Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:20]=4[CH:21]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[CH:24][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][C:20]=4[CH:21]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: Nc1ccc2c(c1)CCN(Cc1cc3cc(N)ccc3o1)CC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN(Cc1cc3cc(NS(C)(=O)=O)ccc3o1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl cloride (0.28 ml) was added dropwise to a solution of 7-amino-3-(5-aminobenzofur-2-ylmethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine (0.56 g) in pyridine (40 ml) cooled to 0° and the mixture was then stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 4%). The product-containing fractions were combined and evaporated to give the title compound as a foam, yield 0.56 g.
Reaction SMILES: Cl[CH2:2][C:3]([F:6])([F:5])[F:4].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[F:4][C:3]([F:6])([F:5])[CH2:2][S:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)CCl
Reactant: SCc1ccccc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: FC(F)(F)CSCc1ccccc1
Temperature: 70 °C
Yield: 84 %

Procedure:
A mixture of 1-chloro-2,2,2-trifluoroethane (20 g), benzyl mercaptan (12.4 g, 99% strength), sodium hydroxide (22.0 g of a 22% aqueous solution) and hexadecyl tributyl phosphonium bromide (0.51 g) was charged to a resealable Carius tube under a nitrogen atmosphere and heated at 70° C. for 10 hours. The tube was then cooled to 0° C., unsealed and the contents separated into two layers. The lower organic layer was collected, washed with water and purified by short path distillation to give 2,2,2-trifluoroethylthiomethylbenzene, b.p. 60°-70° C./ 10 mmHg, 17.4 g (yield 84%, strength 99%). The identity of the product was confirmed by gc-mass spectroscopy and nuclear magnetic reconance, and by comparison with data provided in C. Bunyagidj et al, J Org. Chem., 1981, 46 3335.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:41]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CCCCCl)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (200 mg, 0.486 mmol) was dissolved in dichloromethane (3 ml) and triethylamine (203 μl, 1.46 mmol) was added followed by dropwise addition of 5-chlorovaleryl chloride (69 μl, 0.535 mmol). The reaction was stirred under nitrogen at room temperature for 2 h. The reaction mixture was quenched with sat. sodium hydrogen carbonate solution (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give the title compound (259 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][CH2:23][C:19]2[CH:18]=[C:17]([CH3:26])[CH:22]=[CH:21][CH:20]=2)=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reactant: Cc1cccc(CCO)c1
Product: CCOC(=O)c1ccc(OCCc2cccc(C)c2)c(OC(C)=O)c1

Procedure:
The compound of step 1 (350 mg, 1.56 mmol) was reacted with 2-m-tolyl-ethanol in analogy to step 3 of example 15 to yield 450 mg of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)CCl.C1C=[N:21]C2N(O)N=NC=2C=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:21])=[O:8]
Reactant: On1nnc2cccnc21
Reactant: COc1ccc(I)cc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(I)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
5-iodo-2-methoxybenzoic acid (1.01 g, 3.63 mmol) was dissolved in DMF (8.0 ml) and EDC (0.86 g, 4.5 mmol), HOAt (0.59 g, 4.3 mmol), ammonium chloride (0.79 g, 14.8 mmol), and iPr2NEt (2.0 ml, 11.5 mmol) were added. The reaction was stirred at room temperature under nitrogen overnight, and then poured into water (40 ml), resulting in the formation of a precipitate. The suspension was filtered and the solid was collected. The filtrate was extracted with EtOAc (3×25 ml), and the organic extracts were combined, dried over sodium sulfate, filtered, combined with the filtered solid, and concentrated. The crude was dissolved in DMF (ca. 10 ml) and poured into water (60 ml). This was then cooled in an ice water bath, and filtered, and the solid was collected and dried in vacuo to give title compound (0.38 g, 38%). MS (ESI pos. ion) m/z: 278 (M+H). Calc'd Exact Mass for C8H8INO2: 277.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[O-].[Na+]>O.C(OCC)(=O)C.CO.O1CCCC1>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: C[O-]
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
Under a nitrogen atmosphere, to a tetrahydrofuran (50 mL) solution containing (R)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol (2.25 g), triphenylphosphine (4.51 g) and 4-nitrobenzoic acid (2.88 g) was dropwise added diisopropyl azodicarboxylate (3.39 mL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes, and then at room temperature for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was crudely purified by silica gel column chromatography (heptane/ethyl acetate 8/2→1/1), to thereby obtain a crude product (3.6 g) of 4-nitrobenzoic acid (S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethyl ester. A solution of the obtained crude product (3.53 g) in methanol (300 mL) was added sodium methoxide (4.39 mL, 28% methanol solution), and the resultant solution was stirred at room temperature for 1 hour. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with ethyl acetate and water. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/1), to thereby obtain the titled compound (1.19 g). The physical properties of the compound were as follows.
Reaction SMILES: C=[C:2]1[C:17]2[C:9](=[CH:10][C:11]3[O:12][CH2:13][O:14][C:15]=3[CH:16]=2)[CH:8]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[C@H:7]2[C@@H:3]1[CH2:4][O:5][C:6]2=[O:30].C[N+]1([O-])CC[O:35]CC1>ClCCl.[Os](=O)(=O)(=O)=O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([CH:8]2[C:9]3[C:17](=[CH:16][C:15]4[O:14][CH2:13][O:12][C:11]=4[CH:10]=3)[C:2](=[O:35])[C@@H:3]3[C@H:7]2[C:6](=[O:30])[O:5][CH2:4]3)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: C=C1c2cc3c(cc2C(c2cc(OC)c(OC)c(OC)c2)[C@@H]2C(=O)OC[C@H]12)OCO3
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Product: COc1cc(C2c3cc4c(cc3C(=O)[C@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC
Temperature: 25 °C
Yield: 125.2 %

Procedure:
(11S,15S)-16-Methylidene-10-(3,4,5-trimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^{3,7}.0^{11,15}]hexadeca-1,3(7),8-trien-12-one obtained in Example 1 (0.730 g, 1.22 mmol) and N-methyl morpholine oxide (50 wt-% solution in water, 1.25. mL, 5.34 mmol) were suspended in dichloromethane (60 mL). Osmium tetroxide (4 wt-% solution in water, 0.37 mL, 0.060 mmol) was added to the suspension. The mixture was stirred vigorously at rt. After most of starting material had been consumed (over week-end), NalO4 (0.52 g, 2.44 mmol) was added and the reaction was stirred for an additional 30 min. The reaction was quenched by addition of aqueous sodium thiosulfate (50 mL) and the phases were separated. The aqueous phase was extracted with dichloromethane (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give 630 mg (85% yield) of the product in 75% purity. Another batch of ketone has been purified by filtration through a pad of silica topped with celite and eluting with Heptane:EtOAc 1:1. LCMS: ACE 3 C8, 50×3.0 mm, 10% to 97% acetonitrile in 0.1% TFA in water, 1 mL/min; Rt=2.091.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[NH:17][CH2:16][CH2:15][NH:14][C:13]=3[CH:20]=2)=[N:6][CH:7]=1.Cl[C:32]1N=C(NC2C=CC=CC=2C(NC)=O)C(Cl)=CN=1.NC1C=CC2C(=O)NCCNC=2C=1.Cl.O.O1CCOCC1>COCCO.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH:26][CH3:32])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[NH:17][CH2:16][CH2:15][NH:14][C:13]=3[CH:20]=2)=[N:6][CH:7]=1
Reactant: NC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NCCNC3=O)ncc1Cl
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: Nc1ccc2c(c1)NCCNC2=O
Solvent: C1COCCO1
Solvent: COCCO
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NCCNC3=O)ncc1Cl
Temperature: 110 °C
Reaction time: 22 h

Procedure:
411 f) 2-[5-Chloro-2-(5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]benzamide (CEP-19626). A solution of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (58 mg, 0.20 mmol) and 8-amino-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (35 mg, 0.20 mmol) in 2-methoxyethanol (5 mL) was treated with 4N HCl in 50% H2O/dioxane (50 μL, 1 equiv.) and the mixture was stirred and heated to 110° C. After 22 hrs. the mixture was cooled to room temperature, neutralized with triethylamine and concentrated. Flash chromatography (silica gel, 20% MeOH/DCM) gave 35 mg of the title compound as a pale amber solid; m.p. 232-237° C.; MS: m/z=438/440 (M+H)+, Cl-isotope pattern; 1H-NMR (DMSO-d6, δ): 11.69 (s, 1H), 9.43 (s, 1H), 8.84 (d, 8 Hz, 1H), 8.76 (s, 1H), 8.22 (s, 1H), 7.76 (d, 7 Hz, 2H), 7.67 (d, 8 Hz, 1H), 7.48 (m, 2H), 7.15 (t, 8 Hz, 1H), 7.03 (s, 1H), 6.90 (d, 9 Hz, 1H), 3.10 (m, 2H), 2.82 (s, 3H), 2.60 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]1([C:18]2[C:19]([C:23]#[N:24])=[CH:20][NH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:21]2[CH:22]=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([C:23]#[N:24])=[CH:20]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1

Procedure:
Prepared from 5-chloro-2nitroaniline, 4-phenyl-pyrrole-3-carbonitrile [CAS-no. 40167-37-1] and NaH in DMF at 150° C. for 3 h according to the general procedure E (method b). Obtained as a dark red solid (168 mg).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O-])(=O)C.[NH4+].[N+:28]([CH3:31])([O-:30])=[O:29]>>[N+:28]([CH:31]=[CH:11][C:10]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=1)([O-:30])=[O:29]
Reactant: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCCCCCOc1ccc(C=C[N+](=O)[O-])cc1OCCCCCC

Procedure:
3,4-Dihexyloxybenzaldehyde (122.6 g; 0.4 mmol) is heated to 100° C. with ammonium acetate (23.12 g; 0.3 mol) and nitromethane (42.7 g; 0.7 mol). Working-up is analogous to Example 6b).
Reaction SMILES: [C:1]([C:3]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])[CH3:4])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([C:3]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(OC(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 3-(1-cyano-1-methylethoxy)benzoate (2.07 g, 9.44 mmol) in methanol (12 mL)/tetrahydrofuran (4 mL) was added 2N aqueous sodium hydroxide solution (9.44 mL, 18.9 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 6N hydrochloric acid (5 mL), 1N hydrochloric acid (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (1.01 g, 51%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 8.5 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (600 mg, 1 mmol), NaOH (80 mg, 2 mmol), H2O (3 mL) and methanol (10 mL) was heated at 70° C. for 2 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to “pH” 2-3 by addition of concentrated HCl. The white solid was collected by filtration to give the title compound as a white solid (50 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].[OH2:23]>ClCCl>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Br:16][C:17]([CH3:22])([CH3:21])[C:18]([O-:19])=[O:23]
Reactant: O
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)[O-]
Reaction time: 0.75 h

Procedure:
N-Hydroxysuccinimide (11.51 g, 0.1 mol) was dissolved in anhydrous dichloromethane (100 ml) with triethylamine (28.1 mL, 0.2 mol) under nitrogen in a 250 ml round-bottomed flask equipped with a magnetic stirrer. The flask was cooled to 0° C. with an ice bath before the dropwise addition of 2-bromo-2-methylpropionyl bromide (13.9 mL, 0.11 mol). Next the mixture was stirred for 45 minutes and allowed to reach room temperature. After this the reaction mixture was poured into an excess of cold water and extracted with diethyl ether (3×50 mL). The organic layer was subsequently washed with a saturated aqueous solution of sodium carbonate (3×50 mL), acidified water (pH=4.5, 3×50 mLl), and again the saturated aqueous solution of sodium carbonate (3×50 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. Finally the solvent was removed under reduced pressure by using the rotary evaporator in order to isolate the title compound in quantitative yield as a white solid. 1H NMR (CDCl3) δ (ppm) 2.08 (s, 6H, C(CH3)2Br), 2.87 (s, 4H, Hcycl). 13C NMR (CDCl3) δ (ppm) 26.03 (2C, Ccycl) 31.09 (2C, C(CH3)2Br), 51.60 (1C, C(CH3)2Br), 167.89 (1C, C═O), 169.02 (2C, Ccycl═O). IR (solid, ATR cell) ν (cm−1) 1803, 1772 (Ccycl═O), 1728 (C═O), 1394, 1359, 1197, 1121, 1071, 996, 924, 856, 811, 731, 648. Mass spectroscopy (+EI, m/z) 266, 265, 156, 151, 149, 123, 121, 116, 115, 91, 87, 70, 69. Elem. Anal. Theoretical for C8H10NO4Br: C, 36.39; H, 3.82; N, 5.30; Br, 30.26. Found: C, 36.35; H, 3.82; N, 5.03; Br, 30.17. Melting point 72-74° C.
Reaction SMILES: OC1C=CC=C2C=1[NH+]=CC=C2.[O:12]=[C:13]1[C@@H:16]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:15][N:14]1S([O-])(=O)=O>C(#N)C>[C:22]1([CH2:21][O:20][C:18]([NH:17][C@H:16]2[CH2:15][NH:14][C:13]2=[O:12])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@H]1CN(S(=O)(=O)[O-])C1=O)OCc1ccccc1
Agent: Oc1cccc2ccc[nH+]c12
Solvent: CC#N
Product: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
(3S)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, 8-hydroxyquinolinium salt (150 mg, 0.337 mmol) was added to acetonitrile (10 ml) and rapidly heated to reflux in a preheated oil bath. After refluxing for a total of 18 minutes, the mixture was cooled to room temperature, filtered through Celite, and solvent was removed in vacuo. The residue was extracted with an acetonitrile-ethyl acetate mixture and the extract chromatographed on a silica gel column (Mallinckrodt SilicAR CC-7). The desired product (31 mg) was eluted with a 5% acetonitrile:95% ethyl acetate mixture.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[CH3:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:27]1[CH:28]=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Reactant: OB(O)c1cncnc1
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 3-iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1) and pyrimidin-5-ylboronic acid to afford a yellow oil. UPLC-MS (Condition 1) tR=2.62 min, m/z=374.0 [M+H]+, m/z=372.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 7.37 (d, J=8.6 Hz, 2H) 7.55 (d, J=8.1 Hz, 1H) 7.88 (d, J=9.0 Hz, 2H) 7.95 (s, 1H) 7.98 (d, J=8.1 Hz, 1H) 8.97 (s, 2H) 9.26 (s, 1H) 10.40 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH2:20][CH2:21][OH:22])[C:18]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:17][N:16]=3)[N:9]=2)[CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C.N1C=CC=CC=1>[CH3:29][S:30]([O:22][CH2:21][CH2:20][N:19]1[C:18]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:17][N:16]=[C:15]1[S:14][CH2:13][C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:28])[O:12][N:11]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[3-({[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}thio)-5-(2-thienyl)-4H-1,2,4-triazol-4-yl]ethanol in a mixture of DMF (1 ml) and pyridine (0.5 ml) was added methanesulfonyl chloride (20 uL). The mixture was stirred at r.t. for 24 h before poured onto water (10 ml). The crude product was filtered off and purified by chromatography on silica gel using 0-5% MeOH in DCM as eluent to give 43 mg of the title compound, which was used directly in the next step.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Br[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C.O>[CH:10]1([O:16][C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Brc1cccc2ccccc12
Reactant: OC1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(OC3CCCCC3)cccc2c1
Temperature: 70 °C
Yield: 59.5 %

Procedure:
An oven dried Schlenk tube equipped with a teflon coated stir bar was charged with NaH (40 mg, 1.50 mmol), toluene (2 mL) and cyclohexanol (94 μL, 0.90 mmol). The mixture was heated to 70° C. for 10 min under an atmosphere of argon. To this was added 1-bromonaphthalene (104 μL, 0.75 mmol), Pd2 (dba)3 (10.3 mg, 0.0113 mmol), (R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl(Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of toluene. The mixture was heated to 70° C. for 20 h at which time water (60 mL) and diethyl ether (60 mL) were added. The aqueous layer was separated and extracted with diethyl ether (60 mL). The organics were combined, washed with brine (60 mL) and dried over anhydrous MgSO4. The drying agent was removed by filtration and the mother liquor concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50:1 hexanes:ethyl acetate) to afford 1-naphthyl cyclohexyl ether (101 mg, 60% yield) as a colorless oil.