Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:38][CH3:39])[N:9]=1.FC(F)(F)C(O)=O>ClCCl.C(Cl)(Cl)Cl.CC(O)C.[OH-].[Na+]>[CH3:39][O:38][C:20]1[CH:21]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:10]1[N:9]=[C:8]([CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][N:11]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (I8) (0.276 g, 0.449 mmol) in dichloromethane (8 mL), was added trifluoroacetic acid (0.669 mL, 8.98 mmol) and the resulting mixture was stirred under a nitrogen atmosphere for 18 hours. The solvents were evaporated in vacuo to give a yellow residue which was dissolved in 3:1 chloroform/2-propanol and 1 M aqueous sodium hydroxide solution. The aqueous layer was extracted with 3:1 chloroform/2-propanol (3×15 mL) and the combined organic extracts were washed with water, brine, dried (magnesium sulfate), filtered and evaporated to give the title compound (1) (0.229 g, 99%) as a yellow foam; 1H NMR (300 MHz, d6-DMSO) δ 2.87-3.10 (m, 12H), 3.46 (s, 2H), 3.78 (s, 3H), 4.32 (d, 1H, J=4.2 Hz), 6.48 (dd, 1H, J=2.2, 8.7 Hz), 6.61 (d, 1H, J=2.1 Hz), 6.88 (brs, 1H), 7.15-7.30 (m, 4H), 7.38 (brs, 1H), 7.46 (brs, 1H), 8.51 (s, 1H) and 8.81 (s, 1H). LCMS Method B: rt 5.65 min; m/z 515.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[C:7]([CH3:19])=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([C:37]([OH:38])=[O:40])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[C:7]=1[CH3:19]
Reactant: C=CCc1c(O)c(Cl)c(C)c2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Cl)c2c(c3oc4ccccc4c(=O)c13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A mixture of 4-allyl-2-chloro-3-hydroxy-1-methyl-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (6.4 g) and chloroform (300 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.6 g of 4-chloro-1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 284°-287° C. This compound showed a mass spectrum having a molecular ion peak at m/e 330.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[C@H:10]([CH3:11])[CH2:9][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1=[O:20])C.[OH-].[Na+]>CCO>[C:16]([O:15][C:13]([NH:12][C@H:8]1[CH2:9][C@@H:10]([CH3:11])[N:6]([CH2:5][C:4]([OH:21])=[O:3])[C:7]1=[O:20])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(=O)O
Reaction time: 1 h

Procedure:
To a solution 13-8 (527 mg, 1.75 mmol) in EtOH was added 1N NaOH (1.93 mL, 1.925 mmol). After stirring for 1 h, the solvents were evaporated, the mixture was diluted with EtOAc, acidified with 10% KHSO4, washed with brine, dried over MgSO4, and evaporated to give 13-9 as a white solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[N:16](OC)=[O:17].S(=O)(=O)(O)O.N([O-])=O.[Na+]>CO.O>[OH:17][N:16]=[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12]#[N:13]
Reactant: CON=O
Reactant: N#CCc1cccc2ccccc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(=NO)c1cccc2ccccc12
Reaction time: 4 h

Procedure:
2-(1-naphthyl)acetonitrile (16.7 g.) was added to a solution of sodium hydroxide (4.2 g.) in methanol (80 ml.). To the mixture was introduced under ice-cooling gaseous methyl nitrite which was prepared by adding a solution of conc sulfuric acid (5 ml.) in water (10 ml.) to a solution of sodium nitrite (8.3 g.) in a mixture of methanol (5.5 ml.) and water (5 ml.). The mixture was stirred for 4 hours at the same temperature and the reaction mixture was treated by conventional method to give 2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.1 g.), oil.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:24][CH:25]=2)[CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:39])(C)(C)C.[OH-].[Li+]>C1COCC1>[CH:36]1([C:21]2[C:20]([CH:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:40])=[O:5])=[C:10]([CH3:39])[CH:11]=3)[CH2:17][CH2:18][CH3:19])=[CH:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)[N:22]=2)[CH2:38][CH2:37]1
Reactant: CCCC(Oc1ccc(OCC(=O)OC(C)(C)C)c(C)c1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
A solution of 150 mg (0.261 mmol) [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butoxy}-2-methyl-phenoxy)-acetic acid tert-butyl ester and 0.52 ml 1N lithium hydroxide solution in 1.5 ml THF were stirred at RT for 2 h. The solution was partitioned between ether, 1N HCl and water and the ether layer then concentrated under reduced pressure. The crude product was repeatedly concentrated in with ether until a foam of 121 mg pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butoxy}-2-methyl-phenoxy)-acetic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[O:13][C:12](=[O:14])[NH:11][CH2:10][CH2:9]1.C(OC(=O)CCC(C1C=CC=CC=1C)=O)C.CC1C=C([C@H]2OC(=O)NCC2)C=C(C)C=1.[H-].[Na+].Br[CH2:49][C:50]1[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[CH:52][C:51]=1[C:60]1[CH:65]=[C:64]([CH:66]([CH3:68])[CH3:67])[CH:63]=[CH:62][C:61]=1[Cl:69]>>[Cl:69][C:61]1[CH:62]=[CH:63][C:64]([CH:66]([CH3:67])[CH3:68])=[CH:65][C:60]=1[C:51]1[CH:52]=[CH:53][C:54]([C:56]([F:57])([F:58])[F:59])=[CH:55][C:50]=1[CH2:49][N:11]1[CH2:10][CH2:9][C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[O:13][C:12]1=[O:14]
Reactant: Cc1ccccc1[C@@H]1CCNC(=O)O1
Reactant: CC(C)c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: CCOC(=O)CCC(=O)c1ccccc1C
Agent: Cc1cc(C)cc([C@@H]2CCNC(=O)O2)c1
Agent: [H-]
Product: Cc1ccccc1[C@@H]1CCN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2Cl)C(=O)O1

Procedure:
(6S)-6-(2-methylphenyl)-1,3-oxazinan-2-one (prepared from ethyl-4-(2-methylphenyl)-4-oxobutyrate by a procedure analogous to that reported for Intermediate 21; 20 mg; 0.10 mmol) was treated with sodium hydride (60% in oil; 8.0 mg; 0.20 mmol) and 2-(bromomethyl)-2′-chloro-5′-isopropyl-4-(trifluoromethyl)biphenyl (Intermediate 27; 41 mg; 0.10 mmol) as described in Example 11 to afford (6S)-3-{[2′-chloro-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-6-(2-methylphenyl)-1,3-oxazinan-2-one as a white solid. LCMS=502.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.78 (s, 1H), 7.67-7.64 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.45 (s, 1H), 7.40-7.37 (m, 1H), 7.28-7.24 (m, 3H), 7.19-7.17 (m, 1H), 7.11 (dd, J=8, 2.1 Hz, 1H), 5.51 (dd, J=9.9, 2.8 Hz, 1H), 4.69 (d, J=15.8 Hz, 1H), 4.45 (d, J=15.8 Hz, 1H), 3.31-3.21 (m, 1H), 3.14-3.10 (m, 1H), 2.98-2.93 (m, 1H), 2.35 (s, 3H), 2.20-2.15 (m, 1H), 2.14-2.04 (m, 1H) 1.29 (d, J=6.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11](=[CH:20]OCC)[C:12]([NH:14][C:15](OCC)=[O:16])=[O:13])#[N:10]>C1C2C(=CC=CC=2)CCC1>[C:9]([C:11]1[C:12](=[O:13])[NH:14][C:15](=[O:16])[N:6]([C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:20]=1)#[N:10]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1ccc(F)cc1
Solvent: c1ccc2c(c1)CCCC2
Product: N#Cc1cn(-c2ccc(F)cc2)c(=O)[nH]c1=O

Procedure:
Following the method of Example 2, 4-fluoroaniline (0.05 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.05 mol) and heated at reflux in tetralin to yield 5-cyano-1-(4-fluorophenyl)uracil, which is then reacted with trichloromethanesulfenyl chloride, in NaOH and dichloromethane, to yield the final product, 5-cyano-1-(4-fluorophenyl)-3-trichloromethanesulfenyluracil, m.p. 163°-165.5°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[CH2:37](O)[C:38]#[C:39][CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C:38]#[C:39][CH3:40])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH3:12])=[O:4]
Reactant: CC#CCO
Reactant: COC(=O)c1cc(-c2ccccc2)cc(CN2CCN(C)CC2)c1N(C)S(=O)(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of 0.810 g (1.59 mmol) of the product of Example 73 and 0.594 mL (7.95 mmol) of 2-butyn-1-ol in 8 mL of THF, was added 2.08 g (7.95 mmol) of triphenylphosphine and then 1.25 mL (7.95 mmol) of diethyl azodicarboxylate. The mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 2% methanol/dichloromethane to provide 0.830 g (93%) of the desired product as a beige solid. Electrospray Mass Spec 562.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([O:13]C)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([OH:13])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)cc1O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 92 %

Procedure:
8-Chloro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine [Formula II: RI=R2 =R4 =H; R3Cl; R5 =CH3 ](0.0789 g, 0.332 mM) was added to a solution of 1.01 mL (1.OM, CH2Cl2) boron tribromide in 1.8 mL dry methylene chloride under nitrogen. The suspension was stirred at room temperature for 0.42 hours. The reaction mixture was poured into 7 mL of saturated aqueous sodium bicarbonate and stirred for 0.25 hours. The homogeneous solution was then adjusted to pH=5 by slow addition of concentrated hydrochloric acid. The precipitate was vacuum filtered and washed with water to give 0.0683 g (92%) of white solid which was recrystallized from 5 mL DMF and 1 mL of water. After cooling in an ice bath, solid was collected by vacuum filtration, washed with water and vacuum dried at 100° C. and 15 Pato give 0.056 g (75%) of product; mp 308.5-310.5 (dec); NMR (DMSO-d6, 300 MHz): 11.57 (s,1H, N--H), 10.86 (brs,1H, O--H), 8.04 (d,1H, Jortho =8.7 Hz), 7.54 (d,1H, Jmeta =2.0 Hz), 7.31 (dd,1H, Jortho =8.7, Jmeta =2.0 Hz), 6.41 (s,1H);
Reaction SMILES: Cl.[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>O>[C:3]([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:2])[CH3:4].[CH3:4][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:2]
Reactant: CC(C)(C)OO
Agent: C=C(C)c1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)(C)OOC(C)(C)c1ccccc1
Reaction time: 0.25 h
Yield: 96 %

Procedure:
235 g of 31% hydrochloric acid (2 moles) are metered into a mixture of 238 g of alpha-methyl styrene (2 moles) and 394 g of 80% tert.butyl hydroperoxide (3.5 moles) with stirring within 15 minutes, while the temperature of the mixture is allowed to rise from 20° C. to 35° C. Subsequently, stirring is continued for a further 2 hours at 40° C. then 250 ml water are added, the mixture is allowed to stand for 15 minutes and the aqueous phase is separated off. The organic phase is washed with 250 ml of 15% sodium hydroxide solution and twice with 500 ml of water in each case. After adding 20 g of water, the product is blown out with air at 50° C. (30 minutes). 395 g of a slightly yellowish liquid with a content of 96% tert.butyl cumyl peroxide and less than 0.4% alpha-methyl styrene are obtained. This corresponds to a yield of 91% based on the alpha-methyl styrene used.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][C:18]1[C:23](I)=[CH:22][N:21]=[C:20]([N:25]=[CH:26][N:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[N:19]=1>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:23]2[C:18]([Cl:17])=[N:19][C:20]([N:25]=[CH:26][N:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:29])[CH3:30])=[N:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Reactant: C#Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)N(C=Nc1ncc(C#Cc2ccc(Br)cc2)c(Cl)n1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
A mixture of 0.5 g of 1-bromo-4-ethynylbenzene, 5.0 mL of triethylamine, 0.031 mg of copper iodide, 0.94 g of 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine and 0.046 g of dichlorobis(triphenyl)phosphine palladium II was magnetically stirred at room temperature for 18 hrs. The mixture was diluted with acetonitrile, filtered and the filtrate evaporated in vacuo. The evaporated filtrate was dissolved in dichloromethane and loaded on a column of silica gel equilibrated in the same solvent. Cuts were monitored by thin layer chromatography. After initial cuts of brown colored eluates, the product subsequently eluted as yellow fractions. Like cuts were pooled and evaporated to give 0.84 g of 5-(4-bromophenylethynyl)-4-chloro-2-diisopropylaminomethyleneaminopyrimidine as a thick amber syrup.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:27][C:20]1[C:19]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2c(Br)c3cccccc-3c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (0.43 g) in CCl4 (20.0 ml) was added N-bromosuccinimide (0.23 g) and α,α'-azobis(isobutyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The mixture was cooled to room temperature and was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/EtOAc, 20:1) to give the title compound (0.52 g) as green crystals; mp 172°-173° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]1([NH:4][S:18]([CH2:17][C:16]2[CH:22]=[CH:23][CH:24]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=2)(=[O:20])=[O:19])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
In this example 5.3 g of cyclopropylamine were mixed with 9.4 g of triethylamine and then added drop-wise to a solution containing 20 g of 3-trifluoromethylbenzylsulfonyl chloride in methylene chloride at 0° C. The resulting reaction mixture was stirred at room temperature (i.e., about 20°-25° C.) for 3 hours. The reaction mixture was then washed with saturated aqueous ammonium chloride and then with aqueous 1 wt. % hydrochloric acid until it was neutral. The organic layer was then separated, washed twice with 50 ml of aqueous saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness affording 20 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13][CH2:12]3)[CH2:4]1.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:13][CH2:12]3)[CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
A solution of phenylmethyl 6-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Step 4, 1.75 g, 4.59 mmol) and pyridine (1.11 mL, 13.77 mmol) in dry CH2Cl2 (23 mL) under N2 is treated with acetic anhydride (0.649 mL, 6.88 mmol), and the mixture is stirred at ambient temperature for 3.5 hrs. The mixture is then washed with H2O (2×15 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (0.5/99.5-2/98), and those fractions with an Rf=0.25 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated to give 1.81 g (93%) of the title compound as an amorphous, white solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 7H), 7.11 (m, 1H), 6.11 (m, 1H), 5.19 (s, 2H), 4.78 (m, 1H), 4.62 (s, 2H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.70 (m, 3H), 3.60 (m, 1H), 2.86 (m, 2H), 2.02 (s, 3H); MS (ESI+) for C23H25N3O5 m/z 424 (M+H)+; [α]25D=−17° (c 0 77, DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:11]([C:13](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14])=[O:12]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:13]([CH3:14])[CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)C=O)cc1

Procedure:
A suspension of 4-methoxybenzaldehyde (10 g, 0.073 mol) and α-formylethylidenetriphenylphosphorane (25.7 g, 0.081 mol) in dried toluene (200 ml)was heated with stirring at reflux under an atmosphere of nitrogen for 24 h. The cooled reaction mixture was decanted to removed insoluble material and evaporated to give a brown oil. The oil was taken up in diethylether and the resulting suspension purified on flash silica eluting with hexane-diethyl ether (3:2). The resulting oil was a mixture of required product and 4-methoxybenzaldehyde and therefore dissolved in dried toluene (150 ml) and reaction continued as described above with α-formylethylidenetriphenylphosphorane (5.76 g, 0.018 ml) for 7 h. Following the work up and chromatography as above 3-(4-methoxyphenyl)-2-methylpropenaldehyde was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([CH2:18][CH2:17][C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:20][CH:21]=2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCc1noc(CCc2ccc(CN)cc2)n1
Product: CCCCCCCCCCCc1noc(CCc2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 68 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-[2-(3-undecyl-1,2,4-oxadiazol-5-yl)ethyl]benzylamine and 4-(trifluoromethyl)benzaldehyde gave the title compound as a pale yellow oil (68%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (d, 2H, J=8.1 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.33 (d, 2H, J=7.9 Hz), 7.19 (d, 2H, J=7.9 Hz), 3.86 (s, 2H), 3.79 (s, 2H), 3.13 (m, 4H), 2.70 (t, 2H, J=7.7 Hz), 1.72 (m, 2H), 1.29 (m, 16H), 0.88 (t, 3H, J=6.8 Hz). M−(LC/MS(ESI)): 516. HPLC (Condition A), Rt: 4.83 min (HPLC purity 93.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]=[C:5]2[CH3:22].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH:6]=[C:5]2[CH2:22][Br:23]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c(=O)c2ccc(Br)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
A solution of 6-bromo-4-methyl-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11c, 4.55 g) in benzene (40 mL) was treated with N-bromosuccinimide (3.00 g) and benzoyl peroxide (0.291 g) under nitrogen. The resulting solution was heated at 80° C. for 3 h. The cooled reaction mixture was evaporated to dryness. Purification (SiO2 chromatography, elution with 60% DCM in isohexane) afforded the subtitle compound (3.40 g) as a white solid.