Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)([O-:13])=[O:12].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:15]=[C:14]([N+:11]([O-:13])=[O:12])[CH:18]=[N:17]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 4-fluorobenzeneboronic acid (2.47 g, 17.7 mmol), 4-nitro-1H-pyrazole (1.00 g, 8.84 mmol), copper (II) acetate (2.41 g, 13.3 mmol) and pyridine (2.86 mL, 35.4 mmol) in CH2Cl2 (40 mL) was stirred at room temperature overnight. The reaction mixture was filtered and diluted with water (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-20% EtOAc/hexanes gradient elution) to give 1-(4-fluorophenyl)-4-nitropyrazole as a white solid (0.820 g, 22%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([C:19](N(OC)C)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([C:19]([C:2]2[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ncc(Br)n1C
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50-mL round-bottom flask containing a solution of 5-bromo-1,2-dimethyl-1H-imidazole (440 mg, 2.51 mmol, Intermediate 24, step a) and THF (20 mL) under nitrogen was added isopropylmagnesium chloride in THF (2.0 M, 1.2 mL, 2.4 mmol) dropwise. The mixture was stirred for 0.5 hours at room temperature, and a solution of 4-chloro-N-methoxy-N-methylbenzamide (500 mg, 2.50 mmol, Intermediate 18, step a) in THF (5 mL) was introduced. After stirring for 7.5 hours at room temperature, the reaction was quenched by addition of 10 mL of EtOH, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 50% EtOAc in petroleum, 0-10% MeOH in CH2Cl2) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].O.Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC
Reaction time: 0.33 h

Procedure:
20 G. of 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester are dissolved in absolute chloroform, whereupon 21 g. of sarcosine ethyl ester are added dropwise during 10 minutes. In so doing, the mixture warms up to 50° C. After 20 minutes, the mixture is cooled, shaken once each time with water, 0.5-N hydrochloric acid and a sodium bicarbonate solution, dried and evaporated. The remaining oil is brought to crystallization with ethanol. There is obtained 3-(N-carbethoxymethyl-N-methyl-sulfamoyl)-thiophene-2-carboxylic acid methyl ester of melting point 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(F)n1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.737 g, 3.76 mmol) and 6-fluoropicolinaldehyde (0.470 g, 3.76 mmol) in N,N-dimethylacetamide (20 mL), NaHSO3 (58.5% SO2 content, 1.0 g, 5.63 mmol) and p-toluenesulfonic acid monohydrate (0.143 g, 0.75 mmol) were added. The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and saturated NaHCO3 solution was added to adjust the pH to 8. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.550 g, 49%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.28-8.33 (m, 1H), 8.19-8.27 (m, 1H), 7.47 (dd, J=8.01, 1.76 Hz, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.62 (d, J=2.34 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −68.08 (d, J=8.03 Hz); ESI MS m/z 302 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4Cl)c3c2s1
Yield: 32 %

Procedure:
Prepared from VII and 2,4-dichloroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 32%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3063, 2231, 1736, 1644, 1611, 1577, 1459, 1380, 1355, 1310, 1242, 1173, 1098, 1051, 983, 830, 818; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 7.80 (d, 1H, J=9.0 Hz), 7.63 (s, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz); HRMS calcd for C16H8N5SCl2 (M+H+): 371.9877, found 371.9877.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17]>>[CH:11]1([CH2:10][S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:22][C:23]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SCC1CC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SCC2CC2)c(F)c1
Yield: 95 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.026 g, 0.12 mmol) obtained in Step C of Preparation Example 18 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.025 g, 0.12 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.042 g, 95%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>ClCCl>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][C:45]5[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccncc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2ccncc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
A mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl-amino)-3-methoxy-benzoic acid (I-22), 0.048 g (0.12 mmole) of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, 0.037 g (0.28 mmole) of ethyldiisopropyl amine, 0.016 g (0.17 mmole) of pyridine-4-ylamine and 0.5 ml of dichloromethane was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 0.5 ml of methanol, and then precipitated by the addition of water. The residue was washed three times with water and then purified by chromatography on reverse phase silica gel, eluting with acetonitrile-water to give 0.01 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-pyridin-4-yl-benzamide (I-129).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C@H:3]([NH:11][C:12]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])[C:4]([O:6]C(C)(C)C)=[O:5].Cl.O1CCOCC1>>[CH3:1][CH:2]([CH3:21])[C@H:3]([NH:11][C:12]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](NC(=O)OC1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OC1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a Compound 46 (S)-tert-butyl 3-methyl-2-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)butanoate (0.21 g, 0.697 mmol) was added HCl in dioxane (15 mL, 60.0 mmol) and the mixture was stirred at room temperature under nitrogen for three hours. The reaction was done and concentrated under reduced pressure to provide F47 (S)-3-methyl-2-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)butanoic acid (0.1694 g, 0.691 mmol, 100% yield) as a clear wax.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([F:9])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
The starting material 5-benzyloxy-2-fluoro-4-methylnitrobenzene was obtained by adding benzyl bromide (3 ml, 25 mmol) to a solution of 2-fluoro-5-hydroxy-4-methylnitrobenzene (3.92 mg, 23 mmol) in DMF (70 ml) containing potassium carbonate (9.5 g, 68 mmol). After stirring for 3 hours at 60° C., the mixture was diluted with water and adjusted to pH2. After extraction with ethyl acetate, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The solid was filtered off, washed with hexane and dried under vacuum to give 5-benzyloxy-2-fluoro-4-methylnitrobenzene (4.83 g, 80%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][O:14][P:15]([O:18]C)[O:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:13][O:14][P:15]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)(=[O:18])[O:16][CH3:17]
Reactant: COP(OC)OC
Reactant: BrCc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc2ccccc2c1)OC
Yield: 92.6 %

Procedure:
A solution of 2-bromomethylnaphthalene (4.42 g, 0.020M) and trimethylphosphite (5 mL, 5.26 g, 0.042M) in dry toluene (100 mL) is heated at reflux temperature for 120 hours The reaction is incomplete, so the volume of the solution is reduced to 25 mL, additional trimethylphosphite (5 mL) is added, and the solution heated to reflux for another 24 hours. Solvent is removed under reduced pressure and the solid white residue is chromatographed over silica gel (40-63 μm, 195 g, ethyl acetate). Elution of the column with ethyl acetate gave title compound (4.63 g) as a white solid which after crystallization from ether-hexane had mp 80°-81° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>>[Br:15][C:16]1[N:17]=[CH:18][N:19]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Clc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: Brc1c[nH]cn1
Product: Clc1ccc(-c2ccnc(-n3cnc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-pyrimidine (example A.14) (0.90 g, 4.0 mmol) and commercially available 4-bromo-imidazole (0.88 g, 6.0 mmol) according to the general procedure IVa. Obtained as a white solid (1.09 g, 81%). MS (ISP) 335.1 [(M+H)+]; mp 166-168° C.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:25][CH:24]=1
Reactant: NC1c2ccccc2CCC1Cc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CN[C@@H]2c3ccccc3CC[C@H]2Cc2ccccc2)cc1
Yield: 20 %

Procedure:
In a procedure similar to preparation C, the title compound was prepared from 1-amino-2-benzyltetralin and 4-carbomethoxybenzaldehyde. The trans isomer was isolated as an oil in 20% yield following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C@@H:43](O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C@@H:43]([CH3:42])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC[C@@H](C)O
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(OC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To an argon-flushed flask containing 2.32 g (8 mmol) of 4'-hydroxy-4-biphenylyl benzoate and 1.25 eq of triphenylphosphine in 200 ml of dry THF was added a solution of 1.052 g (8.08 mmol) of (R)-2-octanol dissolved in 15 ml of dry THF via syringe. Then 1.2 eq of diethyl azodicarboxylate in 30 ml of dry THF was added dropwise over 30 min. The reaction mixture was stirred at room temperature for 20 h and then 5 drops of water was added and stirring was continued for an additional 1 h. The solvent was evaporated and the crude product was triturated for 1 h in a mixture of hexanes/ethyl acetate [70/30]. The solution was filtered through a short silica gel pad and the solvent evaporated. Flash chromatography on silica gel using hexanes/ethyl acetate [98/2] as eluent afforded 2.42 g (75%) of (S) -4'-(1-methylheptyloxy)-4-biphenylyl benzoate (Compound 39, Scheme VIII, R2 =(S)--OCH(CH3)C6H13) as a white solid (top. 84° C.); Rf [hexanes/ethyl acetate 95/5]: 0.34; 1H NMR (300 MHz, CDCl3): δ 0.89(t, 3 H, J=6.8 Hz), 1.14-1.68(m, 9 H), 1.32(d, 3 H, J=6.1 Hz), 1.75(m, 1 H), 4.39(m, 1 H), 6.95(d, 2 H, J=9 Hz), 7.25(d,2 H, J=8.4 Hz), 7.46-7.68(m, 7 H), 8.22(dd, 2 H, J=1.2 Hz J=6.9 Hz); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.73, 22.55, 25.50, 29.24, 31.75, 36.48, 73.96, 116.10, 121.88, 127.72, 128.58, 129.61, 130.21, 132.64, 133.59, 138.79, 149.87, 157.94, 165.30; IR (CHCl3): 3020, 2930, 2850, 1745, 1600, 1500, 1260, 1240, 1170, 1190, 1070, 1000, 840, 820 cm-1 ; Mass spectrum, m/z(rel.intensity): 402(M+ 16), 290(14), 105(100), 77(16), 43(6).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:19])=[C:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]2[C:8]([CH3:19])=[C:9]([CH2:14][CH2:15][C:16](=[O:18])[O:17][N:26]3[C:30](=[O:31])[CH2:29][CH2:28][C:27]3=[O:32])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)=C2C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)ON1C(=O)CCC1=O)=C2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 6 mg (0.018 mmol) of the acid 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in anhy. methylene chloride under argon was added 10.3 mg (5 eq.) of N-hydroxysuccinimide (NHS) (Aldrich) followed by 8.6 mg (2.5 eq.) of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (Sigma). After stirring at RT under argon for 4 hr TLC indicated only traces of starting material were left. The reaction mixture was directly subjected to chromatography on silica gel plates, eluting with 50% EtOAc-hexane. The product band was isolated, washed with a little EtOAc, the washings stripped of solvent under reduced pressure and the residue dried under high vacuum to give 5 mg (65%) of 1-[3-(5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-yl)-1-oxopropoxy]-2,5-pyrrolidinedione as a foam. HR (+) FAB MS: Calc (M+H), 430.2230; Observed, 430.2266.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH2:18][CH2:19][CH2:20]Cl)[S:9]2(=[O:23])=[O:22])=[CH:4][CH:3]=1.[CH3:24][NH2:25].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH2:18][CH2:19][CH2:20][NH:25][CH3:24])[S:9]2(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(Cl)cc1
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(Cl)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 1-(4-chlorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (27 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(4-chlorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (24 mg):
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH:25]1([C:2]2[C:7]3[N:8]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=2)[CH2:27][CH2:26]1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(C3CC3)c2N(c2ccc(F)cc2)C1=O
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6), 200 mg), cyclopropylboronic acid (65 mg), potassium phosphate (410 mg), tetrakis-(triphenylphosphine)palladium(0) (66 mg), water (0.1 mL) and toluene (5 mL) was heated at 100° C. under argon atmosphere for 4 hours. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=95/5→65/35) to give 5-cyclopropyl-4-(4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (146 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH2:2][CH3:3].Cl[C:15]1[C:20]([C:21](OCC)=[O:22])=[CH:19][N:18]=[C:17]([S:26][CH3:27])[N:16]=1>CC(O)C>[CH3:27][S:26][C:17]1[N:18]=[C:19]2[N:8]=[C:7]([C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[NH:9][C:21](=[O:22])[C:20]2=[CH:15][N:16]=1
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC(C)O
Product: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 2 h

Procedure:
2-Propoxybenzamidine (from sodium, 0.3 g, in ethanol, 50 ml, and 2-propoxybenzamidine hydrochloride, 2.77 g) was dissolved in 2-propanol (20 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) solution of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (2 g) in 2-propanol (30 ml). The reaction mixture was stirred at 2° C. for 2 hours and was then left overnight at ambient temperature to yield a white crude product, 1.18 g, m.p. 179°-181° C. Recrystallisation from ethanol yielded the title compound, 0.92 g, m.p. 186°-187° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:34])=[O:5])[S:12][CH:13]=3)=[CH:24][CH:23]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(OCc3ccc(Cl)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
2-{[4-(2-{4-[(4-Chlorobenzyl)oxy]phenoxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (420 mg) obtained in Example 50-3 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (260 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].C(N(C(C)C)CC)(C)C.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>ClCCl>[C:23]([O:26][CH2:27][C:28]([NH:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzonitrile (Intermediate 28, 2.20 g, 11.82 mmol) and di-isopropylethylamine (2.27 mL, 13.0 mmol) in dichloromethane (40 mL) was cooled in an ice-water bath before the addition of 2-chloro-2-oxoethyl acetate (1.40 mL, 13.0 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours. To the reaction was added 2-chloro-2-oxoethyl acetate (0.14 mL) and the reaction stirred at room temperature for a further 18 hours. The reaction was diluted with DCM (100 mL) and the solution washed with 2N HCl (75 mL) and NaHCO3 (75 mL), collected via a hydrophobic frit and the solvent removed to yield the title compound as an orange oil (3.7 g)