Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[CH:20][CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:2]2[CH:1]=[CH:5][CH:4]=[CH:3]2)=[CH:31][CH:32]=1
Reactant: C1=CCC=C1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc(C(=C2C=CC=C2)c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, a reaction vessel equipped with a dropping funnel was charged with 40 mL of dry tetrahydrofuran and 2.15 mL (25.89 mmol) of cyclopentadiene. While cooling this solution to 0° C., 18 mL (28.47 mmol) of a 1.58 mol/L hexane solution of n-butyllithium was slowly added dropwise and the mixture was stirred. Subsequently, a dropping funnel was charged with a solution prepared by dissolving 5.00 g (19.91 mmol) of 4,4′-dichlorobenzophenone in 30 mL of tetrahydrofuran, and the solution was slowly added dropwise. The mixture was left to be stand so that the temperature of the mixture was at room temperature, and stirred for one day. This reaction solution was then subjected to extraction with diethyl ether. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, and then dried over magnesium sulfate. The solvent was removed by distillation under reduce pressure. The residue was purified by using a silica gel column to obtain a target product (yield 3.37 g (57%)). The target product was identified by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH2:11]([NH:18][CH2:19][C@@H:20]([OH:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[CH2:11]([N:18]([CH2:9][C:3]1[C:2]([Cl:1])=[N:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:19][C@@H:20]([OH:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ncc(Cl)nc1Cl
Reactant: C[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](O)CN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 3,5-dichloropyrazine-2-carbaldehyde (3.0 g), (2S)-1-(benzylamino)propan-2-ol (3.36 g) and acetic acid (4.9 mL) in THF (50 mL) was added sodium triacetoxyborohydride (7.18 g), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and basified with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→25% ethyl acetate/hexane) to give the title compound (3.48 g, 63%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6](OC)[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]=1
Reactant: CCn1ncc(OC)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ncc(Cl)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=159.1, 161.1 (M+H+), was prepared in accordance with the general method of example 23c by treatment of 2-ethyl-5-methoxy-2H-pyridazin-3-one with phosphorus oxychloride.
Reaction SMILES: Cl[C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=[S:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>CN(C)C=O>[CH3:17][C:16]1[C:2]2[S:12][C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:4][C:3]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=S)c2ccccc2)c1Cl
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: CN(C)C=O
Product: Cc1cccc2nc(-c3ccccc3)sc12

Procedure:
91.6 g (0.35 mol) of the compound from Example VI in 1 l of dimethylformamide were boiled under reflux with 64 g (0.42 mol) of diazabicycloundecane for 3 h. The mixture was concentrated, the residue was taken up in methylene chloride/water, and the solution was rendered weakly acidic, washed with water, dried and concentrated.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][N:8]([CH3:10])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].CCOC(C)=O>C(#N)C>[CH3:22][O:21][C:19]([C:7]1[N:8]([CH3:10])[CH:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: Cn1cnc(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C(C)(C)C)cn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-tert-butyl-1-methyl-1H-imidazole (800 mg, 5.79 mmol, prepared as described in the previous step) and triethylamine (2.00 mL, 14.4 mmol) in acetonitrile (10 mL) at −30° C. was added methyl chloroformate (0.890 mL, 11.6 mmol) slowly under Ar. The resulting mixture was warmed to room temperature and continued to stir for 16 h. The resulting mixture was then treated with EtOAc (50 mL) and washed with H2O (2×20 mL), brine (20 mL) and then dried with Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (0:100-10:90 MeOH/DCM) to yield 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid methyl ester as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 6.78 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 1.30 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C10H16N2O2: 197.1 (M+H). Measured: 197.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:26][C@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:34][O:33][C:31](=[O:32])[C@H:27]([CH:28]([CH3:30])[CH3:29])[NH:26][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1)=[O:18]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
4′-Nitro-1,1′-biphenyl-4-carboxylic acid (0.60 g, 2.4 mmol) was dissolved in methylene chloride (25 mL), and then oxalyl chloride (0.32 mL, 3.7 mmol) was added, followed by one drop of N,N-dimethylformamide. The resulting mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and further dried under vacuum for 30 min. The residue was dissolved in methylene chloride (20 mL) and added dropwise to an ice-cold mixture of methyl L-valinate hydrochloride (0.54 mg, 3.2 mmol), methylene chloride (25 mL), and triethylamine (1.74 mL, 12.3 mmol). The resulting solution was stirred on ice for 1 h and then at rt overnight. The mixture was diluted with methylene chloride and washed with 1N aqueous HCl solution and brine. The organic layer was separated and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage® system, 2:1 hexanes/EtOAc) to afford methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.70 g, 80%). 1H NMR (400 MHz, CD3OD) δ 1.06 (dd, 6H), 2.38 (m, 1H), 3.77 (s, 3H), 4.52 (d, 1H), 7.82 (d, 2H), 7.91 (d, 2H), 7.97 (d, 2H), 8.33 (d, 2H); LC-MS m/z 357.1 (MH+), retention time 3.07 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[F:32][C:33]([F:62])([F:61])[C:34]1[C:38](B(O)O)=[CH:37][N:36]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:35]=1>>[F:30][C:28]([F:29])([F:31])[S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:38]5[C:34]([C:33]([F:61])([F:62])[F:32])=[N:35][N:36]([C:42]([C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)([C:55]6[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=6)[C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=6)[CH:37]=5)[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1)C(F)(F)F
Product: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5C(F)(F)F)cc34)CC2)cc1)C(F)(F)F
Yield: 93.4 %

Procedure:
150 mg 6-bromo-4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl] quinoline (compound in Production Example 456) and 160 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 221 mg 4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl]-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 106 mg of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])=[O:4].[Br:15]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8](=[O:10])[CH2:9][Br:15])=[O:4]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)COC(=O)C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(COC(=O)C(F)(F)F)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a stirred solution of 2,2-dimethyl-3-oxobutyl trifluoroacetate (W. C. Lumma, Jr. and O. H. Ma, J. Org. Chem., 1970, 35, 2391-2393, 8.45 g, 39.8 mmol) in chloroform (26 mL) was added bromine (1.93 mL, 37.8 mmol) in chloroform (14 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was poured into crashed ice/water, and aqueous Na2S2O3 (20 mL) and aqueous NaH2PO4 (40 mL) were added. After the mixture was extracted with chloroform (3×30 mL), the extract was dried over magnesium sulfate and concentrated. Distillation of the residue at 99-102° C. under diminished pressure (3.4 mmHg) afforded 3.58 g (30%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][CH:2]([Cl:32])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:28][CH:27]([F:29])[CH2:26]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].Cl.C([O-])(O)=O.[Na+]>O.O1CCOCC1>[Cl:32][CH:2]([Cl:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:28][CH:27]([F:29])[CH2:26]3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[OH:7])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CN4CC(F)C4)cc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(CN3CC(F)C3)cc2)cc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a slurry of the product of step 1 (875 mg, 1.81 mmol) in water (10 mL) is added 4 N HCl in dioxane (7 mL) and the mixture stirred at room temperature for 24 hours. Reaction is cooled with ice water and basified slowly using solid NaHCO3. The mixture is partitioned between ethylacetate and brine and subsequently extracted with ethyl acetate (3×30 mL). Combined extracts are dried over Na2SO4 and concentrated. Crude product dissolved in ethyl acetate (2 mL), adsorbed on celite and purified on silica gel eluting from 40 to 80% ethyl acetateheptane to give the title compound (560 mg). 1HNMR (400 MHz, DMSO-d6) δ: (1H-NMR) 3.07-3.20 (m, 2H), 3.49-3.61 (m, 2H), 3.66 (s, 2H), 4.14-4.32 (m, 1.5H), 4.36-4.44 (m, 0.5H), 4.54-4.60 (m, 0.5H), 4.65-4.72 (m, 0.5H), 4.85-4.91 (m, 1H), 5.07-5.14 (m, 0.5H), 5.21-5.29 (m, 0.5H), 5.95 (d, 1H, J=4.0 Hz), 6.53 (s, 1H), 7.34 (d, 1H, J=8 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.57-7.63 (m, 4H), 8.61 (d, 1H, J=8 Hz), (m/z (Cl) 443 [M++1].
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:11][CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
4-(N—BOC amino) piperidine (17 kg, 84.88 mol) was dissolved in DCM (90 kg), triethylamine (10.14 kg, 100.16 mol) was added, and the resulting solution was cooled to 0-5° C. Benzyl chloroformate (16.51 kg, 96.76 mol) was added over 45 minutes while keeping the temperature at <25° C., after which the solution was aged for 30 minutes at 20° C. 2 M HCl (61 kg, 118.13 mol) was then added over 10 minutes while keeping the temperature at <25° C. The mixture was agitated for 10 minutes and then the agitation was stopped and the phases were allowed to separate. The phases were then separated from each other, and the organic phase was distilled in vacuo to a volume of 35 L. Isopropyl acetate (89 kg) was then added, and the batch was concentrated by vacuum distillation at less than 35° C. to a volume of 50 L to crystallize the title product. Heptane (47 kg) was then added over 10 minutes, and the resulting slurry cooled to and aged at 20° C. for 20 minutes, after which the aged slurry was filtered, washed with heptane (17 kg), and dried by N2 sweep on the filter to give the title product as a white solid (24.7 kg, 87%). 1H NMR (CDCl3) 7.33 (5H, m), 5.13 (2H, s), 4.47 (1H, m), 4.11 (2H, m), 3.61 (1H, m), 2.93 (2H, m), 1.94 (2H, m), 1.45 (9H, s) and 1.30 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:23]C(C)([O-])C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:23])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reaction time: 0.17 h

Procedure:
Codeinone (300 g) was added to a stirred suspension of potassium tert-butoxide (153 g) in N,N-dimethylformamide (5 ml) at room temperature. After 10 minutes, methyl trifluoromethanasulphonate (164 mg) was added dropwise to the suspension. The solution was stirred for 5 minutes, diluted with ethyl acetate (30 ml), and then poured into water (50 ml). The aqueous phase was removed, and the organic phase was dried with sodium sulphate and evaporated, producing an orange solid. Analysis by HPLC Against pure thebaine gave a thebaine content of 10%.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[N:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)n1
Reactant: C1COCCN1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Fc1nc(CN2CCOCC2)ccc1Br
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 12.9 %

Procedure:
A solution of 3-bromo-2-fluoro-6-methylpyridine (1.44 g, 7.58 mmol) (Waterstone Technology) in carbon tetrachloride (15 mL) was treated with N-bromosuccinimide (1.42 g, 7.96 mmol) and dibenzoyl peroxide (184 mg, 0.758 mmol) and heated in an oil bath at 80° C. for 2 h, when LCMS detected a mixture of starting material, mono- and bis-brominated products. The reaction mixture was cooled to RT and filtered through a fritted funnel The filtrate was concentrated and the resulting brown oil was purified on a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 1-20% EtOAc in hexanes to give a thick oil containing a mixture of starting material, mono- and bis-brominated products. The residue was dissolved in 5 mL of DMF at 0° C., treated with morpholine (0.715 mL, 8.21 mmol) and potassium carbonate (1.1 g, 7.70 mmol), and stirred at 0° C. for 45 min. Icy water (10 mL) was added and stirred at RT for 15 min. The off-white solid was filtered, rinsed with 2×5 mL of water and collected. The solid was dried in a vacuum oven at 40° C. for 48 h to yield 268 mg of 4-((5-bromo-6-fluoropyridin-2-yl)methyl)morpholine. The filtrate was transferred to a separatory funnel and extracted with 2×50 mL of EtOAc. The EtOAc solution was washed with brine, dried and concentrated. The residue was purified on a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 50-75% EtOAc in hexanes to give 432 mg of 4-((5-bromo-6-fluoropyridin-2-yl)methyl)morpholine. 1H NMR (400 MHz, d6-DMSO) δ 8.26 (1H, m); 7.36 (1H, dd, J=7.8, 1.4 Hz); 3.58 (4H, t, J=4.3 Hz); 3.52 (2H, s); 2.41 (4H, t, J=4.3 Hz). m/z (ESI, +ve ion) 275/277 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])(O)[C:6]=2[CH:23]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])[C:6]=2[CH:23]=1
Reactant: CCOCCCC1(O)c2ccccc2C=Cc2ccc(N)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOCCCC1c2ccccc2C=Cc2ccc(N)cc21

Procedure:
3-Amino-5-(3-ethoxypropyl)-5H-dibenzo[a,d]cyclohepten-5-ol (10 g., 0.032 mole) and sodium borohydride (12.3 g., 0.325 mole) are ground together in a mortar. The mixture is added in portions to 250 ml. of trifluoroacetic acid, cooled in ice, and stirred vigorously under a stream of nitrogen in an efficient fume hood. Upon completion of the addition, the mixture is stirred for 15 minutes and the bulk of the trifluoroacetic acid removed under vacuum.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:24]=[C:25]([CH3:30])[CH:26]=[CH:27][C:28]=1Cl)([O-:22])=[O:21].Cl>CN(C=O)C.O.CCOCC>[C:1]([CH:3]([C:28]1[CH:27]=[CH:26][C:25]([CH3:30])=[CH:24][C:23]=1[N+:20]([O-:22])=[O:21])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
benzyl cyanoacetate (3.50 g; 20 mmol) is added to a suspension of potassium carbonate (6.08 g; 44 mmol) in 5 mL of DMF. The carbonate is washed with 2 mL of DMF. A solution of 3-nitro-4-chlorotoluene (3.41 g, 20 mmol) in 5 mL of DMF is added and the resulting reaction mixture is stirred at 70° C. for 24 hours. After cooling down to ambient temperature, it is treated with a 5N aqueous solution of HCl (12.5 mL). The mixture is divided between ether (100 mL) and water (50 mL) then the organic phase is re-extracted with ether. The ethereal phases are washed with water, dried over anhydrous MgSO4, filtered under vacuum and evaporated. The residue is purified by chromatography on silica gel (eluent: CH2Cl2/pentane, 1/1) in order to produce benzyl 2-cyano-2-(2-nitro-4-methylphenyl)ethanoate with a yield of 75%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[O:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2B(O)O)[CH2:23][CH2:22][CH2:21]1>>[O:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: OB(O)c1cccc2c1OCCC2
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OCCC4)n2)c1

Procedure:
Example 12 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 3,4-dihydro-2H-chromen-8-ylboronic acid (Parkway Scientific LLC).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[N:27]2[CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=[C:26]2[CH:25]=[CH:24][CH:23]=1)=O>C1C=CC=CC=1.C(Cl)(Cl)Cl.O>[CH2:15]([O:14][P:10]([O:11][CH2:12][CH3:13])(/[CH:1]=[CH:20]/[C:22]1[N:27]2[CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=[C:26]2[CH:25]=[CH:24][CH:23]=1)=[O:17])[CH3:16]
Reactant: CCOC(=O)c1cn2c(C=O)cccc2n1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cn2c(/C=C/P(=O)(OCC)OCC)cccc2n1
Reaction time: 2 h

Procedure:
Tetraethyl methylenediphosphonate (Lancaster) in benzene was added to a benzene solution of sodium hydride (NaH). The product from Example 54, also dissolved in benzene, was then added dropwise to the reaction mixture. After stirring the resulting mixture for 2 h under an Ar atmosphere, the reaction was diluted with CHCl3 /H2O (2/1). The CHCl3 layer was separated and the aqueous layer extracted with CHCl3. Chromatography of the residue after removal of all solvent from the combined extracts gave the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-:29].[K+].[K+].OO.[Na]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:29])=[CH:22][CH:21]=2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Agent: OO
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Reaction time: 0.08 h
Yield: 182.4 %

Procedure:
To a solution of 4-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzonitrile (Example 53, 50 mg, 0.13 mmol) in dimethylsulfoxide (1.3 mL) was added potassium carbonate (9 mg, 0.07 mmol) in water (0.65 mL) and the reaction stirred for 5 minutes. Hydrogen peroxide (0.06 mL) was added and the reaction stirred for 2 hours. Saturated aqueous sodium sufite solution was added and the products extracted into ethyl acetate. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to give the title compound as a white solid (51 mg, 98%). (400 MHz, d6 DMSO): 8.15 (1H, s), 8.03 (4H, s), 7.96 (2H, d, J=8.5 Hz), 7.84 (3H, d, J=8.6 Hz), 7.61 (1H, s), 7.39 (2H, d, J=7.2 Hz), 7.33-7.27 (1H, m), 7.15 (1H, td, J=2.3, 8.6 Hz).