Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)CCC>[CH3:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Cc1cccnc1N1CCNCC1

Procedure:
To a slurry of 2-bromo-3-methylpyridine (3.30 mL, 29.6 mmol) in n-butanol was added piperazine (25.0 g, 290 mmol) and the reaction heated to reflux for 3 days. The mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography on silica gel (elution with 15% methanol:dichloromethane) to provide the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7](Cl)[N:6]=2)[CH2:3][CH2:2]1.[NH3:14].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]([NH2:14])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CNc1nc(Cl)nc(NC2CC2)n1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(N)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 12.7 g of 2-cyclopropylamino-4-methylamino-6-chloro-s-triazine, 17.4 g of 28% aqueous ammonia solution and 30 ml of dioxan is heated at 140° C. in an autoclave for 4 hours. After cooling, the reaction mixture is poured into 350 ml of a solution, which has been cooled to 0° C., of potassium carbonate in water and extracted with 1:1 benzene/ether. After drying over sodium sulfate, the solvents are removed in vacuo and the residue is recrystallised from isopropanol/hexane; melting point 159°-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]CC=C)[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1)=[O:14].CN(C)[C:23]1[CH:28]=CC=C[CH:24]=1>CCOCC>[CH2:28]([C:5]1[C:6]([OH:9])=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([C:13]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[O:14])[CH:4]=1)[CH:23]=[CH2:24]
Reactant: C=CCOc1ccc(C(=O)c2ccnn2C)c(Cl)c1Cl
Reactant: CN(C)c1ccccc1
Solvent: CCOCC
Product: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1O
Temperature: 200 °C
Reaction time: 25 h

Procedure:
A suspension of 8.20 g of (2,3-dichloro-4-allyloxyphenyl)(1-methyl-5-pyrazolyl)methanone in N,N-dimethylaniline is stirred at 200° C. under argon gas atmosphere for 25 hours and cooled. The reaction mixture is diluted with ether and extracted with an aqueous 5% sodium hydroxide solution. The aqueous extract is washed with ether, adjusted to pH 5-6 with acetic acid and then extracted with chloroform. The organic layer is washed with water, dried and evaporated to give a solid, which is then purified by silica gel column chromatography to give 5.16 g of 6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][Br:17])=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 3-(4-chlorobenzoyl)toluene (5.48 g, 23.7 mmol) and dibenzoylperoxide (100 mg, 0.413 mmol) in carbon tetrachloride (45 ml) was treated with N-bromosuccinimide (4.65 g, 26.7 mmol) and refluxed 2.5 hours. The mixture was filtered while hot and slowly cooled to ambient temperature. The precipitate was collected by filtration, washed twice with carbon tetrachloride, and dried under vacuum to provide 4.2 g (57%) of 3-(4-chlorobenzoyl)benzyl bromide, m.p. 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(=O)=O.CC(C)=O.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:1][C:2]1[S:3][C:4]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1cccs1
Agent: O=C=O
Solvent: CC(C)=O
Product: O=S(=O)(Cl)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
An 80-g (0.68 mol) sample of 2-chlorothiophene was added dropwise to a cooled (dry ice/acetone bath, about -10° to -15° C.) and stirred solution of 160 g (1.38 mol) of chlorosulfonic acid. After the addition was completed, the reaction mixture was stirred at 50° C for 2hours, cooled, and then poured into 250 g of ice. The aqueous reaction mixture was extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulfate, and evaporated to give 40 g of 5-chloro-2-thienylsulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#N.Cl.CC[O:21]CC>>[CH:5]1[C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=[C:3]([CH:1]=[O:21])[CH:4]=1
Reactant: CCOCC
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2
Agent: Cl
Product: O=Cc1ccc2c(c1)Sc1ccccc1CC2
Temperature: 25 °C
Reaction time: 50 h

Procedure:
Mix 4.74 g (20 mmole) of 3-cyano-10,11-dihydro-dibenzo[b,f]thiepin with 7.56 g (40 mmole) anhydrous stannous chloride and 150 ml ether saturated with anhydrous hydrogen chloride. Stir the mixture at 25° C. for approximately 50 hours to produce a crystalline solid suspended in the reaction mixture. Shake the crystalline solid with 200 ml ice water, and extract with 150 ml ethyl acetate using methanol to dissolve any residual lumpy yellow solid. Separate the ethyl acetate layer containing the product, and after washing with water/saturated chloride solution and drying, the ethyl acetate is removed by evaporation to produce as a residue an amber-colored oil, which crystallizes overnight. Distill the crystalline residue under reduced pressure at 145° C. at 0.04 mm. The distilled product crystallizes, m.p. 55.5°-56.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][C@@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[OH-:12].[Na+].OO>CO>[CH3:10][C:9]([CH:5]1[CH2:4][C:3](=[O:12])[C:2]2([CH3:1])[O:8][CH:7]2[CH2:6]1)=[CH2:11]
Reactant: C=C(C)[C@H]1CC=C(C)C(=O)C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: C=C(C)C1CC(=O)C2(C)OC2C1

Procedure:
Synthesis of epoxide 10 from S-(+)-carvone as illustrated in FIG. 3. A solution of 4 N NaOH (48 mL, 192.0 mmol, 0.3 equivalents) was slowly added to a solution of S-(+)-carvone (100.0 g, 665 mmol, 1.0 equivalent) in MeOH (1000 mL) at 0° C., followed by the dropwise addition of 35% hydrogen peroxide solution (70.0 mL, 792.6 mmol, 1.2 equivalents) over 3 hours. After the reaction was complete as established by TLC analysis, it was quenched by the slow addition of saturated Na2SO3 solution (200 mL) and extracted with CH2Cl2 (3×300 mL). The organic extracts were dried over Na2SO4 and concentrated to afford the carvone epoxide product which was used without further purification. A solution of this epoxide (101.8 g, 612.4 mmol, 1.0 equivalent) and PtO2 (0.72 g, 3.18 mmol, 0.095 equivalents) in EtOH (500 mL) was stirred under a hydrogen atmosphere (1 atm) at 25° C. for 12 hours. The reaction mixture was then filtered through a celite pad eluting with Et2O and concentrated. The crude product was purified by flash chromatography (silica gel, 5% EtOAc in hexane) to afford epoxide 10 (97.8 g, 87%, two steps) as a colorless oil. Rf=0.40 (silica gel, EtOAc-hexane, 1:10); FT-IR (neat) nmax 2959, 2873, 1708, 1466, 1438, 1369, 1111, 884, 814 cm-1.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>CC(C)=O>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CC(C)=O
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
An amount of 500 g of benzoic acid was dissolved in 2000 ml of acetone, and 400 g of thionyl chloride was added dropwise over 3 hours. Thereafter, the mixture was stirred at a room temperature overnight under reflux. The solvent and unreacted thionyl chloride were removed to give 231 g of benzoyl chloride. Subsequently, the thus obtained benzoyl chloride was dissolved in 2000 ml of acetone and decompressed to 25 mmHg with an aspirator in a cooled state at 5° C. or less, and thereafter ammonia gas was purged therein. The reaction was stopped when the reaction system returned to normal pressure, and the reaction mixture was filtered under reduced pressure to obtain 169 g of ammonium benzoate. After the ammonium benzoate was washed with 1000 ml of water and then dissolved in 1N aqueous ice-cooled sodium hydroxide solution, bromine was added thereto. Thereby, the hydrolysis and decarboxylation was caused through the Hoffmann rearrangement to give the target 10.9 g of aniline.
Reaction SMILES: Br[C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13])=[O:4].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[F:14][C:2]1([F:15])[O:13][C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[NH:5][C:3]1=[O:4]
Reactant: O=C(Nc1ccc(F)cc1O)C(F)(F)Br
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1Nc2ccc(F)cc2OC1(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
To 2-bromo-2,2-difluoro-N-(4-fluoro-2-hydroxyphenyl)acetamide (33 g, 116 mmol) in dry toluene was added 1,8-diazabicyclo[5.4.0]undec-7-en (DBU, 17.51 ml, 116 mmol). The resulting mixture was stirred overnight at 80° C. The reaction was quenched in saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with Na2SO4 and concentrated to afford 24.94 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[OH:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[N:10]1([C:8]([C:7]2[C:2]([O:31][C:22]3[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:21]=3[F:20])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=C(c1cccnc1Cl)N1CCCc2ccccc21
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(c1cccnc1Oc1cc(C(F)(F)F)ccc1F)N1CCCc2ccccc21
Temperature: 150 °C
Yield: 66.7 %

Procedure:
To a solution of (2-chloro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone (50 mg, 0.18 mmol, 1.0 equiv; Example 6, Step 1) and 2-fluoro-5-trifluoromethyl-phenol (42.1 mg, 0.23 mmol, 1.3 equiv; [CAS RN 141483-15-0]) in anhydrous toluene (0.5 mL) was added caesium carbonate (176 mg, 0.54 mmol, 3.0 equiv; [CAS RN 534-17-8]) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (20.1 mg, 0.054 mmol, 0.3 equiv; [CAS RN 64443-05-6]). The reaction mixture was heated by microwave irradiation to 150° C. for 1 h. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 50 mg (67%) of the title compound as a light yellow solid. MS (ISP): 417.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:11][C@H:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:17]1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccccc2[N+](=O)[O-])CCN1
Yield: 470 %

Procedure:
To a solution of 2-bromo-nitrobenzene (0.4 g, 2.0 mmol) in 1,4-dioxane (10 mL) was added (R)-(+)-2-methylpiperazine (0.25 g, 0.25 mmol) and powdered K2CO3 (7.5 mmol, 0.8 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (R)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange-red oil (0.26 g, 78%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>O1CCCC1>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([CH2:23][CH:1]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[N:9]2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:29][CH:28]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: c1ccc(Cn2nnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccc(CC(c3ccccc3)n3nnc4ccccc43)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
A solution of 1-benzyl-1H-1,2,3-benzotriazole (750 mg, 3.6 mmol) in tetrahydrofuran (36 mL) was cooled to −78° C. and treated with n-butyllithium (2.8 mL, 1.6 M in hexanes) dropwise. The reaction mixture was stirred at −78° C. for 10 min and 4-bromomethyl-biphenyl (1.0 g, 4.1 mmol) in tetrahydrofuran (4 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, quenched with sat. ammonium chloride (100 mL), and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to a white solid. This material was triturated with diethyl ether (2×50 mL) to yield the desired product (1.12 g, 83%). LCMS found for C26H22N3 (M+H)+: m/z=376.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1.[CH2:17]([CH2:21][C:22](=O)[CH3:23])[C:18]([CH3:20])=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:22]([CH3:23])=[CH:21][CH:17]=[C:18]3[CH3:20])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COc1nn(-c2ccc(N)c(C)c2)c(=O)o1
Solvent: CC(=O)O
Product: COc1nn(-c2ccc(-n3c(C)ccc3C)c(C)c2)c(=O)o1

Procedure:
The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of acetonylacetone in glacial acetic acid at 80° C. Working up took place by dilution with water, extraction by shaking with ethyl acetate and column chromatography (silica gel, methylene chloride) of the crude product obtained after concentration of the dried organic phase.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH2:10]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][C:19]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([O:30][CH2:31][C:32](O)=[O:33])[CH:25]=3)=[N:18][C:17]=2[N:16]([CH2:35][CH2:36][CH3:37])[C:14]1=[O:15])[CH2:11][CH3:12]>>[CH3:37][CH2:36][CH2:35][N:16]1[C:14](=[O:15])[N:13]([CH2:10][CH2:11][CH3:12])[C:22](=[O:23])[C:21]2[C:17]1=[N:18][C:19]([N:20]=2)=[C:24]1[N:28]([CH3:29])[NH:27][C:26]([O:30][CH2:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)=[O:33])=[CH:25]1
Reactant: Cc1ccc(N)cc1C
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)Nc3ccc(C)c(C)c3)NN1C)N=2

Procedure:
Using 3,4-dimethylaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:19]=O)=[CH:10][C:11]=3[C:12]2([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:22]O>C(O)=O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:19]#[N:22])=[CH:10][C:11]=3[C:12]2([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C#N)cc21

Procedure:
An alternative but less satisfactory synthesis was conducted as follows: A mixture of 7-bromo-9,9-diethylfluorene-2-carboxaldehyde (3.29 g, 10.0 mmol), hydroxylamine hydrochloride (0.9 g, 10.0 mmol), and formic acid (15 mL), was held at reflux for 2 hr, cooled and filtered. The filtrate was worked up by extraction into toluene, washing the extract with water, and bicarbonate solution, drying and concentration. The residue was combined with the formic acid-insoluble solids and chromatographed over silica gel. There were obtained, the desired aldehyde product, 1.58 g (49%), m.p. 85-87° C., mass spectrum (m/z): 325, 327 (M+); the amide by-product, 0.42 g (12%), m.p. 179-184° C., mass spectrum (m/z): 343,345 (M+); and the oxime by-product, m.p. 104-107° C., 0.17 g (5%), mass spectrum (m/z): 343 (M+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1.[Si](Cl)(Cl)(Cl)Cl.Cl>O.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
Dry 2-benzyloxy-5-chlorobenzoic acid (1.15 g) was treated, with stirring, with dry pyridine (20 ml) and anhydrous 5-aminotetrazole (3.72 g). The mixture was stirred at 25° C. and treated dropwise with silicon tetrachloride (0.45 g), and the mixture was then stirred at 25° C. for 20 hours. The resulting clear yellow solution was cautiously poured into a mixture of ice and water (50 ml) and the mixture was acidified to pH 1 by treatment with concentrated hydrochloric acid. The white precipitated solid was filtered off, washed with water, with ethanol and with diethyl ether, and recrystallized from a mixture of dimethylformamide and water to give 2-benzyloxy-5-chloro-N-(tetrazol-5-yl)benzamide, (0.29 g), m.p. 256°-257° C. (with decomposition).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH2:15][CH2:16][CH:17]([SH:19])[CH3:18].C([O-])(O)=O.[Na+]>CCOCC.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([NH:15][CH2:16][CH:17]([SH:19])[CH3:18])=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: CC(S)CN
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A solution of p-nitrobenzyl chloroformate (0.95 g, 4.41 mmol) in Et2O (30 ml) was added dropwise over 45 min. to an ice-cold, stirring mixture of 1-amino-2-propanethiol (0.504 g, 3.94 mmol) in Et2O (100 ml), H2O (11 ml), and 10% aqueous NaHCO3 (10 ml). The resulting mixture was stirred an additional 80 min. at 0°-5°, and then separated into two phases. The organic portion was washed with cold 0.025N HCl (30 ml) and brine (20 ml), dried with MgSO4, filtered, and concentrated under vacuum to a yellow oil (1.28 g). The crude product was purified by preparative TLC on silica gel GF using 20:1 CH2Cl2 -EtOAc as developing solvent to afford an off-white solid (1.00 g). Recrystallization of the chromatographed product from Et2O-petroleum ether gave compound (A3) (0.183 g) as a cream colored solid: mp 54°- 56.5°.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:14][SH:15])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.O>O1CCCC1>[C:1]([S:15][CH2:14][C:13]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:18]([OH:19])=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)(C)c1cc(CS)cc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)SCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
S-(3,5-di-tert.-butyl-4-hydroxybenzyl) thiomethacrylate was prepared as follows: Methacryloyl chloride (8.65 grams) was added dropwise over 1 hour at 24° to 28° C. to a solution of 16.7 grams of 3,5-di-tert.-butyl-4-hydroxybenzyl mercaptan and 13.4 grams of triethylamine in 75 milliliters of tetrahydrofuran. The reaction mixture was stirred for 3 hours at room temperature and was then poured into 400 milliliters of water. The yellow oil which precipitated was separated by extraction with hexane. Evaporation of the hexane left 19.9 grams of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccccn3)cc2)CCOCC1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 471 (M++1).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>O>[N+:22]([C:21]1[C:16]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
3.6 g (150 mmol) of sodium hydride were added, a little at a time, to a mixture of 12 g (128 mmol) of phenol and 100 ml of dimethylformamide. After the evolution of gas had ceased, the resulting mixture was treated with 18 g (114 mmol) of 2-chloro-3-nitropyridine. After the reaction mixture had been stirred at room temperature (approximately 25° C.) for 3 hours, it was treated with water. Following extraction with tert-butyl methyl ether, washing and drying the organic phase and removal of the solvent under reduced pressure, the product crystallized out. It was purified further by stirring with tert-butyl methyl ether/n-pentane. This gave 6.6 g (27%) of the title compound. A further 3.0 g (12%) of the title compound were obtained from the mother liquor.