Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1)=[O:27]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=2)=[O:27])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCNCC
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Zinc chloride (27.4 g, 201 mmol), diethylamine (15.6 mL, 151 mmol) and t-butanol (14.4 mL, 151 mmol) were combined in benzene (151 mL) at room temperature under a nitrogen atmosphere and stirred for 2 h. 1-(4-chloro-3-nitrophenyl)ethanone (30.1 g, 151 mmol) and 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone (28 g, 101 mmol) were added. The mixture was stirred vigorously for 20 h, and the solid product was collected by filteration and rinsed with benzene, water, methanol, and dichloromethane. The solid was dried in a vacuum oven.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(F)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in the same way as described for Example 1 to give 2′-fluoro-5′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, DMSO) 1.76 (6H, d, J 22), 7.27 (1H, dd, J 6 and 1), 7.64-7.72 (2H, m), 7.80 (1H, s), 7.89-7.92 (3H, m), 8.04 (1H, s), 8.06 (1H, s), 9.15 (1H, d, J 7); m/z (ES+) 375 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=C)[C:5]([F:10])=[CH:4][N:3]=1.[O:11]1CCCC1.[OH2:16]>O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[OH:16])[C:5]([F:10])=[CH:4][N:3]=1
Reactant: O
Reactant: C1CCOC1
Reactant: C=Cc1nc(Cl)ncc1F
Agent: O=[Os](=O)(=O)=O
Product: OC(O)c1nc(Cl)ncc1F
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of OsO4 in water (0.015 g/ml, 265 mL) was added into a 10-L 4-necked round-bottom flask with 2-chloro-4-ethenyl-5-fluoropyrimidine (303 g, 1.24 mol, 1.00 equiv, 65%), tetrahydrofuran (2400 mL) and water (1600 mL). This was followed by the addition of NaIO4(424 g, 1.94 mol, 1.56 equiv, 98%), in portions at 0-10° C. The resulting solution was stirred for 60 min at 0-10° C. in a water/ice bath. The resulting solution was diluted with water (4 L), then extracted with ethyl acetate (5×1000 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5) to afford (2-chloro-5-fluoropyrimidin-4-yl)methanediol as a white solid and (2-chloro-5-fluoropyrimidin-4-yl)methanediol as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[C:8]([C:10]1[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=1)#[N:9]>CN(C=O)C>[CH:3]1([O:7][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]#[N:9])[CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1cccnc1F
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1OC1CCC1
Reaction time: 1 h

Procedure:
NaH 60% dispersion in mineral oil (100 mg, 2.5 mmol) was added to a rt solution of cyclobutanol (0.13 mL, 1.6 mmol) in DMF (1.5 mL). After stirring for 1 h, 3-cyano-2-fluoropyridine (150 mg, 1.23 mmol) was added and the brown suspension was stirred at rt for 1 h. The rxn mixture was quenched with water and extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield 2-cyclobutoxynicotinonitrile as an orange oil. LC-MS B: tR=0.76 min; [M+H]+=175.21. 1H NMR (DMSO) δH: 8.43 (m, 1H), 8.26 (dd, J1=7.6 Hz, J2=1.9 Hz, 1H), 7.17 (dd, J1=7.6 Hz, J2=5.0 Hz, 1H), 5.25 (m, 1H), 2.43 (m, 2H), 2.13 (m, 2H), 1.82 (m, 1H), 1.66 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C([N:11](CC)CC)C.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](N)=[C:19]([CH3:25])[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[C:4]([NH2:11])=[O:5])=[C:19]([CH3:25])[CH:18]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate that formed was collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15](=[O:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Br:17])[O:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=[O:21]>CO.Cl.O>[C:15]([CH2:14][C:13]1[C:8]([O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=1[Br:17])([OH:21])=[O:16]
Reactant: CCOC(=O)C1Oc2cccc(Br)c2CC1=O
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOC(=O)COc1cccc(Br)c1CC(=O)O
Reaction time: 18 h
Yield: 53 %

Procedure:
A suspension of 2-ethoxycarbonyl-5-bromo-3-chromanone (300 mg, 1 mMol) in methanol (5 mL) and 10% hydrochloric acid (3 mL) was heated at reflux for 2 hours. All of the solid had not dissolved; therefore, trifluoroacetic acid (1 mL) was added, and heating was continued for 18 hours. The reaction mixture was diluted with water and extracted well with diethyl ether. The ether phases were combined, dried over sodium sulfate, and concentrated in vacuo to give a yellow glass. Purification by flash chromatography (1:1 hexane:ether) gave the title compound as a light yellow glass (120 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:19])[C:10]=2[CH3:20])=[CH:5][CH:4]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: COc1ccc(-c2c(C)n(C)c3c(O)cccc23)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1cccc2c(-c3ccc(OC)cc3)c(C)n(C)c12

Procedure:
The above compound was prepared from 3-(4-methoxy-phenyl)-1,2-dimethyl-1H-indole-7-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([CH3:10])[N:4]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br-:1].[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]=1[CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CBr)nc1C
Solvent: CC#N
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc1C
Product: [Br-]
Yield: 85.3 %

Procedure:
The bromide from Step 5 (740 mg, 3.7 mmol) and triphenylphosphine (1.31 g, 5 mmol) were dissolved in acetonitrile (15 mL) and the mixture was refluxed for 6 hours. Evaporation of the solvent in vacuo left a solid that was swished in Et2O. Filtration and vacuum drying of the powder gave 1.46 g (86%) of the desired phosphonium salt.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH2:25][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:24]=[C:20]2[C:19]([CH3:45])=[N:18][CH:17]=1>>[CH:13]1([N:9]([C:4]2[N:5]=[C:6]([CH:7]=[CH:25][C:23]3[N:24]=[C:20]4[C:19]([CH3:45])=[N:18][CH:17]=[C:16]([CH3:15])[N:21]4[N:22]=3)[N:2]([CH3:1])[N:3]=2)[CH3:10])[CH2:11][CH2:12]1
Reactant: Cn1nc(N2CCCC2)nc1C=O
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc12
Yield: 52.6 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (75 mg, 416 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (191 mg, 416 μmol, Eq: 1.00) as starting materials. Chromatography afforded Cyclopropyl-{5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (71 mg, 52.6%) as light yellow solid. MS: m/z=325.4 (M+H+), mp: 196.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.Cl.[NH2:12][OH:13].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][O:13][N:12]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NO
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Product: CC(C)(C)OC(=O)CON=Cc1ccc(Cl)c(Cl)c1

Procedure:
Condensation of 3,4-dichlorobenzaldehyde with hydroxylamine hydrochloride followed by reaction with tert-butyl bromoacetate using a procedure similar to the one described for the preparation of compound 6-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution dichloromethane-hexane 1:1) (94% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.52 (9H, s, t-Bu), 4.63 (2H, s, OCH2), 7.41 (1H, dd, J=1.9 Hz and J=8.6 Hz, aromatic), 7.47 (1H, d, J=8.6 Hz, aromatic), 7.71 (1H, d, J=1.9 Hz, aromatic), 8.13 (1H, s, CH).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[F:25][C:21]1[N:20]=[C:19]([CH2:18][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: Fc1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccc(F)n2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.1 %

Procedure:
A mixture of Intermediate 44 (200 mg, 0.938 mmol), 2-(chloromethyl)-6-fluoropyridine (ALLICHEM, 137 mg, 0.938 mmol) and potassium carbonate (ALDRICH, 157 mg, 0.938 mmol) dissolved in acetonitrile (10 mL) was stirred at 80° C. for 6 h. 0.2 eq. of 2-(chloromethyl)-6-fluoropyridine (ALLICHEM, 27.3 mg, 0.188 mmol) and 5 mL of dry acetonitrile were added. Reaction was stirred at 80° C. overnight. Reaction was diluted with DCM and filtered. Solvent was evaporated to dryness. Residue was purified by silica column chromatography using a linear gradient of hexane/EtOAc to yield the title compound (94 mg, 0.292 mmol, 31% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.02-7.88 (m, 6H), 7.11 (m, 2H), 6.43 (d, 1H), 5.45 (s, 2H). [ES+MS] m/z 323 (MH+).
Reaction SMILES: O[C:2]1[C:3](O)=[CH:4][C:5]2[CH2:6][C@H:7]3[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][C:28](=[O:34])[N:8]3[C@H:9]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14](C(OC(C)(C)C)=O)[CH:13]=3)[C:10]=2[CH:11]=1.[C:36]([O-])([O-:38])=[O:37].[Cs+].[Cs+].CN(C=O)C.BrCCl>CCOC(C)=O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C@H:9]2[N:8]3[C@H:7]([C:31](=[O:32])[N:30]([CH3:33])[CH2:29][C:28]3=[O:34])[CH2:6][C:5]3[CH:4]=[C:3]4[O:37][CH2:36][O:38][C:2]4=[CH:11][C:10]2=3)=[CH:13]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC(=O)N2[C@H](c3cn(C(=O)OC(C)(C)C)c4ccccc34)c3cc(O)c(O)cc3C[C@H]2C1=O
Agent: ClCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC(=O)N2[C@H](c3c[nH]c4ccccc34)c3cc4c(cc3C[C@H]2C1=O)OCO4
Temperature: 150 °C
Yield: 30.7 %

Procedure:
0.665 g (1.4 mmol) (5) and 0.6853 g (2.1 mmol) Cs2CO3 was suspended in 3.3 ml freshly distilled DMF. 0.140 ml (2.1 mmol) BrCH2Cl was added and the mixture was heated at 150° C. for 1.5 h. The heat source was removed and the mixture was allowed to cool to r.t. after which the mixture was filtered and separated with 100 ml EtOAc and 100 ml H2O. The water phase was extracted with 2×100 ml EtOAc. The pooled organic phases were washed with 150 ml brine, dried over Na2SO4, filtered and evaporated. Flash chromatography (Pet. ether:EtOAc, 1:4) gave 0.167 g (0.43 mmol, 31%) (6).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[OH:32][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:12]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)c1cc(B(O)O)ccn1
Reactant: CC(C)(O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(-c2ccc(C(C)(C)O)nc2)ccn1
Temperature: 85 °C
Yield: 46.6 %

Procedure:
A mixture of crude 2-(isopropoxycarbonyl)pyridin-4-ylboronic acid (700 mg, ˜1.0 mmol), dppf(Pd)Cl2 (40 mg, 5 mol %), potassium carbonate (280 mg, 2.0 mmol) and 2-(5-bromopyridin-2-yl)propan-2-ol (216 mg, 1.0 mmol) in degassed toluene (3 mL), degassed water (1 mL) and degassed isopropanol (1 mL) was heated at 85° C. for 1 hour. The aqueous layer was discarded and the solvent removed under reduced pressure. The residue was purified by flash chromatography (rf: 0.53 in 20:1 ethyl acetate:methanol) to give isopropyl 6-(2-hydroxypropan-2-yl)-3,4′-bipyridine-2′-carboxylate (140 mg, 47% yield). 301.1 (M+1).
Reaction SMILES: [Cl:1][C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][C:9]1([CH3:16])[O:13][CH:12](NC)[CH2:11][O:10]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:16][C:9]1([CH3:8])[O:13][CH:12]([CH2:18][NH:17][C:2](=[O:3])[O:4][CH:5]([Cl:7])[CH3:6])[CH2:11][O:10]1.[ClH:1].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CNC1COC(C)(C)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)NCC1COC(C)(C)O1
Product: Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (1.46 g, 1.1 mL, 10.2 mmol) was reacted with (2,2-dimethyl-[1,3]-dioxolan-4-yl)-methylamine (Aldrich, 1.21 g, 1.2 mL, 8.98 mmol) and pyridine (870 mg, 0.89 mL, 11.0 mmol) in methylene chloride (15 mL) at 78° C. for 3 h to give 1-chloroethyl (2,2-dimethyl-1,3-dioxolan-4-yl)methylcarbamate with pyridine hydrochloride (1:1). A portion of this material (622 mg, 1.76 mmol) in dimethylformamide (5 mL) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (201 mg, 0.326 mmol) in the presence of cesium carbonate (806.9 mg, 2.48 mmol) in dimethylformamide (7 mL) overnight to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethylcarbamoyloxy)-ethyl ester as a white solid (97.7 mg, 36% yield). MS (ES+) m/z calcd. for C40H45C12F2N4O8: [(M+H)+]: 817, found: 817
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:20]3[CH:24]=[CH:23][NH:22][CH:21]=3)=[N:19][C:4]1=2)[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O.O>CN(C=O)C.CC#N>[C:30]([C:21]1[NH:22][CH:23]=[CH:24][C:20]=1[C:18]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:3]([CH2:1][CH3:2])[C:4]=2[N:19]=1)#[N:29].[C:30]([C:23]1[NH:22][CH:21]=[C:20]([C:18]2[CH:17]=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[CH:13]=[CH:12][CH:11]=[N:10][C:9]=4[N:3]([CH2:1][CH3:2])[C:4]=3[N:19]=2)[CH:24]=1)#[N:29]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cc[nH]c3)nc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3c[nH]c(C#N)c3)nc21
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cc[nH]c3C#N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.093 g) in DMF (1 mL) and CH3CN (1 mL) was cooled to -50° C., and chlorosulfonyl isocyanate (0.041 g) was added in one portion. The resulting mixture was allowed to warm to room temperature and stirred for 2 h, then poured into water, extracted with CH2 Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was purified by preparative plate chromatography (ether) to give two pure compounds. Crystallization of each of these pure compounds from ethyl acetate/pet ether provided 0.038 g of the title compound, mp 262°-263° C., and 0.038 g of 2-(2-cyanopyrrol-4-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, mp 268°-269° C.
Reaction SMILES: C(O[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.CO[C:16]([C:18]#CC(OC)=O)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH:16]1[C:8]2[C:9](=[CH:12][CH:13]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:18]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc2ccccc2c1
Yield: 142.9 %

Procedure:
p-t-butoxy styrene 35.25 g (0.2 mol) and acetylene dicarboxylic acid dimethyl ester 56.84 g (0.4 mol) were dissolved in nitrobenzene, 200 ml, and then reacted at the temperature of 140° C. for 5 hours. After cooling, nitro benzene was removed under a reduced pressure, silica gel column chromatography (developing solvent n-hexane:acetic acid ethyl=9:1) was performed to the residual, thus 40.78 g crude material was obtained. Further, 36.63 g (yield 57.9%) objective naphthalene compounds were obtained by recrystallizing through diisopropyl ether. Melt points were 82.0-83.0° C. This naphthalene compound's infrared absorption spectrum is indicated in FIG. 4.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=3[Cl:27])[C:14]2=[O:28])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:20]([Cl:27])=[CH:21][C:22]([O:26][CH:32]([CH3:34])[CH3:33])=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:28])[CH2:9][CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(Cl)c(CC2CCN([C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(Cl)c1

Procedure:
Add 1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2,6-dichloro-4-hydroxy-benzyl)-pyrrolidin-2-one (Preparation 72) (0.543 g, 1.15 mmol), 2-bromopropane (0.212 g, 1.72 mmol), and potassium carbonate (0.365 g, 2.64 mmol) together with acetone (10 mL) and reflux overnight. Concentrate the reaction mixture under reduced pressure to give a residue. Purify the residue over silica gel, (98:2 dichloromethane in methanol) to give 0.080 g (14%) of the title compound: mass spectrum m/z: 516(M+1).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH:45]1(N)CC[CH2:46]1.N[C:51]1C=CC=C[CH:52]=1>>[CH:6]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:52][CH2:51][CH2:30]5)=[O:27])=[CH:21][CH:20]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=34)[CH:8]([CH2:45][CH2:46]1)[CH2:9][O:12][CH2:5]2
Reactant: NC1CCC1
Reactant: Nc1ccccc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)NC4CCC4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing cyclobutylamine as the aniline component. (44%, MS=448.4 (M+H))
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([S:19](Cl)(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)=[O:28].Cl>O>[CH2:7]([S:19]([NH:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)=[O:28])(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(C(=O)Nc2ccc(Cl)c(Cl)c2)ccc1OC
Temperature: 25 °C
Yield: 79.7 %

Procedure:
Pyridine (5 mL) was added to a mixture of 1-dodecane-sulfonyl chloride (Maybridge) (0.8 g, 3.0 mmol) and 3-amino-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide from Example 4 (0.73 g, 3.0 mmol) and stirred at room temperature. After 5 days the mixture was heated on a steambath for 1.5 hours, allowed to cool, and added to water (150 mL), acidified with 4N HCl, and stirred for an hour. The precipitate was filtered off, rinsed with water then with ethanol and dried to afford the product (1.3 g); m.p. 151-152° C. after recrystallization from ethanol and chromatography on silica gel in CHCl3/EtOAc (9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1CCNCC1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
A mixture of 250 mg (0.51 mmol) of the 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 103.2 mg (1.02 mmol) of 4-hydroxypiperidine in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr. Saturated sodium bicarbonate was added and the precipitate was filtered and washed with hexane to give the first crop of product. The filtrate was extracted with ethyl acetate and the organic layer with purified by preparative TLC to yield the second crop. The two crops were combined to give 105.8 mg (41%) tan solid: mp >215° C.