Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:29])=[CH:24][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: O=C(c1ccc(O)cc1)c1ccc2ccccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc4ccccc4c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (4-Hydroxy-phenyl)-naphthalen-2-yl-methanone from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C30H28O6 [M+H]+: 485.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccsc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccsc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Chlorosulfonic acid (ClSO3H, 2.31 g, 19.62 mmol) was slowly added at 0° C. to a solution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHCl3 (80 ml) The resulting mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, at room temperature, the residue was suspended in POCl3 (15 ml, 156.96 mmol), and PCl5 (8.2 g, 39.24 mmol) was added slowly. The reaction was stirred at 60° C. for 18 h, then cooled to room temperature and poured onto crushed ice (200 g). The aqueous mixture was extracted with CHCl3 (2×150 ml) and the combined organic layers was dried (MgSO4). The solid was removed by filtration and the filtrate was concentrated to give 3-methoxy-2-thiophenesulfonyl chloride as a brown oil (1.81 g, 43% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.0 g (3.35 mmole) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 1.15 g (13.4 mmole) of piperazine, 1.36 g (13.35 mmole) of triethylamine and 60 ml of acetonitrile is refluxed for three hours and then stirred at room temperature for 16 hours. The precipitate is removed by filtration, washed with acetonitrile and dried in vacuo at 60° C. to give 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, mp 257°-259° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Yield: 85.2 %

Procedure:
To a solution of 2-bromo-5-nitropyridine (DM) (302 mg, 1.49 mmol) in a mixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid (LXXII) (199 mg, 1.64 mmol), Pd(PPh3)4 (86 mg, 0.74 mmol) and K3PO4 (473 mg, 2.23 mmol). The reaction was microwaved at 95° C. for 1 h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane→5:95 EtOAc:hexane) to give 5-nitro-2-phenylpyridine (LXXIII) as off-white needles (254 mg, 1.27 mmol, 85% yield). ESIMS found for C11H8N2O2 m/z 200.9 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][S:16][CH3:17])=[O:12].[CH3:20][C:21]1[CH:27]=[C:26]([CH:28]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[N:31]2)[CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:18][C:14]([NH:13][C:11](=[O:12])[C:3]1[C:4](=[CH:8][CH:9]=[CH:10][C:2]=1[I:1])[C:5]([NH:23][C:22]1[CH:24]=[CH:25][C:26]([CH:28]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[N:31]2)[CH3:29])=[CH:27][C:21]=1[CH3:20])=[O:7])([CH3:19])[CH2:15][S:16][CH3:17]
Reactant: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)O
Reactant: Cc1cc(C(C)n2ccc(C(F)(F)F)n2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(C(C)n2ccc(C(F)(F)F)n2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
3-Iodo-N-(1,1-dimethyl-2-methylsulfanyl-ethyl)-phthalamic acid (0.39 g) and N-(3-dimethylaminopropyl)-N1-ethylcarbonyl diimidazole hydrochloride (0.19 g) were stirred in dichloromethane (10 ml) at room temperature for 30 minutes. Then, 2-methyl-4-[1-(3-trifluoromethyl-1H-pyrazol-1-yl)-ethyl]-aniline (0.30 g) and p-toluenesulphonic acid monohydrate (0.02 g) were added thereto and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain N2-(1,1-dimethyl-2-methylsulfanyl-ethyl)-3-iodo-N1-{2-methyl-4-[1-(3-trifluoromethyl-1H-pyrazol-1-yl)-ethyl]-phenyl}-phthalamide (0.38 g) (compound No. 558). mp. 79-86° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:35]
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([O:9][N+:10]([O-:12])=[O:11])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:13].[CH2:14]([O:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:20]2[C:59]([C:63]([O:65][C:66]([CH3:81])([O:68][C:69](OC3C=CC([N+]([O-])=O)=CC=3)=[O:70])[CH3:67])=[O:64])=[CH:60][CH:61]=[CH:62][C:19]=2[N:18]=1)[CH3:15]>CN(C)C1C=CN=CC=1.ClCCl.CO.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:14]([O:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:20]2[C:59]([C:63]([O:65][C:66]([O:68][C:69]([O:13][C@H:2]3[CH2:1][O:5][CH:4]4[C@H:6]([O:9][N+:10]([O-:12])=[O:11])[CH2:7][O:8][CH:3]34)=[O:70])([CH3:81])[CH3:67])=[O:64])=[CH:60][CH:61]=[CH:62][C:19]=2[N:18]=1)[CH3:15]
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CO
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)O[C@H]3COC4C3OC[C@H]4O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Isosorbide-5-mononitrate (0.203 g, 1.06 mmol) was added to a stirred solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (Intermediate 1, 0.800 g, 0.883 mmol), 4-dimethylaminopyridine (0.162 g, 1.33 mmol) and scandium trifluoromethanesulfonate (0.087 g; 0.177 mmol) in dichloromethane (12 mL). The solution was stirred at room temperature for 24 hours. Then the mixture was diluted with dichloromethane, washed with aqueous sodium dihydrogenphosphate (20 mL) and brine (20 mL); the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 40+M; TLC method: n-hexane/ethyl acetate: 6/4; Rf=0.33) to afford a solid that was dissolved in methanol (8 mL). The mixture was stirred at 40° C. for 5 hours, at 60° C. for 2 hours, and at room temperature for 18 hours. Then the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 25+M; dichloromethane/methanol: 98/2), affording the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, 1H), 7.69-7.58 (m, 2H), 7.48 (d, 1H), 7.31 (d, 1H), 6.88 (t, 1H), 6.80 (d, 2H), 6.76-6.62 (m, 3H), 5.60 (s, 2H), 5.41-5.33 (m, 1H), 5.03 (d, 1H), 4.95 (t, 1H), 4.48 (d, 1H), 4.36-4.15 (m, 2H), 4.10-3.86 (m, 3H), 1.62 (d, 614) 1.43 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]2)([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[SH:21][CH2:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[OH:25][CH2:24][CH2:23][CH2:22][S:21][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]2)([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: OCCCS
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCCC(CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCCO)cc1)N1CCCC(CO)C1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
22.4 g of 1-(4-chloro-phenyl)-2-(3-hydroxymethyl-piperidin-1-yl)-2-methyl-propan-1-one, 8.39 g of 3-mercaptopropanol and 21.0 g of potassium carbonate are mixed in 75 ml of dried dimethylacetamide. After stirring for 18 h at 80° C., the mixture is filtered to remove solids and poured into ice-water. The crude product is extracted with ethyl acetate, washed with saturated NaCl solution and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (40:60) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.02 (m, 1H), 1.29 (s, 3H), 1.30 (s, 3H), 1.52-1.77 (m, 6H), 1.95 (m, 2H), 2.05 (t, 1H), 2.27 (t, 1H), 2.67 (d, 1H), 2.86 (d, 1H), 3.12 (t, 2H), 3.44 (m, 2H), 3.78 (m, 2H), 7.28 (d, 2H), 8.48 (d, 2H).
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:13](=[O:15])[CH3:14].C(O)C.[OH-].[Na+]>Cl.O>[OH:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:13](=[O:15])[CH3:14]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC1CCCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Reaction time: 4.5 h

Procedure:
A solution is prepared from ethyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]acetamido}heptanoate (4.5 g., 0.01 mole), ethanol (50 ml.) and 4 drops of concentrated hydrochloric acid, and kept at ambient temperature for 4.5 hours. Then to the reaction mixture is added a solution of sodium hydroxide (0.72 g., 0.018 mole) in water (8 ml.) and the mixture is kept at ambient temperature for an additional twenty hours. Most of the ethanol is removed by evaportion in vacuo and the resulting solution is diluted with water (100 ml.). This solution is extracted, once with ether, then acidified with hydrochloric acid. The oil that separates is extracted into ether, the ethereal extract is dried over sodium sulfate, then the solvent is removed under vacuum to give 7-[N-(4-hydroxynonyl)acetamido]heptanoic acid as a yellow oil; pmr (CDCl3) δ 0.93 (3H,m CH3), 2.10 (3H,s CH3CO), 3.38 (4H,m NCH), 7.03 (2H,s COOH, OH).
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.Br[CH:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[CH2:21]([O:20][C:18]([CH:17]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[CH3:22]
Reactant: Oc1ncn(-c2ccccc2)n1
Reactant: CCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCCCC(Oc1ncn(-c2ccccc2)n1)C(=O)OCC
Yield: 27.7 %

Procedure:
The process was carried out as shown in Example 7 above, beginning with 1.4 g of sodium, 30 ml of methanol, 150 ml of dimethylsulfoxide, 10 g of 3-hydroxy-1-phenyl-1,2,4-1H-triazole and 13.8 g of ethyl 2-bromohexanoate. The product was distilled at 205° and 1 mm of mercury to obtain 5.2 g of the desired product, an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:16](=[O:18])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[CH:3]=3)[C:10]2=[O:12])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: Cc1cccc(COc2cccc(C(=O)O)c2C(=O)O)c1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(COc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Yield: 49.6 %

Procedure:
A mixture of 3-(3-methyl-benzyloxy)-phthalic acid (1.8 g, 6.4 mmol), alpha-amino-glutarimide hydrochloride (1.1 g, 6.8 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(3-methyl-benzyloxy)-isoindole-1,3-dione as a white solid (1.2 g, 48% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.16 min (99.9%); mp, 195-197° C.; 1H NMR (DMSO-d6) δ 2.00-2.07 (m, 1H, CHH), 2.33 (s, 3H, CH3), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.33 (s, 2H, CH2), 7.15-7.85 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.00, 21.96, 30.92, 48.74, 70.08, 115.49, 116.58, 120.19, 124.40, 127.85, 128.40, 128.60, 133.26, 136.03, 136.98, 137.64, 155.53, 165.30, 166.77, 169.91, 172.75. Anal Calcd For C21H18N2O5: C, 66.66; H, 4.79; N, 7.40. Found: C, 66.50; H, 4.79; N, 7.34.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[N:23][OH:24])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].ClN1[C:34](=[O:35])[CH2:33][CH2:32]C1=O.C(O)C#C.CCN(CC)CC>CN(C=O)C>[OH:35][CH2:34][C:33]1[O:24][N:23]=[C:22]([C:17]23[CH2:20][CH2:21][C:14]([C:7]4[NH:8][C:9]5[N:10]([CH2:11][CH2:12][CH3:13])[C:2](=[O:1])[N:3]([CH2:26][CH2:27][CH3:28])[C:4](=[O:25])[C:5]=5[N:6]=4)([CH2:19][CH2:18]2)[CH2:15][CH2:16]3)[CH:32]=1
Reactant: CCCn1c(=O)c2nc(C34CCC(C=NO)(CC3)CC4)[nH]c2n(CCC)c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2nc(C34CCC(c5cc(CO)on5)(CC3)CC4)[nH]c2n(CCC)c1=O
Temperature: 25 °C
Yield: 31.9 %

Procedure:
A solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbaldehyde oxime (87 mg, 0.22 mmol) and N-chloro succinimide (1.2 eq, 0.27 mmol, 36 mg) in DMF (6 ml) was heated in an oil bath at 60° C. for 1.5 h. The reaction flask was removed from the bath and allowed to cool to rt and propargyl alcohol (2.0 eq, 0.44 mmol, 25 mg) was added. The flask was returned to the oil bath, Et3N (2.0 eq, 0.44 mmol, 44 mg) was added over a period of 15 minutes and the resulting mixture was heated at 60° C. for 3.5 h. The cool reaction mixture was evaporated in vacuo to afford a solid residue that was purified by radial chromatography (2 mm plate) using a gradient of 2-10% MeOH in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 31 mg (26%) of a white solid. MS: 442 (MH+).
Reaction SMILES: [NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([OH:5])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[NH:1]([C:6]([CH3:8])=[O:7])[CH2:2][C:3]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:5]
Reactant: CC(=O)NCC(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC(=O)NCCC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ac-Gly-OH a (3.77 g, 32.2 mmol) and triethylamine (6.7 mL, 48.1 mmol) were dissolved in 160 mL THF and cooled to −10° C., and isobutylchloroformate (5.02 g, 38.6 mmol) was added. The mixture was stirred at −10° C. for 1 hr. H-beta-Ala-OBzl.PTSA e (11.26 g, 32.0 mmol) and triethylamine (6.7 mL, 48.1 mmol) was dissolved in 160 mL THF, and added into mix anhydride solution. The reaction mixture was stirred at room temperature overnight. The salt was filtrated off and THF was removed in vacuum. The residue obtained was purified by column chromatography using ethyl acetate and heptane as eluent to obtain 5.95 g Ac-Gly-beta-Ala-OBzl f.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([N:13]([CH3:14])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CNc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)N(C)c1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
3,3-Dimethylacryloyl chloride (3 mL, 27 mmol) was added to a solution of 4-bromo-N-methyl-aniline (4.55 g, 25 mmol) in 150 mL of dichloromethane followed after 5 minutes by triethyl amine (5 mL, 33 mmol). After 2.5 h at ambient temperature, the reaction mixture was washed with water and the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title product as a brown oil in quantitative yield.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].C([N:9](CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.NC1C=CC=CC=1.Cl>C(Cl)Cl>[Br:1][C:2](=[CH2:6])[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: C=C(Br)C(=O)Cl
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: C=C(Br)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A vigorously stirred solution of 4.5 grams (0.027 mole) of 2-bromopropenoyl chloride (Step B product) in 150 ml of dried methylene chloride was cooled to 5°±5°. To this was added dropwise 4.0 grams (0.027 mole) of N,N-diethylaniline at such a rate that the reaction mixture temperature did not exceed 10°. Upon completion of addition, 2.5 grams (0.027 mole) of aniline was added dropwise while continuing to maintain the reaction mixture temperature below 10°. The reaction mixture was allowed to warm to ambient temperature where it was stirred for two hours. After dilution with 100 ml of aqueous 1N hydrochloric acid, the reaction mixture was poured into a separatory funnel. The organic layer was separated and extracted with 50 ml of aqueous 1N hydrochloric acid, then with 100 ml of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was dissolved in methylene chloride and decolorized with silica gel. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was recrystallized from hexane to give 4.0 grams of 2-bromo-N-phenyl-2-propenamide; mp 90.5°-92.5°.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH2:18])[C:14]1=[O:19].[Cl:20][C:21]1[N:26]=[C:25]2[CH:27]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[S:29][C:24]2=[CH:23][CH:22]=1>>[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][S:30]([C:28]2[S:29][C:24]3[C:25](=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:27]=2)(=[O:31])=[O:32])[C:14]1=[O:19]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Reactant: N#Cc1ccc(N)c(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1ccc(N)c(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1

Procedure:
The title compound is prepared from 4-amino-3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile dihydrochloride as described in EXAMPLE 17, Part F using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2 cl2 to afford a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[C:2]([Cl:1])[C:11]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2ccc3c(c2Cl)NCCO3)OC1(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c21
Temperature: 70 °C
Yield: 84.2 %

Procedure:
A solution of 5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.504 g, 1.426 mmol, Ref. WO20100130034) and K2CO3 (0.504 g, 3.65 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed and then heated (70° C.) for 22 h, then cooled and diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was washed with water, brine, then dried (Na2SO4), filtered, concentrated, and purified by biotage chromatography (4 g SiO2, 0% (3 CV), 0-40% (15 CV), 40% (2 CV); EtOAc in hexanes) to afford the desired product (0.403 g, 1.201 mmol, 84% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.15-6.02 (m, 1H), 5.31 (dd, J=17.2, 1.4 Hz, 1H), 5.28-5.21 (m, 1H), 4.18-4.13 (m, 2H), 3.59 (d, J=6.0 Hz, 2H), 3.14-3.07 (m, 2H), 1.36 (s, 12H). LCMS (M+H)=336.9.