Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid (936 mg, crude) in DMF (10 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (442 mg), HOBt (588 mg), and EDCI (676 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (945 mg) as pale yellow form.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH2:17]([N:19]([CH2:33][CH3:34])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31])[CH3:18]>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:19]([CH2:17][CH3:18])[CH2:33][CH3:34])=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=1)=[O:8]
Reactant: CCN(CC)CCOc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 4-(2-diethylamino-ethoxy)-3-nitro-phenylamine (Z31a).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Li][CH2:10]CCC.CI>O1CCCC1>[CH3:10][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccsc1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1sccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.32 g (41.5 mmol) of 3-thiophenecarboxylic acid in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 57.1 ml (91.4 mmol) of 1.6M n-BuLi in hexanes. The cloudy suspension was stirred at -78° C. under a blanket of argon for 40 minutes, and was then transfered via canulla onto a solution of 59.05 g (25.9 ml, 416 mmol) of methyl iodide dissolved in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting clear, colorless solution was allowed to warm to room temperature and stirred for 20 hours. A white solid was formed. The reaction mixture was concentrated in vacuo, partitioned between 75 ml of sat. NH4Cl solution and 150 ml of ethyl ether, and the layers separated. The aqueous phase was washed with 100 ml of ethyl ether and layered with 100 ml of ethyl ether and acidified with 1N sulfuric acid solution until all of the yellow emulsion dissapated. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to yield an off-white solid. Purification by flash chromatography (silica gel, 75% ethyl acetate in hexane) yielded the title compound as an off white solid.
Reaction SMILES: Br/[CH:2]=[C:3]1/[C:4]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=2[O:6][CH2:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]/1=2.[N:19]1([CH2:25][CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][C:34](C4(O)CCCB4O)=[CH:35][C:30]=3[NH:29][C:28]2=[O:43])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:18][C:15]1[CH:16]=[CH:17][C:4]2=[C:5]([CH:14]=1)[O:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:3]/2=[CH:2]\[C:34]1[CH:33]=[CH:32][C:31]2[N:27]([CH2:26][CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:28](=[O:43])[NH:29][C:30]=2[CH:35]=1
Reactant: O=c1[nH]c2cc(C3(O)CCCB3O)ccc2n1CCN1CCOCC1
Reactant: Fc1ccc2c(c1)OCc1ncccc1/C2=C\Br
Product: O=c1[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4ncccc43)ccc2n1CCN1CCOCC1
Yield: 38.6 %

Procedure:
Following procedures essentially as described in Example 219, beginning with (E)-5-bromomethylene-8-fluoro-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cycloheptene (192 mg, 0.63 mmol) and 1-(2-morpholinyl-ethyl)-5-(dihyroxyborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (219 mg, 0.75 mmol). Partition the reaction mixture between ethyl acetate (50 mL) and 1N aqueous hydrochloric acid solution (50 mL). Separate the layers and extract the aqueous layer with methylene chloride (2×50 mL). Combine the organic layers and extract with 1N aqueous hydrochloric acid solution (50 mL). Adjust the pH of the combined aqueous layers to 8.0 with 5N aqueous sodium hydroxide solution, and extract the product with ethyl acetate (3×50 mL). Purify the crude product by flash chromatography (25% ethanol/ethyl acetate) to provide 115 mg (39%) of purified product.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[CH3:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[N:40][C:41]=2[Sn](CCCC)(CCCC)CCCC)[CH:38]=1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[N:40]=[CH:39][N:37]5[CH:38]=[C:33]([CH3:32])[CH:34]=[CH:35][C:36]=45)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(C)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)N[C@H](C)C(=O)N3CC(C#N)C3)cn4COCC[Si](C)(C)C)ncn2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) and 6-methyl-1-tributylstannyl-imidazo[1,5-a]pyridine (crude from step 5, 307 mg, 0.36 mmol) were dissolved in DMF (1.8 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.010 mmol) and copper (I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 98 mg (89%) of 2-(6-methyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow oil.
Reaction SMILES: C(O[C@H]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[C:21]([CH:27]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][CH:30]=3)[OH:28])[CH:20]=2)[O:7][C@@H]1COC(=O)C)(=O)C.[CH3:42][CH2:43][O:44][C:45]([CH3:47])=[O:46]>C1(C)C=CC=CC=1>[C:45]([O:44][C@H:43]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[CH2:25][O:28][CH:27]3[C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH3:36])=[CH:33][CH:34]=2)[O:7][C@@H:42]1[CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:46])[CH3:47]
Reactant: CCc1ccc(C(O)c2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2CO)cc1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccc(C2OCc3ccc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc32)cc1
Temperature: 90 °C
Yield: 79 %

Procedure:
Step 5) To a solution of compound 150 (500 mg, 0.87 mmol) in toluene (10.0 mL) was added p-TsCl (183 mg, 0.96 mmol) and the reaction mixture was heated to 90° C. for 12 h. The resulting mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide (2R,3R,4R,5S,6S)-2-(Acetoxymethyl)-6-(3-(4-ethylphenyl)-1,3-dihydroisobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (151, 380 mg, 79%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:33]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1ccccc1)CC2
Agent: C=O
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCNc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-phenylamino-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.Cl.[F:18][C:19]([F:25])([F:24])[C:20](=O)[CH2:21][CH3:22]>O1CCCC1>[F:18][C:19]([F:25])([F:24])[C:20]([CH2:21][CH3:22])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(CC)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5.6 g of sodium hydride (60% in oil) in 500 ml of tetrahydrofuran was added dropwise 31.6 g of ethyl diethylphosphonoacetate under ice-cooling. After the mixture was stirred at the same temperature for 10 minutes, the a solution of 1,1,1-trifluoro-2-butanone in diethyl ether obtained in Step 1 was added dropwise thereto. The mixture was stirred at the same temperature for 1 hour, and then warmed to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude ethyl 3-trifluoromethyl-2-pentenoate.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1)(=O)=O.O[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:27][C:26]=3[F:46])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[OH:12][C:9]1([CH2:8][CH2:7][CH2:6][O:5][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:24][C:25]4[CH:30]=[CH:29][C:28]([N:31]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:32]([C:34]5([C:37]([NH2:39])=[O:38])[CH2:35][CH2:36]5)=[O:33])=[CH:27][C:26]=4[F:46])=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 99.9 %

Procedure:
To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (170.7 mg, 0.877 mmol, from example 9) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.656 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36 hrs, then the reaction mixture was warmed to 40° C. for 8 hrs. The reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (4:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (364.1 mg, 74%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(C3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine HCl salt (0.040 g, 0.13 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (55 uL, 0.26 mmol), and cesium carbonate (120 mg, 0.38 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 50 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([CH3:26])[CH2:25][CH2:24][C:19]4([C:21]([F:23])([F:22])[CH2:20]4)[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[N:39]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40]1>ClCCl.CN(C)C1C=CN=CC=1>[N:39]1([S:43]([NH:46][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([O:14][CH2:15][C:16]3([CH3:26])[CH2:17][CH2:18][C:19]4([C:21]([F:22])([F:23])[CH2:20]4)[CH2:24][CH2:25]3)=[CH:6][C:7]=2[F:13])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40]1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2(F)F
Reactant: NS(=O)(=O)N1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CCC2(CC1)CC2(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
To a stirred solution of 5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]-octan-6-yl)methoxy)-2-fluorobenzoic acid (0.039 g, 0.106 mmol) in dichloromethane (3 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (0.031 g, 0.159 mmol) and 4-dimethylaminopyridine (0.030 g, 0.244 mmol). The reaction was stirred at ambient temperature for 10 minutes, azetidine-1-sulfonamide (0.023 g, 0.17 mmol) was added and the stirring was continued at ambient temperature for 17 hours. The reaction was concentrated, diluted with ethyl acetate (10 mL) and washed with 5% aqueous hydrochloric acid solution (5 mL). The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 30% ethyl acetate in hexanes) afforded the title compound (0.043 g, 83%) as a white solid [mixture of cis/trans diastereomers]: 1H NMR (300 MHz, CDCl3) [second diastereomer peaks in italics] δ 8.64 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 6.58 [6.56](d, J=14.0 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.77 [3.72](s, 2H), 2.32-2.19 (m, 2H), 2.06-1.94 (m, 1H), 1.82-1.37 (m, 6H), 1.29-1.10 (m, 5H), 1.08-0.83 (m, 4H), 0.70-0.60 (m, 2H); MS (ES−) m/z 485.3 (M−1).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:11][C:10]2=[O:31])(=[O:5])[CH3:4].CO.Cl>C1C=CC=CC=1>[C:3]([O:6][C:7]1[C:8]([CH3:32])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:11][CH:10]2[OH:31])(=[O:5])[CH3:4]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
160 mg of sodium borohydride were added to a mixture of 1.8 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 47), 15 ml of methanol and 1 ml of benzene in an ice bath, and the mixture was stirred for 30 minutes. The reaction mixture was then poured into ice-water, neutralized with 10% w/v aqueous hydrochloric acid and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give crystals. These crystals were recrystallized from a mixture of benzene and hexane to give the title compound, melting at 139°-141° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>CC(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([OH:18])=[O:17]
Reactant: CC(=O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CC(C)O
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
2,3,4-Trifluoronitrobenzene (5.03 g) and pyruvic acid (2.75 g) were dissolved in IPA (40 ml). After adding 10% Pd—C (0.21 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (6.09 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: CCCCO
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Yield: 189.2 %

Procedure:
Dissolve 5-fluoro-2-nitrobenzaldehyde (9.43 g, 55.81 mmol), 1-butanol (12.41 g, 167.4 mmol) and 4-toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (84 mL). Heat the reaction mixture to reflux, and remove the water using a Dean-Stark apparatus. Continue to heat the reaction mixture for 3 hours. Add water and extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure and purify by flash column chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to obtain 15.8 g (95%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH3:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1.C(Cl)Cl>C(O)CCC>[Cl:18][C:15]1[N:16]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[C:12]([CH3:11])=[CH:13][N:14]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
3,4-Dichloroaniline (639 mg, 3.94 mmol) and concentrated hydrochloric acid (ca. 12M, 0.2 ml, ca. 2.4 mmol) were sequentially added to a solution of 5-methyl-2,4-dichloropyrimidine (643 mg, 3.94 mmol) in n-butanol (20 ml). The mixture was stirred at ambient temperature for 20 hours, after which time a gelatinous precipitate had fallen out of solution. DCM was added until a solution was obtained, and silica (2.5 g) was added. Volatile material was removed by evaporation and the residue was loaded on a Varian Mega Bond Elut column pre-conditioned with ethyl acetate. The column was eluted with 0-10% methanol solution in ethyl acetate containing 0.5% aqueous ammonia. The appropriate fractions were concentrated, and the residue was triturated with n-butanol (20 ml). The filtrate was evaporated onto silica (2.5 g) and loaded on a Varian Mega Bond Elut column pre-conditioned with isohexane. The column was eluted with 0-50% ethyl acetate solution in isohexane. Concentration of the appropriate fractions gave the product as a white solid (340 mg, 26%). NMR: 2.17 (s, 3H), 7.60 (d, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.11 (s, 1H), 8.97 (s, 1H); MS (MH+): 288.1, 290.1, 292.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:32][CH3:33])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC=CC=4)=[CH:16][CH:15]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:12]2[CH:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]=[C:11]2[CH2:32][CH3:33])=[CH:19][CH:18]=1)=[O:24])(=[O:43])=[O:42]
Reactant: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-(4-cyanophenyl)-2-ethyl-1H-imidazol-1-yl]phenyl}ethylcarbamate and 2-chlorobenzenesulfonamide. MS (ESI) m/z 534 [M+H]+, 532 [M−H]−, 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.7 Hz), 2.86 (2H, t, J=7.1 Hz), 3.47-3.55 (2H, m), 6.58 (1H, br), 7.23-7.31 (3H, m), 7.36 (1H, s), 7.41-7.47 (1H, m), 7.57-7.66 (4H, m), 7.89 (2H, d, J=8.6 Hz),8.01 (1H, d, J=8.4 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 82.8 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (113i) (0.21 g, 0.42 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (5 mL), to obtain 153 mg of the title compound as a colorless solid (82%).