Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]2[N:21]([CH2:25][C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH2:25][C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31][CH3:32])=[O:30])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cccc(CN2CCOc3cc(N)ccc32)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2cccc(C(=O)OC)c2)nc1Cl
Yield: 65.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (4 mL), methyl 3-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (100b) (0.28 g, 0.97 mmol) and pyridine (5 mL). The resulting solid was washed with dichloromethane/hexane=1/1 to obtain 0.29 g of the title compound as a colorless solid (66%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([O:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 92 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 92%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 111-112° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]1[O:13][CH2:12]1.[CH2:14]=O>ClCCl.O>[CH2:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:14][CH2:12][O:13]1
Reactant: C1CO1
Reactant: c1ccccc1
Reactant: C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: c1ccc2c(c1)CCOC2
Temperature: -20 °C
Yield: 70 %

Procedure:
31 g (0.398 mol) of benzene was put in a 500 ml four-necked flask equipped with a stirrer, a Liebig condenser having the upper portion thereof provided with a calcium chloride tube, and a thermometer, then stirred under a nitrogen stream at 300 rpm, and then mixed with 53 g (0.398 mol) of aluminum chloride and 17.3 g of dichlorometahne at room temperature. The resulting solution was cooled to -20° C. A solution of 17.5 g (0.398 mol) of ethylene oxide in 146.5 g of dichloromethane was dropwise added to the cooled solution over 4 hours. During this dropwise addition, the temperature of the reaction system was maintained at -20° C. to -30° C. After the completion of the dropwise addition, the resulting mixture was stirred at the same temperature for 15 minutes. Thereafter, 18 g (0.282 mol) of a 47% aqueous solution of formaldehyde was added to this mixture at 5° C. over 30 minutes. The resulting mixture was heated up to a temperature of 20° C. under stirring, and then further stirred at the same temperature for 2 hours and 30 minutes. 100 g of water was carefully added dropwise to the resulting mixture at a temperature of 30° C. or below. The resulting mixture was heated up to a temperature of 40° C. under stirring, and then further stirred at the same temperature for 1 hour. The resulting reaction mixture was allowed to stand still to effect phase separation. After the removal of the lower layer, the remaining organic phase was mixed with 50 g of a 10% aqueous solution of caustic soda. The resulting mixture was stirred at 40° C. for 1 hour, and then allowed to stand still to effect phase separation. After the removal of the lower layer, the remaining organic phase was distilled to remove the solvent. Subsequently, the residue was subjected to vacuum distillation (under 20 Torr) to obtain 37.4 g (0.278 mol) of isochroman as a fraction boiling at 105 to 106.5° C. (under 20 Torr). The yield was 70%.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])N=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21]1(C)C=CC=CC=1>>[F:8][C:7]1[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[CH:21][CH:4]=[N:3][C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Cc1ccccc1
Reactant: CCC#CCOc1ncnc(F)c1F
Product: CCC#CCOc1ccnc(N2CCCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.1 g of 4,5-difluoro-6-(2-pentynyloxy)pyrimidine and 0.05 g of piperidine were added to 0.2 ml of toluene, then the reaction mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.12 g of 5-fluoro-4-(2-pentynyloxy)-6-piperidinopyridine (referred as the present compound (6) hereinafter).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=[S:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:18][C:19](OCC)=[O:20].N1C=CC=CC=1>CCO>[CH2:1]([N:5]1[C:19](=[O:20])[CH2:18][S:7][C:6]1=[N:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CCl
Reactant: CCCCNC(=S)Nc1cccc(C#N)c1
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCN1C(=O)CSC1=Nc1cccc(C#N)c1
Yield: 67.9 %

Procedure:
To a 100 mL flask was added anhydrous EtOH (25 mL), 1-butyl-3-(3-cyanophenyl)thiourea (0.99 g, 4.2 mmol), ethyl chloroacetate (0.51 mL, 5.0 mmol), and anhydrous pyridine (0.5 mL, 5 mmol). After heating under reflux 16 h, the product mixture was concentrated under reduced pressure and chromatographed (silica gel, 2:98 MeOH/DCM) to afford the title product (0.78 g, 67%) as a colorless oil. 1H-NMR (CDCl3): δ 7.40–7.47 (2H, m), 7.25 (1H, m), 7.19 (1H, m), 3.84 (2H, t), 3.84 (2H, s), 1.69 (2H, m), 1.39 (2H, m), 0.97 (3H, t); MS(ESI): 274 (MH+).
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1.Cl>O1CCCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:29]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[OH:30])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cccnc1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccnc2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
aa) 10 ml of tert.butyl lithium solution (1.4M in hexane) are added dropwise at -70° within 10 minutes to 4.1 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 40 ml of tetrahydrofuran. After stirring at -70° for 2 hours. 1 ml of pyridine-3-carbaldehyde is added within 5 minutes. The reaction mixture is stirred at -70° for 1 hour and at 0° for 2 hours, and poured into 100 ml of 1N hydrochloric acid. The mixture is extracted three times with 50 ml of ether each time. The combined ether phases are washed with 100 ml of 1N hydrochloric acid and 20 ml of water. The combined aqueous phases are made alkaline with aqueous ammonia solution and extracted three times with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. There is obtained alpha-[4-(benzyloxy)-3 -methoxyphenyl]-3-pyridinemethanol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].CN(C)[CH:26]=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:1][O:2][CH2:3][CH2:4][O:27][CH3:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CN(C)C=O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
13.39 g of N-tert-butoxycarbonyltyrosine methyl ester was dissolved in 65 ml of tetrahydrofuran and 65 ml of dimethylformamide, and to the solution was added 1.9 g of 60% sodium hydride with stirring in an ice bath. After removing from the ice bath, the mixture was stirred at a room temperature for 30 minutes, and after addition of 5.4 g of methoxyethoxymethyl chloride with ice cooling, stirred for 15 hours allowing to warm to a room temperature. The reaction mixture was poured on ice, saturated with sodium chloride and extracted twice with 800 ml of chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (4:1) to obtain 13.85 g of the title compound in a colorless amorphous form.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21](=[O:26])[CH2:22][C:23]([CH3:25])=O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27]/[C:28](/[CH3:34])=[CH:29]\[C:30]([O:32][CH3:33])=[O:31].[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O)([O-:37])=[O:36]>>[CH3:34][C:28]1[NH:27][C:23]([CH3:25])=[C:22]([C:21]([O:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[O:26])[CH:41]([C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([N+:35]([O-:37])=[O:36])[CH:39]=2)[C:29]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(=O)CC(=O)OCCc1ccc(OCCOCc2ccccc2)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCOCc3ccccc3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
The ω-phenylalkylacetoacetate derivative (5) is then reacted with an alkyl β-aminocrotonate (or methoxyethyl β-aminocrotonate depending on the desired R5) and a benzaldehyde derivative (depending on the desired R4, e.g. for compounds in which R4 is meta --NO2, 3-nitrobenzaldehyde is used) under Hantzsch Dihydropyridine synthesis conditions (see, e.g., Fox, et al., J. Org. Chem., 16, 1259 (1951)) to form a 4-phenyl-2,5-dimethyl-1,4-dihydropyridine dicarboxylate diester (6). For example, 2-[4-(2-benzyloxyethoxy)phenyl]ethylacetoacetate (5) is reacted with methyl β-aminocrotonate and 3-nitrobenzaldehyde to produce 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-benzyloxyethoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine. (Step 6.)
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([CH3:20])=[CH2:19].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:17]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH:18]([CH3:20])[CH3:19]
Reactant: O=Cc1ccccc1O
Reactant: C=C(C)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccccc1C=O
Reaction time: 0.5 h

Procedure:
70.0 g of salicylaldehyde and 158.5 g of potassium carbonate were suspended in 700 mL of N,N-dimethylformamide, to which 68 mL of 3-chloro-2-methyl-1-propene was added dropwise over 30 minutes at 70° C., and this mixture was stirred for 30 minutes at the same temperature. Then, the reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 350 mL of ethanol, to which 7.0 g of 5% palladium-carbon was added, and this mixture was stirred for 4 hours at 35° C. in a stream of hydrogen. After the reaction mixture was filtered through Celite, the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:toluene=2:1] to yield 92.4 g of 2-isobutoxybenzaldehyde as light yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:3]1.[ClH:20].[NH2:21][OH:22]>O>[ClH:20].[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:4])[CH:3]=[N:21][OH:22].[C:14]1([CH:5]([NH2:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]([CH3:1])[CH2:3][NH2:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: CC1C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CC(C=NO)CC=CCCC=CCC(N)c1ccccc1
Product: CC(CN)CCCCCCCCC(N)c1ccccc1

Procedure:
Reaction of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene with hydroxylamine hydrochloride, in the presence of hydrochloric acid and water, to 2-methyl-11-phenyl-11-amino-undeca-4,8-dienal-oxime, and hydrogenation of this to give 1-phenyl-10-methyl-1,11-diaminoundecane; b.p. 138°-140° C./1 Pa; nD20 =1.5095.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([P:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:35][Br:36]>C1C=CC=CC=1>[Br-:36].[CH3:35][P+:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH2:33][CH3:34])([CH3:31])[CH3:32])=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][C:6]([C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])=[CH:7][CH:8]=1
Reactant: CBr
Reactant: CCC(C)(C)c1ccc(P(c2ccc(C(C)(C)CC)cc2)c2ccc(C(C)(C)CC)cc2)cc1
Solvent: c1ccccc1
Product: CCC(C)(C)c1ccc([P+](C)(c2ccc(C(C)(C)CC)cc2)c2ccc(C(C)(C)CC)cc2)cc1
Product: [Br-]
Reaction time: 24 h
Yield: 97 %

Procedure:
A mixture containing 28.3 g (0.06 mole) of tris(p-t-amylphenyl)phosphine, 28.5 g (0.3 mole) of methyl bromide and 200 cc of benzene was prepared and stored at ambient temperature for 24 hours. The solvent was then removed under reduced pressure and the solid residue was stirred together with a quantity of diethyl ether for one hour. The recovered solid material weighed 33 g (97% yield) after drying and was found to contain 71.3% carbon, 8.44% hydrogen, 5.15% phosphorus and 14.0% bromine. The calculated values for the expected compound are 72.0% carbon, 8.47% hydrogen, 5.47% phosphorus and 14.1% bromine.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:53]([N:60]1[CH2:64][CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH:62]([CH:73](O)[CH3:74])[CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[CH2:53]([N:60]1[CH2:61][CH:62]([CH:73]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:29])([F:30])[F:20])=[CH:27][CH:26]=2)[CH3:74])[CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH2:64]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (1.80 g, 5.59 mmol) in THF (40 mL) at 0° C. were added 4-trifluoromethyl-phenol(0.618 g, 3.81 mmol) and then DBAD (0.936 g, 4.07 mmol). After 5 minutes was added (SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-1) (0.89 g, 2.54 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:6) yielded 0.990 g (79%) of the title compound as a colorless oil. ES-MS m/e: 493.0 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([N:14](C)[C:15]([NH:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])(=[O:13])=[O:12])[CH:8]=2)[CH2:3]1.[OH-].[Na+].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32](Cl)=[O:33].[CH2:38](Cl)Cl>O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH:14][C:15]([NH:17][CH2:18][CH:22]3[CH2:21][CH2:20][CH2:19][CH2:38]3)=[O:16])(=[O:12])=[O:13])[CH:8]=2)[CH2:3]1)=[O:33]
Reactant: ClCCl
Reactant: CN(C(=O)NC1CCCC1)S(=O)(=O)c1ccc2c(c1)CC(N)C2
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NC1Cc2ccc(S(=O)(=O)NC(=O)NCC3CCCC3)cc2C1
Reaction time: 1 h

Procedure:
2.4 g of N-(2-aminoindane-5-sulfonyl)-N'-cyclopentyl-methylurea (melting point 192° - 194° C, prepared by saponification of 2-N-(acetamido-indane-5-sulfonyl)-N'-cyclopentyl-methyl-urea, melting point 107° - 109° C) were dissolved in 10 ml of water and 3.6 ml of 2N-sodium hydroxide solution. Then, a solution of 1.7 g of 5-chloro-2-methoxy-benzoyl chloride in 6 ml of methylene chloride was added dropwise, while cooling, and the whole was stirred for 1 hour; the mixture was slowly heated and the methylene chloride was evaporated. The sulfonyl-urea that had precipitated was filtered off with suction and dissolved in dilute sodium hydroxide solution. The whole was then treated with active charcoal, filtered and the sodium salt was precipitated by the addition of concentrated sodium hydroxide solution. The sodium salt was dissolved in water and precipitated again by the addition of sodium hydroxide solution. Finally, the free compound was precipitated from the alkaline solution with hydrochloric acid and recrystallized from methanol. Melting point 194° - 196° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.Cl.[NH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][CH2:45]1>C(#N)C.C(O)C.C(N(CC)CC)C>[C:50]1([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:49][CH2:48]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCCN1CCN(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: O=C(NCCCCN1CCN(c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 0.90 g (7.82 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.51 g (7.88 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 2.02 g (5.89 mM) of 1-(4-aminobutan-1-yl)-4-phenylpiperazine trihydrochloride and 4.1 ml (29.4 mM) of triethylamine in ethanol (10 ml) and the mixture was further stirred for one hour. The solvent was distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 50% methanol-chloroform=1:10). After concentration, ethanol was added to the residue and the resulting crystal crop was harvested by filtration to provide the title compound as rouge-colored crystals.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Oc1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To an argon-flushed flask containing a suspension 0.486 g (1.68 mmol) of 4'-hydroxy-4-biphenylyl benzoate in 10 ml of acetic acid at 10°-15° C., 0.345 ml of HNO3 (d: 1.41) was added dropwise (about a drop per min). Then the reaction mixture was vigorously stirred at the same temperature for 30 min. Water (40 ml) was added and the mixture was again stirred for 30 min. The yellow precipitate was filtered, washed several times with water, dried and purified by flash chromatography on silica gel using dichloromethane/hexanes [65/35] as eluent to give 4'-hydroxy-3'-nitro-4-biphenylyl benzoate (compound 15, Scheme II) as a yellow solid (0.539 g, 96%). This material was recrystallized from ethanol to give product of mp. 163° C.; . Rf [hexanes/dichloromethane 40/60]: 0.42; 1H NMR (300 MHz, CDCl3): δ 7.25(d, 1H, J=8.7 Hz), 7.33(d, 2H, J=8.7 Hz), 7.50-7.70(m, 5H), 7.84(dd, 1H, J=2.7 Hz, J=8.7 Hz), 8.23(d, 2H, J=7.2 Hz), 8.32(d, 1H, J=2.7 Hz), 10.60(s, 1H); 13C NMR (300 MHz, CDCL3): δ 120.54, 122.45, 122.81, 127.85,, 128.65, 129.33, 130.23, 133.04, 133.78, 136.04, 136.22, 150.91, 154.44, 165.15; IR (CHCL3): 3250(broad), 3020, 1740, 1620, 1540, 1510, 1490, 1325, 1270, 1225, 1220, 1170, 1080, 1065, 1025, 1000, 850 cm-1 ; Mass spectrum, m/z(rel.intensity): 335(M+ 7), 105(100), 77(16) .
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[N:33]=[CH:32][C:31](Br)=[CH:30][C:27]=1[C:28]#[N:29]>>[NH2:25][C:26]1[N:33]=[CH:32][C:31]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N#Cc1cc(Br)cnc1N
Product: N#Cc1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 g, 1.0 mmol) and 2-amino-5-bromo-nicotinonitrile (example C.23 step 1) (200 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (240 mg, 52%). MS (ISP) 455.3 [(M+H)+]; mp 255° C.