Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].B([O-])([O-])O[CH:14]1[CH2:16][CH2:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:14]1[CH:16]([C:2]2[C:3]3[CH2:4][CH2:5][C:6](=[O:11])[C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:15]1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: [O-]B([O-])OC1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCc2c1cccc2C1CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a toluene (6.0 mL) solution of 4-bromoindan-1-one (300 mg, 1.42 mmol), water (0.30 mL), cyclopropyl borate (158 mg, 1.85 mmol), potassium phosphate (1.05 g, 4.97 mmol), tricyclohexylphosphine (a 0.48 M toluene solution, 0.295 mL, 0.142 mmol), and palladium acetate (16 mg, 0.071 mmol) were sequentially added, and the resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 4 hours. After the reaction solution was cooled to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20 (v/v)), whereby the objective title compound was obtained as a light yellow solid (211 mg, yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1cccs1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNCc1cccs1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-thiophenemethylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1B(O)O>>[F:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Product: N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Yield: 55 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate A-11) was reacted with 2-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as brown viscous oil in 55% yield. MS: 311.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15].C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=[O:19])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NC(=O)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1

Procedure:
To a suspension of 24.78 g (165 mmol) of benzylurea and 25 ml (165 mmol) of diethyl malonate in 84 ml of methanol, 40.2 ml (165 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 32.12 g (89.2%, white crystal) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)CCC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 55.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.95 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.61 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[O-].[Na+].[N+:4]([C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-:6])=[O:5]>CO>[N+:4]([C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1/[CH:9]=[CH:9]/[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N+:4]([O-:6])=[O:5])([O-:6])=[O:5]
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccccc1/C=C/c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 90 %

Procedure:
In a solution of 1.6 g. of sodium methylate in 20 ml. of methanol, 8.2 g. of diethyl ortho-nitrobenzyl phosphonate was dissolved. To this solution was dropwise added a solution of 5.5 g. of 2-nitro-4-chlorobenzaldehyde in 20 ml. of methanol with stirring at ambient temperature. After stirring continuously for one hour, crystalline materials formed which were filtered and washed with a small amount of ethanol and water to give 8.2 g. (90% yield) of trans-2,2'-dinitro-4-chlorostilbene. Recrystallization of this compound from ethyl acetate gave a product having a melting point of 158.5° to 159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[CH:15]([F:17])[F:16]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:15]([F:17])[F:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: FC(F)Cl
Reactant: O=C(O)c1cc(O)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Cl)cc(OC(F)F)c1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
3-Chloro-5-hydroxybenzoic acid (6.4 g, 37.2 mmol; see step (ii) above) dissolved in chloroform (200 mL) was transferred to a 500 mL three-necked round-bottomed flask fitted with a dry ice condenser and a gas inlet tube. Sodium hydroxide (100 mL, 5 M) was added and with vigorous stirring. Chlorodifluoromethane (Freon 22; 25 g, 290 mmol) was added portionwise through the gas inlet tube at ambient temperature. After 2 hours, the reaction was complete. Extractive work up gave 6.2 g, 28 mmol (yield: 75%) of the sub-title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2S(C)(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To 4-(2-methanesulfonyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.6 g, 7.3 mmol) was added HCl in dioxane solution (4M) (15 mL). The reaction mixture was stirred at RT for 5 h. After completion of the reaction (monitored by TLC), the excess dioxane was removed in vacuo affording an off white solid. The crude material was washed with diethyl ether (3×20 mL) to afford 4-(2-(methylsulfonyl)phenoxy)piperidine hydrochloride (1.3 g, 80.7%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].O>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:22](=[O:24])[CH3:23])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To an ice-cold solution of 4-phenoxy-phenylamine (1.0 g, 5.39 mmol) in 10 ml of DCM was added triethylamine (0.90 ml, 5.93 mmol) followed by acetyl chloride (0.50 g, 6.47 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), water was added extracted with DCM (3×50 mL). The combined organics was dried (Na2SO4), filtered and concentrated to get the desired product (1.20 g, crude yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[C:40]([NH2:45])[CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[NH:44][C:41]2[CH:42]=[CH:43][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][C:40]=2[N:45]=1)[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of (2S)-2-[(tert-butoxycarbonyl)amino]-4-methoxy-3-methyl-4-oxobutanoic acid (Preparation 62, 8.45 g, 32.3 mmol) in THF (300 mL) was cooled to −78° C. and NMM (5.3 mL, 48.5 mmol) was added followed by a solution of isobutylchloroformate (4.44 mL, 34 mmol) in THF (20 mL) dropwise over 30 minutes. The resulting solution was added to a solution of 4-tert-butyl-1,2-diaminobenzene (5.95 g, 36.22 mmol) in THF (100 mL) via cannula at −78° C. The reaction was stirred at −78° C. for 1 hour, then allowed to warm to room temperature for 3 hours. The reaction was concentrated in vacuo and diluted with EtOAc (300 mL). The solution was washed with saturated aqueous NaHCO3 solution (2×100 mL), brine (3×100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in AcOH (150 mL) and stirred at room temperature for 4 days. The reaction was evaporated to dryness azeotroping with dioxane. The residue was purified using reverse phase column chromatography eluting with 5-40% MeCN in 0.1% formic acid in water. The acetonitrile was evaporated and the remaining aqueous solution was basified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified using silica gel column chromatography eluting with DCM/TBME 9/1 to afford the title compound as a yellow solid (7.25 g, 58%).
Reaction SMILES: BrCC(N[CH:6]1[C:28](=[O:29])[N:8]2[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH2:11][S:12][C@H:7]12)=O.[SH:30][C:31]1[S:35][N:34]=[N:33][N:32]=1>>[S:35]1[C:31]([S:30][CH:6]2[C:28](=[O:29])[N:8]3[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:23])[CH:11]([NH:14][C:15](=[O:24])[CH3:16])[S:12][C@H:7]23)=[N:32][N:33]=[N:34]1
Reactant: O=C(CBr)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3c(Cl)cccc3Cl)CS[C@H]12
Reactant: Sc1nnns1
Product: CC(=O)NC1S[C@@H]2C(Sc3nnns3)C(=O)N2C(C(=O)O)=C1CNC(=O)c1c(Cl)cccc1Cl
Yield: 65 %

Procedure:
1.0 g. of 7-bromoacetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid and 0.24 g. of 5-mercapto-1,2,3,4-thiatriazole were reacted and worked up according to the method of Example 15. Thus 0.73 g. (65%) of 7-(1,2,3,4-thiatriazole-5-ylthio)-acetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].O=S(Cl)Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>>[C:13]1([NH:12][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=CC(=O)O
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOCl2 was removed under reduced pressure. CH2Cl2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0° C. The mixture was stirred at room temperature for 1 h and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6](=[O:72])[CH:7]([NH:11][C:12](=[O:71])[C@H:13]([NH:35][C:36]([C:38]1([NH:41][C:42](=[O:70])[CH2:43][C@H:44](O)/[CH:45]=[CH:46]/[CH2:47][CH2:48][S:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:37])[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8]([CH3:10])[CH3:9].[Li+].[OH-:75].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1COCC1.O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:8]([CH:7]1[NH:11][C:12](=[O:71])[C@@H:13]([CH2:14][S:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:35][C:36](=[O:37])[C:38]2([CH2:39][CH2:40]2)[NH:41][C:42](=[O:70])[CH2:43][C@@H:44](/[CH:45]=[CH:46]/[CH2:47][CH2:48][S:49][C:50]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:75][C:3](=[O:2])[CH2:4][NH:5][C:6]1=[O:72])([CH3:10])[CH3:9]
Reactant: [OH-]
Reactant: COC(=O)CNC(=O)C(NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C1(NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)C2(CC2)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 4 (171 mg, 0.17 mmol, 1 eq) in THF (6 mL) at 0° C. was added a solution of LiOH (6.0 mg, 0.25 mmol, 1.5 eq) in H2O (2 mL) dropwise. The mixture was stirred for 2 h, then quenched with 1N HCl (2 mL) and brine (10 mL). The organic layer was separated and the resulting aqueous layer was further extracted with EtOAc (2×15 mL) and CH2Cl2 (15 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The resulting carboxylic acid was then dried under high vacuum for 2 h, To a solution of MNBA (69 mg, 0.21 mmol, 1.2 eq) and DMAP (49.3 mg, 0.40 mmol, 2.4 eq) in CH2Cl2 (150 mL) was added a solution of the crude carboxylic acid in CH2Cl2 (60 mL) and THF (10 mL) dropwise over 3 h. The reaction mixture was then left to stir at rt overnight. The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (2:3) to yield 5 as a white solid (83 mg, 50%).
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][CH:7]([C:9]1[N:10]=[C:11]([CH2:31][CH2:32][CH3:33])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:13](=[O:15])[CH:14]=1)[CH3:8].[Br:34]Br>C(O)(=O)C>[Br:34][C:14]1[C:13](=[O:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:11]([CH2:31][CH2:32][CH3:33])=[N:10][C:9]=1[CH:7]([F:6])[CH3:8]
Reactant: CCCc1nc(C(C)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C(C)F)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of sodium acetate (1.2 g) and 4′-{[4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (5 g) in acetic acid (50 mL) was added bromine (0.72 mL), and the mixture was stirred for 4 hr. Acetic acid was removed in vacuo, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (5 g, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:34])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:34])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of compound 13 (1.0 equiv., 0.207 g, 0.45 mmol) in a mixture of DMF (5 ml) and concentrated aqueous HCl (10 ml) was heated at reflux for 2 days. After cooling to room temperature, the reaction product was filtered off and washed with isopropanol and isopropylether successively to give the hydrochloride salt of 2-[[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]oxy]-acetic acid (14) (0.165 g, yield=96%, purity (LC)=90%) as a light brown powder.
Reaction SMILES: C([N:5]1[C:9]2[NH:10][C:11](=[O:20])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[C:21]1([C:7]2[NH:6][N:5]=[C:9]3[C:8]=2[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11](=[O:20])[NH:10]3)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)n1nc(-c2ccccc2)c2c(-c3ccccc3)cc(=O)[nH]c21
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2ccccc2)c2c(-c3ccccc3)[nH]nc2[nH]1
Temperature: 70 °C
Reaction time: 18 h
Yield: 19.1 %

Procedure:
To 1-tert-butyl-3,4-diphenyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-6-one (1.0 g, 3.1 mmol) was added neat TFA (15 mL) and the resulting solution was heated to 70° C. After 18 hr, the reaction was concentrated under reduced pressure to remove TFA. The resulting tan solid was diluted with EtOAc and washed with an aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by recrystallization from MeOH to give the title compound (0.17 g, 20% yield) as a colorless solid. LRMS m/z (APCl) 288 (M+1); 500 MHz 1H NMR (DMSO-D6) δ 7.29-6.92 (m, 10H), 5.90 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:10]([OH:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[S:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1(C)[CH:30]=CC(S([O-])(=O)=O)=C[CH:26]=1.[NH+]1C=CC=CC=1.COC(C)=C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[S:12])[O:18][C:25]1([CH3:30])[CH3:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=S)OC(C)(C)C
Agent: C=C(C)OC
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)[C@H](C(=S)OC(C)(C)C)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1268.2 %

Procedure:
A solution of t-butyl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylthiopropionate (0.060 g, 0.17 mmol) in toluene (8.0 ml) was treated with pyridinium p-toluene sulfonate (2.14 mg) and freshly distilled 2-methoxypropene (0.384 ml). The mixture was stirred at RT for 5 min, and at 80° C. for 4 h. After dilution with ethyl acetate (8 ml), the organic phase was washed with aqueous NaHCO3 sat. solution (3 ml), brine (2×3 ml), dried (Na2SO4), and evaporated to give a crude mixture. Purification via flash chromatography (hexanes-ethyl ether 95:5) gave pure t-butyl [(4S,5R)-N-tertbutoxycarbonyl-2,2-dimethyl-4-phenyl-1,3-oxazolidin-5-yl]thiocarboxylate (42.5 mg, 65.6%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.CS(O[CH2:19][C:20]1[C:21]2[CH:29]=[C:28]([CH:30]3[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31]3)[S:27][C:22]=2[N:23]=[C:24]([CH3:26])[N:25]=1)(=O)=O>O>[CH3:36][C:33]1([CH3:37])[CH2:34][CH2:35][CH:30]([C:28]2[S:27][C:22]3[N:23]=[C:24]([CH3:26])[N:25]=[C:20]([CH2:19][N:1]4[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]4)[C:21]=3[CH:29]=2)[CH2:31][CH2:32]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCS(=O)(=O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of thiomorpholine-1,1-dioxide (70 mg) and DMF (4 mL) were added [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (120 mg) and TEA (150 μL), followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-(4,4-dimethylcyclohexyl)-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (102 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)c(C)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated salt solution 50 ml, saturated sodium bicarbonate solution 50 ml, and saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 350 ml of hexane:ethyl acetate=1:1) and concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 2 ml/hexane 5 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 322.9 mg.