Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]=[N+:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:20]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methyl-benzylidene)-piperidinium chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:7][CH2:8][CH3:9])=[CH:5][CH3:6])[CH3:2].[C:10]([NH:13][CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[C:16]([O:18][CH3:19])=[O:17])(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([NH:13][C@@H:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([CH3:21])[O:22][C:4]([O:7][CH2:8][CH3:9])([O:3][CH2:1][CH3:2])[C@H:5]1[CH3:6])(=[O:12])[CH3:11]
Reactant: CC=C(OCC)OCC
Reactant: COC(=O)C(=CNC(C)=O)C(C)=O
Solvent: Cc1ccccc1
Product: CCOC1(OCC)OC(C)=C(C(=O)OC)[C@@H](NC(C)=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Diethoxyprop-1-ene (1.0 ml) was added to a solution of methyl 2-acetylaminomethylene-3-oxobutanoate (1.0 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octandionato)ytterbium (0.05 g) in toluene (3.0 ml) at 20° C. After stirring for 2 hr at ambient temperature, the reaction mixture was filtered to give methyl trans-4-acetylamino-2,2diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g), m.p. 153°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([F:13])[F:12].[H-].[Na+].Br[CH2:17][C:18]([NH2:20])=[O:19].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([NH2:20])=[O:19])[C:6](=[O:11])[C:5]2([F:13])[F:12]
Reactant: NC(=O)CBr
Reactant: O=C1Nc2ccc(Cl)cc2C1(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN1C(=O)C(F)(F)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-chloro-3,3-difluoro-1,3-dihydro-2H-indol-2-one 4 (2.55 g, 12.5 mmol) is dissolved in dry DMF (20 ml) under a nitrogen atmosphere. The solution is cooled at 0° C. and NaH (0.547 g, 13.8 mmol, 60% dispersion) is carefully added portionwise. When the nitrogen evolution ceases, bromoacetamide (2.05 g, 15.0 mmol) is added. After 30 minutes, the mixture is poured into cold water and the solid is filtered off and washed with water. The crude material is directly recrystallized in acetone/water affording of 2-(5-chloro-3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 12 as a pink solid.
Reaction SMILES: [CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52]([C:31]2[CH:32]=[CH:33][C:28]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:21])([F:22])[F:20])[C:15]([F:17])([F:18])[F:16])=[C:8]([CH3:27])[CH:7]=3)[CH2:1][CH3:2])=[CH:29][C:30]=2[CH3:43])[CH:53]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 56.6 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 47.7 mg, 0.1 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 26.8 mg, 0.11 mmol), tetrakistriphenylphosphine palladium (12.5 mg, 0.0108 mmol) and potassium phosphate (24.7 mg, 0.11 mmol) in N,N-dimethylformamide (0.25 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (36.0 mg, 72%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][NH:59][CH2:58][C@H:57]4[CH3:62])[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]>>[ClH:3].[ClH:51].[ClH:1].[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][N:59]([CH3:4])[CH2:58][C@H:57]4[CH3:62])[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)C[C@H]4C)ncc3Cl)cc12

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 473 (35Cl) and 475 (37Cl) [M+H].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.I[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2cnccn2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 86-1 (2.2 g, 10 mmol), 2-iodopyrazine 86-2 (2.06 g, 10 mmol), Pd(PPh3)4 (577 mg, 0.5 mmol), toluene (70 mL), ethanol (15 mL) and 2M Na2CO3 (15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with 1M HCl aqueous solution (50 mL). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting suspension was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give 5-(pyrazin-2-yl)pyridin-2-amine 86-3 as white solid. MS m/z 173.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.12 (d, 1H, J=1.6 Hz), 8.73 (m, 1H), 8.60 (m, 1H), 8.46 (d, 1H, J=2.8 Hz), 8.12 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.55 (d, 1H, J=8.8 Hz), 6.46 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH2:28][O:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32](CC3C=[NH+]C=CC=3)[C@@H:31]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CN(C)C=O.O>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:20]([CH2:28][O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[C@H:31]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:19]=[C:18]([C:17]([F:50])([F:16])[F:49])[CH:23]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3ccc[nH+]c3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: ClCc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3cnccn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
2-(Chloromethyl)pyrazine (0.17 g), potassium carbonate (0.6 g) and the compound of Description 3 (0.35 g) were suspended in dimethylformamide (3 ml); the reaction mixture was heated at 60° C. for 12 h. The mixture was cooled, diluted with water (30 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil. The product was purified by column chromatography on silica gel using a gradient elution of 15-35% ethyl acetate in hexane. This afforded the product as a white solid, which was recrystallised from pentane to give colourless crystals: mp 108°-110° C. 1H NMR (360 MHz, DMSO-d6) d 1.42-1.60 (2H, m NCH2CH2CH2), 1.77-1.92 (1H, m, NCH2CHH), 2.13-2.25 (2H, m, NCHH+NCH2CHH), 2.84-2.92 (1H, m, NCHH), 3.12 (1H, d, J=14.0 Hz, NCHH-pyrazine), 3.55 (1H, m, CHO), 3.63 (1H, m, CHPh), 3.78 (1H, d, 14.0 Hz, NCHH-pyrazine), 4.11 (1H, d, J=13.0 Hz, OCHHAr), 4.64 (1H, d, J=13.0 Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H, s, ArH), 7.93 (1H, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI+) 496 (M+ +1, 60%). Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C25H23F6N3O: C, 60.60; H, 4.68; N, 8.48%.
Reaction SMILES: [Cl:1][C:2]1[C:21]([CH2:22][O:23]COCCOC)=[CH:20][CH:19]=[C:18]([Cl:30])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]>Cl>[Cl:1][C:2]1[C:21]([CH2:22][OH:23])=[CH:20][CH:19]=[C:18]([Cl:30])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COCCOCOCc1ccc(Cl)c(C(=O)Nc2cccc3c(C)c(C)oc23)c1Cl
Agent: Cl
Product: Cc1oc2c(NC(=O)c3c(Cl)ccc(CO)c3Cl)cccc2c1C
Yield: 88.4 %

Procedure:
A solution of 7-[2,6-dichloro-3-(2-methoxyethyl)oxymethoxymethylbenzoylamino]-2,3-dimethylbenzo[b]furan (305 mg) in 10% methanolic hydrogen chloride (4.5 m.l) was refluxed for 1 hour. The reaction mixture was cooled and the separated solid was collected to give 7-(2,6-dichloro-3-hydroxymethylbenzoylamino)-2,3-dimethylbenzo[b]furan (217 mg).
Reaction SMILES: C([Li])CCC.C(#N)C.[CH2:9]([O:16][C:17]1C=C(OC(CCCC2C=CC=CC=2)C)C=[C:21]2[C:26]=1[CH:25](C(OC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:24][C:23](C)(C)[CH2:22]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:26]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(CCCc1ccccc1)Oc1cc2c(c(OCc3ccccc3)c1)C(C(=O)Oc1ccc([N+](=O)[O-])cc1)CC(C)(C)C2
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.4 ml. of 2.1M n-butyllithium in 3.7 ml. tetrahydrofuran at -78° C. is added a solution of 0.26 ml. (5 mmole) acetonitrile in 3.7 ml. THF and the mixture is stirred for one hour. at -78° C. A solution of 1.1 g. (2.0 mmole) p-nitrophenyl 8-benzyloxy-3,3-dimethyl-6 -(5-phenyl-2-pentyloxy)tetralin-1-carboxylate in 3.7 ml. THF is added and stirring continued at -78° C. for 30 minutes. The reaction mixture is warmed to room temperature, quenched with 7 ml. 10% hydrochloric acid and extracted with ethyl ether. Isolation of product as in the preceding Example affords 1.13 g. of crude benzyl ether which gives 500 mg. of purified intermediate by silica gel chromatography: mass spectrum-molecular ion, 495.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3]1.Cl.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24]N)=[CH:23][C:18]=2[O:17][CH2:16]1.Cl>O>[O:17]1[C:18]2=[CH:23][C:22]3[NH:24][C:2]4[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][C:3]=4[C:21]=3[CH:20]=[C:19]2[O:15][CH2:16]1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl
Solvent: O
Product: CC(C)C(=O)NC1CCc2[nH]c3cc4c(cc3c2C1)OCO4
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Add N-(4-oxo-cyclohexyl)-isobutyramide (974 mg, 5.32 mmol) a suspension of benzo[1,3]dioxol-5-yl-hydrazine hydrochloride salt (Clemo, G. R.; Weiss, J. J. Chem. Soc. (1945), 702.) (1.00 g, 5.32 mmol) to water (7 mL) and concentrated hydrochloric acid (3 mL). Heat the reaction to 90° C. for 12 h and cool to ambient temperature. Collect the resultant solid by vacuum filtration, rinse with water and place under high vacuum for 12 h to afford the titled compound (1.20 g, 75%) as a dark brown solid. m.p.=198-200° C.; 1H NMR (300 MHz, CDCl3): δ 7.77 (br s, 1H), 6.81 (s, 1H), 6.78 (s, 1), 5.91 (s, 2H), 5.57 (br s, 1H), 4.40 (br s, 1H), 3.00 (dd, J=15.4, 5.1 Hz, 1H), 2.80-2.69 (m, 2H), 2.50 (dd, J=15.4, 6.5 Hz, 11H), 2.30 (septet, J=6.9 Hz, 1H), 2.05-1.96 (m, 2H), 1.14 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH2:1][C:2](=[C:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[NH:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:21]=O>C(Cl)Cl>[CH3:15][N:13]1[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]2[CH:21]=[N:1][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:14]1
Reactant: C=O
Reactant: CCOC(=O)C(N)=C1CN(C)C(=O)c2ccccc2N1
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of ethyl α-amino-1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene-acetate are dissolved in 20 ml of methylene chloride, treated with 0.65 ml of 37 percent aqueous formaldehyde solution and stirred in the presence of air at room temperature for 2 hours. The solution is subsequently washed twice with 10 ml of water each time. The organic phase is separated, dried and decolourised with active carbon. After filtration of the carbon, the filtrate is evaporated in vacuo and the residue is chromatographed on 20 g of silica gel. Elution is carried out firstly with chloroform and subsequently with chloroform/ethanol (985:15). The fractions which contain ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as the main component are combined and evaporated in vacuo. The residue is dissolved in ethanol and crystallised by the addition of diisopropyl ether. There is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 162°-164° C.
Reaction SMILES: COC(C1SC([I:22])=C(C#N)C=1C1C=CC(C(C)(C)C)=CC=1)=O.[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30](N)=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[N:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30]([I:22])=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[N:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)c1sc(I)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Product: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1

Procedure:
Using a method substantially in accordance with the method of 3-(4-tert-butyl-phenyl-4-cyano-5-iodo-thiophene-2-carboxylic acid methyl ester starting with the compound, 5-amino-4-cyano-3-(2′-cyano-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81-7.46 (m, 8H), 4.22 (q, 2H, J=7.2 Hz), 1.20 (t, 3H, J=7.0 Hz), MS found (M+1)+NH3 502.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.Cl[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].[NH4+].[Cl-]>C1COCC1>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: Cc1ccc2ccccc2n1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15 g, 150 mmol) in THF (250 mL) was added n-BuLi (2.5 M in hexane, 59 mL, 150 mmol) at −78° C. under a nitrogen atmosphere. The resulting solution was stirred at −45° C. for 0.5 h, then cooled to −78° C., and 2-methylquinoline (10 g, 70 mmol) was added. The resulting solution was stirred at −78° C. for 0.5 h and then diethyl chlorophosphonate (14 g, 80 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h and then at rt for 1 h. The reaction mixture was treated with saturated NH4Cl (300 mL) and extracted with EtOAc (3×350 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 58a as a yellow oil. Mass Spectrum (LCMS, ESI pos.) Calcd. For C14H18NO3P: 280.1 (M+H). Found 280.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=O)[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH:5]=1.B.C1COCC1>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:21])[CH3:22])[CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(NC(=O)CNc2cccc(C(C)C)c2)c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NCCNc2cccc(C(C)C)c2)c1
Yield: 73 %

Procedure:
3-[2-(3-Isopropylphenylamino)acetylamino]benzoic acid methyl ester (3.26 g, 10.0 mmol) prepared above was treated with BH3.THF (1.0 M, 40.0 mL, 40.0 mmol) at room temperature for 24 h. The excess borane was destroyed by the addition of HCl (6 M, 10 mL). THF was removed in vacuum and the residue was diluted with water and basified. The organics were separated and the aqueous phase was extracted with dichloromethane. The organics were combined and washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude product obtained after the removal of the solvent in vacuum was chromatographed (silica gel, dichloromethane:ethyl acetate, 9.5:0.5) to furnish 3-[2-(3-isopropylphenylamino)ethylamino]benzoic acid methyl ester as a colorless oil (2.28 g, 73.1%). MS (ES+) m/z: 313.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.B([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([OH:43])=[O:42])(O)O.O1CCOCC1>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.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:38]4[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=4)[C:41]([OH:43])=[O:42])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:22][CH:23]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
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: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (3.5 g, 10.7 mmol) was added to Pd(Ph3P)4 (108 mg, 0.093 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (3.0 g, 7.19 mmol), 3-boronobenzoic acid (1.97 g, 11.86 mmol). Dioxane (60 ml) and water (12 ml) was added at rt. The reaction was degassed 3× and then heated to 95° C. and allowed to stir overnight. It was allowed to cool to rt. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The precipitate that formed was filtered and dried overnight at 55° C. under vacuum. The remaining organic phase was concentrated and triturated with DCM, followed by hot DCE and finally hot MeOH to afford the titled compound which was combined with the previously collected precipitate (2.4 g, 87%). LC-MS retention time: 1.19 min; m/z (MH+): 390. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCNCC3)ncnc21
Reaction time: 16 h
Yield: 96.8 %

Procedure:
tert-Butyl 4-[(9-{(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-[3-(tert-butyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate (500 mg) was dissolved in trifluoroacetic acid:dichloromethane (1:9, 20 ml) and the mixture kept at 3° C. for 16 h. The mixture was then quenched with saturated sodium bicarbonate solution (100 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (100 ml) and evaporated to dryness in vacuo to afford the title compound (407 mg) as a yellow glassy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][B:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:29][C@@H:28]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][B:30]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[O:29][C@@H:28]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: COc1ccc(B2O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)C)O2)cc1
Product: COc1ccc(B2O[C@H](CCn3c(C(C)C)cc(-c4ccccc4)c3-c3ccc(F)cc3)C[C@H](CC(=O)OC(C)(C)C)O2)cc1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-(4-methoxyphenyl)-1,3,2-dioxaborinan-4-yl)acetate.