Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[C@H:10]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:5][CH:4]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[C@H:10]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:25][CH:26]=1
Reactant: COC(=O)[C@H]1CC[C@H](NCc2ccc(OC)cc2)[C@@H]1c1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](N(Cc2ccc(OC)cc2)C(=O)OCc2ccccc2)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.1 g of methyl 3-(S)-(4-methoxybenzyl-amino)-2-(S)-(4-fluorophenyl)cyclopentane-1-(S)-carboxylate, prepared as in Example 61, in 50 mL of methylene chloride was added 1.36 mL of benzyl chloroformate and after 5 min 3.0 mL of DIPEA. After stirring at room temperature for 16 h, the reaction was poured into water containing 3 mL of 2N HCl and was extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to obtain 3.95 g of title compound as an oil. T.l.c. (10% ethyl acetate in hexanes) Rf =0.35
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:32].Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:30]=[CH:31][C:2]([NH:1][C:34]([NH:50][CH:46]4[CH2:49][CH2:48][CH2:47]4)=[O:35])=[C:3]([F:32])[CH:4]=3)[CH2:9][C:10]2([CH3:29])[CH3:28])[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NC1CCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2(C)C)c1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2(C)C)c1
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To 3-((4-(4-amino-3-fluorobenzoyl)-2,2-dimethylpiperazin-1-yl)methyl)-N-tert-butylbenzamide (0.1 mmol, 45 mg) in dichloromethane (1.5 mL) was added 4-nitrophenyl chloroformate (0.11 mmol, 23 mg). The mixture was allowed to stir for 2 hours before the addition of cyclobutylamine (1.757 mmol, 125 mg, 150 μl). The mixture was allowed to stir for a further 16 hours before being concentrated under vacuum and purified by acidic reverse phase HPLC. The free base of the product was obtained using strong cation exchange column chromatography. This material was lyophilised to yield the title compound (16 mg).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][CH3:35])[CH2:28][CH2:27]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1.N1CCOCC1>ClCCl>[ClH:10].[CH3:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]([N:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH2:30][CH2:31]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:18][CH:19]=1
Reactant: CNCCN1CCN(c2nccnc2-c2ccc(COC)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: COCc1ccc(-c2nccnc2N2CCN(CCN(C)S(=O)(=O)c3ccccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
Dissolve benzenesulfonyl chloride (0.087 g, 0.49 mmol, 1.1 eq.) in dichloromethane (4 mL). Add {2-[3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amine (0.150 g, 0.440 mmol, 1 eq.). Add morpholine, polymer-bound (0.201 g, 0.490 mmol, 1.1 eq.). Stir at room temperature for 2 hr. Purify by SCX chromatography (column washed with methanol and extracted with 7N NH3/MeOH) to afford the free base of the title compound (0.202 g, 95% yield). MS (loop): m/z=482.3 [M+H].
Reaction SMILES: C([O:5][NH:6][C:7]([CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:8])(C)(C)C.[Cl:26]C(Cl)C>C(O)C>[ClH:26].[OH:5][NH:6][C:7]([CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:8]
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2C(=O)NOC(C)(C)C)cc1
Reactant: CC(Cl)Cl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N2CCNCC2C(=O)NO)cc1
Product: Cl
Temperature: -10 °C
Reaction time: 24 h

Procedure:
To a solution of (+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-2-piperazinecarboxamide (30 mg, in dichloroethane is added ethanol (1 drop). The solution is cooled to -10° C. and hydrogen chloride gase is bubbled through for 5 minutes. The reaction is then sealed and stirred for 24 hours at which time the volume is reduced to 1/3 by evaporation and the precipitated solids are filtered and dried (in vacuo) to give (+)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-2-piperazinecarboxamide hydrochloride as a white solid. Melting point 167° C. (dec.). Mass spectrum (thermospray): m/Z 343 (m+1 100%). 1H NMR (CD3OD, 250 MHz, ppm): δ7.76 (d, J=8.9 Hz, 2 H), 7.07 (d, J=8.9 Hz, 2 H), 3.87 (bs, H2O ), 4.19 (d, J=3.3 Hz, 1 H), 3.87 (s, 3 H), 3.58 (bd, J=6.2 Hz, 1 H), 3.42 (bd, J=6.1 Hz, 1 H), 3.30 (bs, CD3OD), 3.16 (d, J=13.5 Hz, 1 H), 2.87 (bd, J=13.3 Hz, 1 H), 2.69 (dd, J=13.3, 3.0 Hz, 1 H), 2.51 (dt, J=12.5, 3.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17].O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([O:12][CH3:13])[C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COc1c(Cl)ccc2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(Cl)ccc2ccc(Cl)nc12

Procedure:
7-Chloro-8-methoxy-2-quinolinol (4b) (2.85 g, 13.6 mmol) was mixed with POCl3 (6 mL) and allowed to reflux for 1.5 hours. To the concentrated contents, H2O and AcOEt were added followed by NaHCO3 to neutralize the mixture. The water layer was extracted with AcOEt, washed with saturated NaCl and dried with MgSO4. The product was filtered through silica gel using CHCl3 and recrystalized from CHCl3-hexanes to afford the desired product as off white crystals (2.53 g, 82% yield): mp 103-104 □C; 1H NMR (400 MHz, CDCl3) 8.07 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.19 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.Cl.[C:12]([Si:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:17][C:18]1([CH3:22])[CH2:21][NH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].CO.CN(C=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:12]([Si:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1([CH3:22])[CH2:19][N:20]([CH2:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH2:21]1)([CH3:13])([CH3:14])[CH3:15]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC1(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC1(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a stirred solution of 4-formylbenzonitrile (68 mg, 0.51 mmol) and 3-(tert-Butyl-diphenyl-silanyloxy)-3-methyl-azetidine hydrochloride (188 mg, 0.51 mmol) in 1:1 MeOH/DMF (26 mL) was added acetic acid (catalytic). The reaction mixture was stirred under N2 at 0° C. for 1 h. Sodium cyanoborohydride (1M in THF, 0.6 mL, 0.57 mmol) was added and the reaction mixture stirred at RT, under N2 for 18 h. The reaction mixture was concentrated in vacuo, the residue suspended in H2O (10 mL), washed with CH2Cl2 (2×10 mL) and the solution passed through a phase separation cartridge. The combined organic layers were concentrated in vacuo and the crude residue purified by silica gel chromatography eluting with 100% isohexane and increasing the polarity 100% EtOAc to afford 4-[3-(tert-butyl-diphenyl-silanyloxy)-3-methyl-azetidin-1-ylmethyl]-benzonitrile as a colourless oil (196 mg, 86%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[C:19](O)=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:32][C@:33]1([C:38]([NH:40][S:41]([CH:44]2[CH2:46][CH2:45]2)(=[O:43])=[O:42])=[O:39])[CH2:35][C@H:34]1[CH:36]=[CH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:44]1([S:41]([NH:40][C:38]([C@@:33]2([NH:32][C:19]([C@@H:9]3[CH2:10][C@@H:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:12][N:8]3[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:20])[CH2:35][C@H:34]2[CH:36]=[CH2:37])=[O:39])(=[O:43])=[O:42])[CH2:46][CH2:45]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Reaction time: 14 h
Yield: 79.2 %

Procedure:
To a mixture of (2S,4S)-Boc-4-phenylpyrrolidine-2-carboxylic acid (0.711 g 2.44 mmol) (purchased from Chem-Impex International, Inc.), diisopropylethylamine (0.948 g, 7.33 mmol), and cyclopropanesulfonic acid (1-(R)-amino-2-(S)-vinyl-cyclopropanecarbonyl)amide HCl salt (0.561 g, 2.44 mmol) in dichloromethane (24 mL) was added HATU (1.21 g, 3.18 mmol). After stirring the reaction mixture for 14 hours, it was washed with 5% aqueous NaHCO3 (50 mL), and 5% aqueous citric acid (50 mL). Each aqueous layer was sequentially extracted with 2×25 mL dichloromethane. The combined organic layer was dried over MgSO4, filtered, and concentrated. The resulting brown viscous oil was purified by flash column chromatography (SiO2, 97:3, dichloromethane:methanol) to give (2S,4S)-tert-butyl 2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-phenylpyrrolidine-1-carboxylate as a brown foamy solid (0.973 g, 79% yield). 1H NMR (CD3OD, 500 MHz) δ 0.91 (br s, 1H), 1.03 (d, J=6.4 Hz, 1H), 1.16-1.23 (m, 1H), 1.31-1.38 (m, 1H), 1.44 (dd, J=9.6, 5.6 Hz, 1H), 1.48 (s, 4H), 1.52 (s, 5H), 1.89 (t, J=6.4 Hz), 2.09 (q, J=8.4 Hz, 0.4H), 2.19 (q, J=8.6 Hz, 0.6H), 2.85-2.90 (m, 0.4H), 2.92-2.97 (m, 0.6H), 3.44 (t, J=9.6 Hz, 1H), 3.65 (p, J=8.0 Hz, 1H), 3.93-4.01 (m, 1H), 4.29 (dd, J=10.1, 6.7 Hz, 1H), 5.12 (d, J=10.1 Hz, 1H), 5.30 (d, J=18.0 Hz, 1H), 5.75-5.82 (m, 1H), 7.24 (t, J=6.9 Hz, 1H), 7.29-7.33 (m, 5H); MS m/z 504 (M+Na).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:27][CH:26]=1)[CH:20]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:19]2=[O:44])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:53])C=1>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:53])[CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[N:27][CH:26]=1)[CH:20]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:19]2=[O:44])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CSC12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12
Yield: 93.4 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (24 g) in methylene chloride (370 cc) is oxidised with 85% pure meta-chloroperbenzoic acid (7.92 g) in accordance with the procedure described in Example 2 to give 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (23 g) in the form of a brown-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=O)([O-:3])=[O:2].C(#N)C([CH2:19][C:20]#[N:21])O.C([N:25](CC)CC)C>CN(C=O)C>[NH2:25][C:12]1[C:19]([C:20]#[N:21])=[C:9]([OH:11])[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=2)[N:13]=1
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Reactant: N#CCC(O)C#N
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the solution of 47.25 g of 5-nitroisatoic anhydride in 230 mL of DMF 15 g of malonitrile and 63.3 mL of triethylamine were added and the reaction mixture was stirred at 60° C. for 2 hours. The solvent was evaporated at reduced pressure and the residue was mixed with 570 mL of acetonitrile and 114 mL of concd. HCl and the solution was stirred at room temperature overnight. The precipitate was then filtered off, washed with water and ethanol to give 49.7 g of product, m.p.: >360° C. LC-MS: MH+ 231; Ret. time: 4.78 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]([OH:17])=[O:16]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(F)c1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)COCCc1cccc(F)c1
Reaction time: 36 h
Yield: 63.2 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-ethanol (4.0 g, 28.5 mmol) in DMF (60 ml) was added sodium hydride (60% dispersion in oil, 2.40 g, 60 mmol). The suspension was heated to 60° C. for 0.75 hours before chloroacetic acid (4.72 g, 50 mmol) was added dropwise. After 36 hours at 60° C. the brown reaction mixture was brought to dryness under reduced pressure, dissolved in EtOAc and washed with 1M HCl, water and brine. The organic layers were dried (MgSO4), filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane 3:1) to yield the title compound (2.02 g, 18 mmol; 36%) as colorless liquid. MS: m/e=197.4 [M−H]−.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1.I([O-])(=O)(=O)=[O:21].[Na+]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[CH2:19]1[CH:10]2[CH:11]([C:12](=[O:16])[NH:13][C:14]3[CH:15]=[C:6]([C:2]([OH:1])=[O:21])[CH:7]=[CH:8][C:9]=32)[CH2:17][CH2:18]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)NC(=O)C1CCCC21
Reaction time: 24 h

Procedure:
A suspension of 0.37 g (1.5 mmol) of 7-(2-furanyl)-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one is suspended in 50 ml of acetonitrile-carbon tetrachloride-water (2:1:2) and mixed with 4.81 g (22.5 mmol) of sodium periodate and 40 mg (0.3 mmol) of ruthenium(IV) oxide. After 24 hours at room temperature, the batch is diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is dissolved in 100 ml of 0.5 M potassium hydroxide solution. The solution is washed with methyl-tert-butyl ether (2×100 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum: 213 mg of product.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][CH:14]=[N:13][C:11]=2[N:12]=1.[I:22]I>CCCCCC.C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:10]2[S:15][C:14]([I:22])=[N:13][C:11]=2[N:12]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M of n-butyllithium (9.4 mL, 22.48 mmol) in hexane solution was added to a mixture of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.CNC.[H][H]>C1(C)C=CC=CC=1.[C].[Pt]>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Reactant: [H][H]
Agent: [Pt]
Agent: CNC
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 96 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 0.1 g of platinum carbon, 150 ml of a toluene solvent and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 96% of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 30.5 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 87%; melting point, 79° to 81° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:24])[CH:18]=2)[CH:8]=1)[CH3:2].FC1C=CC([NH:34][C:35]([C:37]2([C:40](O)=[O:41])[CH2:39][CH2:38]2)=[O:36])=CC=1.C1(C(O)=O)(C(O)=O)CC1.[F:52][C:53]1[CH:59]=[CH:58][C:56](N)=[CH:55][CH:54]=1>>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([C:56]3[CH:58]=[CH:59][C:53]([F:52])=[CH:54][CH:55]=3)[C:40]([C:37]3([C:35]([NH2:34])=[O:36])[CH2:38][CH2:39]3)=[O:41])=[C:19]([CH3:24])[CH:18]=2)[CH:8]=1)[CH3:26]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)c(C)c3)c2s1
Agent: O=C(O)C1(C(=O)O)CC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)c(C)c3)c2s1

Procedure:
Prepared from 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-2-methylbenzenamine (0.070 g, 0.1322 mmol), and 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.04424 g, 0.1982 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) according to the procedure for Example 73. The crude was purified by preparative TLC eluting with EtOAc/MeOH (9:1). The product was a light yellow oil (3.9 mg, 5%). 1H NMR (CDCl3, 400 MHz) δ 9.19 (s, 1H), 8.88 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 7.87 (d, J=9.8 Hz, 1H), 7.57 (s, 1H), 7.48 (m, 2H), 7.04 (m, 4H), 6.58 (d, J=5.5 Hz, 1H), 3.73 (s, 2H), 2.68 (q, J=7, 14 Hz, 4H), 2.34 (s, 3H) 1.73 (m, 4H), 1.15 (t, J=7.2 Hz, 6H). LRMS (APCI pos) m/e 571 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a stirred solution of 4-bromobenzonitrile (1.807 g, 0.009929 mol) in anhydrous tetrahydrofuran (30 mL) at −85° C. under nitrogen was added dropwise over 15 minutes a 2.1 M solution of n-butyl lithium in hexanes (4.7 mL, 0.0099 mol), and the mixture was stirred. After 20 minutes, trimethylborate (1.0 mL, 0.0088 mol) was added in one portion, and the mixture was allowed to slowly warm. After 40 minutes, the reaction was quenched with 1 M aqueous hydrochloric acid (2.2 mL, 0.0022 mol) and stirred. Solids began crystallizing after 1 hour. The solids were filtered, washed with diethyl ether, and dried under house vacuum (air bleed, T=40° C.) to give 0.918 g of crude (4-cyano-phenyl)boronic acid. This material was used in the next reaction without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:30][CH:32]2[CH2:33][O:34]2)=[C:9]([CH:22]=1)[C:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)=[O:11])(=[O:3])[CH3:2]
Reactant: BrCC1CO1
Reactant: CC(=O)Nc1ccc(O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCC2CO2)c(C(=O)Nc2cccc3[nH]ccc23)c1

Procedure:
A mixture of 3.5 g of the product of Step C, 150 ml of acetone, 1.5 g of potassium carbonate and 9 ml of epibromohydrin was refluxed for 2 hours and after the addition of another 9 ml of epibromohydrin, the mixture was refluxed for 20 hours and was filtered. The filtrate was washed with acetone and evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ether and was filtered. The product was dried at 80° C. to obtain 3.4 g of 5-acetylamino-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide melting at 230° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][NH:8][CH3:9].[NH2:14][C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[NH2:14][C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:8]([CH3:9])[CH2:7][C:6]2[S:5][C:4]3[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=3[C:2]=2[CH3:1])=[O:25])=[CH:17][CH:16]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1sc2ccccc2c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)sc2ccccc12
Reaction time: 16 h
Yield: 72.2 %

Procedure:
To a stirred solution of 3-methyl-2-(methylaminomethyl)benzo[b]thiophene (0.30 g, 1.6 mmole) in 1:1 DMF/CH2Cl2 was added (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.33 g, 2 mmole), HOBt.H2O (0.27 g, 2 mmole), and DCC (0.41 g, 2 mmole). The reaction was stirred for 16 hr. then was concentrated under vacuum. The residue was taken up in CHCl3, washed with H2O, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (4% methanol/CHCl3) gave the title compound (0.39 g, 72%) as a pale yellow solid: LCMS (ES) m/e 338.2 (M+H)+.