Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCCCC>[CH3:20][N:21]([CH3:25])[C:22]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[OH:12])=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: CCCCCCCCCCNO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCN(O)C(=O)N(C)C
Temperature: 5 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred slurry of N-decylhydroxylamine (1.71 g, 9.91 mmol) in the THF (20 ml) at room temperature under nitrogen was added triethylamine (1.51 ml, 1.1 equiv.). The reaction mixture was cooled to 5° C. and dimethyl carbamyl chloride (0.92 ml, 1.05 equiv.) was added dropwise over five minutes. After stirring for two hours, the mixture was poured into 1% aqueous citric acid, and worked up as in Example 1 above. Trituration with pentane gave the named compound as a white solid (2.15 g, 89% Yield), mp 44°-45° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[CH:6](C(OCC)=O)[C:5]12[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[Li+].O>CS(C)=O>[Br:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[CH2:6][C:5]12[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C1C(=O)c2c(C)cc(Br)c(=O)n2C12CCCCC2
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Br)c(=O)n2c1C(=O)CC21CCCCC1

Procedure:
To a solution of ethyl 6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate (6, 1.0 mmol, 1.0 eq) in dimethylsulfoxide (15 mL) add lithium chloride (5.0 mmol, 5 eq) and heat the reaction at 140° C. for 16 h. After completion cool the reaction, add water and extract with dichloromethane. Remove the solvent under reduced pressure and purify the crude by silica gel column chromatography to get 6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione (7).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([F:23])([F:22])[C:17]([F:21])=[C:18]([F:20])[F:19]>C(#N)C>[F:19][C:18]([F:20])([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)[CH:17]([F:21])[C:16]([F:23])([F:22])[F:15]
Reactant: O=C1OCC(CO)O1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1OCC(COC(F)(F)C(F)C(F)(F)F)O1
Temperature: 45 °C

Procedure:
Example 2 was prepared by combining 4-(hydroxymethyl)-1,3-dioxolan-2-one (100 g, 0.84 moles) (Huntsman, Salt Lake City, Utah) with potassium carbonate (23 g, 0.166 moles) and acetonitrile (200 mL) in a 600 mL Parr reactor. The reactor was warmed to 45° C. and hexafluoropropene (139 g, 0.92 moles) was added at a constant rate. The reactor was stirred until the decrease in pressure stopped. Volatile material was removed from the reaction mixture by rotary evaporation. The olefin of the desired product was present and was saturated by reaction with anhydrous HF at room temperature. Vacuum distillation was done to purify the product. The fraction that boiled at 145-150° C. at 3 T (0.4 kPa) was collected. The fraction was 97.5% pure. The product was analyzed by GC/MS and F-19 NMR. MCMB/LiFePO4 coin cells (2325) made and cycled as per Test Method E with Example 2 as the only electrolyte solvent had high impedance, and the capacity fade rate could not be calculated.
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([CH2:26][CH2:25][CH:27]3[CH2:29][CH2:28]3)=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: C#CC1CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Examples 1d tole, using 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and ethynylcyclopropane as starting materials; yield 189 mg, 46% over two steps; m/z (ISP+): 399.2, 401.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([NH2:6])=[O:5].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:18][C@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[C:4]([NH2:6])=[O:5]
Reactant: CC(C)(C)C(=O)C(N)=O
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](N=C(C(N)=O)C(C)(C)C)c1ccccc1
Yield: 67.8 %

Procedure:
A solution of 35.0 g (271 mmol) of 3,3-dimethyl-2-oxobutyramide and 75.0 g (619 mmol) of (S)-1-phenylethylamine in 250 ml of toluene was boiled under reflux on a water separator for 92 hours. Subsequently, the solvent and excess amine were removed in a vacuum. The residual oil was crystallized from 300 ml of hexane. 51 g of crude material of melting point 96°-97° C. were obtained. After recrystallization from 400 ml of hexane there were obtained 42.7 g (68%) of analytically-pure (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of melting point 100°-101° C. [α]=-58.5 (c=1.0, CHCl3).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C1C(=O)N([I:27])C(=O)C1>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([I:27])=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2[nH]c(I)nc2n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 5.7 %

Procedure:
A stirred solution of 1,3-di-N-butyl xanthine (100 mg, 3.39 mmol) in anhydrous DMF (3 ml) was treated with NIS (94 mg, 3.75 mmol) and left to stir at rt. under nitrogen for 23 hours. The mixture was partitioned between sat. Na2SO3(aq) solution and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified by passing down an SPE (Si, 5 g) cartridge eluting with EtOAc/cyclohexane mixtures. The product fraction was concentrated to afford the title compound as a white solid (75 mg, 51%); NMR; δH (400 MHz, d6-DMSO) (app.td, 6H, J=7.5 and 4 Hz), 1.21-1.34 (m, 4H), 1.45-1.54 (m, 2H), 1.56-1.66 (m, 2H), 3.84 (t, 2H, J=7.5 Hz), 3.93 (t, 2H, J=7.5 Hz), 14.10 (s, 1H); m/z 391.3[MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21](OCC)=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[Li+].[BH4-].C(Cl)Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:9]2[CH2:10][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH2:21][OH:22])[CH:26]=[C:27]([F:29])[CH:28]=3)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:12]2)[C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:36]#[N:37])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(F)C(c1cc(F)cc(CO)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of 42 mg (0.08 mmol) of ethyl 3-(1-{1-[(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoate in 3 mL of THF was added 0.18 mL (0.36 mmol) of 2 M LiBH4 solution in THF and the solution was stirred overnight at rt. Then it was poured into 20 mL of CH2Cl2 and 5 mL of water. The water layer was extracted with CH2Cl2 and the combined organic layer was concentrated. The residue was purified by silica gel chromatography with hexane/ethyl acetate to afford the title compound as a white solid; Mass Spectrum: m/e=481 (M+1, 35Cl), 483 (M+1, 37Cl).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH-].[NH4+:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: [OH-]
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 1 h

Procedure:
A mixture of 37.0 gm. (0.14 mole) of 2-chloro-3,5-dinitrobenzoyl chloride and 100 ml. of concentrated ammonium hydroxide is placed in a mortar, ground for ten minutes and allowed to stand for one hour. The yellow precipitate is removed by filtration and washed with water. There is obtained 32.3 gm. (94%) of material melting at 181°-3°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH:26]([CH3:32])[O:27][C:28](=[O:31])[C:29]=1[CH3:30])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][CH:26]1[C:25]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[C:2]2=[O:1])=[C:29]([CH3:30])[C:28](=[O:31])[O:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)C(C)OC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)C(C)OC1=O
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate, Xantphos (45.5 mg, 0.079 mmol), water (0.043 mL, 2.4 mmol) and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was degassed by nitrogen for 20 min followed by addition of palladium acetate (8.8 mg, 0.039 mmol). The resulting mixture was heated at 65° C. for 16 h. After filtration the filtrate was concentrated and the residue was purified on silica gel column eluting with EtOAc/hexane to give the title compound. LC/MS: (M+1)+: 365.20.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[N:29]1[O:30][N:31]=[C:32]2[CH:37]=[C:36]([CH2:38][N:39]3[CH2:43][CH2:42][N:41]([C:44]4[S:45][C:46]([C:50]([O:52]CC)=[O:51])=[C:47]([CH3:49])[N:48]=4)[C:40]3=[O:55])[CH:35]=[CH:34][C:33]=12>>[N:29]1[O:30][N:31]=[C:32]2[CH:37]=[C:36]([CH2:38][N:39]3[CH2:43][CH2:42][N:41]([C:44]4[S:45][C:46]([C:50]([OH:52])=[O:51])=[C:47]([CH3:49])[N:48]=4)[C:40]3=[O:55])[CH:35]=[CH:34][C:33]=12
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc4nonc4c3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)O
Yield: 89 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 89% yield: MS (ES+) m/z 360.1 (M+1).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][SiH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11]>>[C:1]([O:4][CH2:7][SiH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COC(OC)[SiH2]CCl
Agent: [Na+]
Product: COC(OC)[SiH2]COC(C)=O

Procedure:
The top, Hydroseal phase and the middle, catalyst phase from Example 5b were admixed with 180 g (2.2 mol) of sodium acetate and the suspension was dried by distilling 10 mL of Hydroseal G 400 H off through a Vigreux column (80 cm) at 1-2 mbar (head), 120-135° C. (head), 150-160° C. (pot). The suspension was cooled down to 130° C., at which point 308 g (2.00 mol) of (chloromethyl)dimethoxymethylsilane were metered in over 47 minutes. The product was distilled out through a Vigreux column (80 cm); the product (acetoxymethyl)dimethoxymethylsilane was obtained at 30 mbar (head), 71-73° C. (head) and 73-80° C. (pot) in the distillate (334 g, 1.87 mol, 94% of theory; purity 99.1% (GC area %)) as a colorless liquid. The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of the chloride, bromide and acetate salt of tetrabutylphosphonium remained in the residue.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[C:18](=O)[CH3:19].[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>CO>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8]([CH:18]=[CH:19][C:25]3([O:6]2)[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CN1CCC(=O)CC1
Reactant: COc1cc(O)c(C(C)=O)cc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])C=CC1(CCN(C)CC1)O2
Temperature: 50 °C
Yield: 68.3 %

Procedure:
Pyrrolidine (1.15 mL, 13.8 mmol) was added to 1-(2-Hydroxy-4-methoxy-5-nitro-phenyl)-ethanone (2.57 g, 12.2 mmol) (Banks, C. K.; Hamilton, C. S. J. Am. Chem. Soc. 1938, 60, 1370) and 1-Methyl-piperidin-4-one (1.60 mL, 13.0 mmol) in Methanol (50.0 mL) and the reaction was stirred under an atmosphere of nitrogen. After overnight stirring, ˜50% conversion was achieved. The mixture was heated at 50° C. for 30 h. Following basic workup, the crude material was purified on ISCO (0-12% MeOH:DCM) to afford 7-methoxy-1′-methyl-6-nitrospiro[chromene-2,4′-piperidin]-4-((3H)-one (2.42 g; Yield=64.9%).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:42]=[CH:41][C:17]([O:18][CH2:19][CH2:20][N:21]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:22][C@H:23]([OH:34])[C@H:24]([C@H:26]2[C@H:31]([OH:32])[CH2:30][O:29][CH:28]([CH3:33])[O:27]2)[OH:25])=[CH:16][CH:15]=1.I.[NH2:44][C:45]1[C:46]([C:53]([NH:55][C:56](SC)=[NH:57])=[O:54])=[N:47][C:48]([Cl:52])=[C:49]([NH2:51])[N:50]=1.CCN(C(C)C)C(C)C>CCO>[NH2:44][C:45]1[C:46]([C:53]([NH:55][C:56](=[NH:57])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][N:21]([CH2:22][C@H:23]([OH:34])[C@@H:24]([OH:25])[C@H:26]3[C@H:31]([OH:32])[CH2:30][O:29][CH:28]([CH3:33])[O:27]3)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:41][CH:42]=2)=[O:54])=[N:47][C:48]([Cl:52])=[C:49]([NH2:51])[N:50]=1
Reactant: CCCCCCN(CCOc1ccc(CCCCN)cc1)C[C@H](O)[C@@H](O)[C@@H]1OC(C)OC[C@H]1O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCCCCCN(CCOc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1)C[C@H](O)[C@@H](O)[C@@H]1OC(C)OC[C@H]1O
Temperature: 70 °C
Yield: 65.3 %

Procedure:
To a solution acetic acid salt 28 (189 mg, 0.313 mmol) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate hydroiodic acid salt (18, 192 mg, 0.502 mmol) in EtOH (8 mL) was added DIPEA (0.42 mL, 2.50 mmol) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 2 h, then cooled to room temperature, and concentrated in vacuum. The residue was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH, 80:18:2 CHCl3/MeOH/NH4OH) to afford carboxamide 20 (142 mg, 65%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.10 (d, J=8.1 Hz, 2H), 6.84 (d, J=8.1 Hz, 2H), 4.66 (q, J=5.1 Hz, 1H), 4.06-4.01 (m, 3H), 3.94-3.89 (m, 1H), 3.82-3.74 (m, 2H), 3.49 (dd, J=9.3, 2.4 Hz, 1H), 2.96-2.78 (m, 3H), 2.67-2.61 (m, 5H), 1.68-1.67 (m, 4H), 1.50-1.48 (m, 2H), 1.29 (br s, 6H), 1.25 (d, J=5.1 Hz, 3H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])C1C=C2C(C=CN2)=CC=1.C(O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([NH2:29])=[O:28])[CH:22]=[C:21]2[N:30]=[C:31]=[O:32])C=C>COCCOC>[F:1][C:2]([F:13])([F:12])[C:26]1[CH:25]=[C:24]2[C:20]([C:21]([N:30]=[C:31]=[O:32])=[CH:22][N:23]2[C:27]([NH2:29])=[O:28])=[CH:19][CH:18]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Solvent: COCCOC
Product: NC(=O)n1cc(N=C=O)c2ccc(C(F)(F)F)cc21

Procedure:
was prepared from 6-trifluoromethylindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide except that the acyl azide intermediate was prepared in 1,2 dimethoxyethane instead of toluene.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16]C(=O)OC(C)(C)C)=[O:10].[O:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH2:35][CH2:34][CH2:33]1>>[NH2:16][C:15]1[S:14][C:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:33]1[O:32][CH2:37][CH2:36][CH2:35][CH:34]=1)=[O:10]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Reactant: CC1(C)OB(C2=CCCCO2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1=CCCCO1
Yield: 8 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl (4-((5-chloro-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate and 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester gave 102 as a white solid (25 mg, 8% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.18 (s, 1H), 7.34-7.28 (m, 1H), 7.06-6.98 (m, 2H), 6.13 (s, 2H), 5.11 (t, J=3.9 Hz, 1H), 4.25 (t, J=5.1 Hz, 2H), 3.89 (s, 3H), 2.32-2.26 (m, 2H), 2.03-1.96 (m, 2H). LCMS (ES+) m/z 418 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:18]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(COCC3CCCNC3)cc2)cc1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(COCc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 49.8 %

Procedure:
Using 3-[(4′-chlorobiphenyl-4-yl)methoxymethyl]piperidine (237 mg, 0.750 mmol) and 3-(methoxycarbonyl)phenylboric acid (270 mg, 1.50 mmol), the same procedure was followed as in Example 2 to give 168 mg (50%) of the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][OH:31].C[O-].[Na+]>CN(C=O)C>[CH3:30][O:31][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(CN2CCOCC2)n1)Nc1csc(-c2ccnc(Cl)c2)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(NC(=O)Nc3cccc(CN4CCOCC4)n3)cs2)ccn1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea (100 mg, 0.23 mmol, Example 90) and MeOH (50 mL) was added solid NaOMe (1.6 g, 29.6 mmol) and DMF (20 mL). The reaction mixture was heated to 130° C. After 2 h, the reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo and diluted with EtOAc and filtered to remove the solid. The filtrate was concentrated in vacuo to afford an orange oil which was purified by silica flash chromatography (5% MeOH/CH2Cl2) to afford the title compound as a white solid. MS m/z: 427.2 (M+H). Calc'd for C20H22N6O3S: 426.15.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][CH2:9][C@@H:8]3[CH2:14][O:15][CH2:16][CH2:17][N:7]3[C:6]=2[N:5]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>CN(C=O)C>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C@@H:8]3[CH2:14][O:15][CH2:16][CH2:17][N:7]3[C:6]=2[N:5]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Sodium hydride (60% in oil, 19.41 mg, 0.485 mmol) was added to a solution of (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 100 mg, 0.441 mmol) in DMF (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, after which tert-butyl bromoacetate (0.078 mL, 0.529 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20-80% EtOAc/hexane gradient) to afford the title compound as an off-white solid (101 mg, 67.2%). 1H NMR (400 MHz, CDCl3) δ 1.44-1.49 (m, 9H), 3.01-3.11 (m, 1H), 3.15-3.29 (m, 2H), 3.37 (dd, J=11.37, 8.84 Hz, 1H), 3.58 (td, J=11.94, 2.91 Hz, 1H), 3.64-3.76 (m, 2H), 3.88-4.07 (m, 3H), 4.53 (dd, J=13.89, 2.02 Hz, 1H), 7.22 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O3, 341.13. found 341.2
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][CH:22]=[O:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:23][CH:22]=[N:21][N:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1N2C[C@@H](CC[C@H]2c2nnco2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
To a −10° C. solution of (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (11 g) in dry DCM (200 mL) was added pyridine (28 mL), followed by dropwise addition of (CF3SO2)2O (28 mL). The reaction mixture was allowed to warm to rt and was stirred for 3 hrs. The reaction mixture was then cooled to −10° C. and quenched with sat. NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 1:3 to 2:1 EtOAc/hexanes) to give (2S,5R)-6-(benzyloxy)-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (4.6 g, 86% for two steps) as a slightly yellow solid. ESI-MS (EI+, m/z): 301.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([N-:14]C(C)C)(C)[CH3:12].[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.BrCC#N.Cl>C1COCC1.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:1]1([CH2:12][C:11]#[N:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCCCC1
Agent: Cl
Agent: N#CCBr
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1(CC#N)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
Treat a −78° C. solution of methyl cyclohexane carboxylate (15.0 g, 0.105 mol) in THF (150 mL) with a 2M solution of lithium diisopropylamide in heptane/THF/ethylbenzene (63.3 mL, 0.126 mol) and stir at −78° C. for 20 minutes under N2. Treat the reaction with bromoacetonitrile (25.31 g, 0.211 mol) and stir at −78° C. for 15 minutes. Warm the reaction to room temperature and stir 4 hours. Acidify the reaction with 1 N HCl and then dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product. Purify with a 0 to 30% ethyl acetate in hexanes gradient on silica gel to afford 7.78 g (41%) of the titled product. Rf=0.32 (3/1 hexanes/ethyl acetate).