Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1

Procedure:
4-Biphenylsulfonic acid (3.0 g, 12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 crude 4-biphenylsulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12][Br:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCO)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.8 %

Procedure:
To a suspension of 1-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (1.28 g, 2.60 mmol) in anhyrous THF (32 ml) at 0° C. was added CBr4 (1.03 g, 3.1 mmol)) followed by Ph3P (0.75 g, 2.9 mmol) and the reaction was stirred at rt for 24 h. The reaction mixture was poured into H2O (100 ml) and extracted with 150 ml EtOAc. The organic layer was washed with satd. aq NaHCO3, brine and dried over Na2SO4 and was concentrated to give a yellow oil (1.6 g), which was used without further purification. MS [M+H]+=557.2; LCMS RT=3.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:20][O:21][C:22]([C@@H:24]1[CH2:26][C@H:25]1[CH2:27]OS(C)(=O)=O)=[O:23].S([O-])(=O)(=O)C>CN(C=O)C>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:26][C@H:25]1[CH2:27][O:13][C:5]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[O:8][C:7](=[O:12])[CH:6]=1)=[O:23]
Reactant: COC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H]1COc1cc(=O)oc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
6-chloro-4-hydroxycoumarin (5.09 mmol, 1.0 g) is dissolved in 80 mL of DMF, and Cs2CO3 (7.63 mmol, 2.49 g), and trans-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester (6.14 mmol, 1.28 g) are added. The reaction is heated to 100° C. for 5 hrs, a further 0.2 eq of the mesylate is added, and heating is continued for an additional 2 hrs. After cooling to ambient temperature, the DMF is removed in vacuo. The residue is dissolved in EtOAc and is washed with H2O. The organic layer is dried over MgSO4, is filtered, and the EtOAc is removed under reduced pressure to afford a yellow solid which is chromatographed on SiO2 (35 g) using DCM as the eluent to afford the title compound as a white solid (0.98 g, 62%). 1H NMR (DMSO-d6, 300 MHz) δ 7.75 (2H, m), 7.45 (1H, d), 5.97 (1H, s), 4.22 (2H, m), 3.65 (3H, s), 1.90 (2H, m), 1.19 (2H, m); MS (ESI, Pos.) calcd for C15H13ClO5 m/z [M+H]=309.0, found 309.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 84 %

Procedure:
Prepared in analogy to example 8 from 2-chloro-4-nitrophenol and 3-fluoro-benzylbromide. Colorless solid. Yield=84%. MS: m/e=281.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1.N1C=CC=CC=1.[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](Cl)=[O:29].Cl>C1COCC1>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=3)[CH:4]=2)[NH:8][CH:7]=1)=[O:29]
Reactant: CCOc1ccc(-c2cc3cc[nH]c3cc2Cl)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOc1ccc(-c2cc3c(C(=O)C(Cl)(Cl)Cl)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9 %

Procedure:
To a solution of 6-chloro-5-(4-ethoxyphenyl)-1H-indole (500.0 mg, 1.84 mmol) in anhydrous THF (5 mL) was added pyridine (436.0 mg, 5.52 mmol) and trichloroacetyl chloride (10 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature under N2 for 12 hours. The mixture was poured into 0.5 N HCl (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (9-25% EtOAc/petroleum ether:EtOAc) to give the title compound (70.0 mg, 9%) as a green solid. 1H NMR (400 MHz, CDCl3) δ 8.80 (br, 1 H), 8.40 (s, 1 H), 8.36 (d, J=3.2 Hz, 1 H), 7.59 (s, 1 H), 7.42 (d, 2H), 6.97 (d, 2 H), 4.12 (q, J=7.00 Hz, 2 H), 1.45 (t, J=7.00 Hz, 3 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[N:35]12[CH2:42][CH2:41][CH:38]([CH2:39][CH2:40]1)[C@@H:37]([NH:43][C:44]([C:46]1[S:47][C:48]3[C:54]([C:55]4[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=4)[C:58]([OH:60])=O)=[CH:53][CH:52]=[CH:51][C:49]=3[CH:50]=1)=[O:45])[CH2:36]2.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CN(C=O)C>[ClH:34].[N:35]12[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42]1)[C@@H:37]([NH:43][C:44]([C:46]1[S:47][C:48]3[C:54]([C:55]4[CH:63]=[CH:62][CH:61]=[C:57]([C:58]([N:64]5[CH2:69][CH2:68][O:67][CH2:66][CH2:65]5)=[O:60])[CH:56]=4)=[CH:53][CH:52]=[CH:51][C:49]=3[CH:50]=1)=[O:45])[CH2:36]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CCOCC4)c3)c2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
103 mg (0.27 mmol) of HATU and 70.8 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 19.7 μl (0.23 mmol) of morpholine in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 18 h. After purification by preparative HPLC, the product fractions are concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 43 mg (74% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl-].[Cl-].[Mg+2].C(N(CC)CC)C.[CH2:20]=[O:21].Cl>C(#N)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:20]=[O:21]
Reactant: C=O
Reactant: COc1ccc(O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of compound p-methoxyphenol (3 g, 24.2 mmol), anhydrous magnesium dichloride (3.48 g, 37.0 mmol) and dry triethylamine (12.8 mL, 92.1 mmol) in 100 mL of acetonitrile was added dry paraformaldehyde (5 g, 167 mmol). The reaction mixture was refluxed for 8 hours and cooled down to room temperature. Then the reaction mixture was poured into 5% HCl (300 mL) and extracted with diethyl ether (200 mL) for three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (20% EtOAc in n-hexane) to yield 3.35 g of 2-hydroxy-5-methoxybenzaldehyde (91% yield).
Reaction SMILES: [NH:1]([C:3](=[O:17])[CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)[NH2:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[C:21]([F:28])[CH:20]=1>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:2][NH:1][C:3](=[O:17])[CH2:4][C@@H:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6]2)=[O:27])=[C:21]([F:28])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NN)C1
Reactant: O=C=Nc1ccc(Br)cc1F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-(2-hydrazino-2-oxoethyl)-1-pyrrolidinecarboxylate (6.58 mmol) in dichloromethane (15 mL) was cooled to 0° C. and was treated drop-wise with 4-bromo-2-fluoro-1-isocyanatobenzene (6.58 mmol). The reaction was allowed to warm to room temperature, and after ˜30 min a white solid had formed. The reaction contents were concentrated to dryness in vacuo. No further purification was carried out on the resulting white solid (3.01 grams, 100%). MS(ES)+ m/e 459/461 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15]I)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17]1([O:24][CH3:25])[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:24][CH3:25])[O:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1O
Reactant: Clc1ccc(-c2coc(CCCI)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(3-iodopropyl)oxazole (0.5 g), guaiacol (0.19 ml), potassium carbonate (0.24 g) and N,N-dimethylformamide (5 ml) was stirred for 30 minutes at 60 ° to 65° C. and poured into water. precipitated crystals were collected by filtration to obtain 4-(4-chlorophenyl)-2-[3-(2-methoxyphenoxy) propyl]oxazole (0.445 g, 90%). Recrystallization from ether-hexane gave colorless prisms of mp 94°-95° C.
Reaction SMILES: [CH:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc2c(C3CCCCC3)noc2c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: c1cc2c(C3CCCCC3)noc2cc1OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 3-cyclohexyl-1,2-benzisoxazol-6-ol (2.69 g, 12 mmol), 1-(2-chloroethyl)-piperidine hydrochloride (2.39 g, 13 mmol) and K2CO3 (3.59 g, 26 mmol) in CH3CN (30 ml) was heated at reflux for 3 h and stirred at room temperature overnight. The reaction mixture was poured into H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated to give a residue (3.78 g). This residue was purified by flash chromatography (toluene/1,4-dioxane 8/2). Crystallisation from EtOH gave white crystals (0.53 g, 13.4%). mp 69° C.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:9][O:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6].O.O.O.C([O-])(=O)C.[Na+].[NH2:21][C:22]([NH2:24])=[S:23].C(=O)([O-])O.[Na+]>O1CCCC1.O>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:9][O:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6])[N:21]=1
Reactant: CON=C(C(=O)CBr)C(=O)OC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)OC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
In 350 ml of tetrahydrofuran is dissolved 52 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate, followed by addition of 250 ml of water. Then, 89.1 g of sodium acetate trihydrate and 33.2 g of thiourea are added and the mixture is reacted with stirring at room temperature for 18 hours. To this reaction mixture is added 200 ml of a 5% aqueous solution of sodium hydrogen carbonate and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and distilled under reduced pressure to remove the solvent. To the residue is added 200 ml of ether and the resultant crystals are collected by filtration. By the above procedure is obtained 24.8 g of methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn-isomer) as crystals melting at 164.9° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>O>[C:5]([CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][N:13]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH2:14][CH2:15]1)#[N:6]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: N#CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 4-chlorobutyronitrile (3.3 g; 0.032 mol), 1-(2-pyrimidinyl)piperazine (3.3 g; 0.032 mol), sodium carbonate (6.4 g; 0.0608 mol) and n-butanol (50 ml) was heated under reflux for 19 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give 1-(3-cyanopropyl)-4-(2-pyrimidinyl)-piperazine. M.P., 56°-57° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[Cl:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Solvent: CC#N
Product: CC(=O)N1CCc2cc(Br)cc(Cl)c21
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A mixture of 1-acetyl-5-bromo-indoline (1.20 g, 5 mmol) and N-chlorosucinimide (0.734 g, 5.5 mmol) in acetonitrile (80 mL) was heated to reflux for 12 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel to provide 0.548 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:28][S:29]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:31])=[O:30])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>>[CH2:32]([S:29]([NH:28][CH:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=3[CH:8]=2)=[O:13])=[CH:21][CH:20]=1)[C:24]([O:26][CH3:27])=[O:25])(=[O:31])=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCS(=O)(=O)NC(Cc1ccc(N)cc1)C(=O)OC
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Product: CCCCS(=O)(=O)NC(Cc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1)C(=O)OC
Yield: 36.3 %

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and methyl 3-(4-aminophenyl)-2-(n-butylsulfonylamino)propionate (371 mg, 1.18 mmol) were condensed to give 188 mg of methyl 2-(n-butylsulfonylamino)-3-[4-[(5-cyano-2-benzofuranyl)carbonylamino]phenyl]propionate as a yellow solid (36%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2].O1CCC[CH2:23]1.C[Mg]Br.C(OCC)(=O)C>C(OCC)C>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH2:23])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1ccc2nc(N)n(C(C)C)c2c1
Reaction time: 8 h

Procedure:
Three grams (10.7 mmoles) of 1-isopropyl-2-amino-6-benzoylbenzimidazole were dissolved in 25 ml. of tetrahydrofuran, after which was added 27 ml. of a 2M solution of methyl magnesium bromide in ethyl ether. After stirring overnight, ethyl acetate was added, and the solution was washed three times with a saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. One hundred milliliters of 98% formic acid were added to the residue. The solution was refluxed for 2 hours. The formic acid was evaporated under reduced pressure. Ethyl acetate was added, and the resulting solution was washed with a saturated sodium bicarbonate solution. After drying over magnesium sulfate, the solution was filtered and concentrated. Upon the addition of a small volume of ether, 2.0 g. of the title product solidified out of solution which was recovered by filtration, M+ =277.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:46]([O:49]CC)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([OH:49])(=[O:48])/[CH:47]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To the trans-2-tetradecenal (2.3 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene) triphenylphosphorane (4.4 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). Potassium hydroxide (2.8 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-hexadecadienoic acid (2.2 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-hexadecadienoic acid (2.0 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml), and para-nitrophenol (1.1 g) and N,N'-dicyclohexylcarbodiimide (1.6 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-hexadecadienoic acid (0.8 g). To the active ester (340 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK283 in the yield of 270 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([NH:32][C:33](=[O:38])C(Cl)(Cl)Cl)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH2:30][CH3:31])=[O:38])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Product: CCNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminocarbonyl-aminosulfonyl)-7-methoxychroman ##STR32## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminocarbonyl-aminosulfonyl)-7-methoxychroman is synthesized analogously to Example 1 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-ethyltrichloroacetamide. Melting point: 211°-213° C.
Reaction SMILES: CO.[OH-].[Na+].[F:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[S:14][C:10]=2[C:9]([F:22])=[CH:8][C:7]=1[F:23]>O>[F:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:14][C:10]=2[C:9]([F:22])=[CH:8][C:7]=1[F:23]
Reactant: CCOC(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a mixture of methanol (8 ml), water (6 ml) and 2N sodium hydroxide (2 ml, 4 mmol) was added ethyl 3-(4,5,7-trifluorobenzothiazol-2-yl)propionate (1.1 g, 3.8 mmol) and the mixture was stirred for 15 min. at ambient temperature. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was recrystallized from hexane-isopropyl ether to give 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (840 mg, 85%) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:10][CH2:11][CH2:12]2)[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: O=P([O-])([O-])O
Reactant: Nc1c(F)c(C2CCC2)nc(C=O)c1Cl
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(C2CCC2)nc(C(=O)O)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinaldehyde (209 mg, 0.914 mmol) and t-butanol (4.57 mL). The mixture was treated with water (1.523 mL), 2-methylbut-2-ene (0.8 mL, 0.914 mmol), sodium hydrogenphosphate (260 mg, 1.828 mmol), and finally sodium chlorite (248 mg, 2.74 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. After stiffing at room temperature overnight, an aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was triturated with Et2O and the Et2O removed giving 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinic acid (94 mg, 39.9%) as a yellow solid: 1H NMR (400 MHz, CDCl3) 11.60 (s, 1H), δ 4.94 (d, J=18.2 Hz, 2H), 3.86 (ttdd, J=9.1, 8.2, 2.1, 1.0 Hz, 1H), 2.35 (dddd, J=13.1, 6.9, 3.4, 1.8 Hz, 3H), 2.12 (m, 2H), 1.95 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −140.30; ESIMS m/z 243 ([M−H]−).