Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[C:4]1=[CH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24]C)=[CH:19][CH:20]=3)[CH:15]=1)[CH2:10]2.C1C=CC2C(=CC=CC=2[OH:36])C=1.[CH2:37]([S-])[CH3:38].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[C:4]1=[CH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:37](=[O:36])[CH3:38])=[CH:19][CH:20]=3)[CH:15]=1)[CH2:10]2
Reactant: CC[S-]
Reactant: Oc1cccc2ccccc12
Reactant: COc1ccc2ccc(C=C3C4CC5CC(C4)CC3(OC)C5)cc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC12CC3CC(CC(C3)C1=Cc1ccc3ccc(OC(C)=O)cc3c1)C2
Temperature: 50 °C
Yield: 25.8 %

Procedure:
Crude methoxy(7-methoxynaphth-2-yl)methylene adamantane (247 mg, 0.739 mmol) was added to sodium ethylthiolate (62 mg, 0.743 mmol) in dry DMF (4 ml) and the solution was refluxed under argon for 4 hours deprotecting the aromatic methoxy moiety to the naphthol. Excess sodium ethanethiolate (122 mg, 1.45 mmol) was added in two portions during the reflux to push the demethylation to completion. The naphthol was worked up by partitioning the cooled solution between EtOAc and minimal H2O. Traces of naphthol in the aqueous layer were recovered with two EtOAc washes. The EtOAc layers were dried and evaporated. The crude naphthol was immediately acylated upon dissolution in acetic anhydride (1 ml) and pyridine (2 ml) with gentle warming to 50° C. After evaporation, the reaction mixture was chromatographed on a silica gel column prewashed with 10% EtOAc/hexanes containing 1% triethylamine, eluting with the same EtOAc/hexanes/TEA solvent mixture. The four-step reaction sequence--oxidation, enol ether formation, aromatic demethylation and acylation--gave 69.3 mg (25.8%) of methoxy(7-acetoxynaphth-2-yl)methylene adamantane, m.p. 125° C.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=O)C.[CH2:17](O)[CH3:18]>Cl>[CH2:17]([O:11][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([NH2:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])[CH3:18]
Reactant: CC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(N)cc1[N+](=O)[O-]

Procedure:
A solution of 4-acetylamino-2-nitrobenzoic acid (1.80 g, 8.0 mmol) in 12 N hydrochloric acid (14 mL) and absolute ethyl alcohol (10 mL) was heated to 90°-100° C. for 5 h. Concentrated down in vacuo to remove ethyl alcohol only, adjusted pH to 4 with 1N sodium hydroxide and filtered off precipitate to give 140 mg (Y: 8%) of the title compound; 1H-NMR (CDCl3): δ7.61 (d, J=8.5 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.74 (dd, J=8.5, 2.1 Hz, 1H), 6.52 (bs, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); MS (DCI) m/e: 211 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[C:12](=[CH:15][C:16]3[N:17]=[CH:18][N:19]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>[Pd].CN(C)C=O.C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 6 h

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (2.0 g) and 10% palladium on carbon (0.4 g) in N,N-dimethylformamide-ethanol (6:1, 49 ml) was hydrogenated at an atmospheric pressure for 6 hours. After filtration of the catalyst, the filtrate was evaporated in vacuo to give 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one as an oil, which was used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][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])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[Cl:30].C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH:44]1([NH2:48])[CH2:47][CH2:46][CH2:45]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:28]=[CH:29][C:2]([NH:1][C:41]([NH:48][CH:44]4[CH2:47][CH2:46][CH2:45]4)=[O:42])=[C:3]([Cl:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)c1
Reactant: NC1CCC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(Cl)c3)CC2)c1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
3-((4-(4-Amino-3-chlorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (200 mg, 0.466 mmol) and 4-nitrophenylchloroformate (94 mg, 0.466 mmol) were heated to reflux in dichloromethane (10 ml) for 2 hours. Cyclobutylamine (99 mg, 1.398 mmol) was added and the reaction stirred overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC to afford the title compound (20 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH:16]([C:18]2[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)[OH:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC1(C(O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCC1(C(=O)c2cc(Cl)c(Cl)s2)CCN(C(=O)OC(C)(C)C)C1
Yield: 64.3 %

Procedure:
A mixture of 3-[(4,5-dichloro-thiophen-2-yl)-hydroxy-methyl]-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.423 g, 1.07 mmoles) and manganese (IV) oxide (1.3 g, 12.7 mmoles) in toluene (20 ml) was refluxed for 2 hours and filtered through a celite pad. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to yield 3-(4,5-dichloro-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester as pale yellow solid (0.27 g, 64%). M+Na: 414.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: ClCCCN1CCOCC1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC1(C)C(=O)N(CCCN2CCOCC2)c2cc([N+](=O)[O-])c(N)cc21
Reaction time: 96 h
Yield: 101.3 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.5 g) is alkylated using 4-(3-chloro-propyl)-morpholine hydrocloride (0.57 g; 2.85 mmol), Cs2CO3 (1.55 g; 4.75 mmol) and a catalytic amount of nBU4NI at 70° C. for 4 days. After aqueous work-up the crude material is de-acetylated in hydrochloric acid (6 N, 20 ml) at 80° C. in 4 h. After aqueous work-up 5-amino-3,3-dimethyl-1-(3-morpholin-4-yl-propyl)-6-nitro-1,3-dihydro-indol-2-one (0.67 g) is obtained.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19])(=O)OC.O.[NH2:24][NH2:25]>>[C:18]([C:17]1[CH:16]=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:25][N:24]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COP(=O)(CC(=O)C(C)(C)C)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: CC(C)(C)c1cc2c(nn1)C1CCC2C1

Procedure:
off-white crystalline solid. MS (EI): 245.2 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, (3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Br[C:10]1[N:15]2[N:16]=[CH:17][N:18]=[C:14]2[C:13]([NH:19][C:20]2[CH:36]=[CH:35][C:23]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[O:25])=[C:22]([OH:37])[CH:21]=2)=[N:12][CH:11]=1.[C:38]([O-])([O-])=O.[K+].[K+].S(O)(C)(=O)=O.CO>CO.C(Cl)Cl>[CH3:38][O:37][C:22]1[CH:21]=[C:20]([NH:19][C:13]2[C:14]3[N:15]([N:16]=[CH:17][N:18]=3)[C:10]([C:4]3[CH:3]=[N:2][NH:1][CH:5]=3)=[CH:11][N:12]=2)[CH:36]=[CH:35][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:25]
Reactant: Cc1ccc(CNC(=O)c2ccc(Nc3ncc(Br)n4ncnc34)cc2O)cn1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cn[nH]c1
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)ccc1C(=O)NCc1ccc(C)nc1
Reaction time: 0.01 h

Procedure:
Pyrazole-4-boronic acid (19 mg, 0.17 mmol), 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-2-hydroxy-N-[(6-methyl-pyridin-3-yl)methyl]benzamide (40 mg, 0.085 mmol), K2CO3 (24 mg, 0.17 mmol) and Pd(dppf)Cl2CH2Cl2 (4 mg, 0.005 mmol) are weighed into a sealable tube. The tube is flushed with nitrogen and dioxane-water (4:1, 4 mL) is added. The tube is sealed, placed in an ultrasonic bath under a flow of nitrogen gas for 30 seconds and then placed into an oil bath at 85° C. The reaction is stirred for 28 hours, adding additional portions of boronic acid (10 mg) and catalyst (2 mg) after 2 h and 18 h. The crude mixture is absorbed onto SiO2 and purified by column chromatography, eluting with 1%-10% MeOH/DCM. The product obtained is redissolved in MeOH/DCM (4:1, 10 mL) and 0.1 M MsOH/MeOH (2 eq) is added, the solvents evaporated and the residue taken up in water and lyophillised to afford the title compound as its bis-mesylate salt (38 mg). LCMS: Rt 0.92 min (93.9%) m/z (ESI) 455 (M+H)+.
Reaction SMILES: [H][H].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH2:12]>>[CH2:3]([N:10]1[CH:4]2[CH2:9][CH:8]1[CH2:11][NH:12][CH2:6][CH2:5]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: NCc1ccccc1
Reactant: [H][H]
Product: c1ccc(CN2C3CCNCC2C3)cc1

Procedure:
Compound (I) wherein R2 is derived from compound (III) wherein n is 1, m is 2 and Q is hydrogen is formed on reacting benzylamine rather than monomethylamine with compound 16 in Scheme III. Proceeding as in Scheme III, 8-benzyl-3,8-diazabicyclo[4.1.1]octane is formed which is coupled with compound (II) and then debenzylated by catalytic hydrogenation, as before.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[OH:11]
Reactant: COc1cccc(O)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(I)c(O)c1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
I2 (40.9 g, 161.1 mmol) was dissolved in CHCl3 (850 mL) with stirring over 1 hour. The solution was added slowly into a reaction mixture of 3-methoxyphenol 5-A (20 g, 161.1 mmol) and silver trifluoroacetate in 200 mL CHCl3 over 1.5 hours. The reaction was stirred at room temperature for 16 hours. Solids were removed by filtration. The filtrate was washed with 5% Na2S2O3(500 mL), saturated NaHCO3, brine, dried over MgSO4 and concentrated. The crude mixture was triturated with carbon tetrachloride to give 2-iodo-5-methoxyphenol 5-B (13.6 g) as a white solid. The remaining crude products were purified by silica gel column chromatography eluted with CH2Cl2to give 28.2 g of compound 5-B.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:28].[CH2:38]([NH:40][CH2:41][CH2:42][OH:43])[CH3:39]>>[F:37][C:32]1[CH:31]=[C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:40]([CH2:38][CH3:39])[CH2:41][CH2:42][OH:43])[CH2:7][CH2:8]2)[CH3:1])[CH:35]=[C:34]([F:36])[CH:33]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: CCNCCO
Reactant: O=C(Cl)Oc1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2cc(F)cc(F)c2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 3,5-difluoro-phenyl chloroformate were reacted, followed by treatment with 2-ethylamino-ethanol to give trans-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-methyl-carbamic acid 3,5-difluoro-phenyl ester, MS: 427 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:27]1[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:26]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)c(F)cc3F)[C@@H](N)C1)C2
Reaction time: 2 h

Procedure:
Intermediate obtained in Step A above (379 mg, 0.734 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (10 mL) at room temperature. After 2 h, the reaction was concentrated and the crude material was purified on a silica gel column (40S Biotage™) eluting with in 0-2% methanol, containing 10% NH4OH, in dichloromethane to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 1.50 (q, 1H, J=12 Hz); 2.43-2.49 (m, 1H); 2.88 (td, 1H, J=12, 6 Hz); 3.11-3.18 (m, 1H); 3.34 (s, 3H); 3.40 (t, 1H, J=12 Hz); 3.48-3.92 (m, 4H); 4.23-4.28 (m, 2H); 7.14-7.20 (m, 1H); 7.36-7.42 (m, 1H); 7.86 (s, 1H). LC-MS: 417.12 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.C(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC1C=CC(C(C)C)=CC=1>[OH:9][CH:7]([C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)c1cccnn1
Solvent: Cc1ccc(C(C)C)cc1
Product: OC(c1ccccc1)c1cccnn1
Temperature: 135 °C
Yield: 18.6 %

Procedure:
Pyridazine-3-carboxylic acid [prepared as described by Leanza, Becker and Rogers, J.A.C.S., 75, 4086 (1953); 18.6 g.] was mixed with benzaldehyde (44 g.) and p-cymene (360 ml.) and decarboxylated by heating for 3 hours at 135° C. The hot solution was then filtered, cooled and the precipitate collected to give (±) 3-α-hydroxybenzylpyridazine (5.2 g.), m.p. 130°-135° C., in the form of fawn coloured needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][CH2:15][NH2:16])[N:13]=2)=[CH:5][CH:4]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][CH2:15][NH:16][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: COc1ccc(-c2nc(CCN)co2)cc1
Product: COc1ccc(-c2nc(CCNC(=O)c3cncc(-c4noc(C(F)(F)F)n4)c3)co2)cc1
Yield: 19 %

Procedure:
This compound was synthesized from 2-(2-(4-methoxyphenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (35 mg, yield 19%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.47 (m, 1H), 9.34 (m, 1H), 8.90-8.89 (t, J=2.0 Hz, 1H), 8.08-8.06 (m, 1H), 8.03-8.00 (d, J=8.8 Hz, 2H), 7.55 (s, 1H), 6.99-6.97 (d, J=8.8 Hz, 2H), 3.88 (s, 3H), 3.87-3.84 (m, 2H), 2.96-2.93 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated for C21H16F3N5O4: 459.12. found: 460.1 (M+H)+.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.C(OCC)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:11]([S:9][C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)C(Sc1ccc(C)cc1)Sc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Sodium (3.54 g) is dissolved in methanol (140 cc) and a solution of 4-methylthiophenol (21.8 g) in methanol (25 cc) is added. The mixture is stirred for 1 hour at 20° C. and a solution of ethyl dichloroacetate (12.5 g) in methanol (30 cc) is then added. The mixture is allowed to cool, the white precipitate obtained is filtered off, and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil obtained is taken up in diethyl ether (250 cc) and washed four times with N sodium hydroxide solution (50 cc each time) and four times with distilled water (50 cc each time). The ethereal phase is dried over anhydrous sodium sulphate, filtered, treated with animal charcoal, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylthiophenoxy)acetate (18 g) is thus obtained as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.O([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:7][CH:8]1[CH2:9][CH:10]([O:12][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC1CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)OC1CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a stirred mixture of 3-hydroxycyclobutyl pivalate (16.60 g, 96.4 mmol) and diea (25.2 ml, 145 mmol) in DCM (100 ml) at 0° C. was added tert-butyldimethylsilyl triflate (31.0 ml, 135 mmol) dropwise. The reaction was stirred for 2 h, then quenched with H2O. The layers were separated, and the organic layer was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated to give the title compound as a light brown oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH2:11]([S:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=[CH:19]2)[CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:11]([S:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26]([S:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]=[C:2]=[S:3])=[CH:5][CH:6]=1)=[O:27])[CH:20]=[CH:19]2)[CH2:12][CH2:13][CH3:14]
Reactant: S=C=Nc1ccc(S)cc1
Reactant: CCCCSc1ccc2cc(C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCSc1ccc2cc(C(=O)Sc3ccc(N=C=S)cc3)ccc2c1

Procedure:
Quantities: compound 3 (0.64 g, 2.0 mmol), compound 13 (0.33 g, 1.9 mmol), 4-(dimethylamino)pyridine (0.10 g, 0.80 mmol), N,N'-dicyclohexylcarbodiimide (0.50 g, 2.4 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:18][CH2:17][C@H:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)(=[O:12])[CH3:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)C1CN(C(C)=O)CCC1=O
Product: CCOC(=O)[C@@H]1CN(C(C)=O)CC[C@@H]1N1CCc2ccccc21
Yield: 21.5 %

Procedure:
Indoline (12.5 g), ethyl 1-acetyl-4-oxo-3-piperidinecarboxylate (22.3 g) and triacetoxylated sodium borohydride (48.7 g) were treated as in Example 1 to give the title compound (7.12 g) as a pale yellow powder (yield: 22%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=O.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(OCC)=O.[CH3:41][O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:15]1([C:21]([NH:10][CH:7]2[C:8](=[O:9])[N:4]3[CH:3]([C:11](=[O:13])[NH:48][CH2:47][C:46]4[CH:49]=[CH:50][C:43]([O:42][CH3:41])=[CH:44][CH:45]=4)[C:2]([CH3:1])([CH3:14])[S:6][C@H:5]23)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 0 °C
Reaction time: 64 h

Procedure:
To a stirred slurry of 86.4 g. (0.4 mole) of 6-aminopenicillanic acid in 600 ml. of anhydrous chloroform is added 111.2 ml. (0.8 mole) of triethylamine, and the mixture is stirred at ambient temperature until a clear solution is obtained (ca. 15 minutes). To this solution is then added, portionwise over about 25 minutes, 134.9 g. (0.44 mole) of 90% pure triphenylmethyl chloride, at ambient temperature. Stirring is continued for a further 64 hours, and then 5.6 ml. of triethylamine is added. The solution is cooled to 0°-5° C., and then an ice-cold solution of 38 ml. (0.4 mole) of ethyl chloroformate in 80 ml. of chloroform is added dropwise during 30 minutes with the reaction temperature being maintained between 4 and 9° C. After a further 15 minutes of stirring, 52.4 ml. (0.4 mole) of 4-methoxybenzylamine is injected into the reaction medium, below the surface of the solvent, at 4° to 9° C., and over a period of 30 minutes. Stirring is continued for a further 30 minutes at 3° to 6° C., for 20 minutes while the reaction medium warms to 20° C. The reaction mixture is then washed with water, followed by brine. Finally, it is dried using magnesium sulfate to give a chloroform solution of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methoxybenzyl]carbamoyl)penam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C:10](=[CH2:17])[O:9]2)=[CH:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[I-].[C:39]([NH3+])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.O>[CH2:30]([O:14][C@@H:13]1[C@@H:12]([O:15][CH2:40][C:39]2[CH:42]=[CH:17][CH:10]=[CH:11][CH:41]=2)[C@H:11]([O:16][CH2:18][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:10](=[CH2:17])[O:9][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH:24]=2)[CH:4]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[NH3+]
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 912.2 %

Procedure:
To a solution of (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran-3,4,5-triol (300 mg, 0.77 mmole) in dry DMF (3 mL), sodium hydride (166 mg, 3.46 mmole) was added at 0° C. and stirred at room temperature for 2 hours. Benzyl bromide (0.3 mL, 2.54 mmole), t-butylammoniumiodide (10 mg) was added and reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2×200 mL). The crude product was purified by silica gel column chromatography (2% ethylacetate in hexane) to furnish 300 mg of (2S,3S,4R,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran.