Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:15](=[O:28])[C:16]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]=3[N:18]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[OH2:36].[OH2:37].O.O.O.O.C1(=O)OOOOC(=O)C2=CC=CC=C12.[Mg]>ClCCl.CO>[C:1]([O:4][CH2:5][S:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[C:15](=[O:28])[C:16]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]=3[N:18]=2)=[CH:11][CH:12]=1)(=[O:37])=[O:36])(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)OCSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCS(=O)(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-(5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenylthio)methyl acetate (1.00 g, 1.98 mmol) in dry dichloromethane (30 mL) and methanol (10 mL), magnesium monoperoxy phthalate hexahydrate (1.08 g, 2.18 mmol) is added at 0° C. and the resulting mixture is stirred for 18 h at rt. Then the reaction mixture is quenched with the addition of 10% sodium bicarbonate solution and extracted with dichloromethane (3×). The organic part separated is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (silica gel, 60-120 mesh) to afford (4-(5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenylsulfonyl)methyl acetate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].C([O-])([O-])=O.[K+].[K+].O.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[C:9]([C:3]1[S:4][C:5]([CH3:8])=[C:6]([NH:7][C:22](=[O:23])[CH2:21][Cl:20])[C:2]=1[CH3:1])([O:11][CH3:12])=[O:10]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1sc(C)c(N)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1sc(C)c(NC(=O)CCl)c1C

Procedure:
To 12.25 g (0.066 mol) of methyl 3,5-dimethyl-4-aminothiophene-2-carboxylate, 9.1 g (0.066 mol) of K2CO3, 25 ml of water and 150 ml of methylene chloride are added without cooling 7.5 g (0.066 mol) of chloroacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.ClCCl.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(C(F)(F)F)ccc2N)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C
Temperature: 80 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (326 mg) and (S)-tert-butyl 3-(2-amino-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (485 mg) was dissolved in dioxane (4 ml), p-toluenesulfonic acid (26 mg) was added. The reaction mixture was heated at 80° C. for about 5 h. The mixture was diluted with dichloromethane and 10% aq. K2CO3 solution. The organic layer was separated, passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica gel; solvent:100% iso hexane→4:1 H:E).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(Cl)[C:10](=[CH:14][C:15](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[N+:16]([O-:18])=[O:17])[N+:11]([O-:13])=[O:12]>[Cu]>[N+:21]([C:20]1[CH:19]=[C:15]([N+:16]([O-:18])=[O:17])[CH:14]=[C:10]([N+:11]([O-:13])=[O:12])[C:9]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Product: Cc1ccc(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
4-iodotoluene is reacted with picryl chloride in the presence of copper bronze at 215° C. to yield 2′,4′,6′-trinitro-4-methylbiphenyl (1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2C#Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (300 mg, 747 μmol) and 4-(dimethylamino)pyridine (13.8 mg, 113 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11p (291 mg, 448 μmol, 60.0%) as a brown solid. Rf=0.19 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.10 (s, 6H), 0.20 (s, 6H), 0.90 (s, 9H), 0.93 (s, 9H), 3.65 (s, 2H), 6.63-6.73 (AA′BB′, 2H), 6.92-7.02 (AA′BB′, 2H), 7.17-7.27 (AA′BB′, 2H), 7.33-7.48 (m, 5H), 7.96-8.05 (AA′BB′, 2H), 8.99 (s, 1H), 10.69 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) 8-4.60 (2C), −4.61 (2C), 17.8, 17.9, 25.5 (6C), 41.7, 85.8, 94.5, 119.5 (2C), 120.4 (2C), 121.2, 128.2, 128.28 (2C), 128.34, 128.6 (2C), 129.5, 130.3 (2C), 131.8 (2C), 133.1, 138.5, 146.6, 148.0, 153.8, 156.9, 169.4; IR (KBr, cm−1) 530, 689, 756, 781, 839, 914, 1007, 1125, 1169, 1258, 1379, 1433, 1510, 1605, 1672, 2214, 2857, 2930, 2955, 3235.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]1O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1=Cc2c(cccc2-c2ccccc2)C1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
To a 1-liter four-necked round flask (equipped with a stirrer, a dropping funnel and a thermometer) were fed 29.3 g (123.9 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 51.6 g (371.4 mmol) of triethylamine, 0.75 g (6.3 mmol) of 4-dimethylaminopyridine and 294 ml of methylene chloride. Then, a solution obtained by dissolving 19.2 ml (247.5 mmol) of methanesulfonyl chloride in 19.5 ml of methylene chloride was dropwise added slowly to the system while cooling with ice in a nitrogen atmosphere. After the addition was completed, the resulting mixture was reacted for another 3.5 hours at the same temperature. The reaction mixture was poured in 500 ml of ice water, then the organic phase was separated, and the aqueous phase was further extracted twice with 150 ml of methylene chloride. The whole organic phase was successively washed with a saturated NaHCO3 solution and a saturated salt solution, and dried with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography (developed with hexane), to obtain 19.7 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41](=[NH:44])[NH:42][OH:43])=[CH:37][CH:36]=3)[CH:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:46](OC(=O)C)(=[O:48])[CH3:47]>>[C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([O:34][C:35]3[CH:36]=[CH:37][C:38]([C:41](=[NH:44])[N:42]([OH:43])[C:46](=[O:48])[CH3:47])=[CH:39][CH:40]=3)[CH:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C(=N)NO)cc3)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(O)C(=N)c1ccc(Oc2cc(Oc3ccc(CNC(=O)OC(C)(C)C)cc3)cc(C(=O)N3CCCC4CCCCC43)c2)cc1

Procedure:
{4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1-carbonyl)-phenoxyl]benzyl}carbamic acid tert-butyl ester, 1.4 g (2.28 mmol) was acetylated with 0.26 g (2.5 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 1.04 g of the required product. Percentage purity (LCMS): 36.1%, (M+1)=654.3+1.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[NH:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:28])[CH3:27])[C:19](Cl)=O.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][N:9]=[CH:10]4)[N:4]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH:26]([CH3:27])[CH3:28]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Yield: 87.2 %

Procedure:
N-hydroxy-5-isoquinolinecarboximidamide (D1; 1.18 g, 6.30 mmol) was added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (D4; 1.54 g, 6.62 mmol), triethylamine (0.966 ml, 6.93 mmol) and N,N-dimethylformamide (DMF) (10 ml) at 0° C. under a blanket of nitrogen. The mixture was allowed to warm to room temperature over 1 h and then heated at 120° C. under nitrogen overnight. The mixture was allowed to cool and then filtered. An off-white solid was collected and washed with acetonitrile to give the title compound (2.01 g).
Reaction SMILES: O[CH:2]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[N:32]([CH:2]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:3])=[N+:33]=[N-:34]
Reactant: CCOC(=O)c1cc2ccc(C(C)O)cc2s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccc(C(C)N=[N+]=[N-])cc2s1
Reaction time: 24 h

Procedure:
To a solution of ethyl 6-(1-hydroxyethyl)-1-benzothiophene-2-carboxylate (2.0 g, 8.06 mmol) in toluene (30 mL) was added diphenylphosphorylazide (2.64 g, 9.58 mmol), then DBU (1.31 mL, 8.79 mmol) dropwise. After 24 h, added more azide (0.5 mL) and DBU (0.3 mL) to the thick solution. After an additional 24 h, the reaction mixture was concentrated and purified via column chromatography yielding the desired product. 1H NMR (CDCl3, 600 MHz) δ 8.03 (d, J=0.9 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.81 (m, 1H), 7.36 (dd, J=8.2, 0.9 Hz, 1H), 4.75 (q, J=6.8 Hz, 1H), 4.40 (q, J=7.3 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.41 (t, J=7.3 Hz, 3H). MS: cal'd 276 (MH+), exp 276 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[F-:6].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:24][C:25]1[CH:26]=[C:27]([N+]([O-])=O)[C:28]([C:31]#[N:32])=[N:29][CH:30]=1.Cl>CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:6])[C:28]([C:31]#[N:32])=[N:29][CH:30]=1
Reactant: [F-]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1F
Temperature: -40 °C

Procedure:
Sulfuric acid (0.02 eq) was added to a solution of tetrabutylammonium fluoride (3 eq) in DMF (5 vol) and the mixture cooled to −40° C. A solution of the compound of Step 2 (1 eq) in DMF (2 vol) was added maintaining the temperature <−35° C. After about 20 minutes 2N HCl (3 vol) was added followed by 1N HCl (15 vol). The precipitated product was collected by filtration to give the desired product.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([C:14]([NH:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@H:19]2[OH:31])=[O:15])[C:6]2[O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]=2[CH:13]=1>Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:14]([NH:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[OH:31])=[O:15])[C:6]2[O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)cc3c2OCCCO3)[C@H](O)C1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: O=C(NC[C@@H]1CCNC[C@H]1O)c1cc(Cl)cc2c1OCCCO2
Yield: 5.6 %

Procedure:
A mixture of intermediate (12) (0.095 mol) in a mixture of HCl in 2-propanol (100 ml) and HCl (500 ml) was stirred and refluxed for one hour. The reaction mixture was cooled. The solvent was evaporated. The residue was taken up into DCM and washed with NH3/H2O. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent CH2Cl2/(CH3OH/NH3) 90/10). The product fractions were collected and the solvent was evaporated. A sample (2 g) of this fraction was crystallized from DIPE with a small amount of ACN, filtered off, washed and dried, yielding 1.8 g of (3S-trans)-8-chloro-3,4-dihydro-N-[(3-hydroxy4-piperidinyl)methyl]-2H-1,5-benzodioxepin-6-carboxamide (intermediate 3-t) (mp: 114 ° C.) [α]D20=−14.34° (c=24.41 mg/5 ml in CH3OH).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[N:18]1[CH2:17][C:16]([CH3:30])([CH3:31])[NH:15][CH2:20][C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(F)ccc2Cl)CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(c2cc(F)ccc2Cl)C(=O)CN1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
4.2 ml of trifluoroacetic acid (54.7 mmol) was added to a solution of 1.80 g of 4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (62c) (5.47 mmol) in methylene chloride (8.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 1.25 g of the title compound (yield: quant.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([N:19]1[C:23](=[O:24])[C:22](Cl)=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:20]1(=[O:33])=[O:32])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[C:23](=[O:24])[N:19]([C:15]([CH3:17])([CH3:16])[CH3:18])[S:20](=[O:33])(=[O:32])[C:21]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(Cc3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 58 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent 1-benzylpiperidine-4-amine, 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA with a reaction time of 30 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using 35% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.132 g, 58%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.7.47 (m, 2H), 7.46-7.42 (m, 3H), 7.31-7.26 (m, 2H), 7.26-7.21 (m, 3H), 5.20 (d, 1H), 3.35 (s, 2H), 2.99-2.90 (m, 1H), 2.67-2.62 (m, 2H), 1.74 (s, 9H), 1.71-1.56 (m, 4H), 1.44-1.33 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.9, 138.5, 134.2, 131.8, 129.9, 129.1, 128.8, 128.4, 127.3, 125.4, 106.7, 62.9, 61.7, 51.9, 50.3, 32.6, 27.8; Mass spectrum: M+H+ 454.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH:10][C:13]([NH:14][N+:15]([O-:17])=[O:16])=[NH:18])=[N:2]1
Reactant: NCCNCc1ccsn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1ccsn1)N[N+](=O)[O-]

Procedure:
Reaction of N-(3-isothiazolylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(3-isothiazolylmethylamino)-ethyl]-N'-nitroguanidine.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.FC(F)(F)C(O[C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])=O.N1C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Yield: 90 %

Procedure:
4-(2-Fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (90%). 1H NMR [400 MHz, (CD3)2SO] δ 9.02 (s, 1H), 8.60 (s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.20 (dd, J=11.6, 1.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 5.24 (d, J=1.6 Hz, 1H), 3.48 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:10])([CH3:9])[CH2:6][C:7]#[CH:8].CN(C)C=O.N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([O:10][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][C:7]#[CH:8]
Reactant: C#CCC(C)(O)CCCCl
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C)(CCCCl)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-chloro-4-hydroxy-4-methyl-1-heptyne in 80 ml. of dimethylformamide at 0° C., is added 43.8 g. (0.644 moles) of imidazole and 35.02 g. (0.322 moles of) chlorotrimethylsilane. The mixture is stirred at room temperature for 45 minutes, poured into water and extracted with hexane. The hexane solution is washed with dilute sodium bicarbonate solution, dried over magnesium sulfate and the solvent removed leaving an orange liquid. This liquid is distilled giving the desired product in the fraction boiling at 83°-88° C., 1.5 mm. as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C1CCCN1CCO
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCN1CCCC1=O
Reaction time: 2 h
Yield: 70 %

Procedure:
Into a solution of 50 mL of 1-(2-hydroxyethyl)-2-pyrrolidone and 85 mL of triethylamine in 150 mL of chloroform, a solution of 50 mL of acryloyl chloride in 100 mL of chloroform was dropped over 2 hours with stirring. The reaction mixture was stirred at 4° C. for 20 hours, then at 50° C. for 2 hours. After being cooled, the solution was filtered and the filtrate was washed with a 15% aqueous sodium carbonate solution and then concentrated under vacuum. The obtained oily material was distilled under vacuum to give the title compound in a yield of 70%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].[Br:17]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:17][C:10]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:2]([Cl:1])[C:3]([OH:16])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(F)(F)F)c(Cl)c1O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C(F)(F)F)c(Cl)c1O
Temperature: 15 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate (6.30 g) in DMF (65.0 mL) was added N-bromosuccinimide (4.41 g), and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.00 g).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[C:2]([NH2:4])=[S:3].BrBr.C(OCC)C>ClC1C=CC=CC=1>[NH2:4][C:2]1[S:3][C:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=[CH:14][C:5]=2[N:1]=1
Reactant: COC(=O)c1cccc(NC(N)=S)c1
Agent: BrBr
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc2nc(N)sc12
Reaction time: 4 h
Yield: 83 %

Procedure:
8.4 g of methyl 3-thioureido-benzoate are suspended in 120 ml of chlorobenzene, 2.2 ml of bromine in 30 ml of chlorobenzene are added at 0° C. in the course of 1 hour, while stirring as thoroughly as possible, and the mixture is then stirred to room temperature. It is then kept at 70° C. for 4 hours and subsequently cooled, a little diethyl ether is added and the precipitate is filtered off, mixed thoroughly with 70 ml of aqueous sodium bicarbonate solution, filtered off again and washed with water. 7.7 g (88%) of crude product of melting point 231-2320° C. result. HPLC analysis shows a content of more than 83% of the pure title compound, in addition to 8-18% of isomeric methyl 2-amino-benzothiazole-5-carboxylate. Suspension in and brief heating at 70° C. with ethyl acetate, cooling to 30° C. and filtration give the pure title compound of melting point >250° C. If the reaction is carried out in acetic acid (instead of in chlorobenzene), the content of the undesired isomeric methyl 2-amino-benzothiazole-5-carboxylate is only about 5%.