Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Cl:8].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[Cl:8][C:4]1[N:3]([O:2][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccnc1Cl
Agent: Cl
Product: CN(C(=O)On1ccnc1Cl)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (77%, oil).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:7]=[CH:8][C:9]=1[Cl:10].CCN(C(C)C)C(C)C.[CH:46](=O)[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.[BH3-]C#N.[Na+]>C(CO)(F)(F)F>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:46][CH2:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:34][CH2:35]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCNCC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: O=CCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(CCCc4ccccc4)CC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 1 obtained from Example 9 (0.4 g, 0.7 mmol) in CF3CH2OH (5 mL) was added Hunig's base (0.21 g, 1.6 mmol) at 0° C. After stirring at 0° C. for 10 min, hydrocinnamaldehyde (94 mg, 0.7 mmol) was added. The reaction was stirred at 0° C. for additional 2.5 h, and NaBH3CN (100 mg, 1.6 mmol) was added. The mixture was stirred at 0° C. and gradually warmed to RT overnight. After reaction was complete, it was worked up and purified as described in Example 7 to give the title compound as a white solid, m.p. 52°-54° C.; FAB MS [M+1]+ 35 Cl 621.3.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.O>C(O)(=O)C.OO>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]2=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:7][N:16]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(-c3ccccc3)onc2c1
Yield: 33.5 %

Procedure:
A solution of 31.6 g (0.15 mole) of 4-methyl-2-aminobenzophenone in 350 ml of glacial acetic acid and 175 ml of 30% hydrogen peroxide was let stand at ambient temperature for 72 hr. The solution was poured into 3 liters of water and a solid gradually crystallized. The solid was collected by filtration, washed with water and recrystallized from 2-propanol. The precipitate was slurried in 200 ml of carbon tetrachloride and filtered. The filtrate was concentrated to yield 10.5 g (35%) of title compound, m.p. 77.78° C. after recrystallization from 2-propanol.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:26]=[CH:25][C:20]2[S:21][C:22]([Cl:24])=[CH:23][C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:24][C:22]1[S:21][C:20]2[CH:25]=[CH:26][C:17]([N:12]3[CH2:13][CH2:14][N:10]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:4]=4[CH:1]4[CH2:3][CH2:2]4)[C:11]3=[O:15])=[CH:18][C:19]=2[CH:23]=1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Clc1cc2cc(Br)ccc2s1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3sc(Cl)cc3c2)CCN1c1cnccc1C1CC1
Yield: 33 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.491 mmol) was reacted with 5-bromo-2-chloro-benzo[b]thiophene-(134.6 mg, 0.541 mmol), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (7.0 mg, 0.0491 mmol), potassium phosphate (260.9 mg, 1.23 mmol) and 1,4-dioxane (5 mL to yield the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM), afforded 60.0 mg of the product (33% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:38])[C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2C
Temperature: 80 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a mixture of 6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (1.61 g, 3.30 mmol) and potassium carbonate (684 mg, 4.95 mmol), was added DMF (30 ml). Methyl iodinate (562 mg, 3.96 mmol) was added dropwise to the resultant mixture, and thereafter stirred for four hours at a bath temperature of 80° C. The solvent of the reaction mixture was removed under reduced pressure. Water was added to the mixture, and the organic phase was extracted therefrom with a mixture of chloroform-methanol (10:1). The organic phase was dried over sodium sulfate anhydrate, subjected to silica gel column chromatography (with chloroform-methanol (50:1)), and concentrated under reduced pressure. The resultant residue was recrystallized from a chloroform-n-hexan-ether mixture, to thereby obtain the title compound (1.35 g, 2.68 mmol, 81.1%) as pale yellow powder.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)=[CH:11][CH:10]=2)O1.Cl[C:30]1[N:35]=[C:34]([C:36]([OH:38])=[O:37])[CH:33]=[C:32]([CH:39]=[CH2:40])[N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:30]3[N:35]=[C:34]([C:36]([OH:38])=[O:37])[CH:33]=[C:32]([CH:39]=[CH2:40])[N:31]=3)=[CH:27][CH:26]=2)=[CH:15][C:16]=1[C:22]([F:25])([F:24])[F:23])#[N:19]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C
Reactant: C=Cc1cc(C(=O)O)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Temperature: 90 °C

Procedure:
A 100 mL round bottom flask was charged with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile (1.5 g, 3.86 mmol), 2-chloro-6-vinylpyrimidine-4-carboxylic acid (709.5 mg, 3.86 mmol), PdCl2(PPh3)2 (190 mg, 0.27 mmol), and cesium carbonate (2.5 g, 7.72 mmol) in DME (8 mL), EtOH (4 mL), and water (8 mL). The reaction mixture was heated to 90° C. for 10 hours. The reaction mixture was diluted with 100 mL water, acidified to pH 5 with aqueous 4N HCl, and extracted with 2×100 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated to give 2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid as a light brown solid. The material was used in the next step without purification. LC/MS: m/z=412 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[CH3:34]>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:29]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1N
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B. 11) according to general procedure II. Yellow solid. MS (ISP) 614.2 [(M−H−]; mp 240° C.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].[OH-:26].[Na+].[BH4-].[Na+]>O.O1CCCC1>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][C:19]([OH:26])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)C(C)=O
Reactant: [OH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, ethyl 8-acetyl-12-methyl-11-heptadecenoate (4.2 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution is 3M sodium hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 4.4 g. of ethyl 8-acetyl-12-hydroxy-12-methylheptadecanoate as a yellowish oil used in the next step without further purification; pmr (CDCl3) δ 0.88 (3H,t), 1.13 (3H,s, CH3COH), 1.25 (3H,t, CH3CH2OCO--), 2.12 (3H,s, CH3CO), 4.12 (2H,q).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][CH:22]=[C:20]([CH2:19][Cl:18])[N:15]=2)=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(CCl)CCl
Product: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Yield: 46 %

Procedure:
In substantially the same manner as in Reference Example 47, 4-benzoylbenzamide was allowed to react with 1,3-dichloroacetone to give 2-(4-benzoylphenyl)-4-chloromethyloxazole. The yield was 46%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 138-139° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC=CC=1)([O-])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:21]([C:27](Cl)=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>>[C:27]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Oc1ccccc1
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(=O)c1ccc(O)cc1
Yield: 82 %

Procedure:
There are charged to a half-liter reactor 9.4 g. (0.1 mole) of phenol in 150 ml. of nitrobenzene. The contents of the reactor are stirred and the mixture is cooled below 5° C. Then 27 g. (0.2 mole) of AlCl3 is added in small portions over 1/2 hour. The resulting mixture is stirred vigorously and then there is added a solution of 15.5 g. of C6H13COCl (~ 0.011 mole) in 50 ml. of nitrobenzene over an hour while the temperature is kept below 5° C. The mixture is stirred at ambient temperature for 12 hours and then the mixture is poured in 100 g. of ice and 50 ml. of concentrated HCl and stirred for 1/2 hour. The organic fraction is removed by decantation and the aqueous fraction is washed twice with CCl4 (100 ml.). The organic fractions are collected and washed three times with water (to neutrality). The solvent is evaporated under reduced pressure. The organic solution is dried over anhydrous Na2SO4. The solid obtained is recrystallized in benzene. There are obtained 16.9 g. of pure product (yield 82%), melting point: 93° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.S=C1N([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:31])[CH3:30])=[C:24]([O:32][CH3:33])[CH:23]=2)=[O:19])CCS1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18](=[O:19])[NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:23][C:24]=1[O:32][CH3:33])(=[O:31])[CH3:30]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(COC(=O)NC2Cc3ccccc3C2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
2-Aminoindane hydrochloride (166 mg, 1.1×0.891 mmol) was suspended in solution of VII (304.2 mg, 0.891 mmol) in anhydrous THF (10 mL), triethylamine (198 mg, 275 μL, 2.2×0.891 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to afford 134 mg (42%) white solid, 14: mp=114-116° C. (uncorrected); Rf=0.45 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.20 (bs, 2H), 7.15 (m, 2H), 6.98 (d, 3J=8.0 Hz, 1H), 6.93 (d, 1H), 6.90 (dd, 3J=8.0 Hz, 1H), 5.04 (s, 2H, CH2O), 4.51 (bs, 2H), 3.81 (s, 3H, OCH3), 3.28 (dd, 3J=16 Hz, 4J=7.1 Hz, 2H), 2.80 (dd, 3J=16 Hz, 4J=4.5 Hz, 2H, NCH2), and 2.29 (s, 3H). Exact mass (ESI) calculated for C20H22NO5 [M+H]=356.1492. found 356.1496.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[C:28](Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Cc1ccccc1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.250 g, 0.940 mmol), Et3N (0.13 mL, 0.94 mmol), benzoyl chloride (0.109 mL, 0.94 mmol), CH2Cl2 (2.0 mL), acetonitrile (5.0 mL), acetone cyanohydrin (0.01 mL, 0.09 mmol), Et3N (0.27 mL, 1.9 mmol), glacial acetic acid (10.0 mL), sodium cyanoborohydride (0.133 g, 2.11 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 4/1 hexane/ethyl acetate to 3/2 hexane/ethyl acetate) to provide a solid (0.105 g, 63-65° C.) 1H NMR (400 MHz, DMSO-d6) δ 11.136 (s, 1 H), 7.501-7.280 (m, 11 H), 6.997-6.932 (m, 2 H), 6.566 (d, 2 H, J=7 Hz), 3.530 (s, 2 H), 3.432 (s, 2 H),
Reaction SMILES: ClCCl.[Cl:4][C:5]1[N:6]=[C:7]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([C:27]4[N:31](CCC#N)[N:30]=[N:29][N:28]=4)=[C:24]([CH3:26])[N:25]=3)[CH2:17][C@H:16]2[O:36][CH3:37])=[O:13])[NH:8][C:9]=1[CH2:10][CH3:11].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl>C(OCC)(=O)C.O>[Cl:4][C:5]1[N:6]=[C:7]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([C:27]4[NH:28][N:29]=[N:30][N:31]=4)=[C:24]([CH3:26])[N:25]=3)[CH2:17][C@H:16]2[O:36][CH3:37])=[O:13])[NH:8][C:9]=1[CH2:10][CH3:11]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnnn4CCC#N)s3)C[C@H]2OC)nc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnn[nH]4)s3)C[C@H]2OC)nc1Cl
Yield: 51.6 %

Procedure:
Dichloromethane (1.5 mL) was added to cis(±)-4-chloro-N-(1-{5-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]-4-methyl-1,3-thiazol-2-yl}-3-methoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxylic acid amide obtained in Example (262a) (16 mg, 0.03 mmol). While the mixture was stirred, diazabicycloundecene (15 mg, 0.10 mmol) was added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and water. The organic layer was neutralized with 1 N hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was solidified with diethyl ether and hexane to obtain 7 mg of the title compound as a white solid (47%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:37]=[N:36][N:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[CH:37]=[N:36]1)[CH3:39]
Reactant: CCn1ncc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (2.20 g; compound B50) is reacted with 4-(chloromethyl)-2-ethyl-2H-1,2,3-triazole (748 mg; compound D19) in the presence of potassium carbonate (1.42 g) in DMF (39 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 1/1 (v/v)] as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2OC)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:24]1C(OC)=C(C(CBr)=CC=1)C(OC)=O.C1(S)CCCCC1>>[Br:1][C:2]1[C:3]([O:22][CH3:24])=[C:4]([C:9]([CH2:12][S:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: SC1CCCCC1
Product: COC(=O)c1c(CSC2CCCCC2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and cyclohexanethiol and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[N:6]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:23][CH2:22][O:21][CH2:26][CH2:25]6)=[CH:32][CH:31]=5)=[O:35])=[CH:43][CH:42]=4)[NH:18][C:11]=3[CH:10]=2)[N:6]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: Cc1nc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cs1
Product: Cc1nc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)cs1

Procedure:
Compound 622 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methylthiazol-4-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C29H27N5O3S: 526.18; found: 526.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([O:17][C@H:18]([C@H:20]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:21][CH2:22]O)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:10]([O:17][C@H:18]([C@H:20]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:21][CH2:22][O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCO)n1cnc(C(N)=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc(Cl)c(Cl)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a stirred mixture of 3,4-dichlorophenol (129 mg, 0.791 mmol), 1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (80 mg, 0.264 mmol), and triphenylphosphine (90 mg, 0.343 mmol) in tetrahydrofuran (5 ml) was added dropwise diethyl azodicarboxylate (59.7 mg, 0.343 mmol) at ice-bath temperature. After the mixture was stirred for 2 h at room temperature, the solvent was removed in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (100:1 to 30:1) to give a mixture (120.6 mg, 102%) of 1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide (3) and by-products. This material was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[I:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=1.C(N(C(C)C)CC)(C)C>ClCCl.[Cl-].[NH4+]>[CH3:1][S:2]([O:15][CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: OCCc1cccc(I)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Methanesulfonyl chloride (1.5 mL, 1.2 eq.) was added dropwise to a stirred solution of 2-(3-iodophenyl)ethanol (3.6 g) in dichloromethane (100 mL) and diisopropylethylamine (3.8 mL, 1.5 equiv.) at 0° C. The solution was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with dichloromethane. The organic layers were combined, washed with aqueous sodium hydrogencarbonate solution, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified using column chromatography (SiO2 cartridge) using DCM-cyclohexane (70:30) to afford the title compound (3.2 g, 45% yield).