Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[C:9](=[CH:18]OC)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:18]=1)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC=C(Br)C(=O)c1ccccc1
Reactant: CC(=N)NC(C)C
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ncc(C(=O)c2ccccc2)n1C(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the same manner as in Reference Example 1), 26.0 g (0.108 mol) of 2-bromo-3-methoxy-1-phenyl-2-propen-1-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to give 2.47 g (yield: 10%) of 5-benzoyl-1-isopropyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: O=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:6][CH:5]=[N:4][NH:3]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccnnc1Cl
Yield: 89 %

Procedure:
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.1 g, 4.27 mmol) was mixed with phosphoryl chloride (10 mL) and heated to reflux for 1 hour. After completion of the reaction, phosphoryl chloride was removed under reduced pressure. The resulting residue was diluted with chloroform and water. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the desired product (89% yield).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:36][S:37]([CH:40]4[CH2:42][CH2:41]4)(=[O:39])=[O:38])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.CC1C=CN=CC=1C1C(OC)=CC=C2C=1C=CN=C2OC1CC2N(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C:2]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[C:7]3[O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:36][S:37]([CH:40]5[CH2:42][CH2:41]5)(=[O:38])=[O:39])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)=[CH:49][CH:48]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1cnccc1C
Product: COc1ccc(-c2c(OC)ccc3c(OC4CC5C(=O)NC6(C(=O)NS(=O)(=O)C7CC7)CC6C=CCCCCN(C)C(=O)N5C4)nccc23)cc1

Procedure:
The title product was prepared from N-[17-(5-bromo-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (51, example 13) and 4-methoxybenzeneboronic acid following the procedure described for N-[17-[5-(4-methyl-3-pyridyl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (52, Example 14): m/z=718 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][C:14]([N+:29]([O-:31])=[O:30])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.B>O1CCCC1>[CH2:21]([NH:20][CH2:19][CH2:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:29]([O-:31])=[O:30])[CH:15]=2)[NH:10][C:9]=1[C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNC(=O)c2ccccc2)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNCc2ccccc2)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a stirred solution of N-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}benzamide (1.7 g in 130 mL dry tetrahydrofuran) was added 35 mL of a IM solution of borane in tetrahydrofuran and the mixture heated slowly to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane quenched by the careful addition of methanol. The mixture was concentrated to half-volume, treated with N,N-dimethylethanolamine (13 mL) and heated to reflux on an oil bath. After 3 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (1.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(O)cc2nc1C
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(OCc3cccc(Cl)c3)cc2nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of ethyl 7-hydroxy-2-methylquinoline-3-carboxylate (100 mg, 0.43 mmol) in DMF (3.0 mL) was added Cs2CO3 (212 mg, 0.65 mmol) and 3-chlorobenzyl chloride (0.052 mL, 0.43 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was loaded directly onto a column and purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (86 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.37-7.30 (m, 3H), 7.29-7.26 (m, 1H), 5.19 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 2.97 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=356.3.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[S:34][C:11]2[NH:12][C:13]([C:15]([NH:17][CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:28][C:29]([NH:31][NH2:32])=[O:30])[C:19]3=[O:33])=[O:16])=[CH:14][C:10]=2[CH:9]=1.[N:35]#[C:36]Br.C([O-])([O-])=O.[Na+].[Na+]>O.CCOC(C)=O.C1COCC1>[NH2:35][C:36]1[O:30][C:29]([CH2:28][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][CH:18]([NH:17][C:15]([C:13]3[NH:12][C:11]4[S:34][C:8]([Cl:7])=[CH:9][C:10]=4[CH:14]=3)=[O:16])[C:19]2=[O:33])=[N:31][N:32]=1
Reactant: NNC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nnc(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)o1
Reaction time: 18 h
Yield: 19.8 %

Procedure:
1,4-Dioxane (5 mL), 2-chloro-N-[1-(2-hydrazino-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 15; 300 mg, 0.72 mmol), cyanogen bromide (80 mg, 0.75 mmol) and 1,4-dioxane (2 mL) were added to a solution of Na2CO3 (77 mg, 0.72 mmol) in H2O (1.7 mL) and stirred for 18 hours. The mixture was diluted with EtOAc (50 mL) and THF (20 mL) and washed with H2O (25 mL). The organic was dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase column chromatography to give a brown solid. This was triturated with refluxing Et2O (25 mL), filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compound (63 mg, 20%) as a brown powder.
Reaction SMILES: [CH3:1][Si:2]([O:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])([CH3:4])[CH3:3].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][Si:2]([O:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH2:9][Br:11])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/C(=O)O[Si](C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)OC(=O)/C=C/CBr
Temperature: 77 °C
Yield: 64.7 %

Procedure:
A stirred mixture of trimethylsilylcrotonate (131 g, 0.828 mol), N-bromosuccinimide (206 g, 1.16 mol), benzoyl peroxide (3.41 g, 0.141 mol) and carbon tetrachloride (1 L) is warmed to reflux (77° C.) under visible light for 5 hours. The mixture is cooled to room temperature and the precipitated solid is removed by filtration. The filtrate is concentrated to a residue, which is distilled under reduced pressure. The product fractions are collected at 93–106° C. (9–15 mmHg) to give 127 g of the title compound (65%). GC-MS purity is 83–89%, 1HNMR is consistent with expected structure.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
A solution containing the product from Example 10B (1.33 g, 3.68 mmol) in dichloromethane (20 mL) was treated with trifluoracetic acid (20 mL), stirred at 25° C. for 2 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 0-100% acetonitrile/water (0.1% TFA) to give the title compound (1.44 g, 94% yield) as the trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH2:15][Si](C)(C)C)[CH:14]=2)[C:7]([C:20]([F:23])([F:22])[F:21])=[CH:6][C:5]=1[NH2:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[C:7]([C:20]([F:23])([F:21])[F:22])=[CH:6][C:5]=1[NH2:24]
Reactant: COC(=O)c1cc(-c2cn(C[Si](C)(C)C)nn2)c(C(F)(F)F)cc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cn(C)nn2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
2-Amino-4-trifluoromethyl-5-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-benzoic acid methyl ester (420 mg, 1.12 mmol) was dissolved in THF (10 mL). After addition of a solution of TBAF in THF (1M, 2.25 mL, 2 equiv), the mixture was stirred at r.t. for 30 min. The solvent was removed in vacuo and the residue was taken in AcOEt. The organic phase was washed with water, dried (Na2SO4) and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography (EtOAc/hexanes (1:9) to EtOAc/hexanes (6:4)) to yield 2-amino-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (240 mg, 71%) as a yellow solid. (ESI-MS: m/z 301.3 [M+H]+, rt 4.62 min).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[N:14]=[C:13]1[CH3:20].C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:19][C:15]1[N:14]=[C:13]([CH3:20])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:17](=[O:18])[CH:16]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CC(=O)N=C2C)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of methyl 4-methyl-3-(2-methyl-4,6-dioxo-5,6-dihydropyrimidin-1(4H)-yl)benzoate (0.1 g, 0.00036 mol, from Step 2), K2CO3 (0.075 g, 0.00054 mol) and 2,4 difluorobenzylbromide (0.075 g, 0.00036 mol) in DMF (2.0 mL) containing 18-crown-6 (0.005 g) is stirred at room temperature for 1 h under argon atmosphere. DMF is distilled in vacuo and the residue is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=401) are combined and concentrated to a small volume (˜20 mL). After cooling, 5% NaHCO3 solution (10 mL) is added and the solution is extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.12 g, 82%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.16 Hz), 7.55 (m, 2H), 7.00 (m, 2H), 5.79 (s, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 2.14 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 401.1346 (M+H calcd for C21H19N2O4F2 requires 401.1307).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.C(O)(=O)C.[Br:12][CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15]>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[N:7][C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:6]=2)[C:14]=1[OH:15]
Reactant: CCOC(=O)C(Br)C(C)=O
Reactant: Cc1cc(N)[nH]n1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc2nc(C)c(Br)c(O)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 3-methyl-1H-pyrazol-5-amine (0.186 g, 1.92 mmol) and acetic acid (3.71 mL, 65.2 mmol) was slightly heated until complete dissolution and the resultant solution was cooled to RT and mixed with ethyl 2-bromo-3-oxobutanoate (1.20 g, 5.74 mmol). The resultant reaction mixture was stirred at RT for 16 h, after which time the reaction mixture was diluted with diethyl ether, cooled to 0° C. and stirred at that temperature for 30 min. The white solid precipitate was separated by filtration and washed with cold diethyl ether and dried to give the desired product (363 mg, 78%) as a white solid. LCMS calculated for C8H9BrN3O (M+H)+: m/z=242.0, 244.0. found: 241.9, 244.0.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C@H:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].B(F)(F)F.CCOCC.C(O)(=O)[CH2:44][C:45](CC(O)=O)([C:47](O)=O)[OH:46]>O1CCCC1.CC(C)=O>[C:11]([O:15][C:16]([N:18]1[C:22](=[O:23])[CH:21]([C:45]([OH:46])([CH3:47])[CH3:44])[CH2:20][C@H:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: FB(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C(C(C)(C)O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of lithium hexamethyldisilazide in tetrahydrofuran is cooled to −78° C. and treated with a solution of 15.95 g of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester in 100 mL of tetrahydrofuran maintaining the temperature at −78° C. The resulting mixture was stirred for 40 minutes and a mixture of 40 mL of acetone and 7 mL of boron trifluoride diethyl etherate added within 20 minutes. The reaction mixture is stirred for 2.5 hours at −78° C. and 300 mL of a 10% solution of citric acid added and the reaction mixture warmed to room temperature. The layers are separated and the aqueous layer is re-extracted with 300 mL of dichloromethane. The combined organic layers are dried, filtered and the solvent removed to give (S)-4-(1-hydroxy-1-methyl-ethyl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzylester 1-tert-butyl ester as an oil.
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21](=S)=[S:22].C(O)C.[OH-].[K+]>O>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:21]([SH:22])=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: S=C=S
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A mixture of 5.28 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 2.3 parts of carbon disulfide, 80 parts of ethanol, 1.68 parts of potassium hydroxide and 11 parts of water was stirred for 3 hours at reflux temperature. After evaporation, 100 parts of water were added to the residue and the mixture was neutralized with 1.8 parts of a 0.03M acetic acid solution. After stirring, the precipitated product was filtered off, washed with 2-propanone and dried, yielding 4.3 parts (70.1%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzimidazole-2-thiol; mp. 260.1° C. (compound 225).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:29]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][OH:26])=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OCCNCCO
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCO)CCO)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-(2-hydroxy-ethylamino)-ethanol
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.I[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH2:11][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[C:7]=2[CH:12]=1
Reactant: COc1ccc2onc(C)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2onc(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Yield: 87.8 %

Procedure:
The procedure described in Example 1d was followed using 5-methoxy-3-methyl-1,2-benzisoxazole (0.32 g, 1.96 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.70 g, 2.15 mmol), and 1M LDA (2.0 mL, 2.0 mmol) in dry THF (2 mL). After purification, the title compound (0.62 g, 87%) was obtained as a clear oil.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
Ethylsulfonyl chloride (113 uL, 1.2 mmol) was added dropwise to a stirred solution of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) and pyridine (247 uL, 3.1 mmol) in DCM (5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 14 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 95%) in hexanes to afford the title compound (345 mg, 94%) as an amber oil that solidified upon standing. LCMS (M+H)+=371.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:58])[CH2:46][N:47]3[C:51]4[CH:52]=[CH:53][C:54]([OH:56])=[CH:55][C:50]=4[O:49][C:48]3=[O:57])[CH2:41][CH2:40]2)=[CH:35][C:34]=1[O:59][CH3:60].[O:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[O:67][CH2:68][CH2:69]O>C1COCC1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:40][CH2:41][N:42]([C:45](=[O:58])[CH2:46][N:47]3[C:51]4[CH:52]=[CH:53][C:54]([O:56][CH2:69][CH2:68][O:67][CH:62]5[CH2:63][CH2:64][CH2:65][CH2:66][O:61]5)=[CH:55][C:50]=4[O:49][C:48]3=[O:57])[CH2:43][CH2:44]2)=[CH:35][C:34]=1[O:59][CH3:60]
Reactant: OCCOC1CCCCO1
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCOC5CCCCO5)ccc43)CC2)ccc1Cl
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a mixture of PPh3 (70 mg, 0.27 mmol, 1.1 eq), and DEAD (40 mg, 0.23 mmol, 1 eq) in THF (0.5 ml), was added 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54) (100 mg, 0.24 mmol, 1 eq) in THF (1 ml). The reaction mixture immediately turned clear and was heated to 85° C. 2-(Tetrahydro-pyran-2-yloxy)-ethanol (38.5 mg, 0.27 mmol, 1.1 eq), was then added to the reaction solution, and stirred for 3 hours at rt. The isolated crude product was purified with HPLC to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[Cl-].[Cl-].[Al+3].[C:15]1([C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[CH:27][N:26]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:27]1[N:26]=[C:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12)=[O:6]
Reactant: c1ccc2c(-c3ncc4ccccn34)cccc2c1
Reactant: O=C(O)c1ccccc1I
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1I)c1nc(-c2cccc3ccccc23)n2ccccc12
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a solution of 2-iodobenzoic acid (487 mg, 1.83 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (266 mg, 2.00 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-naphthalen-1-yl-imidazo[1,5-a]pyridine (212 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (76 mg, 18%). 8.37 (1H), 8.18 (1H), 8.10 (2H), 7.92 (1H), 7.85 (1H), 7.71 (2H), 7.56 (5H), 7.20 (1H), 7.07 (1H); m/z (M+H)=475.1.