Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[OH:27])[OH:18])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:34](Br)[CH:35]=[CH2:36].C(OCC)(=O)C>O1CCCC1>[CH2:36]([O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH:17]([OH:18])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14]1)[CH:35]=[CH2:34]
Reactant: C=CCBr
Reactant: COc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1cc(OC)ccc1C(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
53 mg (2.2 mmol) of sodium hydride was suspended in 5 ml of tetrahydrofuran. To the resultant suspension was added a solution which had been prepared by dissolving 837 mg (2 mmol) of 2-(4-diphenylmethylpiperazinyl)-1-(2-hydroxy-4-methoxyphenyl)ethanol in 5 ml of tetrahydrofuran under ice-cooled conditions. Thereafter, 2 ml of a tetrahydrofuran solution of 266 mg (2.2 mmol) of allylbromide was added and heated with refluxing for 4 hours. After being cooled to room temperature, the resultant mixture was added with 50 ml of ethyl acetate. The mixture was then washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed, and the residue was subjected to thin-layer chromatography to give 419 mg of 1-(2-allyloxy-4-methoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol as a colorless oily substance (yield: 46%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH:25]([CH3:26])[C@H:24]([OH:27])[O:23][C:22]3=[O:28])=[CH:16][C:15]=2[F:29])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(=O)(O)[O-].[Na+].C(=O)=O>ClCCl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:15]([F:29])=[CH:16][C:17]([N:21]3[CH:25]([CH3:26])[C@H:24]([O:27][C:30](=[O:32])[CH3:31])[O:23][C:22]3=[O:28])=[CH:18][C:19]=2[F:20])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1[C@H](O)OC(=O)N1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1OC(=O)N(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C1C
Reaction time: 1 h

Procedure:
3-(4-(1-Benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-hydroxy-methyloxazolidin-2-one (20 g, 50 mM, see WO 97-30995) was suspended by stirring in dry dichloromethane (400 ml) under nitrogen at 0°, and treated with triethylamine (5.5 g, 54.4 mM) and 4-dimethylaminopyridine (0.3 g, 2.7 mM). Acetic anhydride (5.3 g, 52 mM) was added dropwise to give a solution, which was stirred for 1 hour, allowing the temperature to rise to ambient. The mixture was shaken with 5% aqueous sodium bicarbonate (200 ml) until carbon dioxide evolution ceased. The organic phase was separated, dried (magnesium sulfate) and evaporated, then azeotroped with toluene (2×50 ml) to give semi-crystalline product of sufficent purity for the next stage (24 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Na].[C:14](OCC)(=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=O>C(O)(=O)C>[CH2:21]([O:20][C:18]([C:16]1[CH:15]=[C:14]([OH:23])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:19])[CH3:22]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
A solution of 6.83 g 4-(trifluoromethyl)phenylhydrazine and 9.05 g diethyl oxalacetate sodium salt in 120 ml acetic acid was stirred at 100° C. for 2 h. The product precipitated was filtered, codistilled twice with toluene and suspended with heptane/ethyl acetate 3:1. The suspension was filtered again and the cude product obtained dried in vacuo.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (example 165) (0.3 g, 0.57 mmol) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.24 g, 90%). MS (ISP) 570.3 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:14]1[CH:15]=[C:16]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]1[CH:21]=[CH:20][C:19]([N:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][C:17]2=1.[C:46]([CH2:48][C:49]([OH:51])=[O:50])#[N:47]>C(O)(=O)C.C([O-])(=O)C.[NH4+]>[C:46](/[C:48](=[CH:12]\[C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[C:3]([C:14]3[CH:15]=[C:16]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]3[CH:21]=[CH:20][C:19]([N:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:18][C:17]4=3)=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)/[C:49]([OH:51])=[O:50])#[N:47]
Reactant: CCCCCCn1c2ccc(-c3ccc(-c4ccc(C=O)s4)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCCCn1c2ccc(-c3ccc(-c4ccc(/C=C(\C#N)C(=O)O)s4)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21

Procedure:
As shown in scheme 3, 3,6-dibromo-9-hexyl-9H-carbazole (31) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32) is reacted with diphenylamine to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33). n-butyl lithium is reacted with N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributyl-stannylpyrrole (34). N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributylstannylpyrrole (34) is reacted with 5-bromo-2-thiophene-carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35). Finally, 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9y-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (36) is obtained.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[N:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc(-c2ccc(F)nc2)cc1C(Cl)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2ccc(F)nc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-2-fluoropyridine (0.77 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.75 g), sodium carbonate (0.3 g) and sodium iodide (0.5 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.7 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (667 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:65])[NH:4][CH:5]([C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1)[C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:58])[CH:46]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:47]6[CH2:52]COC[CH2:48]6)=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7].C(OC(N1CC(=C)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)C>>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:46]([C:45]([N:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[C:37]1[NH:36][C:35]([C:30]2[CH:29]=[CH:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:22]4[CH:21]=[CH:20][C:19]([C:16]5[NH:15][C:14]([CH:9]6[CH2:10][C:11](=[CH2:13])[CH2:12][N:8]6[C:6](=[O:7])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:65])[C:59]6[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=6)=[N:18][CH:17]=5)=[CH:24][CH:23]=4)[CH:26]=3)[CH:31]=2)=[CH:39][N:38]=1)=[O:58])[CH:47]([CH3:48])[CH3:52]
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C7CCOCC7)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)c2cccnc2)C1
Agent: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)c2cccnc2)C1

Procedure:
Prepared as {2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamic acid methyl ester (Example CL) from 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS-ESI+: calc'd for C47H49N9O6: 835.9 (M+) found: 836.4 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[C:18]#[N:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1.C(=O)([O-])O.[Na+].N#N>C1(C)C=CC=CC=1.O.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>[C:13]([C:12]1[CH:11]=[C:10]([Cl:16])[C:9]([CH3:17])=[C:8]([C:18]#[N:19])[C:7]=1[C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 98.7 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl trifluoromethanesulfonate (3.07 g, 8.98 mmol) and (3,5-difluorophenyl)boronic acid (1.70 g, 10.8 mmol) in toluene (30 mL)/0.8 M sodium hydrogencarbonate in water (30 mL, 30 mmol) (this was saturated NaHCO3 in water) was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (0.414 g, 0.359 mmol) was added. The mixture was degassed with N2 for 5 min. and heated at 80° C. for 2 h. After cool to rt, the mixture was diluted with EtOAc. The layers were separated and the aq. layer was extracted with more EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to crude, dark solid. The material was dissolved in CHCl3 and purified on silica gel column, eluting with 0 to 20% of EtOAc in hexanes, to give the desired product (2.71 g, 99%). LCMS calculated for C16H11ClF2NO (M+H)+: m/z=306.0; Found: 306.1.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:33].C1C([N+]([O-])=O)=CC=C([Cl-][C:44]([O-])=[O:45])C=1.[CH2:47]([NH2:52])[C:48]([CH3:51])([CH3:50])[CH3:49]>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:2]=1[NH:1][C:44]([NH:52][CH2:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C(F)(F)F
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C(F)(F)F)c3)CC2)cc1F
Yield: 66.1 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-y)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (0.480 mmol, 224 mg) and 4-nitrophenylchloroformate (0.528 mmol, 108 mg) were stirred together in dichloromethane (2 mL) for 16 hours. Neopentylamine (2.4 mol, 300 μL) was added and the volatiles were removed under vacuum. The residue was purified by silica chromatography to yield the title compound (184 mg). MS (ESI) m/z 580.1 [M+H]+
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc2c(c1)OCO2

Procedure:
To a suspension of 3,4-methylenedioxyphenylacetic acid (569 mg, 3.16 mmol) in chloroform (6 ml) was added thionyl chloride (1.2 ml). The mixture was refluxed for about 3 hours, and was evaporated. Toluene was added to the residue and the mixture was evaporated to remove the excess of thionyl chloride. To the residue was added dichloromethane (3 ml) to give a dichloromethane solution of 3,4-methylenedioxyphenylacetyl chloride. To an ice-cold mixture of 2-amino-4-(4-piperidinyl)quinazoline (600 mg, 2.63 mmol) and triethylamine (319 mg, 3.16 mmol) in dichloromethane (16 ml) was added dropwise the solution of 3,4-methylenedioxyphenylacetyl chloride prepared above under a nitrogen atmosphere. The mixture was stirred for about two hours and to the reaction mixture was added dichloromethane and saturated sodium hydrogencarbonate aqueous solution followed by extraction. The organic layer was washed with water, and then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). Crystallization from methanol gave the titled compound (617 mg).
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[C:18]([CH2:19][C:20]([OH:22])=[O:21])=[C:17]([Cl:23])[N:16]=[C:15]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][C:20]([OH:22])=[O:21])=[C:17]([Cl:23])[N:16]=[C:15]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(O)cc1
Yield: 13.6 %

Procedure:
1.3 g of 1-(4-benzyloxybenzyl)-4-chloro-2-phenylimidazole-5-acetic acid was boiled in 50 ml of ethanol saturated with hydrogen chloride for 7 hours. The reaction solution was evaporated to dryness under reduced pressure, and 50 ml each of a 5% aqueous sodium carbonate solution and ethyl acetate were added to the residue to shake to mix. The ethyl acetate layer was washed and evaporated to dryness under reduced pressure. Recrystallization of the residue from 10 ml of acetonitrile yielded 140 mg of 1-(4-hydroxybenzyl)-4-chloro-2-phenylimidazole-5-acetic acid as colorless crystals, m.p. 196°-199° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:24]([CH3:26])[CH3:25])=[N:4][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CO>C(=O)=O>[F:1][C:2]1[C:3]([CH:24]([CH3:26])[CH3:25])=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)c1nc(N2CC3CSC(N)=NC3(c3cccnc3)C2)ncc1F
Agent: O=C=O
Solvent: CO
Product: CC(C)c1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3cccnc3)C2)ncc1F
Yield: 33.8 %

Procedure:
Racemic 6-(5-fluoro-4-isopropyl-pyrimidin-2-yl)-7a-(3-pyridyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (210 mg, 0.564 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralcel OD-H (5μ), 21.2×250 mm; eluent: 25% methanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The first eluting isomer is further purified again by chiral SFC (Column: Chiralcel OD-H (5μ), 21.2×250 mm; eluent: 15% methanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm) to obtain the title compound (71 mg). ES/MS (m/e): 373 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=2)[NH:6][C:5]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[O:30][CH2:29][CH2:28][O:27]2)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].[I-].[K+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH:31]3[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]4[C:13](=[O:14])[C:12]5[C:7](=[CH:8][CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=5)[NH:6][C:5]4=[O:18])[CH2:33][CH2:32]3)[O:30][CH2:29][CH2:28][O:27]2)=[CH:22][CH:21]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1CCCl
Reactant: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1CCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Yield: 64 %

Procedure:
A mixture of 16.2 parts of 3-(2-chloroethyl)-6-nitro-2,4(1H,3H)-quinazolinedione, 15 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine, 10 parts of sodium hydrogen carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 100°-120° C. The reaction mixture was cooled and poured onto water. Stirring was continued till complete precipitation. The precipitate was filtered off and dissolved in trichloromethane. The thus formed emulsion was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 18.6 parts (64%) of 3-[2-[4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]-6-nitro-2,4(1H,3H)-quinazolinedione; mp. 250.9° C. (28).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.ClC1OC2C=CC=CC=2N=1.[CH:21]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[N:30]=[N:31][C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:33][CH:34]=2)=[O:28])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[N:30]=[N:31][C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)[CH2:37][CH2:36]3)=[CH:33][CH:34]=2)=[O:28])[CH2:23][CH2:22]1
Reactant: Clc1nc2ccccc2s1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Agent: Clc1nc2ccccc2o1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3nc4ccccc4s3)CC2)nn1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variation only as required to use 2-chlorobenzothiazole to replace 2-chlorobenzooxazole to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 27% yield (0.040 g). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9.5 Hz, 1H), 7.99 (t, J=5.4 Hz, 1H), 7.59 (m, 2H), 7.32 (t, J=6.5 Hz, 1H), 7.12 (t, J=8.2 Hz, 1H), 7.03 (d, J=9.4 Hz, 1H), 3.94 (m, 4H), 3.81 (m, 4H), 3.53 (m, 2H), 1.50 (m 2H), 0.75 (m, 1H), 0.45 (m, 2H), 0.06 (m, 2H). MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.Cl>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
Acryloylchlorid (0.8 ml, 9.8 mmol, 1 eq) was added dropwise to a stirred ice-cold solution of piperazine 1-carboxylic acid tert butyl ester (2 g, 9.8 mmol, 1 eq) and triethylamine (1.4 ml, 9.8 mmol, 1 eq) in dichloromethane (50 mL) at 0° C. The mixture was then stirred and allowed to come to room temperature over 2 hours. 1M Hydrochloric acid solution (50 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2×50 ml) and saturated sodium chloride solution (50 ml) and dried over MgSO4. After filtration, the solvent is evaporated. The residue was purified by chromatography (ethyl acetate/n-hexane 1/1) to give the product (1.26 g, 49%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccccc1Cl
Product: N#Cc1cccnc1-c1ccccc1Cl
Yield: 18 %

Procedure:
Prepared in 18% yield from 2-chloro-3-cyanopyridine and 2-chlorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 215.0 (M+H)+; 1H NMR (CDCl3) δ 7.41-7.49 (m, 4H), 7.53-7.56 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.90 (dd, J=5.1, 1.7 Hz, 1H).