C.;
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[N:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][CH2:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCN1CCOCC1
Product: CCCCN1C(=O)C(NCCCN2CCOCC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 3-morpholin-4-ylpropan-1-amine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz, CDCl3): δ 7.58 (bs, 1H), 7.58-7.52 (m, 2H), 7.48-7.40 (m, 3H), 3.84-3.78 (m, 4H), 3.70 (t, 2H), 2.98-2.92 (m, 2H), 2.50-2.38 (m, 6H), 1.86-1.80 (m, 2H), 1.62-1.52 (m, 2H), 1.50-1.40 (m, 2H), 0.98 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.3, 136.4, 131.8, 129.5, 128.7, 125.7, 105.9, 66.9, 58.3, 54.0, 45.6, 40.2, 30.5, 24.1, 20.3, 13.8; Mass Spectrum: M+H+ 408.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH:18]([OH:19])[CH3:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccc(Br)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)[C@H](CCc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled solution of [(5)-3-(4-bromo-phenyl)-1-formyl-propyl]-carbamic acid tert-butyl ester (7.3 g) in THF (40 ml) and Et2O (30 ml) at 0° C. was added dropwise over 30 min a solution of methylmagnesium bromide (20.0 ml, 3 M solution in Et2O). The reaction mixture was then stirred at room temperature for 4 hours before being quenched by dropwise addition of water (gas formation!). The reaction mixture was then poured into EtOAc, the layers were separated and the organic layer was washed sequentially with diluted aq. HCl (pH 5) and saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 80% EtOAc in hexane) to afford {(1S,2RS)-1-[2-(4-bromo-phenyl)-ethyl]-2-hydroxy-propyl}-carbamic acid tert-butyl ester as a colourless amorphous solid comprising a mixture of epimers (5.1 g, 66%). MS (EI): 303 ([{81Br}M−C4H8]+), 301 ([{79Br}M−C4H8]+), 258 ([{81Br}M−C4H8—CO2H]+), 256 ([{79Br}M−C4H8—CO2H]+), 214, 212, 171, 169, 57 ([C4H9]+).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:33]=[CH:32][CH:31]=[CH:30][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([O:28]C)=[O:27])=[N:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.[OH-].[Li+]>O.C1COCC1>[OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:33]=[CH:32][CH:31]=[CH:30][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 50 °C

Procedure:
To a solution of methyl 5-({3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carboxylate (0.150 g, 0.337 mmol) in 2 mL of water and 2 mL of THF was added lithium hydroxide (0.016 g, 0.67 mmol). The mixture was heated to 50° C. for 2 h, cooled to rt, and quenched with saturated aqueous potassium phosphate to pH 5. The aqueous solution was extracted 3× with ethyl acetate and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 432.1560 for [M+H]+ [Calc'd for C24H22N3O5, [M+H]+=432.1554]: 1H NMR (400 MHz, CDCl3) δ 896-8.94 (m, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.13-8.10 (m, 1H), 7.98 (s, 1H), 8.89 (d, J=8.2 Hz, 1H), 7.78-7.67 (m, 3H), 5.26 (d, J=5.3 Hz, 1H), 4.63 (s, 2H), 4.14-4.03 (m, 1H), 3.94-3.88 (m, 2H), 3.41 (t, J=11.0 Hz, 1H), 3.27 (br s, 1H), 3.12-3.08 (m, 2H), 2.28-2.19 (m, 1H), 1.87-1.83 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:14])[CH3:13]>ClCCl.N1C=CC=CC=1>[C:12]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of 3-bromo-4-hydroxy-benzoic acid (3.0 g, 13.83 mmol) in dichloromethane (100 mL) and pyridine (20 mL) was added acetyl chloride (1.1 mL, 15.20 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (50 mL) and acidified with HCl (1 N) to adjust pH=1˜2. The mixture was extracted with dichloromethane (3×100 mL) and concentrated to afford 4-acetoxy-3-bromo-benzoic acid (3.6 g, 100%). To a solution of 4-acetoxy-3-bromo-benzoic acid (3.60 g, 13.83 mmol) in dichloromethane (100 mL) at rt was added oxalyl chloride (1.8 mL, 20.75 mmol) and DMF (0.5 mL), sequentially. The resulting mixture was stirred at rt for 1 h. The mixture was concentrated to afford the acid chloride. To a solution of the freshly prepared acid chloride in dichloromethane (100 mL) were added 2′-hydroxyacetophenone (2.5 mL, 20.75 mmol) and triethylamine (3.9 mL, 27.66 mmol). This mixture was stirred at rt for 2 h. The reaction was quenched with water (100 mL) and extract with dichloromethane (3×150 mL). The combined organic layers were concentration to afford an oily residue, which was purified by column chromatography using 30% EtOAc in hexane to give the phenol ester (4.5 g, 86%). A solution of the phenol ester (4.0 g, 10.61 mmol) in THF (100 mL) was mixed with potassium t-butoxide (1.6 g, 14.32 mmol) and stirred at 60° C. for 1.5 h. This mixture was cooled to rt, diluted with water (100 mL) and acidified with HCl (1 N) to adjust pH=5-6. The mixture was extract with dichloromethane (3×100 mL) and the combined organic layers were concentration to give a yellow solid residue. The residue was purified by column chromatography using 30% EtOAc in hexane to give the diketone (2.3 g, 58%). A solution of the diketone (1.50 g, 3.98 mmol) in AcOH (100 mL) and HCl (conc., 2 mL) was stirred at reflux for 16 h. This mixture was cooled to rt, diluted with water (100 mL), extracted with dichloromethane (3×100 mL) and concentrated. The residue was purified by column chromatography using 50% EtOAc in hexane to give the flavone acetate (0.4 g, 28%). A solution of the flavone acetate (0.53 g, 1.48 mmol) in MeOH (80 mL) and water (20 mL) was mixed with potassium carbonate (1.10 g, 8.00 mmol) and was stirred at rt for 1 h. The solid was filtered off, washed with water, hexanes, and dichloromethane sequentially to give 390 mg of product (83%) as a light yellow solid. MS (ES) m/z: 318.84+316.84 (two isotopes of M); Mp. 273.5-274.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C@@H:12]([C:17]([OH:19])=[O:18])[C:13]([SH:16])([CH3:15])[CH3:14]>CO.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[NH:11][C@@H:12]([C:17]([OH:19])=[O:18])[C:13]([CH3:15])([CH3:14])[S:16]1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CO
Product: CC1(C)SC(c2ccc(Cl)cc2Cl)N[C@H]1C(=O)O

Procedure:
3.5 g (20 mmoles) of 2,4-dichlorobenzaldehyde dissolved in 17 ml of methanol are added to a solution containing 3.0 g (20 mmoles) of D-penicillamine in 65 ml of water while stirring. After stirring for 16 hours, the precipitate is filtered, washed with 50% methanol and dried to give the title acid in a yield of 5.82 g (95%), m.p.: 150°-151° C., [α]D20 =+353° (c=0.45, dimethylsulphoxide).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 6.93 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.58-7.61 (m, 3 H), 7.67 (d, J=8.8 Hz, 2H), 8.03-8.05 (m, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.79 & 8.80 (dd, J=6.0 Hz, 1.6 Hz, 1H), 9.73 (s, 1H). MS: M/z 456.9 (M++1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C)C=O>[N:1]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]2=[O:23])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1cncn1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
A mixture of 9.0 g of 1H-1,2,4-triazole, 6.24 g of approximately 50% sodium hydride in oil and 130 ml of dimethylformamide was stirred for 1.5 hours. Then, 33 g of N-(4-bromobutyl)phthalimide was added and this mixture was heated on a steam bath for 6 hours, then concentrated to a solid residue. Water and methylene chloride were added, the organic layer was separated, washed with water, dried and concentrated to a residue. This residue was recrystallized from ethanol, giving 27.3 g of 2-[4-(1H-1,2,4-triazol-1-yl)butyl]-1H-isoindol-1,3(2H)-dione.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH:5]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[CH:17]=[O:18])[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[CH:17]([OH:18])[CH2:1][CH3:2])[CH2:6][CH2:7]1
Reactant: CC[Mg]Br
Reactant: O=Cc1cc(C(=O)O)ccc1C1CC1
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(=O)O)ccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen and containing THF (60 mL), was placed a solution of ethylmagnesium bromide (3 M in diethyl ether) (24.6 mL, 73.8 mmol). A solution of 4-cyclopropyl-3-formylbenzoic acid (compound 10.4, 3.5 g, 18.4 mmol) in THF (40 mL) was added drop-wise at room temperature over 45 min. The resulting mixture was stirred for 1.5 h at room temperature, then carefully quenched with water/ice (50 mL). The mixture was diluted with EtOAc (100 mL) and the organic layer was washed with aqueous NH4Cl (sat., 2×100 mL) and the aqueous layers combined. The pH of the aqueous phase was adjusted to 3-4 with aqueous hydrogen chloride (2 M) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate:PE (1:10-2:1) as the eluent to yield 3.4 g (84%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:13]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([S:11][CH3:12])=[N:9][C:10]=2[I:13])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1ncc2c(Cl)nccn12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(I)c2c(Cl)nccn12
Temperature: 55 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
P To a solution of 8-chloro-3-methylsulfanyl-imidazo[1,5-a]pyrazine (1.75 g, 0.00876 mol) in DMF (15 mL) was added N-iodosuccinimide (3.94 g, 0.0175 mol), the resulting mixture was stirred at 55° C. for 6 hrs. The mixture was diluted with EtOAc (200 mL), washed with sat. aq. NaHCO3 (40 mL), water (2×40 mL), brine (40 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography to give the title compound as a yellow solid, 2.68 g, 94% yield. 1H NMR (CDCl3, 400 MHz): δ 2.72 (s, 3H), 7.36 (d, J=4.8 Hz, 1H), 7.76 (d, J=4.8 Hz, 1H).