Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[C:25]([F:29])[CH:26]=[C:27]([F:28])[C:22]=2[F:21])[CH2:2][CH2:3]3)=[N:11]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2F)c2c(N)ncnc21
Yield: 49.8 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.330 mmol), (2,3,5-trifluorophenyl)acetic acid (69.1 mg, 0.363 mmol), HATU (151 mg, 0.396 mmol), DIEA (0.173 mL, 0.991 mmol) was stirred overnight at room temperature. At this time, LCMS analysis indicated complete conversion, so the reaction mixture was poured into water (10 mL), whereupon a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and dry-loaded onto silica, then purified by flash chromatography (0-10% methanol in DCM) to afford 1-methyl-3-{1-[(2,3,5-trifluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (72 mg) as a white solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 3.26-3.32 (m, 2H), 3.94 (s, 3H), 4.06 (s, 2H), 4.28-4.37 (m, 2H), 7.09-7.20 (m, 1H), 7.41-7.52 (m, 2H), 7.53-7.57 (m, 1H), 8.11-8.18 (m, 1H), 8.25 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=2)[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-:33].[Na+].[Na+].OO>C(O)C>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([NH2:24])=[O:33])[CH:8]=2)[N:3]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: N#Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ccccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a suspension of 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile (0.24 g, 0.57 mmol) in ethanol (20 mL) was added 3 M aqueous sodium carbonate (2 mL) and 30% w/w aqueous hydrogen peroxide (2 mL). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was triturated in water to afford 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide (0.23 g, 93%) as a colorless solid: mp 220-222° C. (water); 1H NMR (300 MHz, CDCl3) δ 8.46-8.42 (m, 1H), 7.82 (s, 1H), 7.81-7.74 (m, 2H), 7.65 (d, J=1.5 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.28 (dd, J=7.0, 5.0 Hz, 1H), 7.19 (s, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.50 (s, 1H), 6.33 (s, 1H), 5.14-4.97 (ABq, 2H), 4.81-4.68 (ABq, 2H), 4.19-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 167.6, 155.4, 155.1, 149.7, 145.7, 144.7, 138.3, 137.6, 132.4, 129.4, 129.2, 123.3, 123.3, 122.3, 121.6, 112.1, 109.3, 99.2, 79.8, 64.7, 64.1, 57.7, 45.3; MS (ES+) m/z 429.9 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH:7]3[CH2:6][CH2:5]3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 15% yield: mp 137-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.88 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.09 (t, J=7.8 Hz, 2H), 3.58 (t, J=8.7 Hz, 2H), 3.37 (t, J=7.8 Hz, 2H), 2.60 (s, 3H), 1.46 (m, 2H), 0.70-0.58 (m, 1H), 0.46-0.37 (m, 2H), 0.13-0.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.4, 155.3, 153.0, 137.9, 128.7, 127.8, 127.6, 44.8, 44.0, 42.5, 42.0, 32.4, 17.1, 8.4, 4.3; MS (ES+) m/z 385.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:14][O:15][CH2:16]Cl.C(N(C(C)C)CC)(C)C.[OH-].[Na+:28]>CN(C)C=O.O>[Na+:28].[Na+:28].[CH3:14][O:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([O-:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxyphthalic acid (0.45 g, 2.47 mmol) in anhydrous N,N-dimethylformamide (5 ml) under nitrogen was added chloromethyl methyl ether (1.13 ml, 14.8 mmol) and diisopropylethylamine (2.6 ml, 14.8 mmol). The reaction was stirred at ambient temperature for 18 hours and then concentrated in vacuo. The crude material was partitioned between ethyl acetate (50 ml) and water (15 ml). The layers were separated, the organic layer washed with water (3×10 ml), brine (2×10 ml), dried (Na2 SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in ethanol (5 ml) and sodium hydroxide (0.12 g, 7.4 mmol) dissolved in water (1 ml) was added to the reaction. The solution was stirred at ambient temperature for 48 hours and then concentrated in vacuo affording 4-methoxymethoxy-phthalic acid di-sodium salt, which was used without purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])[CH:18]=2)=[CH:13][CH:12]=1.FC1C=CC(CC(C2C=CC=CC=2)=O)=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:68][C:69]1[CH:70]=[N:71][CH:72]=[C:73]([O:75][CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH:74]=1>CN(C=O)C.O>[Cl:68][C:69]1[CH:74]=[C:73]([O:75][CH:76]2[CH2:81][CH2:80][N:79]([C:26](=[O:28])[CH2:25][NH:24][C:22]([C:19]3[CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)[NH:21][N:20]=3)=[O:23])[CH2:78][CH2:77]2)[CH:72]=[N:71][CH:70]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccc(F)cc2)[nH]n1
Reactant: Clc1cncc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(Cc1ccc(F)cc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cc(-c2ccc(F)cc2)[nH]n1
Reaction time: 8 h
Yield: 53870.8 %

Procedure:
DIPEA (200 mg, 1.6 mmol) was added to a stirred solution of {[5-(4-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (120 mg, 0.45 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (4′-fluorophenyl)acetophenone) in DMF (2 mL) followed by HOBt (65 mg, 0.48 mmol) and EDCI.HCl (92 mg, 0.48 mmol). After 2 minutes 3-chloro-5-(piperidin-4-yloxy)-pyridine hydrochloride (0.114 g, 0.00045 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 111 mg (55.5% Yield) of 5-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 458, 97.78%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.3 (m, 1H), 8.21 (m, 1H), 8.04 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H), 7.3 (m, 2H), 7.1 (s, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 2H), 3.7 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Br:24])=[CH:30][N:29]=3)=[O:32])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(N)c2)COC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1

Procedure:
To an at 0° C. stirred solution of 105 mg (0.325 mmol) (R)-[5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester, 72 mg (0.357 mmol) 5-bromo-pyridine-2-carboxylic acid, 57 mg (0.422 mmol) HOAt and 82 mg (0.812 mmol) Et3N in 3 ml DCM were added 81 mg (0.422 mmol) EDC.HCl. After 18 h the mixture was diluted with EtOAc and washed with water, 5% aqueous NaHCO3 and brine. Chromatography on silica gel (hexane/EtOAc 3:1) gave the desired product as a colorless solid.
Reaction SMILES: FC1C=C(F)C=CC=1O.BrCCCCCCCCCO.[F:21][C:22]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C=C(F)C=CC=1OCCCCCCCCC(O)=O.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:23]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:22]=1[F:21])[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: OCCCCCCCCCOc1ccc(F)cc1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccc(F)cc1F
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccc(F)cc1F

Procedure:
The title compound, m/e=413.6 ([M−H]−), was produced in analogy with example 18, steps 1 to 4. Thus, 2,4-difluorophenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(2,4-difluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(2,4-difluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(2,4-difluoro-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: Br[CH:2]1[CH2:14][CH2:13][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[S:8][C:4]=2[C:3]1=O.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[S:19]>CO.[OH-].[O-2].[P-3].[Mo]>[C:17]([C:18]1[S:19][C:2]2[CH2:14][CH2:13][C:5]3[N:6]=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[S:8][C:4]=3[C:3]=2[N:20]=1)([CH3:22])([CH3:21])[CH3:16]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Reactant: CC(C)(C)C(N)=S
Agent: [Mo]
Agent: [O-2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1nc2c(s1)-c1nc(C(C)(C)C)sc1CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
N-(6-Bromo-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage T.3, 473 mg, 1.635 mmol) was dissolved in MeOH (10 mL), 2,2-dimethylthio propionamide (230 mg, 1.962 mmol) and ammonium phosphomolybdate (307 mg, 0.164 mmol) were added, and the RM was stirred at 25° C. for 20 h. The RM was then stood for 2 days before stirring at 50° C. for 24 h. The mixture was extracted with EtOAc/H2O. The organic layers were dried over Na2SO4 and evaporated. The crude material was chromatographed with 30 g of silica gel, eluent DCM/MeOH=99:1. Fractions containing the product were evaporated and lyophilized from dioxane to give 225 mg of the title compound as a white solid (M+H=308; M−H=306; tR 5.525 min (Method F)).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10])([O-])=O.N.[H][H]>C(O)C.[Ni]>[NH2:1][CH2:4][CH:5]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:6][P:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:11])[O:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccccc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC

Procedure:
A solution of 5.7 g of ethyl 3-nitro-2-phenylpropyl(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 50 g of an 8% solution of ammonia in ethanol. To this are added 9 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.4 ppm (CDCl3).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].[C:51]([C@@H:54]1[CH2:58][C@H:57]([SH:59])[CH2:56][N+:55]1([CH3:61])[CH3:60])(=[O:53])[NH2:52]>C(#N)C.O1CCCC1.P([O-])([O-])([O-])=O.[Pd]>[C:51]([C@@H:54]1[CH2:58][C@H:57]([S:59][C:32]2[C@H:33]([CH3:34])[C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]3[C:31]=2[C:36]([O-:38])=[O:37])[CH2:56][N+:55]1([CH3:61])[CH3:60])(=[O:53])[NH2:52]
Reactant: C[N+]1(C)C[C@@H](S)C[C@H]1C(N)=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(N)=O)[N+](C)(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h

Procedure:
0.20 ml of diisopropylethylamine and 0.24 ml of diphenylphosphoryl chloride were added dropwise, whilst ice-cooling, to a solution of 400 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 4 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time, 0.46 ml of diisopropylethylamine and a solution of the salt prepared in step (1) above in 3 ml of acetonitrile were added to the reaction mixture, whilst ice-cooling, and the mixture was then stirred for 7 hours and then allowed to stand for 2 days at the same temperature. The solvent was then distilled off under reduced pressure, and the residue was washed repeatedly by decantation using diethyl ether and dried under reduced pressure to afford a crude product. This crude product was then dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 555 mg of 10% w/w palladium-on-charcoal. At the end of this time, an insoluble material was removed by filtration with the help of a Celite (trade mark) filter aid, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure. The residue was adsorbed on a column of Diaion (trade mark) HP-20AG (Mitsubishi Chemical Industries, Ltd.) and the fractions eluted with a 5% by volume aqueous acetone solution were concentrated by evaporation under reduced pressure, and the residue was lyophilized to afford a crude product as a yellow powder. This crude product was purified by chromatography using a Lobar column (Merck Co., LiChroprep RP-8, size B). The fractions eluted with 5% and 10% by volume aqueous methanolic solutions were collected and concentrated by evaporation under reduced pressure, and the residue was lyophilized to afford 100 mg of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Product: O=C(C1CC1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 3.7 g (0.011 mol) of (--)-3-phenoxy-N-methylmorphinan in 50 ml of toluene, 5.8 g of cyclopropane carboxylic acid chloride in 25 ml of toluene was added dropwise at 5°. The mixture was allowed to warm to room temperature and was then refluxed for 15 hours. The solvent was removed in vacuo and the residue partitioned between ether and dilute hydrochloric acid. The ether solution was washed with water and dried. Removal of the solvent in vacuo afforded 4.2 g (99%) of (--)-3-phenoxy-N-cyclopropylcarbonylmorphinan. For analysis, a sample of this compound was distilled, bp 230°-240°/0.05 mmHg, [α]25D-173.45° (c 0.99, MeOH).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[B:20]1[O:24]C(C)(C)C(C)(C)[O:21]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(OCC)(=O)C.O.O1CCCC1>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:19]([B:20]([OH:21])[OH:24])=[C:9]([O:8][CH3:7])[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Yield: 89.3 %

Procedure:
Sodium metaperiodate (0.157 g) was added to a mixture of ethyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.075 g), water (1 mL) and tetrahydrofuran (4 mL) at room temperature with stirring, and the mixture was stirred at that temperature for 10 minutes. To the mixture was added 2 mol/L hydrochloric acid (0.082 mL), and the resulting mixture was stirred at that temperature for additional 2 hrs, then water and ethyl acetate were added. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-ethoxycarbonyl-2-methoxyphenylboronic acid (0.049 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:30]3[CH2:31][CH2:32][CH:28]([CH2:27][O:26][CH3:25])[CH2:29]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: COCC1CCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(methoxymethyl)pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.66 (m, 1H) 1.83-1.99 (m, 1H) 2.36 (s, 3H) 3.14 (s, 1H) 3.22 (s, 2H) 3.37-3.62 (m, 4H) 7.56-7.61 (m, 1H) 7.65 (s, 1H) 7.74 (d, J=8.1 Hz, 1H) 8.03-8.15 (m, 2H) 8.31 (d, J=8.3 Hz, 1H) 8.55-8.62 (m, 1H) 13.07 (br. s., 1H). MS m/z [M+H]+ 418.4.
Reaction SMILES: CO/[CH:3]=[C:4]1\[C:5](=[O:20])[N:6]([C:17](=[O:19])[CH3:18])[N:7]([C:14](=[O:16])[CH3:15])[C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][CH:9]=2.Cl.[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26][NH2:27].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[C:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)/[C:4](=[CH:3]/[NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:23]([OH:22])[CH:24]=2)/[C:5](=[O:20])[N:6]1[C:17](=[O:19])[CH3:18])(=[O:16])[CH3:15]
Reactant: CO/C=C1\C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Reactant: COc1ccc(CN)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CN/C=C2\C(=O)N(C(C)=O)N(C(C)=O)c3ccccc32)cc1O
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of (Z)-1,1′-(4-(methoxymethylene)-3-oxo-3,4-dihydrocinnoline-1,2-diyl)diethanone (0.18 g, 0.66 mmol) in tetrahydrofuran (5 mL) is added 3-hydroxy-4-methoxybenzylamine hydrochloride (0.13 g, 0.66 mmol). The suspension is treated with triethylamine (0.21 mL) and dimethylformamide (1 mL). The mixture is stirred at room temperature until LC/MS analysis revealed the consumption of the starting materials. Following concentration under reduced pressure, the crude mixture is purified by semi-preparative reverse-phase HPLC, employing a gradient elution from 40% acetonitrile in water with 0.1% trifluoroacetic acid to 70% acetonitrile in water over 60 minutes. The desired fractions were concentrated under reduced pressure to afford 0.14 g of (4Z)-1,2-diacetyl-4-{[(3-hydroxy-4-methoxybenzyl)amino]methylene}-1,4-dihydrocinnolin-3(2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23]O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:25])([CH3:26])[CH2:22][CH2:23][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
To a solution of 5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-ol (F15, 75 mg), phthalimide (93 mg) and triphenylphosphine (165 mg) in tetrahydrofuran (3.5 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (332 μL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 92 to 52% hexane in ethyl acetate) to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-yl)isoindoline-1,3-dione (F16, 129 mg) as pale yellow solid.