Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)[CH:4]=[N:3]1.C(O)(=[O:35])C.OO>O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:35])[CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)O
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cn1
Agent: OO
Solvent: O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 25 (1.00 g, 2.20 mmol), glacial acetic acid (5.0 mL), H2O (5.0 mL) and 30% aq. H2O2 (370 μL, 3.30 mmol) were stirred for 8 h and partitioned between AcOEt/brine. The layers were separated, the aqueous phase extracted with more AcOEt and the combined organic extracts dried (MgSO4) and concentrated to give 27 as a creamy white solid (731 mg, 96%); 1H NMR (400 MHz, CDCl3) δ-0.058 (s, 9H), 0.92 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 4.01 (s, 3H), 2.01 (s, 2H), 7.37 (s, 1H), 7.56 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 8.17 (d, J=2.2 Hz, 1H), 9.00-9.60 (bs, OH).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:61](=[O:62])[N:13]3[C:14]([C:45]([O:47]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:46])=[C:15]([S:18][CH2:19][CH2:20][C:21]4[CH:22]=[N:23][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:61](=[O:62])[N:13]3[C:14]([C:45]([OH:47])=[O:46])=[C:15]([S:18][CH2:19][CH2:20][C:21]4[CH:22]=[N:23][NH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCCc3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CS[C@H]12
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCCc3cn[nH]c3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a solution of benzhydryl 7β-(2-phenylacetamido)-3-[2-(1-tritylpyrazol-4-yl)ethylthio]-3-cephem-4-carboxylate (930 mg) in a mixture of dichloromethane (3 ml) and anisole (1 ml) was added trifluoroacetic acid (2 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diisopropyl ether (100 ml). The precipitate was collected by filtration. The precipitate was added a 90% formic acid (4 ml) and stirred for 15 minutes at room temperature. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and ice-water (50 ml). The separated organic layer was added buffer solution (pH 6.86, 100 ml), adjusted to pH 7 with sodium bicarbonate. The separated aqueous layer was added ethyl acetate (60 ml) and tetrahydrofuran (30 ml), adjusted to pH 2.5 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β-(2-phenylacetamido)-3-[2-(pyrazol-4-yl)ethylthio]-3-cephem-4-carboxylic acid (275 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@@H:17]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(O)=O.C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1CC[C@@H](c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 113.9 %

Procedure:
(S)-tert-Butyl 3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate (456 mg, 1.12 mmol, Eq: 1.00) was dissolved in a mix of formic acid (20.0 ml) and formaldehyde, 37% (40 ml). The reaction mixture stirred at 70° C. for 18 h. The solution was cooled to room temperature and water was added. The aqueous solution was extracted once with DCM. The aqueous layer was Brought to pH=14 with solid K2CO3. A solid formed and was filtered to give (S)-6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (408 mg, quantitative yield). LC/MS-ESI observed [M+H]+ 320.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:15])=[O:7])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Product: O=C(Cl)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 2-nitrobenzoic acid (5 g) and thionyl chloride (5 ml) was heated under reflux for 30 minutes and then concentrated in vacuo. The residue was dissolved in dry toluene (20 ml) and the volatile material was evaporated. This procedure was repeated. The 2-nitrobenzoyl chloride thus obtained was dissolved in methylene chloride (20 ml). This solution was then added to a solution of 3-(aminomethyl)pyridine (3.24 g) and triethylamine (3.03 g) in methylene chloride (50 ml) at 0° C. After the addition was complete, the reaction mixture was washed with water, dried (MgSO4) and evaporated to give 3-(N-(2-nitrobenzoyl)aminomethyl)pyridine as a solid of satisfactory purity and in essentially quantitative yield.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:17]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)=[CH:8][CH:9]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
0.30 g (7.50 mmol) of 60% strength sodium hydride are added in portions to 0.86 g (5.00 mmol) of 2-(4-hydroxyphenyl)pyrimidine in 40 ml of dimethylformamide, and the mixture is stirred at room temperature for 15 minutes. 1.45 g (7.50 mmol) of 1-bromooctane are subsequently added, the mixture is stirred overnight, poured into ice water and filtered, and the residue is purified by chromatography (silica gel/dichloromethane) and by recrystallization from acetonitrile, giving 0.93 g of 2-(4-octyloxyphenyl)pyrimidine. ##STR32##
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C@H:35]1[CH2:41][N:40]2[C:42]([CH:45]=[O:46])=[CH:43][N:44]=[C:39]2[C@H:38]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:37][CH2:36]1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C@H:35]1[CH2:41][N:40]2[C:42]([CH:45]([OH:46])[C:2]([F:4])([F:3])[F:1])=[CH:43][N:44]=[C:39]2[C@H:38]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:37][CH2:36]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C(F)(F)F)cnc21
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
(Trifluoromethyl)trimethylsilane (0.5 M in tetrahydrofuran; 2.15 mL, 1.07 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 0.107 mL, 0.107 mmol) were sequentially added to neat tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (0.14 g, 0.36 mmol). After 15 min, the reaction mixture was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (110 mg). MS 462.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]C(C)(C)C)=[O:32])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)cc1
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 39 (0.51 g, 1.02 mmol) in CH2Cl2 (5 mL) at 0° C. was added TFA (5 mL) and the mixture was stirred for 1 h. Solvent was evaporated and coevaporated with CH2Cl2 (2×10 mL) and the residue dissolved in EtOAc and washed with water (2×10 mL). The organic layer was dried (Na2SO4) and evaporated. The residue was triturated with hexanes, filtered, and dried in vacuo to provide 37 (0.43 g, 96%) as an off-white solid. 1H NMR and MS as described in Example 23. Anal. calculated for C28H26O5: C, 76.00; H, 5.92; Found: C, 75.90; H, 6.12.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][CH:12]2[C:11](=[O:19])[CH:10]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]3[CH2:31][NH:30]3)=[CH:28][C:23]=2[O:22][CH2:21]1>O1CCCC1>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]3[CH2:31][N:30]3[C:9]3[CH:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][CH:12]4[C:11](=[O:19])[CH:10]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: c1cc2c(cc1C1CN1)OCO2
Reactant: CC1(C)OC2C(=O)C=C(Cl)C2O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OC2C(=O)C=C(N3CC3c3ccc4c(c3)OCO4)C2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Triethylamine (0.4 mL, 3.0 mmol, 2.0 equiv) and β-chloroenone 53 (280 mg, 1.5 mmol, 1.0 equiv) were sequentially added to a stirred solution of aziridine 15 (360 mg, 2.2 mmol, 1.5 equiv) in tetrahydrofuran (10 mL) at 25° C. The resulting white mixture was stirred at 25° C. for 3 h. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (1% triethylamine and 49% benzene in ethyl acetate) to afford 54 (400 mg, 85% yield) as a yellow foam. Rf=0.68 (1% triethylamine and 49% benzene in ethyl acetate); 1H NMR (500 MHz, C6D6) δ 6.55-6.70 (m, 3H, ArH), 5.24-5.28 (m, 2H, OCH2O), 5.14-5.18 (m, 1H, NCCH), 4.50-4.56 (m, 1H, CH(OR)), 4.19-4.27 (m, 1H, CH(OR)), 2.46-3.18 (m, 1H, ArCHN), 1.84-2.17 (m, 1H, CH2N), 1.63-1.78 (m, 1H, CH2N), 1.28-1.32 (m, 3H, CH3), 1.10-1.12 (m, 3H, CH3); IR (neat film) 2989 (w), 1703 (m), 1586 (s) cm−1; HRMS (ESI) m/z: Calcd for C17H18NO5 (MO 316.1185; observed 316.1186.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]2=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=[CH:18][N:4]2[N:3]=1.[C:25]([NH:29][S:30]([C:33]1[C:34]([CH:48]([F:50])[F:49])=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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].C(Cl)Cl>[C:25]([NH:29][S:30]([C:33]1[C:34]([CH:48]([F:49])[F:50])=[N:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[C:5]3=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[CH:18][N:4]3[N:3]=2)[CH:38]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cnc1C(F)F
Temperature: 100 °C
Yield: 71.4 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.500 g, 1.49 mmol) and N-(tert-butyl)-2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.697 g, 1.79 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added K2CO3 (0.412 g, 2.98 mmol). The reaction mixture was purged with nitrogen gas for 10 min. Then PdCl2(dppf)-CH2Cl2 (0.122 g, 0.149 mmol) was added and heated at 100° C. for 1 h in micro wave. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was filtered through CELITE® bed and the bed was washed with EtOAc (2×50 mL). The filtrate was diluted with water (50 mL) and extracted with EtOAc (100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 40% EtOAc/hexanes) to obtain N-(tert-butyl)-2-(difluoromethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.600 g, 71.5% yield) as a pale yellow solid. LCMS Condition B-83: retention time 1.84 min, [M+1]=564.0. 1H NMR (400 MHz, CD3OD) δ ppm 1.26 (s, 9H), 4.94 (s, 2H), 6.81 (d, J=2.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.44-7.55 (m, 3H), 7.59-7.63 (m, 4H), 7.77-7.82 (m, 2H), 8.43 (d, J=4.4 Hz, 1H), 9.19 (dd, J=2.0 Hz, J=1.2 Hz, 1H), 9.64 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To methyl 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.36 g) dissolved in THF (10.8 ml)/methanol (5.4 ml) was added a 1 N aqueous solution (2.4 ml) of sodium hydroxide, and the resulting mixture was stirred at 65° C. for 16 hours. After cooling to the room temperature, the reaction mixture was concentrated under reduced pressure to remove a half of the solvent. A 1 N aqueous solution (3.0 ml) of sodium hydroxide was added to the resulting mixture, which was washed with ethyl acetate. After being adjusted to pH=about 5 with a 1 N aqueous solution of hydrochloric acid, the resulting aqueous layer was extracted with ethyl acetate, and the extract was washed with an aqueous saturated solution of sodium chloride and was then dried with magnesium sulfate. After evaporation to remove the solvent, the resulting residue was washed with hexane/ethyl acetate (=8/1) to obtain 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.27 g).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].[OH-].[Li+].Cl>C(O)C.O1CCCC1.O>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:19])[CH3:20])=[O:6]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OCC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)COC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A solution of 6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylic acid 2,2-dimethylpropyl ester (Intermediate 49, 0.198 g, 0.42 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL) was treated with 1N lithium hydroxide (1.5 mL, 1.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a greenish-yellow solid (0.16 g, 84%).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:25])[CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=CC=1)([O-])=O.[NH2:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30]>>[C:15]([NH:14][CH2:13][CH2:12][C:11]([NH:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30])=[O:25])([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(CCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCS(=O)(=O)O
Product: O=C(CCNC(=O)OCc1ccccc1)NCCS(=O)(=O)O
Yield: 81.7 %

Procedure:
1.9 g (5.5 mmoles) of N-carbobenzoxy-β-alanine-p-nitrophenyl ester (Biochemistry 4, 1884 1965) are reacted with 0.63 g (5 mmoles) of taurine as described in Example 1 to obtain 1.35 g (82%) of N-carbobenzoxy-β-alanyl-taurine.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31].CCCCCC>ClCCl>[N+:30]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 8 h
Yield: 92088.6 %

Procedure:
Triethylamine (66.8 g, 0.66 mmol) was added to a solution of tert-butyl (N-2-aminoethyl)carbamate (55.0 g, 0.34 mmol) in anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline (68.2 g, 0.33 mmol) was slowly added. The reaction mixture exothermed. The reaction mixture was allowed to stir overnight The resulting precipitate was isolated by filtration and rinsed with water to provide a yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated to provide a yellow solid. The two batches of solid were combined, slurried with hexane, filtered and then dried to provide 101 g of 1,1-dimethylethyl N-{2-[(3-nitroquinolin-4-yl)amino]ethyl)carbamate as a yellow solid.
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH:31]=[CH:30][C:13]=3[N:14]=[C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH3:19])[N:16]=2)C2C=CC=CC=2N=N1.[CH:41]1(O)[CH2:43][CH2:42]1>COCCOC>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]2[CH:31]=[CH:30][C:13]3[N:14]=[C:15]([NH:17][C@@H:18]([C:20]4[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=4)[CH3:19])[N:16]=[C:11]([O:10][CH:41]4[CH2:43][CH2:42]4)[C:12]=3[N:33]=2)=[CH:35][CH:36]=1
Reactant: OC1CC1
Reactant: C[C@@H](Nc1nc(On2nnc3ccccc32)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Solvent: COCCOC
Product: C[C@@H](Nc1nc(OC2CC2)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (R)-4-(1-(4-(1H-benzo[d][1, 2, 3]triazol-1-yloxy)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (80 mg), cyclopropanol (0.1 ml) and CsCO3 (94 mg) in DME (3 ml) was stirred at room temperature over the weekend. The reaction mixture was concentrated and purified by reverse phase HPLC (eluting with ACN/H2O+0.1% TFA) to give the title compound, which was characterized by its NMR and mass spectrum as follows: 1H NMR (CD3OD): d 0.83-1.04 (m, 4H), 1.66-1.70 (m, 3H). 4.50-4.58 (m, 1H), 5.40-5.49 (m, 1H), 7.19 (t, 2H), 7.61-7.88 (m, 4H), 7.99-8.02 (m, 1H), 8.08-8.13 (m, 2H), 8.30 (s, 1H); MS (m/z): 480.3 ([M+H]+, 100).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([O:5][C:6]2([CH3:9])[CH3:8])=[O:4].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:1][CH:7]1[C:6]([CH3:8])([CH3:9])[O:5][C:3](=[O:4])[CH2:2]1)(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)Cl
Reactant: CC1(C)OC(=O)C2OC21
Product: C=CC(=O)OC1CC(=O)OC1(C)C
Yield: 87 %

Procedure:
The obtained 3-hydroxy-4,4-dimethyl-γ-butyrolactone was allowed to react with acrylyl chloride in the same manner as in Production Example 16 to thereby yield the title compound (yield: 87%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:21])=[C:5]2[C:12](I)=[C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:10][C:6]2=[N:7][C:8]=1[CH3:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.O.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>[CH2:1]([C:3]1[C:4]([CH3:21])=[C:5]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:10][C:6]2=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(C)nc2sc(C(=O)OC(C)(C)C)c(I)c2c1C
Reactant: COc1ccc(B(O)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: COCCOC
Solvent: O
Product: CCc1c(C)nc2sc(C(=O)OC(C)(C)C)c(-c3ccc(OC)cc3)c2c1C
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a solution of compound tert-butyl 5-ethyl-3-iodo-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (42 mg, 0.1 mmol) in 0.5 mL of DME/H2O (1/1) was added K2CO3 (41 mg, 0.3 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), p-methoxyphenyl boronic acid (18 mg, 0.12 mmol). The mixture was then heated to reflux for 16 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved with ethyl acetate (2 mL), washed with water (2 mL×3), brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude solid was purified by preparative HPLC to provide t-butyl 5-ethyl-3-(4-methoxy-phenyl)-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (12 mg, 30%).
Reaction SMILES: [C:1]([C:4]1[N:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)=[N:13][C:10]=3[O:11][CH2:12][C:7]2=[N:6][N:5]=1)(=[O:3])[NH2:2].CO>ClCCl>[NH2:33][C:29]1([C:26]2[CH:27]=[CH:28][C:23]([C:14]3[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:9]4[N:8]5[C:4]([C:1]([NH2:2])=[O:3])=[N:5][N:6]=[C:7]5[CH2:12][O:11][C:10]=4[N:13]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(N)=O)CO4)cc2)CCC1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 15 h
Yield: 60 %

Procedure:
Tert-butyl (1-(4-(1-carbamoyl-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.019 mmol) was dissolved in dichloromethane (0.5 ml); this solution was added to a scx-2 catch and release cartridge (1 g), precalibrated using methanol (15 ml) and dichloromethane (15 ml). After allowing to binding for 15 hours, the column was washed with methanol (6 ml) and then the product eluted with 7M ammonia in methanol (4 ml×2). The combined product fractions were concentrated to dryness under reduced pressure to give the desired product as a white solid (5 mg, 61% yield). LCMS (Method D) RT=0.695 min, M+1=440. 1H-NMR (500 MHz, CD3OD) δ 8.80 (1H, s), 7.27-7.24 (4H, bs), 7.22-7.17 (3H, m), 7.16-7.13 (2H, m), 5.57 (2H, s), 2.49-2.38 (2H, m), 2.19-2.10 (2H, m), 2.03-1.92 (1H, m), 1.71-1.60 (1H, m).