Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=1)[CH:12]=[CH:11]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.222 g (0.465 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate is dissolved in 60 ml absolute dichloromethane and mixed with 3.98 g (34.9 mmol) trifluoroacetic acid. Having stirred at room temperature for 4 hours, concentration to dryness is carried out on the rotary evaporator. Two admixtures with hexane and respective concentration to dryness on the rotary evaporator leave as a crude product a brownish solid which is purified on an RP-HPLC column by means of chromatography (stationary phase: cromasil, mobile phase acetonitrile/water 80:20) and yields the product as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH2:26][CH3:27])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:22])[F:23])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: CCN
Product: CCNc1c(C(C)=O)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 75.7 %

Procedure:
3-Acetyl-6-chloro-8-trifluoromethyl-4-methylsulfoxy-2-quinolinone (3.5g, 0.01 mol) and ethylamine(70 wt % solution; 0.65g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.52g, yield: 76%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CCO.[Pd]>[F:24][C:21]([F:22])([F:23])[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: FC(F)(F)Oc1ccccc1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccccc1C1CCNCC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-4-(2-trifluoromethoxy-phenyl)-1,2,3,6-tetrahydro-pyridine (described herein below) in EtOH was added (0.2 wt %) 10% Pd/C, followed by (5 eq.) TFA in a sealed tube. The reaction mixture was stirred at 50° C. under 3.0 bar of H2 for 12 h. The reaction mixture was filtered over Celite and the filtrate evaporated down to dryness. Redissolution in EtOAc, washing with 1N NaHCO3 and concentration gave the crude product which was directly used for the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH3:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1c(F)cccc1F
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3c(F)cccc3F)nc2n1
Temperature: 4 °C
Yield: 40.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (5.1 g), N,N'-carbonyldiimidazole (5.2 g) and 2-amino-7-methoxy-1,8-naphthyridine (4.4 g). The product produced by precipitation in water (4.5 g; m.p. 215°-217° C.) is dissolved in boiling ethanol (70 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-2,6-difluorobenzamide (3.2 g) is produced, m.p. 219°-220° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[CH:26][CH:25]=1.C(O)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[O:1]=[C:2]1[NH:6][C:5]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([B:30]3[O:31][C:32]([CH3:38])([CH3:37])[C:33]([CH3:36])([CH3:35])[O:34]3)=[CH:28][CH:29]=2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC(=O)N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Ethyl (2S)-5-oxopyrrolidine-2-carboxylate (0.200 g, 1.27 mmol) was azeotroped three times from toluene (25 mL each), dissolved in tetrahydrofuran (4.4 mL) and cooled to −78° C. 1 M lithium hexamethyldisilazide in tetrahydrofuran (1 M, 3.75 mL) was added via syringe and the colorless solution was stirred 30 min before addition of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4 g, 1.0 mmol) in tetrahydrofuran (2.0 mL). The slightly yellow solution was stirred at −78° C. for 30 min and then at −10° C. for 1 h and warmed to rt for an additional 1 h before it was cooled back to −78° C. and quenched with acetic acid (1.00 mL, 17.6 mmol). Evaporation and purification by preparative LCMS gave the desired product as a colorless glass, (296 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 7.67 (d, J=7.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.08 (d, J=13.0 Hz, 1H), 3.05 (d, J=13.0 Hz, 1H), 2.35 (m, 1H), 2.23 (m, 1H), 2.15 (m, 1H), 1.79 (m, 1H), 1.35 (s, 12H), 1.25 (t, J=7.0 Hz, 3H); LCMS found for C20H29BNO5 (M+H)+: m/z=374.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@H:7]([NH:22]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6](=[O:30])[C@H:7]([NH2:22])[CH2:8][CH2:9][CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](N)CCCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of the title G compound, (2R)-(t-butyloxycarbonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (4.83 g, 11.55 mmol) in 18 mL of dichloromethane is treated with trifluoroacetic acid (TFA; 6.00 mL, 78 mmol) at 0° C. After stirring for 1 h at this temperature, the solution is concentrated under reduced pressure without heating, and the residue is partitioned between 100 mL of ethyl acetate and 50 mL of 1M aqueous NaHCO3. The organic phase is dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 1/1—ethyl acetate/hexane) affords 2.58 g (70%) of (2R)-amino-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a colorless foam: NMR(CDCl3) 1.46 (s, 9H), 1.80-2.06 (m, 4H), 3.73 (t, 2H, J=6.2), 3.97 (t, 1H, J=6.3), 7.68-7.71 (m, 2H), 7.82-7.85 (m, 2H).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1>>[F:11][C:12]1([F:16])[CH2:15][N:14]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13]1
Reactant: N#Cc1cccnc1F
Reactant: FC1(F)CNC1
Agent: Cl
Product: N#Cc1cccnc1N1CC(F)(F)C1
Yield: 84 %

Procedure:
Prepared in 84% yield from 2-fluoronicotinonitrile and 3,3-difluoroazetidine hydrochloride according to the procedure described for Example 178A. 1H NMR (DMSO-d6) δ 4.65 (t, J=12.4 Hz, 4H), 6.94 (dd, J=7.6, 4.9 Hz, 1H). 8.08 (dd, J=7.8, 1.7 Hz, 1H), 8.40 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([I:19])=[CH:17][N:16]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:14]=2[N:15]=1.N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Si:1]([O:22][CH2:21][C:20]([N:16]1[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:18]([I:19])=[CH:17]1)([CH3:24])[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)n1cc(I)c2cnc(Cl)nc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
t-Butyldimethylsilyl chloride (78.8 g, 518 mmol) was added to 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-1-ol (140 g, 398 mmol) (see Preparation 43) and imidazole (67.8 g, 996 mmol) in DMF (996 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into saturated aqueous sodium bicarbonate (1500 mL) and extracted with heptane:EtOAc (1:1, 1500 mL). The organic extract was washed with brine (2×900 mL) then dried over magnesium sulfate and evaporated in vacuo to afford the title compound as a brown gum in 96% yield, 178.2 g.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(O)(=[S:21])C>ClCCl>[SH:21][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: CC(O)=S
Reactant: O=C(CCCl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCS)c1ccccc1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Triethylamine (1.49 mL, 10.7 mmol, 1.50 equiv) was added to a solution of 3-chloropropiophenone (1.20 g, 7.12 mmol, 1 equiv) in dichloromethane (100 mL) at 23° C. Thioacetic acid (602 μL, 8.54 mmol, 1.20 equiv) was then added dropwise to the solution. After 1 h, the reaction mixture was concentrated in vacuo. The crude residue was dissolved in tetrahydrofuran (50 mL) and aqueous hydrochloric acid (6 N, 50 mL) was added to the solution. Thee reaction mixture was then heated to reflux. After 36 h, the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution (400 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL), and the combined organic layers were dried over sodium sulfate, were filtered, and were concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in hexanes) to afford 3-mercaptopropiophenone (E2-30, 703 mg, 59.4%) as a colorless oil. 1H NMR (500 MHz, CDCl3, 20° C.): δ 7.93 (d, J=7.5, 2H, COPh-o-H), 7.55 (t, J=7.5, 1H, COPh-p-H), 7.45 (app-t, J=7.5, 2H, COPh-m-H), 3.31 (t, J=7, 2H, CH2CH2SH, 2.89 (dt, J=8.5, 6.0, 2H, CH2CH2SH), 1.74 (t, J=8.5, 1H, SH). 13C NMR (125.8 MHz, CDCl3, 20° C.): δ 198.2 (C═O), 136.8 (COPh-ipso-C), 133.6 (COPh-p-C), 128.9 (COPh-m-C), 128.2 (COPh-o-C), 42.7 (CH2CH2SH), 19.1 (CH2CH2SH). FTIR (thin film) cm−1: 3061 (w), 2941 (w), 1683 (s), 1597 (m), 1580 (m) 1448 (m). HRMS (ESI) (m/z): calc'd for C9H11OS [M+H]+: 167.0525. found 167.0526. TLC (20% ethyl acetate in hexanes), Rf: 0.28 (UV, CAM).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 417 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:3]=1[C:18]#[N:19].O1CCO[CH2:22][CH2:21]1>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:18]([C:3]1[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[CH:21]=[CH2:22])#[N:19]
Reactant: C1COCCO1
Reactant: COc1cccc(-c2nc(SC)nc(Cl)c2C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1nc(SC)nc(-c2cccc(OC)c2)c1C#N

Procedure:
6-Chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthio-pyrimidine (example 1b, 1.46 g) was suspended in 1,4-dioxane (10 ml). Tetrakis(triphenylphosphine)palladium(0) (350 mg) was added and the mixture was flushed with a nitrogen atmosphere. Tetravinyltin (1.26 ml) was added and the mixture was refluxed for 5 h. The reaction mixture was then poured in a mixture of EtOAc (100 ml) and H2O (100 ml). The organic layer was washed with sat. aq. NaCl, dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/CH2Cl2=1/0 to 1/3 (v/v).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccccc1Nc1cccc2ccccc12
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1N(c1ccc(Br)cc1)c1cccc2ccccc12
Temperature: 110 °C
Yield: 13.5 %

Procedure:
A mixture of N-(o-tolyl)naphthalen-1-amine (Compound 20) (2.0 g, 8.6 mmol), 1-bromo-4-iodobenzene (8.67 g, 30 mmol), Pd(dppf)Cl2 (0.365 g, 0.5 mmol), potassium tert-butoxide (1.96 g, 20 mmol) in toluene was degassed and heated at 110° C. overnight. The resulting mixture was worked up with ethyl acetae/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1. After removal of solvents, a yellow solid (Compound 21) was obtained, 0.45 g in 13.5% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:21][C:22]#[N:23]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]#[N:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CCN1CCN(Cc2ccccc2)CC1
Yield: 77.3 %

Procedure:
To a suspension of 1-benzylpiperazine (18 g) and sodium carbonate (8.3 g) in acetone (50 ml) was added chloroacetonitrile (12 g) under ice-cooling, and mixed at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, to the residue were added water and diethyl ether, and the organic layer was collected by separation. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column (ethyl acetate) to obtain the title compound as pale yellow liquid (17 g, 80%).
Reaction SMILES: [C:1]1(=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>O>[N+:15]([C:8]1[C:3]2[CH2:2][C:1](=[O:9])[C:4]=2[CH:5]=[CH:6][CH:7]=1)([O-:17])=[O:16]
Reactant: O=C1Cc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Cc2c1cccc2[N+](=O)[O-]

Procedure:
Benzocyclobutenone (1.20 g) was added slowly to concentrated sulfuric acid (5 mL) at 0° C. with vigorous stirring. The mixture of concentrated sulfuric acid (1.0 mL) and nitric acid (70%, 1.05 g) was added at such a rate that the solution temperature remained at 10° C. After the completion of addition of nitrating solution, the reaction mixture was then poured into icey water (30 mL). The resulting mixture was filtered. The filtrate was neutralized with sodium carbonate powders and the water was then evaporated under vacuum. The residue was then extracted with methylene chloride (3×50 mL). After removal of methylene chloride, the pure product (3-nitrobenzocyclobutenone) was isolated from the residue by chromatography on silica gel: 55 mg; IR (KBr) 1349, 1525, 1772 cm-1 ; 1H NMR (200 MHz, CDCl3) 4.42 (s, 2H), 7.68 (m, 2H), 8.31 (m, 1H); MS (EI, m/e, relative intensity %) 164 (M+. +H, 2.5), 135 (M+. -CO, 10.3), 89 (135 -.NO2, 38).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].B(O)O>>[C:26]([O:25][C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:34][CH:33]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: OBO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and [4-(N-Boc-aminomethyl)phenyl]boronic acid as a boronic acid, 4-(4-tert-butoxycarbonylaminomethyl-phenyl)-2-(morpholin-4-yl)-7-(pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained. This was dissolved in 1N hydrochloric acid-acetic acid, followed by stirring at room temperature for 40 minutes, and diethyl ether was added to the reaction mixture, to filter off a solid, whereby the desired compound was obtained.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]3)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[O:29]=[C:19]1[CH:20]=[CH:21][C@@:22]2([CH3:23])[C:17]([CH:16]=[CH:15][C@@H:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])=[CH:18]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
In 100 ml of acetone was dissolved 0.410 g (1.0 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one, followed by addition of 10 mg (0.05 mmole) of p-toluenesulfonic acid. The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distilled off under reduced pressure and the residue was diluted with methylene chloride. The methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to recover 0.243 g of 3-oxopregna-1,4,6-triene-20-carbaldehyde (yield: 75%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[OH:14]/[N:15]=[C:16](\[NH2:18])/[CH3:17].C(N(CC)CC)C>ClCCl>[NH2:18]/[C:16](=[N:15]\[O:14][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])/[CH3:17]
Reactant: C/C(N)=N/O
Reactant: COC(=O)c1ccnc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccnc(C(=O)O/N=C(/C)N)c1

Procedure:
To a solution of methyl 2-(chlorocarbonyl)isonicotinate in dichloromethane (500 mL) was added (Z)-N′-hydroxyacetimidamide and triethylamine, keeping the temperature at 25-30° C. for 1 day. The reaction was concentrated in vacuo to afford (Z)-methyl 2-((1-aminoethylideneaminooxy)carbonyl)isonicotinate as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH3:10][NH:11][CH3:12]>>[CH3:10][N:11]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:12]
Reactant: CNC
Reactant: Cc1cccc(CBr)n1
Product: Cc1cccc(CN(C)C)n1

Procedure:
2-bromomethyl-6-methylpyridine is treated with dimethylamine to give the corresponding tertiary amine, 2-dimethylaminomethyl-6-methylpyridine. The tertiary amine is treated with cyanomethyl benzenesulfonate, as in Preparation II, to give dimethylcyanomethyl-(6-methyl-2-picolyl) ammonium benzene sulfonate. The quaternary ammonium salt is rearranged using sodium hydride and alkylated with benzylbromide according to the procedure described in Example 2. The alkylated cyanoamine is decyanated with sodium borohydride in ethanol to give the desired product which can be purified through its picrate.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[C:12]4B3OC(C)(C)C(C)(C)O3)=[N:7][N:8]=2)[CH2:3][CH2:2]1.Br[C:38]1[N:43]=[C:42]([CH:44]2[CH2:46][CH2:45]2)[CH:41]=[CH:40][N:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH:13]=[C:12]4[C:38]3[N:43]=[C:42]([CH:44]4[CH2:46][CH2:45]4)[CH:41]=[CH:40][N:39]=3)=[N:7][N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Reactant: Brc1nccc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To a 20 mL glass microwave tube containing 2-cyclopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (340 mg, 0.673 mmol) was added 2-bromo-4-cyclopropylpyrimidine (154 mg, 0.774 mmol) (CombiPhos Catalysts Inc.), potassium phosphate (428 mg, 2.018 mmol) (Sigma-Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (19.24 mg, 0.040 mmol) (Strem), and Pd2(dba)3 (18.48 mg, 0.020 mmol) (Strem). The tube was purged with argon, the solids were treated with dioxane (6.0 mL) and water (0.600 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 20 min. The mixture was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (20-70% EtOAc in Hex) affording 2-cyclopropyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (78.6 mg, 0.158 mmol, 23.48%) as an amorphous, rust-coloured solid. MS (ESI, pos. ion) m/z: 498.1 (M+1).