Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([CH3:31])=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl>O1CCOCC1>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:32])[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]=5[CH3:31])[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)c(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2ccc(=O)[nH]c2C)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 19.2 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (70 mg, 0.154 mmol) in 1,4-dioxane (1.9 mL) was added aqueous 4 M HCl (417 μL, 1.67 mmol) drop-wise. The reaction was stirred at 90° C. for 1.5 hours. The reaction was allowed to cool down to room temperature and then quenched with Et3N. The solvent was evaporated under reduced pressure. The crude compound was dissolved in ethyl acetate and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a yellow solid (13 mg, 20%); ESI-MS m/z calc. 439.41. found 440.5 (M+1)+. Retention time 1.58 minutes.
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][N:23]=1.C.IC>O>[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:28]2[N:32]([CH3:2])[N:31]=[C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[N:29]=2)=[N:17][C:18]=1[C:19]1[O:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: O
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: -5 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (19.87 mL, 132.90 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (48 g, 102.23 mmol) in 2-methylTHF (300 mL). A dark solution was obtained after 5 minutes which was treated with charcoal and filtered through a celite pad, washing the charcoal and charcoal with additional 2-methylTHF (100 mL). The filtrate was stirred with an air stirrer at −5° C. in a 3 L jacketed fixed vessel under an atmosphere of nitrogen. 2-methylTHF (100 mL) was added to help stir the yellow suspension. Iodomethane (7.96 mL, 127.78 mmol) was added dropwise over 15 minutes. The mixture was stirred for 2 hours and the reaction mixture was warmed to room temperature. After 16 hours, additional iodomethane (6 mL) and DBU (20 mL) was added and stirring was continued for 16 hours. The mixture was poured into water and stirred for 5 minutes. The insoluble material was isolated as a beige solid and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (24.77 g, 50.1%). The mother liquors were concentrated under reduced pressure and the residue was purified by flash column chromatography on silica using MTBE as the eluant. A second crop of the desired product (13.04 g, 26%), was thus obtained as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.47 (9H, s), 1.51 (9H, s), 1.57-1.76 (2H, m), 1.94-2.1 (2H, m), 2.87-3.09 (3H, m), 3.9-4.08 (2H, m), 4.26 (3H, s), 7.97 (2H, br, s), 8.92 (1H, s); Mass Spectrum [M+H]+=484
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:18]2[CH2:19][CH:20]3[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]3)[CH2:17]2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C1CC2CCC1CNC2
Reactant: Cc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CC3CCC(CC3)C2)c2ccccc12

Procedure:
The title compound was prepared by reacting 4-methyl-1-naphthalenesulfonyl chloride (0.69 g) with 3-azabicyclo[3.2.2]nonane (0.43 g) in the presence of DIEA using a procedure similar to that of Example 5. Yield 1.00 g of a grey solid, mp: 143.3°-147.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(F)cccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(F)cccc1Br
Reaction time: 1 h
Yield: 89.6 %

Procedure:
20.0 g (0098 mol) of 2-bromo-6-fluorobenzaldehyde are dissolved in 500 ml of methanol and cooled in an ice bath; 3.72 g (0.098 mol) of sodium borohydride are then added thereto, portionwise. The mixture is stirred under cold conditions for 1 hour and the solvent is then evaporated off under reduced pressure. The residue is taken up between water and dichloromethane, and the organic phase is separated, dried and concentrated under reduced pressure. The residue is crystallized from pentane. 18.1 g of compound are obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:18]2[C:19]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]3[OH:28])[C:17]=2[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[C:18]2[C:19]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])[C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C1CCCCC1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of oxalyl chloride (910 mg) in dichloromethane (3 mL) was added DMSO (670 mg) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 30 min, and a solution of 2-(4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexanol (350 mg) in dichloromethane (2 mL) was added thereto. The reaction mixture was stirred at −78° C. for 1 hr, and triethylamine (1.2 g) was added thereto. The reaction mixture was stirred at −78° C. for 1.5 hr, and added to ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (190 mg).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:11]2[CH2:10][C@H:9]3[NH:8][C@H:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(N2CC3CCC(C2)N3Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(N2C[C@H]3CC[C@@H](C2)N3)cc1
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 94.4 %

Procedure:
To the stirred solution of 8-benzyl-3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane (3.5 g, 11.81 mmol) in methanol (30 ml) was added 10% palladium on charcoal (100 mg, 0.940 mmol) at 25° C. The reaction mixture was stirred under hydrogen atmosphere for 3-4 h at 40° C. The reaction mixture was then cooled to 25° C. and filtered through a celite bed. The celite bed was washed with methanol (2×25 ml). The combined filtrate was concentrated under reduced pressure to obtain title compound (2.3 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:7](=[O:18])[N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:5]2=[O:30].[CH2:31](Br)[C:32]#[CH:33].C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:6]1[C:5](=[O:30])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH2:33][C:32]#[CH:31])[CH:3]=2)[N:8]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7]1=[O:18]
Reactant: COc1ccc(Cn2c(=O)c3cc(N)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNc1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Yield: 56.8 %

Procedure:
A mixture of 0.25 g of the compound obtained in Step 6.4, 0.094 g of propargyl bromide, 0.12 g of K2CO3 and 0.009 g of sodium iodide in 8.25 ml of DMF is irradiated in a microwave field for 3 hours at 100° C. The resulting mixture is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0/100) to (2/98, v/v) to give 0.155 g of the expected product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:55][OH:56])[CH2:53][OH:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 9.1 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 7j (1.1 g, 1.39 mmol) was dissolved in 30 mL of mixed solution (THF and MeOH, v:v=1:2), followed by addition of sodium borohydride (106 mg, 2.78 mmol) in batch. The reaction mixture was stirred for 30 minutes before 20 mL of water, then 30 mL of water were added. The reaction mixture was extracted with ethyl acetate (50 mL×3). The organic extract was washed with saturated sodium chloride solution (30 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 7k (100 mg, yellow grease), yield: 9.1%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[CH3:13][O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:27])[CH2:25][CH3:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O.O1CCCC1.ClCCl.CCOC(C)=O.O>[C:7]([CH2:9][C:10]([NH:27][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][O:14][CH3:13])=[CH:19][CH:20]=1)[CH2:25][CH3:26])=[O:12])#[N:8]
Reactant: CCC(N)c1ccc(OCCOC)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(NC(=O)CC#N)c1ccc(OCCOC)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Oxalyl chloride (0.19 g, 1.49 mmol) was added to a stirred solution of cyanoacetic acid (0.107 g, 1.25 mmol) in a mixture of dichloromethane (5 mL) and 2 drops of dimethylformamide under nitrogen at ice bath temperature. After 2 hours the solution was added in one portion to a solution of 1-(4-(2-methoxyethoxy)phenyl)propan-1-amine (0.25 g, 1.2 mmol) and triethylamine (0.13 g, 1.3 mmol) in tetrahydrofuran/dichloromethane 1:1 (4 mL) at 0-5° C., and the mixture was allowed to warm slowly to room temperature. After 4 hours 80 mL of water was added and after half an hour more (30 mL) dichloromethane was added. The layers were separated and the aqueous layer extracted with additional dichloromethane. The combined extracts were washed with 1N aq sodium bicarbonate, and then sat brine, and dried over magnesium sulfate. The solvent was removed in vacuo, leaving a cloudy amber syrup which was dissolved in EtOAc/Hxa 1:1 and filtered through a short column of silica gel under pressure. The effluent was concentrated in vacuo to afford 0.24 g of the product as a cloudy pale amber syrup, sufficiently pure for the next step.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:21]([NH:23][N:24]([C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[C:13]([O:15]C(C)(C)C)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:21]([NH:23][N:24]([C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.907 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 6 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The residue was dried in vacuo to give 2(R)-[3-benzamido-1(S)-(carboxy)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 17.1 %

Procedure:
To a mixture of 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.0 mg (0.12 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 8.8 μL (0.069 mMol) 4-chlorobenzoyl chloride. The reaction mixture was mixed for 1 day at ambient temperature. To this mixture were then added 160 mg (0.128 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was diluted with 1.0 mL methanol, treated with potassium carbonate, and filtered through a short column of sodium sulfate. The filtrate was then evaporated to give 2.9 mg (17%) of the title compound as a beige solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH:18]=[O:19])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Zn]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH:18]([OH:19])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:17]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: O=CC1(c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)C1(c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
A mixture of zinc dust (4.0 g, 61.2 mmol), ethyl bromoacetate (6.5 mL, 58.3 mmol) and 1-(p-chlorophenyl)-cyclopropanecarboxaldehyde (10.0 g, 55.4 mmol) in toluene is stirred at 70° C. for 45 minutes, cooled with an ice-water bath, treated with 100 mL of 10% sulfuric acid, stirred at room temperature for one hour, and diluted with ethyl acetate. The organic phase is separated, washed sequentially with 10% sulfuric acid, water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Chromatography of the oil using silica gel and a 9:1 to 7:3 hexanes/ethyl acetate gradient gives the title product as a colorless oil (11.3 g, 76%) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1](=[S:3])=S.Cl.[CH2:5]([O:7][C:8](=[O:11])[CH2:9][NH2:10])[CH3:6].C(N(CC)CC)C.ClC(OCC)=O.[N-]=C=S>C(Cl)(Cl)Cl.C(Cl)Cl>[C:8]([CH2:9][N:10]=[C:1]=[S:3])([O:7][CH2:5][CH3:6])=[O:11]
Reactant: S=C=S
Reactant: CCOC(=O)CN
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [N-]=C=S
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN=C=S
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
Carbon disulfide (22.8 g., 0.3 mol.) in chloroform (40 ml.) was added over a period of one hour to a stirred suspension of glycine ethyl ester hydrochloride (41.7 g. 0.3 mol.) and triethylamine (60.7 g., 0.6 mol.) in methylene chloride (300 ml.) at -10° C. The reaction mixture was allowed to warm up to 10° C. and was stirred for 10 minutes at this temperature. The mixture was treated dropwise with ethyl chloroformate (32.6 g., 0.3 mol.) in chloroform (50 ml.) at 0°-5° C. over a period of 0.5 hour. The mixture was stirred for another 40 minutes at room temperature and triethylamine (30.4 g., 0.3 mol.) was added dropwise over a period of 15 minutes. The mixture was stirred for 1/4 hour at 0° C. and an additional 1/2 hour at room temperature and finally stored over night at 25° C. The mixture was washed with water (250 ml.), 2N hydrochloric acid (2 × 300 ml.), 5% sodium bicarbonate solution (4 × 300 ml.) and dried over anhydrous sodium sulfate. The solvent was evaporated at 40° C. (15 mm.) to yield 38.1 g. of crude isothiocyanate. Upon storage overnight, a red dye was produced. This may be eliminated by distillation of the isothiocyanate.*
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[CH2:13][CH2:12]2)(=O)=O)=CC=1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[CH3:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([CH3:25])[C:17]=1[N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(c3c(C)cc(C)cc3C)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(N2CCNCC2)c(C)c1
Yield: 69 %

Procedure:
To a stirred mixture of 180 parts of 1-[(4-methylphenyl)sulfonyl]-4-(2,4,6-trimethylphenyl)piperazine and 450 parts of water were added dropwise 675 parts of sulfuric acid. The whole was stirred and refluxed for 4 hours. After cooling, the whole was treated with an ammonium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 70 parts (69%) of 1-(2,4,6-trimethylphenyl)piperazine as a residue (intermediate 14).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1 g of caffeic acid was dissolved in 25 mL of pyridine. 1.14 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 2.8 mL of phenethyl bromide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 100 mL of 10% HCl and extracted with methylene chloride (2×50 mL). The combined organic extract was washed with water (2×50 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 120 mg and the purity was by TLC single spot.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].O>CN(C=O)C>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: O=C1CC(C(F)(F)F)=NN1c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
To a solution of 2,4-dihydro-2-phenyl-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =CF3 ; R3 =H) (1.12 g; 4.91 mmol) in DMF (25 ml) was added 280 mg (4.83 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.3 mmol) and the resulting mixture was stirred at room temperature for 24 hours and then was poured into water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.29 g (18%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a solid
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([NH2:9])=[N:17][C:15]3[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=3[CH:18]=2)[CH:2]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1cccnc1
Product: Nc1ncc2cc(-c3cccnc3)c(N)nc2n1

Procedure:
The procedure of Example 1 was followed to react 3-pyridylacetonitrile and 2,4-diamino-5-pyrimidine-carboxaldehyde to afford the title compound; mp 317-319° C. (dec).