Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][C:18]=1[S:29](=[O:32])(=[O:31])[NH2:30]>O1CCCC1>[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[O:22])=[CH:19][C:18]=1[S:29]([NH2:30])(=[O:32])=[O:31]
Reactant: CON(C)C(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3cc[nH]c3c2)ccc1F
Temperature: -50 °C
Reaction time: 3 h

Procedure:
A solution of 0.997 g of 6-bromoindole in tetrahydrofuran (20 mL) is cooled to −50° C. and treated by slow addition of 8.79 mL of tert-butyllithium (1.5 M in pentane). After 2 h at −50° C. the reaction mixture is treated with 0.4 g of 4-fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (10 mL), stirred for an additional 3 h at −50° C. and quenched by addition of 2 mL of saturated aqueous ammonium chloride. The reaction mixture is taken up in ethyl acetate, washed with a saturated sodium chloride solution and dried (magnesium sulfate). After concentration in vacuo the residue is purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-fluoro-5-(1H-indole-6-carbonyl)-benzenesulfonamide as an amorphous solid. MS (m/z): 317 (M−1); Rf 0.32 (1:1 hexanes/ethyl acetate).
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1.N([O-])=O.[Na+].[ClH:20]>O>[Cl:20][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1
Reactant: Cl
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(Cl)c2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
In a mixture of 45 ml of hydrochloric acid and 30 ml of water was dissolved 3.35 g (15.0 mmol) of Compound 13 prepared in Example 10, and 1.05 g (15.2 mmol) of sodium nitrite was added to the solution under ice-cooling, followed by stirring for 30 minutes. Then, a solution of 1.80 g (18.2 mmol) of cuprous chloride in 30 ml of hydrochloric acid was added thereto and the temperature of the mixture was raised slowly to room temperature, followed by stirring for one hour. The precipitated crystals were collected by filtration and then washed with water, followed by recrystallization from chloroform/ethanol to give 2.64 g (73%) of Compound 24.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1(C)C=CC=CC=1>[CH3:23][S:24]([O:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(OS(C)(=O)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
2.50 g (0.012 mol) of 3,5-di-tert-butylphenol and 1.27 g (0.013 mol) of triethylamine were dissolved in 15 mL of toluene followed by dropping in 1.45 g (0.013 mol) of methanesulfonyl chloride over the course of 10 minutes at 5° C. Following completion of dropping, the mixture was stirred for 3 hours at 25° C. and the 3,5-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in ice water and following separation of the organic layer, was washed twice with saturated brine followed by drying with MgSO4 and concentrating to obtain 3.21 g (yield: 98%) of 3,5-di-tert-butylphenyl methanesulfonate. A purified product crystallized with n-hexane (white crystals, melting point: 76° C.) was used in a battery test.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:18]1(B(O)O)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]1([C:2]2[CH:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=CCCCC3)c2)CC1
Temperature: 100 °C
Yield: 123 %

Procedure:
A mixture of 102 mg (0.340 mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example 9, step (a)), 59.7 mg (0.474 mmol) cyclohexen-1-ylboronic acid, 43.8 mg (0.0379 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar was treated with 206 μL (0.412 mmol) of 2.0 M degassed aq Na2CO3, 0.6 mL degassed anh toluene and 0.2 mL degassed anh EtOH and the mixture was heated at 100° C. for 21 h. After cooling to RT, the mixture was poured into EtOAc (10 mL), washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Chromatography on a 5-g silica SPE column with 1-3% EtOH in dichloromethane afforded 126 mg of the title compound (74% purity by RP-HPLC (C18 column) as a mixture with triphenylphosphine) as a yellow oil that was used in the following reaction without further purification. Mass spectrum (ESI, m/z): Calcd. for C17H23N3O3, 302.2 (M+H). found 302.2.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[C:5]=2[O:4][CH:3]=1
Reactant: COc1cccc2c(=O)c(O)coc12
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1coc2c(OC)cccc2c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A mixture of 3-hydroxy-8-methoxychromone (1.92 g, 0.01 mole), methyl chloracetate (1.08 g, 0.01 mole) and potassium carbonate (1.0 g, 0.01 mole) in dimethylformamide (20 ml) is stirred at 100° C. under nitrogen for 4 hrs. The reaction mixture is allowed to stand at room temperature overnight, poured into water, filtered, washed with water and sucked dry. Recrystallization from ethanol gives white crystals (2.3 g, 88%), mp 137°-138° C.
Reaction SMILES: [OH:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][CH:25]=[C:18]4[C:19]=3[C:14](=[CH:15][CH:16]=[CH:17]4)[C:13]2=[O:26])[CH2:4][CH2:3]1.[BH4-].[Na+]>>[OH:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:21]([OH:22])[C:20]3[CH:23]=[CH:24][CH:25]=[C:18]4[C:19]=3[C:14](=[CH:15][CH:16]=[CH:17]4)[C:13]2=[O:26])[CH2:6][CH2:7]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1c2cccc3cccc(c23)C(O)N1CCCCN1CCC(O)(c2ccccc2)CC1

Procedure:
The product from part (a) is reacted with sodium borohydride as taught in either example 1 or 38 to yield the titled compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:12][CH3:13])(=[O:11])[CH:8]([CH3:10])[OH:9].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:9][CH:8]([CH3:10])[C:7]([O:12][CH3:13])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)O
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a pre-cooled solution of potassium tertiary butoxide (538.4 g) in DMF (1750 ml) at −20 to −10° C., added racemic methyl lactate compound of formula-11 (500 g) followed by benzyl chloride (547 g) at −20 to −10° C. and the reaction mixture was stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and 10% sodium chloride solution and then distilled off the solvent from ethyl acetate layer under reduced pressure to get the title compound as a residue. The obtained residue was taken into next step without isolation.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[K].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:16][N:17]([CH3:21])[C:18]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)=[O:19]
Reactant: Cc1cc2ccccn2n1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [K]
Product: Cc1nn2ccccc2c1C(=O)N(C)C
Temperature: 0 °C
Yield: 32.5 %

Procedure:
2-Methylpyrazolo[1,5-a]pyridine (3.6g) was dissolved in N,N-dimethylcarbamoyl chloride (10.8g). Aluminum chloride (8.0g) was added to the resulting solution and the mixture was heated at 130° for 3 hr and poured into ice water. The solution was made basic with potassium hydroxied solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated. The residue was distilled to give 1.8g of the objective product, bp 149°-150° (2 mmHg). Yield 32%.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[OH:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[CH3:17])[CH:9]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Product: Cc1ccccc1C(=O)Oc1cc(O)ccn1
Yield: 44.3 %

Procedure:
The general procedure of Example 27 was followed using 4.0 g of 2,4-bis(trimethylsilyloxy)-pyridine and 2.92 g of 2-methylbenzoyl chloride, thereby producing 1.59 g of the title compound in a yield of 44.18%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[C:23]1([CH2:22][O:21][C:19](=[O:20])[NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
A solution of 5.00 g (36.7 mmol) of 2-(4-aminophenyl)ethylamine in 100 mL of chloroform was cooled to 0° C. and 3.72 g (5.20 mL, 36.8 mmol) of triethylamine was added. A solution of 6.26 g (5.2 mL, 36.8 mmol) of benzyl chloroformate in 40 mL of chloroform was then added dropwise over a 30-min period. The reaction was allowed to stir at 0° C. for 2 h. It was diluted with 100 mL of chloroform, washed with 100-mL portions of water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in 50% ethyl acetate/hexane and stirred with 30 g of silica gel, filtered, and concentrated. Further purification by recrystallization from ethyl acetate/hexanes gave 4.82 g (49%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) 7.33 (s, 5H), 6.94 (d, 2H, J= 8.2 Hz), 6.60 (d, 2H, J=8.2 Hz), 5.07 (s, 2H), 4.84 (broad s, 1H), 3.55 (broad s, 2H), 3.37 (m, 2H), 2.67 (t, 2H, J=6.9 Hz). FAB MS m/z 271 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].S([O-])(O[CH3:16])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]([C:4]1[C:5]([O:11][CH3:16])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: COS(=O)(=O)[O-]
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(O)c1C(C)=O
Yield: 60 %

Procedure:
A mixture of 25 mmoles of 2,6-dihydroxy acetophenone, 26 mmoles of methyl sulphate, 75 mmoles of K2CO3 and 60 ml of acetone are heated to reflux for 12 hours. Then the reaction medium is cooled, the mineral matter is separated by filtration and rinsed with dichloromethane. After evaporation of the organic phase and flash chromatography, the expected product is obtained in a practically quantitave way (mp =55° C).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[CH2:13][CH2:12]2)=[O:10])[N:3]=1.[BH4-].[Na+]>[Pd].CO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]2)[CH2:12][CH2:13]1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3[N+](=O)[O-])CC2)n1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3N)CC2)n1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a flask containing 2-(3,5-dimethyl-pyrazol-1-yl)-1-[4-(2-nitro-phenyl)-piperazin-1-yl]-ethanone (0.201 g, 0.584 mmol) and Pd/C (0.100 g) under Ar is added 10 mL of MeOH. To this mixture NaBH4 (0.022 g, 0.584 mmol) is added and the mixture is stirred for 1 h. The mixture is filtered through diatomaceous earth and concentrated to dryness. The residue is diluted with 100 mL CH2Cl2 and quenched with 50 mL of saturated NH4Cl. The organic phase is dried with MgSO4, filtered and concentrated to give 1-[4-(2-amino-phenyl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone in 93% yield.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[CH:4].CN(C)C=O.N1C=CN=C1.[CH2:24]([Si:26](Cl)([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>CCOCC.O>[CH3:1][C:2]([O:13][Si:26]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:24][CH3:25])([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3]#[CH:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CC(C)(O)CCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: C#CC(C)(CCc1ccccc1)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The hydroxyl group is protected by treating 3.6 parts of 3-methyl-3-hydroxy-5-phenyl-1-pentyne in 15 parts by volume of dimethylformamide successively with 3.5 parts of imidazole and 4.0 parts of triethylsilyl chloride and stirring this mixture for 1 hour at room temperature. The reaction mixture is poured into ether/water and the ethereal layer is washed with water three times, dried over anhydrous sodium sulfate, and then the ether is removed at reduced pressure. Distillation of the residual oil provides 3-methyl-5-phenyl-3-triethylsilyloxy-1-pentyne.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: B
Solvent: C1CCOC1
Product: OCCc1cccc(Br)c1
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 2-(3-bromophenyl)acetic acid (10.0 g, 0.046 mol) in THF (150 mL), 1 M BH3-THF (100 mL, 100 mmol) was dropwise added at RT. The mixture was stirred overnight, concentrated, diluted with H2O (100 mL), and extracted with EtOAc (100 m×3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to afford the crude product 2-(3-bromophenyl)ethanol (9.0 g, 97%) as a colorless oil, which was directly used for next step without further purification. MS (ES+) C8H9BrO requires: 200, 202 found: 201 [M+H]+, 203 [M+2+H]+(1:1).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[P:34](Cl)([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[C:1]1([NH:7][C:8](=[N:9][P:34](=[O:35])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: N=C(Nc1ccccc1)Nc1nc(-c2ccccc2)cs1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CCOP(=O)(N=C(Nc1ccccc1)Nc1nc(-c2ccccc2)cs1)OCC

Procedure:
A stirred suspension of 2.94 g (10 mmol) of 1-phenyl-3-(4-phenyl-2-thiazolyl) guanidine (dried at 110° C./0.1 mm) in 150 ml of methylene chloride was allowed to react with 2.03 g (10 mmol) of N,O-bis(trimethylsilyl) acetamide and 1.73 g (10 mmol) of diethyl chlorophosphate for 3 months by the procedure of Example 4. The reaction mixture was evaporated to dryness then was subjected to "dry column" chromatography (method of B. Loev and M. M. Goodman, Chem. and Industry, 2026 (1967) on 500 g of silica gel, and developed with 700 ml of methylene chloride-ethyl acetate, 9/1 (v/v). A band in the Nylon® column at Rf 0.25-0.4, visualized as a dark band under ultraviolet light at 254 nm, was cut out, and extracted with chloroform-methanol, 3/1 (v/v). Evaporation of the extracts left 1.35 g of product as a pale yellow, thick syrup; NMR (CDCl3, 80 MHz) δ 1.37 (t, 6H, CH3), δ 4.11(5 peaks, 4H, OCH2), 6.98 (s, 1H, =CH--S), 7.35(m, 10H, aromatic); IR (neat) 1653 (C=N) and 1032 cm-1 (P=O); TLC (SiO2, CHCl3 --MEOH, 19/1 (v/v)) showed only one spot under UV light.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]([S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1F
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution (10 mL) of ethyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (100 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 52 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (284 mg) was added dropwise and the mixture was stirred for 30 min. Benzenesulfonyl chloride (151 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1) to give the title compound as a colorless oil (yield 60 mg, 38%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([F:23])([C:19]([F:22])([F:21])[F:20])[C:4]([F:18])([F:17])[C:5]([F:16])([F:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:25])([F:24])[C:3]([F:23])([C:19]([F:22])([F:21])[F:20])[C:4]([F:18])([F:17])[C:5]([F:16])([F:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:28])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)cc1
Product: O=C(Cl)c1ccc(C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
A mixture of p-perfluoroalkylbenzoic acid (8.1 g, 20 20 mmol) prepared in (a) and thionyl chloride (35 ml) is refluxed for 3 hours. Distillation of the reaction mixture affords p-(3-trifluoromethylperfluorobutyl)benzoyl chloride (5.8 g), b.p. 79°-81° C./0.8 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=O)[CH3:11].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[C:15](=[O:16])[O:17][C:10]([CH3:11])=[N:13]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc(Br)cc2)C(=O)O1
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 4-bromobenzaldehyde (2.88 g, 35.10 mmol), N-acetyl-glycine (3.80 g, 32.40 mmol) and sodium acetate (2.88 g, 35.1 mmol) in acetic anhydride (13.79 g, 135 mmol), was refluxed for 1 h with continuous stirring. After cooling, the reaction was quenched with ice and vigorously stirred for 1 h in an ice bath to allow precipitation. Filtration afforded compound in 64% yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([CH2:18]O)[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6])[CH2:2][CH3:3].P(Br)(Br)[Br:24]>ClCCl>[Br:24][CH2:18][C:16]1[CH:15]=[C:9]([CH:8]=[C:7]([C:5]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(CBr)cc(C(=O)OCC)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20–25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20–25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH:5]([NH2:7])=[NH:6].[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12]>CCO.CC(C)=O.C(O)(C)C>[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[NH:7]1[CH2:2][CH2:1][N:6]=[CH:5]1
Reactant: CC(=O)O
Reactant: N=CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Solvent: CC(C)O
Product: C1=NCCN1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Formamidine acetate (654 mg, 6.3 mmol) is added to a solution of the compound obtained in Step 7 (1.5 g, 6.3 mmol) in EtOH (100 ml). After stirring for 14 hours at ambient temperature, the ethanol is evaporated off and the white solid is taken up in acetone (75 ml) and isopropanol (10 ml). The solution is filtered and fumaric acid (694 mg, 6.3 mmol), previously dissolved, with warming, in acetone (25 ml) and isopropanol (10 ml), is added. The title compound is obtained in the form of a solid, which is filtered off and dried in vacuo.