Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=O)([CH2:3][CH3:4])[CH3:2].[CH:16]([NH:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:18])[CH3:17].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([N:19]([CH:16]([CH3:18])[CH3:17])[NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccccc1OCC(=O)O
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)c1ccccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 36.4 %

Procedure:
A solution of (2-sec-butyl-phenoxy)-acetic acid (193 mg, 0.93 mmol), and benzoic acid N′-isopropyl-hydrazide (150 mg, 0.842 mmol) in DMF (5 ml), was treated with triethylamine (0.352 ml, 2.52 mmol), HOBT (136 mg, 1.00 mmol), and EDCI (194 mg, 1.00 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 50% ethyl acetate/hexanes to afford the product as a white solid (113 mg, 33%). MS m/e 369.32 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Yield: 66 %

Procedure:
To 250 mg of 4-(3-chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 210 mg (66%) of 4-(3-chloro-4-fluoro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 131-132° C.; mass spectrum (m/e): M+H 386.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(CCOCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1.0 g) in N,N-dimethylformamide (25 mL) was added 55% sodium hydride (0.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added benzyl bromide (0.77 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1) to give 1-[2-(benzyloxy)ethyl]-4-bromobenzene (1.35 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[C:12]2[CH2:13][CH2:14][N:15]([C:19]3[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=3)[CH2:16][CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Fc1cc(F)cc(C#CC=C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cc(F)cc(F)c3)CC2)n1
Yield: 83.6 %

Procedure:
A solution of Compound 228b (0.046 mg, 0.197 mmol), 2-chloro-6-methoxy-3-nitropyridine (34.6 mg, 0.18 mmol), potassium carbonate (50.3 mg, 0.36 mmol) in N,N-dimethylacetamide was heated in a microwave oven at 165° C. for 3 min. Afterwards, the reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 5:95) affording the title product (0.058 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[N:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[N:3]1[CH2:20][CH:21]=C.[O:24]=[O+][O-].CSC>ClCCl>[O:1]=[S:2]1(=[O:23])[N:7]([CH:8]([CH3:9])[CH3:10])[CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[N:3]1[CH2:20][CH:21]=[O:24]
Reactant: C=CCN1c2c(cccc2C(=O)OCC)CN(C(C)C)S1(=O)=O
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: CCOC(=O)c1cccc2c1N(CC=O)S(=O)(=O)N(C(C)C)C2
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-8-carboxylate (1.1 g)(prepared from ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate and (prop-2-en-1-yl) bromide) was dissolved in dichloromethane (80 ml) and cooled to -75° C. Ozone was passed through the solution until the solution became blue. At which time, dimethyl sulfide (5 ml) was added and the solution allowed to come to room temperature over 1 hour. The solution was washed with water to remove the DMSO present, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a solid, ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate. This was dissolved in dichloroethane (50 ml) containing glacial acetic acid(5 drops) together with 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.8 g, 1.1 equiv.). Sodium triacetoxy borohydride (0.8 g, 1.1 equiv.) was added and the solution stirred overnight at room temperature. After washing with 2N sodium hydroxide (30 ml) and brine, the solution was dried, filtered and evacuated in vacuo to yield an off-white solid. Column chromatography eluting with ethyl acetate/hexane to ethyl acetate gave the required product, ethyl 3,4-dihydro-2,2-dioxo-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate, m.p. 95-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[C:37]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]>>[C:35]([C:32]1([NH:31][C:29]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:44]4[CH2:45][CH2:46][N:41]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:42][CH2:43]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:34][CH2:33]1)#[N:36]
Reactant: CC(C)(C)N1CCNCC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C(C)(C)C)CC4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with 1-tert-butylpiperazine (CAS Reg. No. 38216-72-7) to give the title compound as colorless oil. MS (ESI): m/z=658.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)([CH3:21])=[O:20]>C1COCC1>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:20])[CH3:21]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) and triethylamine (1.53 ml; 11 mmol) in THF (25 ml) at 0° C. was added AcCl (0.85 ml; 12 mmol) and left with stirring at rt. over night. The reaction mixture was filtered and adsorbed onto silica. Column chromatography gave 1.7 g (79%) product. M.p. 153.5-155.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:42][C:43]1[CH:44]=[C:45]([NH:50][CH3:51])[C:46]([NH2:49])=[CH:47][CH:48]=1>CN(C=O)C>[Br:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:6]([CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[O:8])=[C:45]([NH:50][CH3:51])[CH:44]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo, and the residue was diluted with DCM (200 ml) and washed with saturated NH4Cl (100 ml), saturated NaHCO3 (60 ml), water (100 ml) and brine (100 ml). The DCM layer was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.7 g) as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC1CCCC(C)C1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: CC1CCCC(C)C1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c(=O)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,6-dimethyl-cyclohexyloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 69) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,6-dimethyl-cyclohexyloxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as an orange solid as a mixture of diastereomers (1.14 g, 76%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)=[C:4]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[OH:19])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.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>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]([C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[CH:30][N:29]=[C:28]([F:27])[CH:33]=3)[S:6][C:5]=2[C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[OH:19])=[CH:21][CH:22]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: OC(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1ncn(C2CCCCO2)n1
Yield: 93.6 %

Procedure:
A mixture of {5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanol (734 mg, 1.61 mmol), 2-fluoro-4-pyridinylboronic acid (455 mg, 3.23 mmol), tetrakis(triphenylphosphine)palladium(0) (93.3 mg, 0.0807 mmol) and cesium carbonate (1.58 g, 4.84 mmol) in 1,4-dioxane (10.1 mL, 129 mmol) and water (1.45 mL, 80.7 mmol) was irradiated in a microwave oven at 140° C. under argon for 20 min. The reaction mixture was dry loaded onto silica gel and purified by column chromatography (SiO2, elution with EtOAc in hexanes, 0-80% gradient) to afford (4-chlorophenyl) {5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol as a white solid (0.71 g, 92.8%). LCMS: (AA) ES+ 471.1, 473.1
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22]1([N:32]=[C:33]=[O:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:33]([NH:32][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4cccc5ccccc45)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
A heterogeneous mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 1-naphthyl isocyanate (0.26 g, 1.6 mmol), and triethylamine (4.9 g, 4.9 mmol) in 25 mL THF was stirred under nitrogen at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was triturated with 3% aqueous HCl (100 mL) for 1 hour and then filtered, and the filter was washed with additional 3% HCl. The resulting solid was dried, triturated with 30 mL refluxing acetone for 1 hour and filtered, and the filter was washed with additional hot acetone. The resulting solid was dried and then triturated with 30 mL refluxing acetonitrile, filtered, and dried, to provide 0.40 g of the product in 56% yield: 1H NMR (DMSO-d6) δ 2.00-2.09 (m, 1H), 2.35-2.42 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.44 (d, J=17.2 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 4.58 (d, J=17.2 Hz, 1H), 5.16 (dd, J=13.1 Hz, J=5.1 Hz, 1H), 7.11 (t, J=5.8 Hz, 1H), 7.09-7.67 (m, 7H), 7.90 (dd, J=6.6 Hz, J=2.9 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 8.09 (t, J=9.0 Hz, 1H), 8.66 (s, 1H), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 31.2, 40.0, 46.2, 51.6, 117.0, 121.4, 121.6, 122.4, 125.5, 125.8, 125.9, 128.3, 128.4, 130.4, 131.7, 133.7, 134.9, 135.5, 140.0, 155.7, 168.1, 171.0, 172.8; Anal. calcd for C25H22N4O4: C, 67.86; H, 5.01; N, 12.66. Found: C, 67.64; H, 4.99; N, 12.28.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: NCCc1ccccc1F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccccc1F)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-fluorophenethylamine (4.7 mL, 35.9 mmol) and diisopropylethylamine (6.3 mL, 35.9 mmol) in dichloromethane (35 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (5.4 mL, 35.9 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel, extracted with water (35 mL), brine (25 mL), and 1N HCl (25 mL). The dichloromethane layer was separated and formation of more precipitate was observed which was collected by filtration. The solids collected were combined and dried under vacuum to yield N-(2-fluorophenethyl)-4-(trifluoromethyl)benzamide as an off-white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: N#Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C#N)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-cyano-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.69 min; [M+H]+=417.76.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10]([C:20](=[O:28])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][N:8]=1)(=O)=O.[C:31]([C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1)#[CH:32].C(N(CC)CC)C.N>CN(C)C=O>[CH2:13]([C:12]1[C:7]([C:32]#[C:31][C:33]2([OH:41])[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[N:8][CH:9]=[C:10]([C:20](=[O:28])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cnc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
150 mg of 3-benzyl-5-(N-phenylcarbamoyl)-2-pyridyl trifluoromethanesulfonate, 60 mg of 3-ethynyl-3-quinuclidinol, 50 mg of tetrakis (triphenylphosphine)palladium(0), 10 mg of cuprous iodide and 0.15 ml of triethylamine were added to 2 ml of N,N-dimethylformamide, followed by stirring for 3 hours in an oil bath kept at 50° C. After cooling as it was, aqueous ammonia was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography, to synthesize 90 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:40][CH3:41].O>CN(C=O)C>[CH2:40]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:10])[CH3:41]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.6 mmol, 300 mg) and sodium bicarbonate (3.6 mmol, 302 mg) in DMF (4 mL) was added iodoethane (3.6 mmol, 0.29 mL) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into water (50 mL) and was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 155 mg (50% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl ester as a crystalline white solid: mp 262-265° C. ES-HRMS m/e calcd for C25H25Cl2N3O5 (M+Na) 540.1062, found 540.1049.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]2[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH:33]=O)=[CH:28][CH:27]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:42])(=[O:11])=[O:10])#[N:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]2[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH2:33][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:28][CH:27]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:42])(=[O:11])=[O:10])#[N:2]
Reactant: C1CCNC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccc1C#N)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccc1C#N)CNC2=O

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-cyanobenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.140 g, 0.238 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with pyrrolidine (0.398 mL, 4.77 mmol), acetic acid (0.273 mL, 4.77 mmol) and sodium triacetoxyborohydride (0.151 g, 0.715 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15, 80/20) to obtain 4-(2-cyanobenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.0773 g, ESI-MS m/z: 643 [M+H]+; 1H-NMR (CD3OD)8(ppm): 1.18 (s, 9H), 1.83-1.92 (m, 4H), 2.88-2.96 (m, 4H), 3.25 (s, 3H), 4.04 (s, 2H), 4.49 (s, 2H), 6.55 (s, 1H), 7.00 (s, 1H), 7.28 (dd, J=1.6, 8.7 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.77-7.93 (m, 3H), 8.08 (dd, J=1.6, 7.3 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H).