Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[N:23]=[C:22]([NH2:24])[CH:21]=[N:20][CH:19]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[N:23]=[C:22]([NH:24][S:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(=[O:33])=[O:32])[CH:21]=[N:20][CH:19]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
To a solution of 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis(boc-amino))pyrazine (Intermediate 10) (0.845 g, 1.61 mmol) in DCM (8.05 ml) was slowly added TFA (2.48 ml, 32.2 mmol) at 0° C. After stirring for 4 hours at room temperature, the reaction mixture was quenched with 1N NaOH, and extracted with DCM. The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine (0.27 g, 52%) as a yellow solid. To a solution of 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine (0.1 g, 0.308 mmol) in pyridine (1.542 ml) was slowly added benzenesulfonyl chloride (0.050 ml, 0.385 mmol) at 0° C. After stirring for 6 hours at room temperature, the reaction mixture was diluted with DCM and quenched with 1N aq. HCl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc and the resulting solid was collected by filtration to give N-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-yl)benzenesulfonamide (0.02 g, 14%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.82-1.90 (2H, m), 2.14-2.17 (2H, m), 3.57-3.62 (2H, m), 3.92-4.06 (2H, m), 5.59-5.63 (1H, m), 7.63-7.65 (3H, m), 8.10 (2H, dd, J=2.0, 7.6 Hz), 8.43 (1H, s), 8.49 (1H, d, J=8.8 Hz), 8.55 (1H, d, J=8.8 Hz), 8.89 (1H, s), 9.21 (1H, s), 11.96 (1H, s). m/z=465.0 [M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[F:31][CH:32]([F:44])[O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([CH:42]=1)[C:39](O)=[O:40]>>[F:31][CH:32]([F:44])[O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([C:39]([N:25]2[CH2:26][CH2:27][CH:22]([N:20]3[C:19](=[O:28])[C:18]([CH3:30])([CH3:29])[C:17]([C:7]4[C:8]5[CH2:9][C:10]6([O:15][C:16]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12][CH2:13][CH2:14]6)=[N:21]3)[CH2:23][CH2:24]2)=[O:40])[CH:42]=1
Reactant: Cc1ccc(OC(F)F)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)F)ccc4C)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B6) and 5-(difluoromethoxy)-2-methylbenzoic acid (compound F4) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:13][NH2:14])(=O)[CH:9]([CH3:11])[OH:10].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[C:8]([CH:9]([CH3:11])[OH:10])=[N:13][N:14]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(O)C(=O)NN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(-c3ccc([N+](=O)[O-])cc3)nnc2C(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 ml of triethylamine were added at ambient temperature to a solution of 2 equivalents of -lactic acid hydrazide in 60 ml of toluene and then, 4.3 g of N-(4-methoxyphenyl)-4-nitrobenzene carboximidoyl chloride (Step A of Example 1) were added in two lots with stirring for 4 hours at ambient temperature. The mixture was then refluxed for 4 hours to obtain cyclization and the toluene was eliminated under reduced pressure. After washing with water, filtering and drying, 4.34 g of crude product were obtained which was purified by chromatography under pressure (eluent-chloroform-ethyl acetate-methanol: 47:50:3) to obtain 3 g of 5-[4-nitrophenyl]-4-(4-methoxyphenyl)-methyl-4H-1,2,4-triazol-3-methanol melting at 140° C.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][NH2:15])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>CO.C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](/[C:26](=[N:15]/[NH:14][C:12](=[O:13])[C:11]2[CH:16]=[CH:17][CH:18]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)/[CH3:27])[CH:25]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 41.8 %

Procedure:
3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (105 mg, 0.390 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (66.5 mg, 0.390 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (70 mg, 0.163 mmol, 41.7% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.18 (m, 1H), 8.13 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.41 (m, 1H), 7.21 (m, 1H), 6.93 (d, 1H, J=8.8 Hz), 3.23 (m, 4H), 2.39 (s, 3H), 1.75 (m, 4H). Mass [M+H]+:422.1
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=1>CN(C1C=CN=CC=1)C.ClCCl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[O:20][C:1](=[O:2])[N:22]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH:29]=[C:21]3[C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=c1oc2ccc(Br)cc2c2cc3ccccc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Carbonyldiimidazole (490 mg, 2 mmol) and DMAP (50 mg) were added to a solution of 4-bromo-2-(1H-indol-2-yl)phenol (576 mg, 2 mmol) in 20 mL of dichloromethane and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane/EtOAc 20:1) provided 2-bromo-6H-benzo[5,6][1,3]oxazino[3,4-a]indol-6-one as light yellow powder (500 mg, 79.6%). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.41˜7.53 (m, 3H), 7.22 (d, J=8.8 Hz, 1H), 7.07 (s, 1H). MS (M+H)+: 314/316.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]([NH:21][C:22](=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O>CO.C1COCC1>[NH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:18][C:19]([NH:21][C:22](=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:20])=[CH:3][C:2]=1[F:1]
Reactant: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnccc1Oc1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1F
Yield: 73.6 %

Procedure:
A suspension of 1-(3-fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea (125 mg, 0.29 mmol) in 3:1 MeOH/THF (20 mL) was hydrogenated over Pt2O (50 mg) using H2 from a latex balloon for 6 h. The catalyst was filtered off with the aid of Celite® and the filtrate concentrated to give the title compound (85 mg, 74%) as a white solid. 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.55 (s, 1H), 8.03 (s, 1H), 7.75 (dd, 1H, J=2.5, 13.2 Hz), 7.65 (d, 1H, J=5.1 Hz), 7.38-7.35 (m, 3H), 7.23-7.16 (m, 3H), 6.42 (d, 1H, J=5.1 Hz), 5.26 (s, 2H), 3.75 (s, 2H); MS (ESI+): m/z 399.35 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:13][C:14]([OH:16])=O)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(O)=[O:2].C([N:19](CC)CC)C.FC(F)(F)C(N)=O.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:4][C:1](=[O:2])[NH:19][C:14](=[O:16])[CH2:13]2)=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CN(CC(=O)O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(c2ccc(F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 5 g (16.8 mmoles) of tert.-butoxycarbonylmethyl-(4-fluoro-phenyl)-amino]-acetic acid methyl ester in 100 ml of MeOH, 33.7 ml of 1 mole aqueous KOH is added at 0° C. The reaction mixture is stirred for 4 hours and acidified with 1 mole aueous HCl. The mixture is extracted with CH2Cl2 several times and the combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 4.08 g of desired crude mono acid in 85% yield. The crude acid in 200 ml of CH2Cl2 is treated with 31 ml of TFA. After being stirred for 18 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure to give 4.92 g of desied [carboxymethyl-(4-fluoro-phenyl)-amino]-acetic acid in 100% yield as trifluoroacetic acid salt. To a solution of 4.92 g (14.4 mmoles) of [carboxymethyl-(4-fluoro-phenyl)-amino]-acetic acid in 300 ml of CH2Cl2, 9.63 ml (69.2 mmoles) of triethylamine, 4.67 g (34.6 mmoles) of 1H-hydroxybenztriazole and 2.45 g (21.7 mmoles) of trifluoroacetamide are successively added and then 6.64 g (34.6 mmoles) of 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture is quenched with cold H2O and extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-Hexane:AcOEt=1:1) to give 1.15 g of desired 4-(4-fluoro-phenyl)-piperazine-2,6-dione in 38% yield.
Reaction SMILES: [CH3:1][Mg]Cl.[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15](=[O:17])[CH3:16].[NH4+].[Cl-]>CCCCCCC.C1COCC1>[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])([CH3:1])[CH3:16]
Reactant: COc1ccc(C(C)=O)c(F)c1OC
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc(C(C)(C)O)c(F)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methylmagnesium chloride (3M in THF, 1.74 mL, 5.22 mmol) was added dropwise to a stirred solution of 1-(2-fluoro-3,4-dimethoxyphenyl)ethanone (J. Chem. Soc. Perkin Trans. 2 1994, 547-555) (646 mg, 3.26 mmol) in heptane (3.1 mL) and THF (1.4 mL) at −20° C. under N2. The reaction was allowed to warm to room temperature and was stirred for 4 h. 50% Saturated NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil. LCMS calc.=197.1; found=197.1 (M−OH)+. 1H NMR (600 MHz, CDCl3) δ 7.14 (t, J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 1.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.56-2.25 (br s, 1H), 1.58 (s, 6H).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]\[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:41][C:42]1([F:46])[CH2:45][NH:44][CH2:43]1>C(Cl)Cl>[F:41][C:42]1([F:46])[CH2:45][N:44]([C:4](=[O:6])/[CH:3]=[CH:2]\[I:1])[CH2:43]1
Reactant: O=C(O)/C=C\I
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\I)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
A solution of (Z)-3-iodoacrylic acid (1a) (2.75 g, 1.0 eq.) in CH2Cl2 (25.0 mL) was cooled to 0° C. and sequentially treated with DIPEA (1.96 g, 1.1 eq), HATU (5.78 g, 1.1 eq) and 3,3-difluoroazetidine hydrochloride (1.98 g, 1.1 eq). The reaction mixture was stirred at 0° C. for 2-3 hr before being filtered, and concentrated under reduced pressure affording 3.5 g of crude compound. Purification by column chromatography (silica gel, elution with EtOAc/hexane) afforded 1.89 g of pure desired compound. Yield (49.87%). Mass: (ES+) 273.8 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][C:19]#[N:20])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:26]>C1COCC1>[CH3:26][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=3)=[CH:17][CH:16]=2)[C:12]([CH2:18][C:19]#[N:20])=[CH:13]1
Reactant: N#CCc1c[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CC#N)c2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Yield: 59.8 %

Procedure:
[1-Methyl-5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile was prepared from [5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile (0.377 g, 1.26 mmol), sodium hydride (0.117 g, 2.93 mmol of a 60% dispersion on mineral oil), iodomethane ( 0.17 mL, 2.8 mmol) and THF (10 mL) according to the procedure described in Step 2 of Example 1. Purification by flash chromatography using 5-15% ethyl acetate in hexane as an eluant afforded the title compound as a yellow semi-solid (0.237 g, 60%), 1HNMR (300 MHz, DMSO-d6): δ 8.0 (s, 1H), 7.9 (d, 2H, J=7.7 Hz), 7.8 (d, 2H, J=7.7 Hz), 7.6 (s, 2H), 7.45 (s, 1H) 4.15 (s, 2H) and 3.8 ppm (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]#[N:14].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH:22]=O.[OH-].[Na+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13]([NH2:14])=[N:15][C:16]2[C:17]([CH:22]=1)=[CH:18][N:19]=[CH:20][CH:21]=2
Reactant: N#CCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccncc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 23.4 %

Procedure:
A solution of 2,6-dichloro-3-nitrophenyl-acetonitrile (1.02 g, 4.42 mmol), 4-amino-pyridine-3-carbaldehyde (0.4 g, 3.28 mmol) and NaOH (52 mg, 1.31 mmol) in EtOH (2.0 mL) is heated to 105° C. for 24 hours. The reaction mixture is diluted with EtOAc (50 ml) and washed with saturated K2CO3 and brine. The organic layer is dried, filtered and concentrated to give crude product. Flash silica gel column purification eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (100/6) affords the titled intermediate as a solid (257 mg, 23.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=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>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=4[CH3:31])[C:24]([O:23][CH3:22])=[O:35])[CH:3]=3)[C:8]2=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C)c(B(O)O)c1
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
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: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)c1
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (product of step iv)) (1.2 g), intermediate 2 (0.7 g), potassium carbonate (1.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.4 g) in N,N-dimethylformamide (20 mL) was heated to 95° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered and evaporated. The residue was purified (SiO2, 1:2 ethyl acetate:iso-hexane as eluent) to yield the sub-titled compound (1.03 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CN(C)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(Cl)(Cl)Cl>[C:14]([O:1][CH2:2][C:3]([CH2:8][O:9][C:2](=[O:1])[CH:3]=[CH2:4])([CH3:7])[C:4]([OH:6])=[O:5])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CC(CO)(CO)C(=O)O
Agent: CN(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCC(C)(COC(=O)C=C)C(=O)O
Reaction time: 2 h

Procedure:
Into a reactor equipped with a stirrer, a thermometer a gas introducing tube and a dropping funnel, 201 g (1.5 mol) of 2,2-bis(hydroxymethyl)propionic acid, 304 g (3.0 mol) of trimethylamine and 600 ml of chloroform were charged. Under ice cooling, 406 g (4.5 mol) of acryloylchloride were dissolved in 400 ml of chloroform, and the resulting solution was added dropwise to the reaction liquid from the dropping funnel while the temperature of the reaction liquid was kept below 5° C. After the completion of dropping, the reaction liquid was kept under ice cooling and stirred for two hours. Chloroform was then removed from the reaction liquid under reduced pressure. Resulting yellow crystals were purified by column chromatography using as a developing solvent ethyl acetate/n-hexane mixed solvent (1:4 by volume). The solvent was then removed under reduced pressure to obtain 2,2-bis(acryloyloxymethyl)propionic acid as white crystals. ##STR17##
Reaction SMILES: [OH:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH2:18]([O:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[F:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
20 g of 4-hydroxy-3,5-difluorobenzaldehyde are dissolved in dimethylsulfoxide, and potassium carbonate and benzyl chloride are added thereto. After the mixture is stirred at room temperature, water is added thereto. The mixture is extracted with ethyl acetate and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 17.4 g of 4-benzyloxy-3,5-difluorobenzaldehyde.
Reaction SMILES: O[CH:2](CN1CCOCC1)CN1CCCC2NC(C=O)=C(C)C=2C1=O.F[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:36]\[C:37]1[NH:46][C:45]2[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:40](=[O:57])[C:39]=2[C:38]=1[CH3:58].CC1C=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[OH:56][C@H:48]([CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[CH2:47][N:41]1[CH2:42][CH2:43][CH2:44][C:45]2[NH:46][C:37](/[CH:36]=[C:29]3\[C:30](=[O:35])[NH:31][C:32]4[C:28]\3=[C:27]([CH3:2])[CH:26]=[CH:34][CH:33]=4)=[C:38]([CH3:58])[C:39]=2[C:40]1=[O:57]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Reactant: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Agent: Cc1cccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@H](O)CN1CCOCC1)CCC3)C(=O)N2
Temperature: 45 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 4-methyl-1,3-dihydro-indol-2-one (12 mg, 0.08 mmol) were dissolved in 156 μl of ethanol, and added with 4.4 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (R,Z)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-2-((4-methyl-2-oxoindolin-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 76(12 mg, yield 30%) as a orange solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH3:8][SiH:9]([CH3:11])[Cl:10]>C1(C)C=CC=CC=1.[Pt]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[Si:9]([CH3:11])([CH3:8])[Cl:10]
Reactant: C[SiH](C)Cl
Reactant: C1=CC2CCC1C2
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)C1CC2CCC1C2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Norbornene (141 g, 1.50 mol) is dissolved in toluene (100 ml) and heated to 80° C. After the addition of the platinum catalyst ([COD]PtCl2, 70 mg), dimethylchlorosilane (169 g, 1.8 mol) is slowly added dropwise within 60 min, and the temperature rises to 98° C. Heating is continued at 80° C. for a further 1 h. Excess silane, unconverted norbornene and the solvent are distilled off at atmospheric pressure. The residue is fractionally distilled using a membrane pump vacuum. 255 g (93%) of a colorless liquid having b.p. of 120° C./10 mbar are obtained. Purity 99.7% (assessed by GC (gas chromatography)).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 188.8 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min, and the above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle under refluxing allylamine (7 ml) is added thereto within 15 min, the above mixture is further reacted for 0.5 h. The completion of reaction is checked with TCL analysis, and then is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12 g). The yield is about 77.3%.