Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][CH2:6][C:7](=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.OS(O)(=O)=O.O>[CH2:16]([O:15][C:13](=[O:14])[C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:20])[CH2:6][CH2:5][CH2:4][C:3]([CH3:21])([CH3:22])[C:2]([OH:24])=[O:1])[CH3:17]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCC(C)(C)CO
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)CCCCC(=O)CCCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 46 h
Yield: 78.8 %

Procedure:
A mixture of 221 (3.26 g, 10.4 mmol) and pyridinium dichromate (14.0 g, 37.2 mmol) in DMF (45 mL) was stirred at room temperature for 46 h. The solution was diluted with 48% H2SO4 (30 mL) and water (300 mL) and extracted with ethyl acetate (5×100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (5×100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (3.19 g) as greenish oil. The crude product was subjected to column chromatography (silica gel; hexanes/ethyl acetate=3:1, 2:1), affording 223 (2.69 g, 79%) as a pale yellow oil. 1H NMR (CDCl3): δ 11.30 (br., 1H), 4.10 (q, 2H, J=7.2), 2.39 (t, 4H, J=7.2), 1.56-1.48 (m, 8H), 1.25-1.15 (m, 2H), 1.24 (t, 3H, J=7.2), 1.20 (s, 6H), 1.15 (s, 6H). 13C NMR (CDCl3): δ 210.9, 184.4, 178.1, 60.4, 43.1, 42.7, 42.2, 40.5, 39.8, 25.3, 25.0, 24.7, 24.3, 19.3, 14.4. HRMS (LSIMS, gly): Calcd for C18H33O5 (MH+): 329.2328, found: 329.2330.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Br[CH2:20][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:14]([O:13][C:12]([NH:11][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:2]=1[O:1][CH2:20][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:25][CH:26]=1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cc1O)CCC2
Reactant: CCOC(=O)c1cnc(CBr)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(COc2cc3c(cc2NC(=O)OC(C)(C)C)CCC3)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
1.00 g of tert-butyl (6-hydroxy-2,3-dihydro-1H-inden-5-yl)carbamate was dissolved in 10.0 mL of DMF, and 1.08 g of ethyl 5-(bromomethyl)pyrazine-2-carboxylate and 721 mg of potassium carbonate were added thereto, followed by stirring at 60° C. for 1 hour. The reaction liquid was poured into a 5% w/v aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a 5% w/v aqueous citric acid solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to obtain 690 mg of ethyl 5-[({6-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}oxy)methyl]pyrazine-2-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:33]([N:35]([CH2:36][CH3:37])[C:15]([CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:30])([F:32])[F:31])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:16])[CH3:34]
Reactant: CCNCC
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid diethylcarbamoylmethyl-amide (48 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), diethylamine (0.2 ml), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 522. 1H NMR (DMSO-d6, 400 MHz): δ 8.45 (t, 1H), 8.08 (s, 1H), 7.90 (m, 2H), 7.78 (br, 1H), 7.66 (br, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 4.13 (d, 2H), 3.66 (s, 3H), 3.38-3.28 (m, 4H), and 1.05 (t, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[CH:7][C:6]([NH:9]C(OC(C)(C)C)=O)=[C:5]([C:17]([F:20])([F:19])[F:18])[CH:4]=1.C(OCC)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:1][N:2]([CH3:21])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:4]=1
Reactant: CN(C)c1cc(C(F)(F)F)c(NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)c1cc(C(F)(F)F)c(N)cn1

Procedure:
A solution of 0.73 g (2.39 mmol) of 6-dimethylamino-4-trifluoromethyl-3-(tert-butoxycarbonylamino)pyridine, prepared in stage 10.3, in 8.5 ml of 4N hydrochloric acid in dioxane is stirred at reflux for 5 hours. 200 ml of ethyl ether are subsequently added to the cooled reaction mixture. 0.6 g of a precipitate is collected by filtration.
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=4[F:42])=[O:30])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1.ClCCCl.[CH3:48][N:49]([CH3:53])[C:50](Cl)=[O:51]>O1CCCC1>[NH2:3][C:4]1[C:9]2=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=4[F:42])=[C:24]([F:43])[CH:23]=3)[C:11]([CH2:19][O:20][CH3:21])=[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:50]([N:49]([CH3:53])[CH3:48])=[O:51])[CH2:15][CH2:14]3)[N:8]2[N:7]=[CH:6][N:5]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Reactant: CN(C)C(=O)Cl
Agent: N#N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCN(C(=O)N(C)C)CC1
Temperature: 0 °C
Yield: 17.8 %

Procedure:
To a flask charged with N2 was added 1-{4-[4-amino-6-(methoxymethyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (Example 149) (30 mg, 0.052 mmol, 1.0 eq) and 1,2-dichloroethane (2 mL). Tetrahydrofuran was added dropwise until the reaction mixture was a complete solution. The solution was cooled to 0° C. and dimethylcarbamoyl chloride (4.7 μl, 1 eq) was added. The reaction mixture was allowed to gradually warm to rt over 17 hours. The reaction was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and purified via flash column chromatography (6:4 tetrahydrofuran/hexanes). The purified fractions were collected, concentrated, stirred in hexanes and filtered. The filtrate was placed under vacuum overnight to yield the title compound (6 mg, 17.8% yield). 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.65 (d, J=6.5 Hz, 1H), 8.29 (t, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.41 (m, 1H), 7.29 (dd, J=12.3, 1.7 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 4.23 (s, 2H), 3.68 (m, 2H), 3.44 (m, 1H), 3.16 (s, 3H), 2.75 (s, 6H), 2.26 (m, 2H), 1.64 (m, 2H); MS [M+H]+=647; LCMS RT=3.03 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2.C1CCN2C(=NCCC2)CC1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])[NH:7]2
Reactant: BrCc1ccccc1
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2[nH]c(C(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2.65 g of 4-methoxyindole-2-carboxylic acid are dissolved in 15 ml of DMF, 2.11 g of DBU are added and the mixture is then stirred at RT for 1 hour. 2.61 g of benzyl bromide are added dropwise at RT and this mixture is stirred for 5 hours at RT. The mixture is concentrated under vacuum and the residue is taken up in EtOAc, washed with water, with saturated Na2CO3 solution, with sulphate buffer and then with saturated aqueous NaCl. This solution is dried over Na2SO4 and concentrated. 3.57 g of the expected compound are obtained, which product crystallizes from pentane: m.p.=162-164° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]2[C:30]3([CH2:36][O:37][C:26]=2[CH:25]=1)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][C:30]2([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=3[O:37][CH2:36]2)[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC2(CC1)COc1cc(F)ccc12
Yield: 77.8 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.193 g, 0.556 mmol) obtained in Example 22, step 3 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.150 g, 0.616 mmol) obtained in Reference Example 4, the title compound (0.232 g, 77%) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][O:12][CH3:13])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>O1CCCC1.O>[OH:4][C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:2]([NH:1][CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:11][O:12][CH3:13]
Reactant: COC[C@H](N)[C@@H](O)c1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H](NCCCS(=O)(=O)O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (1S,2S)-2-amino-3-methoxy-1-phenyl-1-propanol (1.0 g, 5.5 mmol) in tetrahydrofuran (10 mL) was slowly added 1,3-propane sultone (662 mg, 5.3 mmol). The mixture was stirred at reflux for 2.5 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration and dried in a vacuum oven (50° C.), to afford compound EG (1.0 g, 63%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.77 (d, 1H, J=9.8 Hz), 3.53 (m, 1H), 3.37 (m, 1H) 3.26 (m, 1H), 3.17 (m, 6H), 2.91 (t, 2H, J=7.3 Hz), 2.07 (m, 2H). 13C NMR D2O, 125 MHz) δ ppm 139.09, 129.33, 129.27, 127.11, 70.85, 66.29, 62.62, 58.76, 48.14, 44.24, 21.47. [C]D=+42.6° (c=0.00091 in water), ES-MS 302 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:21]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:21]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:29]2)[N:20]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(F)cc4)ccc3C#N)C2)nc1N
Temperature: 120 °C

Procedure:
55 mg (0.24 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 74 mg (0.28 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 11A) and 0.206 ml (1.18 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 47 mg (48% of theory) of the product were obtained in solid form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A suspension of 3-fluoro-4-hydroxybenzonitrile (1.2 g, 8.76 mmol), anhydrous K2CO3 (2.43 g, 17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=5/1), gave 1.52 g (71%) of the subtitle compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=9.2 Hz, 1H), 7.40 (d, J=12.0 Hz, 1H), 7.03 (dd, J=8.0 Hz, 8.4 Hz, 1H), 4.42 (t, J=6.2 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:16][CH:17]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isatin (2.5 g, 0.017 mol) in anhydrous DMF (50 ml) was cooled to 0° C. under a nitrogen atmosphere and treated with sodium hydride (0.5 g, 1.2 equivalents). A purple solution was formed which was stirred at 0° C. for 30 minutes and then warmed to room temperature. 4-Bromoanisole (2.13 ml, 1 equivalent) was added followed by copper iodide (6.46 g, 2 equivalents). The reaction was heated in an oil-bath at 145° C. for 7 hours. The reaction was then cooled to room temperature and diluted with an equal volume of ethyl acetate. This suspension was filtered and the filtrate was evaporated to dryness. TLC (1:4, ethyl acetate:hexanes) indicated a very clean reaction; Rf (product)=0.5. The crude material was used as such for the next reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][CH:16]1[C:29](=[O:30])[N:18]2[CH:19]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:20]([CH3:23])([CH3:22])[S:21][C@H:17]12.[K+].[Br-]>C(N(CC)CC)C>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:15][CH:16]1[C:29](=[O:30])[N:18]2[CH:19]([C:24]3[NH:25][N:26]=[N:27][N:28]=3)[C:20]([CH3:22])([CH3:23])[S:21][C@H:17]12)=[O:14]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: NCCOc1ccccc1CC(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3OCCN)C(=O)N2C1c1nnn[nH]1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield from 2-(2-[2-aminoethoxy]phenyl)acetic acid (U.S. Pat. No. 3,759,905) and 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, by a procedure analogous to that of Example LXXXV. IR (KBr disc): 1780 cm-1 (β-lactam) and 1667 cm-1 (amide I). NMR (in D2O): 7.1 ppm (m, 4H), 5.7 ppm (d, 1H), 5.5 ppm (d, 1H), 5.2 ppm (s, 1H), 3.7-3.3 ppm (m, 4H), 3.1 ppm (q, 12H), 1.6 ppm (s, 3H), 1.2 ppm (t, 18H), 1.0 ppm (s, 3H). The product is a 1:2 complex of the title compound and triethylamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[C:12](O)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:9]([O:8][P:4]([CH2:3][CH2:2][NH:1][C:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:19])([O:5][CH2:6][CH3:7])=[O:11])[CH3:10]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOP(=O)(CCNC(=O)c1ccncc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
A mixture of diethyl 2-aminoethylphosphonate (12.5 g), isonicotinic acid (10.2 g), 1-hydroxybenzotriazole 11.2 g), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (15.83 g) and dichloromethane (190 ml) was stirred at room temperature for 15 hours. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried over anhydrous, magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (5% methanol-chloroform) to give 7.94 g of N-(2-diethoxyphosphorylethyl)-4-pyridinecarboxamide as an oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(O)(=O)C.C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200.1 %

Procedure:
A solution of 4 N hydrochloric acid in acetic acid (2 mL) was added to a solution of tert-butyl N′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (300 mg) in ethyl acetate (2 mL), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 250 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:28](OCC)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al].[Li]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:28][OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1
Agent: [Al]
Agent: [Li]
Product: OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole-2-carboxylate (step 3 of Example 1) and lithium aluminum in substantially the same manner, as described in step 1 of Example 21. The product was obtained as a white solid, mp: 108-109° C. Mass spectrum (ESI, [M+H]+) m/z 398. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.76 (d, 2H, J=8.86 Hz), 7.42-7.36 (m, 4H), 7.29 (d, 1H, J=7.03 Hz), 7.27 (d, 1H, J=7.63 Hz), 7.23-7.20 (m, 1H), 7.06 (d, 2H, J =7.03 Hz), 6.52 (s, 1H), 5.50 (s, 2H), 5.36 (t, 1H), and 4.60 ppm (d, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]3[CH2:22][O:21][CH2:20][C@H:19]([CH2:23]O)[N:18]3[C:14]=2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[OH-].[Na+]>C(#N)C>[Cl:3][CH2:23][C@@H:19]1[N:18]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=[C:6]([NH2:5])[C:15]=3[N:16]=[C:17]2[CH2:22][O:21][CH2:20]1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](CO)COC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](CCl)COC1
Temperature: 70 °C
Yield: 62.2 %

Procedure:
Thionyl chloride (1.5 mL, 20.7 mmol) was added neat to [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methanol (280 mg, 1.03 mmol). The nearly homogeneous yellow reaction mixture was heated to 70° C. for 2 hours and turned dark red. The reaction mixture was cooled to ambient temperature and poured over ice. While maintaining the temperature at 0° C., the pH of the mixture was brought to 14 by addition of 50% aqueous NaOH. The resulting white suspension was extracted with CHCl3. The layers were separated and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide a tan foam. The tan foam was slurried with acetonitrile and filtered to provide 185 mg of the desired product as a white solid, mp 230-232° C.
Reaction SMILES: [CH3:1][CH:2]([C:16](N)=[O:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1.C(Cl)(=O)C(Cl)=[O:21]>C(Cl)Cl.ClCCCl>[CH3:1][CH:2]([C:16]([OH:17])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(N)=O)c1ccc(-c2ccccc2)c(F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of flurbiprofen amide (3.0 g, 12.33 mmol) in DCM (70 mL) was added oxalyl chloride (1.87 g, 14.79=101) at 0° C. and refluxed for 16 h. Reaction mixture was cooled to RT and treated with LI-2b (2.45 g, 12.33 mmol) in DCE (10 mL) and stirred overnight. After usual aqueous work-up and chromatographic purification, 0.5 g of I-C1-NOPD14a were obtained. 1H NMR (CDCl3, 300 MHz): δ 1.55 (d, 3H, J=6.9 Hz), 2.94-2.97 (bs, 4H), 4.38-4.47 (bs, 3H), 4.68 (t, 2H, J=6.6 Hz), 7.13-7.55 (bs, 8H) MS: ES+ m/z 469.03[M+H]+, 467.16 [M−H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C@H:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[CH:5][CH:4]=1)=[O:2].[C:17]([C@@H:21]([C@H:23]([C:25]([O:27][CH3:28])=[O:26])[OH:24])O)([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:14]([C@H:12]1[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]3[O:24][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[C@H:21]([C:17]([O:19][CH3:20])=[O:18])[O:2]3)=[CH:8][CH:7]=2)=[N:13]1)([CH3:16])[CH3:15]
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: CC(C)[C@H]1COC(c2ccc(C=O)cc2)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(c2ccc(C3=N[C@@H](C(C)C)CO3)cc2)O[C@H]1C(=O)OC
Reaction time: 2.5 h

Procedure:
A solution of 0.8 g of (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline and 1 g of dimethyl L(+)-tartrate in 50 ml of toluene is treated with 0.1 g of toluene-4-sulphonic acid. The mixture is heated to boiling for 2.5 hours and the water formed is distilled off simultaneously. Then, 4 drops of triethylamine are added to the reaction mixture. After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol gives pure dimethyl (4R,5R)-2-(4-[(S)-4-isopropyl-2-oxazolinyl]phenyl)-1,3-dioxolane-4,5-dicarboxylate