Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][CH2:7][CH:8]=[C:9]([F:15])[C:10]([O:13][CH3:14])(F)F>CCCCC>[Br:6][CH2:7]/[CH:8]=[C:9](\[F:15])/[C:10]([O:13][CH3:14])=[O:2]
Reactant: COC(F)(F)C(F)=CCBr
Reactant: O=S(=O)(O)O
Solvent: CCCCC
Product: COC(=O)/C(F)=C/CBr
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.4 %

Procedure:
To a mixture of 3.0 g 75% sulfuric acid and 15 mL n-pentane was added 1.0 g (4.6 mmol) 4-bromo-1-methoxy-1,1,2-trifluoro-2-butene at room temperature in a 50 mL round-bottom flask. The resulting mixture was stirred for 48 hours at room temperature. Excess ice water was added and the liquid extracted with diethyl ether. The ether layer was successively washed with water and brine, then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gave the crude ester which was purified by chromatography on silica gel to give 0.62 g (68.9%) of methyl (Z)-4-bromo-2-fluoro-2-butenoate. Analytical sample distilled a 90°-92° C. (18 mm Hg). 1H-NMR (300 MHz, CDCl3) δ 3.84(3H, s), 4.40(2H, dd, J=2.5, 9 Hz), 6.35(1H, dt, J=9, 30 Hz). 19F-NMR (CDCl3): φ 122.5(d, J=30.2 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-chloro-phenylboronic acid to give [1-(4-chloro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.[N:55]1[CH:60]=[C:59](B(O)O)[CH:58]=[N:57][CH:56]=1>>[CH3:44][C:28]1[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])=[N:30][C:25]([C:59]2[CH:60]=[N:55][CH:56]=[N:57][CH:58]=2)=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:27]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cncnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as off-white amorphous solid. MS: 496.2 (MH+).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:21]/[NH:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: CC(C)(C)OC(=O)NN
Product: CCCCCN1C(=O)/C(=N\NC(=O)OC(C)(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and tert-Butyl carbazate according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.54 9s, 9H), 1.69-1.75 (m, 2H), 3.70 (t, 2H), 3.86 (s, 3H), 6.41 (d, 1H), 6.60 (dd, 1H), 7.66 (d, 1H), 12.201 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[I:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([I:19])=[CH:29][CH:28]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (5.0 g, 18.6 mmol), 4-iodobenzhydrazide (CAS 39115-95-2, 4.88 g, 18.6 mmol) and 1-hydroxybenzotriazole hydrate (2.85 g, 18.6 mmol) were placed in a 250 mL round bottomed flask. Anhydrous THF (120 mL) was added and the mixture was cooled to −20° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (5.35 g, 27.9 mmol) was added, followed by Et3N (3.9 mL, 28.0 mmol). The reaction mixture was stirred at −20° C. for 1 h and room temperature for overnight. The reaction was quenched by adding water and extracted with EtOAc, which was washed with 5% aqueous NaOH, water, brine and dried over Na2SO4. The extracts were filtered and the filtrate was concentrated to provide a brown solid, which was purified by flash chromatography (80% EtOAc in hexanes) to afford the title compound (7.3 g, 77%), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=2)[C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:17](=[O:19])[O:18][C:12](=[O:13])[C:11]3=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)OC2=O
Yield: 96.7 %

Procedure:
To 10 ml of acetic acid were added 1.00 g of 4-(4-chlorobenzoyl)phthalic acid and 1.34 g of acetic anhydride, and the resultant mixture was refluxed under heating for 3.5 hours. After finishing the reaction, the acetic acid was evaporated in vacuo and the resultant residue was mixed with hexane. The precipitated solid was filtered, washed with hexane and dried to give 0.91 g of the titled compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:28]1([NH:34]N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:25])([F:26])[F:24])(=[O:21])=[O:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and phenylhydrazine according to the method described for example 1. MS: M=447.0 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:38])([F:37])[C:28]1[C:33]([C:34](O)=[O:35])=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:34]([C:33]4[CH:32]=[N:31][CH:30]=[CH:29][C:28]=4[C:27]([F:38])([F:26])[F:37])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cnccc4C(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(trifluoromethyl)nicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=10:12:1) to yield the title compound.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl.N([O-])=O.[Na+].[F:18][B-](F)(F)F.[Na+]>C(OC)(C)(C)C.C(OCC)C>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][CH:2]=[C:3]2[F:18])=[CH:8][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2ccc(Br)cc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A solution of the product from Step A (5 g, 21 mmol) in methyl tert-butyl ether (20 ml) was treated with a solution of hydrogen chloride in diethyl ether (16.9 ml, 2 M) and the resulting mixture was stirred at room temperature. After 30 minutes, solids had precipitated and were filtered and washed with methyl tert-butyl ether. These solids were added to 6 M HCl (57.7 ml) and the resulting suspension was cooled to 0° C. Sodium nitrite (4.7 g, 70 mmol) followed by sodium tetrafluoroborate (7.4 g, 70 mmol) were added portionwise keeping the temperature at 0° C. The mixture was stirred at 0° C. for 30 minutes, then filtered. The filtrate was washed with ice cold water and extracted with ice cold methyl tert-butyl ether to give 7-bromo-1-fluoronaphthalene (4 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=1.8 Hz, 1H), 7.97 (dd, J=9.0, 1.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.7, 2.1 Hz, 1H), 7.55 (td, J=7.8, 5.4 Hz, 1H), 7.39 (ddd, J=10.8, 7.8, 0.9 Hz, 1H).
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:40]=[C:39]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)[CH:38]=[CH:37][C:21]=1[CH2:22][NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH3:33])=[C:27]([O:34][CH3:35])[CH:26]=1.[C:47]1([CH2:53][CH:54]=O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCCl>[CH3:35][O:34][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([O:31][CH3:32])[C:28]=1[CH3:33])[C:24]([NH:23][CH2:22][C:21]1[CH:37]=[CH:38][C:39]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[CH:40][C:20]=1[NH:19][CH2:54][CH2:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:36]
Reactant: O=CCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic acid (0.040 mL, 5 eq) and sodium triacetoxyborohydride (42 mg, 0.20 mmol) were added to a suspension of compound 1g (50 mg, 0.13 mmol) and phenylacetaldehyde (0.020 mg, 2 eq) in DCE (1.5 mL). The reaction was stirred at rt for 16 h and concentrated on a rotary evaporator. The residue was purified by preparative tlc (silica gel, 1:1 ethyl acetate/hexane) to afford compound 9a. ESI-MS m/e 487.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[Br:34]C1C=CC(OC2C=CC(S(Cl)(=O)=O)=CC=2)=CC=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Br)cc2)cc1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1

Procedure:
Compound 4d was prepared similar to the procedure described for 4a using 4-(4-bromophenoxy)-benzenesulphonyl chloride (3d) (3.00 g, 8.63 mmol). Yield: 4.13 g, 7.42 mmol, 86% (light yellow solid). 1H NMR (DMSO-d6): δ 7.70 (d, J=8.2 Hz, 2H, ArH), 7.52 (d, J=8.8 Hz, 2H, ArH), 7.01 (d, 3J=8.8 Hz, 2H, ArH), 6.67 (d, 3J=8.9 Hz, 2H, ArH) 4.05 (s, 4H, 2×CH2CO2 tBu), 1.46 (s, 18H, 2×CO2tBu).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[NH:48][NH2:49]>CN(C=O)C>[C:52]([O:51][C:47]([NH:48][NH:49][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N, N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1(/[CH:12]=[CH:11]/[C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1

Procedure:
A mixture of 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium(II) acetate (95 mg), tris(2-methylphenyl)phosphine (0.3 g) and N,N-diisopropylamine (5 mL) was heated for reflux for 24 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =10/1) to give 3-((E)-2-phenylvinyl)nitrobenzene (0.76 g). To the solution of the obtained 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([C:16]1[C:17](=[O:24])[O:18][CH:19]([CH3:23])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH3:14].[C:25](C1C(=O)OC(C)=CC=1O)(=[O:27])C>>[OH:22][C:21]1[CH2:20][CH:19]([CH3:23])[O:18][C:17](=[O:24])[C:16]=1[C:13](=[O:15])/[CH:14]=[CH:5]/[C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[C:10]([O:27][CH3:25])[C:3]=1[O:2][CH3:1]
Reactant: CC(=O)C1=C(O)CC(C)OC1=O
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Reactant: COc1ccc(C=O)c(OC)c1
Product: COc1ccc(/C=C/C(=O)C2=C(O)CC(C)OC2=O)c(OC)c1OC

Procedure:
Proceeding as in Reference 5, Step 5.1, but substituting 2,3,4-timethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and 3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one for 3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided 4-hydroxy-6-methyl-3-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-5,6-dihydro-pyran-2-one.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccco1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCOCCc1ccco1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
2-Furanethanol (2 g) in DMF (5 ml) was added dropwise to a suspension of sodium hydride (0.43 g) in DMF (20 ml). The mixture was stirred for 30 min and added dropwise to 1,6-dibromohexane (21.8 g). The resulting suspension was heated at 60°-70° for 18 h, poured into water (200 ml) and extracted with diethyl ether (3×100 ml). The dried extract was evaporated and the residue was purified on a column of silica eluted with cyclohexane. The resulting oil was fractionally distilled (Kugelrohr) to give the title compound as a colourless oil (1.7 g) b.p. 75°-80°/0.3 Torr.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[C:11]([C:18](=[O:20])[CH3:19])[CH:10]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1.[CH3:22][I:23]>C(#N)C.O1CCCC1>[I-:23].[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([C:18](=[O:20])[CH3:19])[CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=2)[CH:5]=[C:4]([CH3:21])[N+:3]=1[CH3:22]
Reactant: CC(=O)c1cc(Nc2cc(C)nc(N)n2)cc(C(C)=O)c1
Reactant: CI
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)c1cc(Nc2cc(C)[n+](C)c(N)n2)cc(C(C)=O)c1
Product: [I-]

Procedure:
Compound No. 2, FIG. 1A: A suspension of Compound No. 11 (2-amino-4-(3,5-diacetylphenyl)amino-6-methylpyrimidine) (0.284 g), was suspended in 1:1 acetonitrile-tetrahydrofuran was treated with methyl iodide (2 mL) and heated at 40°-45° C. under a reflux condenser for 18 hr. Cooling and filtration gave 0.35 g of 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium iodide, mp 292° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:8][C:9](=[O:26])[CH:10]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:12][S:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[I:28][CH3:29]>C(Cl)Cl>[I-:28].[CH2:18]([O:17][C:16]([NH:15][CH:10]([C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[CH3:27])=[O:26])[CH2:11][CH2:12][S+:13]([CH3:29])[CH3:14])=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CI
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(Br)c1C
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)C(CC[S+](C)C)NC(=O)OCc1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 24.5 h
Yield: 101.7 %

Procedure:
Step 2 A mixture of racemic benzyl 1-(3-bromo-2-methylphenylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (1.31 g, 2.90 mmol) and DCM (4 mL) was diluted with iodomethane (7.5 mL, 120 mmol) and the mixture was stirred at rt. After 24.5 h, the mixture (a solution with an insoluble reddish oil) was concentrated under vacuum. The residue was treated three times with DCM and concentrated under vacuum to provide racemic (3-(benzyloxycarbonylamino)-4-(3-bromo-2-methylphenylamino)-4-oxobutyl)dimethylsulfonium iodide as an orange-yellow glassy foam (1.75 g, 97%). 1H NMR (400 MHz, chloroform-d) δ9.16 (1H, br. s.), 7.28-7.46 (7H, m), 6.99 (1H, t, J=8.0 Hz), 6.71 (1H, d, J=6.8 Hz), 5.11 (2H, s), 4.84 (1H, br. s.), 3.75 (1H, br. s.), 3.54 (1H, br. s.), 3.14 (3H, br. s.), 2.96 (3H, s), 2.75 (1H, br. s.), 2.33-2.41 (1H, m), 2.30 (3H, br. s.). Mass spectrum m/z 465, 467 (M)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([O:9]CC)=O.[NH2:12][NH2:13].O>C(O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: CCOC(=O)CC1CCCO1
Solvent: O
Solvent: CCO
Product: NNC(=O)CC1CCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added a solution of ethyl 2-(tetrahydrofuran-2-yl)acetate (2.00 g, 12.6 mmol, 1.00 equiv) in ethanol (20 mL). NH2NH2.H2O (1.27 g, 25.4 mmol, 2.00 equiv) was added to the reaction. The resulting solution was stirred overnight at 80° C. in an oil bath, then cooled to room temperature and concentrated in vacuo. This resulted in 2.10 g (92%) of 2-(tetrahydrofuran-2-yl)acetohydrazide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O.[ClH:20]>CN(C=O)C>[Cl:20][O:6][N:5]=[CH:4][C:3]1[CH:7]=[C:8]([Cl:12])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cl
Reactant: ON=Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Product: ClON=Cc1cc(Cl)ccc1Cl
Reaction time: 8 h

Procedure:
2,6-Dichloro-benzaldehyde oxime (7.6 g, 40 mmol) is dissolved in 56 mL of DMF and N-chlorosuccinimide (5.9 g, 44.0 mmol) is added followed by a catalytic amount of HCl gas. The reaction mixture is stirred overnight. The reaction mixture is partitioned between ether and water. The layers are separated and the ether layer is washed with brine and is dried over sodium sulfate. The ether layer is filtered and the solvent is removed under reduced pressure to yield the crude product. The crude product is purified via chromatography using a gradient of 10% ethyl acetate in hexanes to 15% ethyl acetate in hexanes to yield the title compound. 1H-NMR (400 MHz, CDCl3) δ 8.76 (broad, 1H), 7.38-7.26 (m, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]#[N:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:20]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:35]
Reactant: CCOC(=O)CCC(Cl)c1ccccc1C#N
Reactant: N#Cc1ccc(OCc2ccsc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1ccccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
2-Hydroxy-4-(3-thienylmethoxy)benzonitrile (2.5 g) is added portionwise to a stirred suspension of sodium hydride (0.44 g, 60% dispersion in mineral oil) in dry dimethyl formamide (30 mL). After stirring at ambient temperature for 30 minutes, ethyl (RS)-4-chloro-4-(2-cyanophenyl)butanoate (2.87 g) is added in one portion and the reaction stirred for 16 hours at 100° C. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residual oil is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-(2-cyanophenyl)-4-[2-cyano-5-(3-thienylmethoxy)phenoxy]butanoate (250 mg) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[H-].[Na+].[Na].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][N:9]1[C:8](=[O:13])[NH:7][C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: BrCCCBr
Reactant: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCBr)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
0.03 mol of 7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 50 ml of absolute DMF, and 0.03 mol of sodium hydride is added. After 15 minutes, formation of the sodium salt was complete. The 0.06 mol of 1,3-dibromopropane is added dropwise and the mixture is heated at 80° C. for 2 hours. The solvent is then distilled out and the residue is purified by column chromatography on silica gel. The eluting agent used was a mixture of CH2Cl2 /CH3OH (98:2).