Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(=O)C.CO.[OH:7][C@H:8]1[CH2:12][NH:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9]1>C(OCC)C>[ClH:4].[OH:7][C@H:8]1[CH2:12][NH:11][C@H:10]([C:13]([O:15][CH3:1])=[O:14])[CH2:9]1
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Product: Cl
Temperature: 25 °C

Procedure:
Acetyl chloride (380 ml) was dropwise added to methanol (3.5 l) at 10°-25° C. with stirring, followed by (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid (500 g). The mixture was refluxed for 3 hours. The mixture was cooled to the ambient temperature and poured into diethyl ether to give precipitates. The precipitates were collected by filtration and dried up in vacuo to give methyl (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride (676 g).
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16]Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CCOCC.C1(C)C=CC=CC=1>[C:1]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH2:16][N:29]2[CH2:28][CH2:27][CH:26]([CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:25])[CH2:31][CH2:30]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCN(c1ccccc1)c1ccccc1
Reactant: OC(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OC(c1ccccc1)C1CCN(CCCN(c2ccccc2)c2ccccc2)CC1
Yield: 16.6 %

Procedure:
A mixture of 9.8 g. (0.040 moles) of 3-[N,N-diphenylamino]-1-chloropropane, 5.7 g. (0.030 moles) of alpha-phenyl-4-piperidine methanol (preparation described in U.S. Pat. No. 3,029,244 to Lyle, Jr. et al, issued Apr. 10, 1962), 4.2 g. (0.040 moles) of sodium carbonate and 0.5 g. of sodium iodide in 90 ml. of toluene is refluxed for about 18 hours. The reaction mixture is cooled, washed with water, and then shaken with dilute hydrochloric acid. The viscous third layer which falls to the bottom is isolated and shaken with ether and dilute caustic. The resulting ether layer is then washed with water, dried, and passed into a column of silica gel. The product is eluted with ethyl acetate and the product fractions are combined, evaporated, and triturated with isopropyl ether. The resulting crystals are isolated by filtration and recrystallized from ethanol to give 2.0 g of 1-[3-(diphenylamino)propyl]-alpha-penyl-4-piperidine methanol, mp. 129.0°-130.5° C. 1-[3-(Diphenylamino)propyl]-alpha-phenyl-4-piperidine methanol shows approximately no inhibition of 3H-haloperidol binding at 10 n moles concentration and approximately 18% inhibition of hu 3H-haloperidol binding at 100 n moles concentration in the 3H-Haloperidol Receptor Binding Assay.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=3)[C:6]=2[CH:20]=1.[C-:25]#[N:26].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[N:13]=[CH:14][C:15]([CH2:18][C:25]#[N:26])=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC#N)cn1
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of 6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromehyl)-1H-benzimidazole (from step 5, 550 mg, 1.5 mmol) in DMF (5 ml) and water (1 ml) was added KCN (470 g, 7.2 mmol) at room temperature, and then the reaction mixture was stirred for 2 h. The mixture was diluted with water and extracted with ethyl acetate/toluene (4/1) solution (3×30 ml). The organic layer was washed with water, dried (MgSO4) and concentrated. This was purified by SiO2 column chromatography developing with hexane/ethyl acetate (1/) gave 198 mg (37%) of title compound as orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:17])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:3]=1[CH2:4][Cl:17]
Reactant: COC(=O)Nc1cccc(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C)c1CCl

Procedure:
To a suspension of 2-methyl-6-methoxycarbonylaminobenzyl alcohol (29.19 g) in methylene chloride (290 ml) was added dropwise thionyl chloride (11.46 ml) at room temperature and the resultant mixture was stirred for 2 hours. After the solvent was evaporated in vacuo, n-hexane was added to the residue to give precipitates. The precipitates were collected by filtration and dried to give 2-methyl-6-methoxycarbonylaminobenzyl chloride (28.26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35](Cl)=[O:36])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.O>ClCCl>[C:22]12([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=3[O:41][CH3:42])[C:35]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([N:8]4[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:7])=[CH:13][CH:14]=3)=[O:36])[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(C(=O)N3CCCC3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 72.7 %

Procedure:
1.7 g (9 mmoles) of N-p-aminobenzoyl pyrrolidine and 1 g (10 mmoles) of triethylamine are dissolved in 30 ml of dichloromethane. With stirring, 2.8 g (9 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride dissolved in 60 ml of dichloromethane are added. The reaction mixture is stirred for 16 hours, at which point water is added and the reaction mixture is extracted with dichloromethane. The extract is washed with water, extracted with methylene chloride and dried on MgSO4. The solvents are evaporated and the residue (yellow foam) is crystallized in ethyl acetate to give 3.0 g (73% yield) of N-[4-[3-(1-adamantyl)-4-methoxy benzamido]-benzoyl] pyrrolidine which melts at 239°-242° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)(O)[O-].[Na+].CI>CN(C)C=O>[CH3:22][O:20][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of t-butyloxycarbonyl-O-benzyl-D-serine (25.0 g, 84.7 mmol) stirring in dimethylformamide (500 mL) at room temperature was added sodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide (26.4 mL, 424 mmol). After 18 h, the reaction mixture was concentrated to approximately 100 mL. Ethyl acetate was added and the mixture washed with aqueous sodium bicarbonate and brine. The organic extract was dried and concentrated to give the desired compound (25 g, 96%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75 (s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310; Anal. calc'd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31; H, 7.49; N, 4.43.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([O-:29])=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1.[Na+].O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:29])=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1
Reactant: O=Cc1cccnc1Cl
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A suspension of 2-chloronicotinaldehyde (228 mg, 1.62 mmol) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (500 mg, 1.62 mmol) in DMSO (2.5 mL) was heated for 12 hours at 80° C. The reaction was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 35-60% ethyl acetate/isohexane, to give the title compound as solid (349 mg). 1H NMR (400 MHz, d6-DMSO): δ 11.00 (1H, s), 8.84-8.82 (2H, m), 8.40-8.34 (3H, m), 8.25 (1H, d, J=8.7 Hz), 8.06-8.02 (2H, m), 7.94-7.84 (3H, m), 7.38 (2H, t, J=8.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][C:12]([O:14]C)=[O:13])[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18]
Reactant: COC(=O)Cc1csc2c1c(=O)n(C)c(=O)n2C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)c2c(CC(=O)O)csc2n(C)c1=O

Procedure:
A mixture of Step 9 intermediate (1.3 g, 4.850 mmol) and 6 N H2SO4 (12 ml) in 1,4-dioxane (12 ml) was stirred at reflux temperature for 1 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue obtained was triturated in diethyl ether, solid obtained was collected by filtration to give 450 mg of the product as a white solid; 1H NMR (DMSO-d6, 300 MHz) δ 3.21 (s, 3H), 3.45 (s, 3H), 3.79 (s, 2H), 7.01 (s, 1H), 12.22 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)=O>>[C:15]1([O:13][C:12]([C:3]2[C:2]([OH:1])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Oc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1ccccc1)c1cc2ccccc2cc1O
Temperature: 100 °C
Yield: 37.6 %

Procedure:
A mixture of 50 g (0.266 mole) 3-hydroxy-2-naphthoic acid, 27.3 g (0.29 mole) phenol, and 21.4 g (0.14 mole) phosphorus oxychloride was stirred and heated at 100° C. for 3.5 hrs. Then 200 ml alcohol was added, and the mixture was heated one hour longer and cooled. The yellow product was collected and recrystallized from benzene to give 26.4 g (38%) of phenyl-3-hydroxy-2-naphthoate, m.p. 126°-130° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:6](=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8].[Sn](Cl)Cl>C(O)C>[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:6](=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1cccc(N)c1C(=O)OC
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 3:1 ethanol-cone. HCl (200 mL) was cooled to 0° C. and then 3-nitrophthalic acid dimethyl ester (15.0 g, 62.8 mmol) was added. Maintaining the cooling, tin (II) chloride (70.8 g, 314 mmol) was added portionwise, over a period of 15 min. Following completion of the addition, the cooling bath was removed and stirring proceeded at room temperature. After 2 h, the mixture was neutralized by the addition of solid sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (3×150 mL) and the combined extracts were washed with water (5×250 mL), were dried (MgSO4) and evaporated, providing 11.3 g of 3-aminophthalic acid dimethyl ester as a yellow oil, in 86% yield; 1H NMR (CDCl3) δ 3.84 (s, 3H), 3.86 (s, 3H), 5.20 (br, 2H), 6.78 (dd, J=8.5 Hz, J=1.0 Hz, 1H), 6.90 (dd, 1H, J=7.3 Hz, J=1.0 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH2:12][NH2:13].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[ClH:1].[ClH:1].[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH2:12][NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: NCc1cc2ccncc2[nH]1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cc2ccncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
A mixture of (1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine dihydrochloride (Example 84) (110 mg, 0.50 mmol), nicotinic acid (62 mg, 0.50 mmol), diisopropylethylamine (0.44 mL, 2.5 mmol), EDCI (110 mg, 0.55 mmol) and HOBt (cat.) in methylene chloride (2.9 mL) and DMF (3 mL) was stirred at room temperature under a nitrogen atmosphere overnight (18 h). The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water. The water layer was concentrated to dryness. The residue was dissolved in ethanol (10 mL) and 2 N HCl in Et2O (10 mL) was added. Methanol (ca. 5 mL) was added to dissolve the majority of material. The remaining brown precipitate was filtered off and discarded. The filtrate was concentrated, and the resulting solid was triturated with EtOH (ca. 4 mL), filtered, and dried to provide N-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)nicotinamide dihydrochloride (31 mg, 19%) as a tan solid: 1H NMR (500 MHz, CD3OD) δ4.99 (2H, s), 7.00 (1H, s), 8.03 (1H, d, J=6.0 Hz), 8.17-8.24 (3H, m), 8.77 (1H, s), 9.04-9.12 (3H, m), 9.38 (1H, s); ESI MS m/z 253 [C14H12N4O+H]+; HPLC (Method A) >99% (AUC), tR=7.78 min.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:27](Br)[CH3:28]>C(OCC)(=O)C.O>[CH2:27]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH3:28]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC=C(c2c[nH]c3ccccc23)CC1
Reaction time: 5 h
Yield: 67.2 %

Procedure:
A mixture of 9.91 g of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 10.6 g of sodium carbonate, 150 ml of dimethylformamide and 4.5 g of ethyl bromide was stirred under an inert atmosphere at 30°-35° C. for 5 hours and was then poured into 1.5 liters of water which caused precipitation. The mixture was stirred for one hour and filtered and the filter was rinsed with water. The recovered product was dried overnight in an oven at 70° C. under reduced pressure in the presence of dehydrating agent to obtain 8.95 g of raw product melting at 205° C. The product was dissolved in 400 ml of refluxing ethyl acetate and the mixture was filtered hot. The filtrate was concentrated to 250 ml and crystallization was effected for one hour. The mixture was filtered and the recovered product was rinsed with ethyl acetate to obtain 6.28 g of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in the form of yellow crystals melting at 205° C. Concentration of the mother liquors yielded another 1.76 g of product after crystallization for a total yield of 8.04 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH2:9]NC(=O)OC(C)(C)C)=[N:6][CH:7]=1.Cl.O1CCOCC1.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.1 %

Procedure:
To a reaction mixture of tert-butyl 2-(5-bromopyridin-2-yl)-2-oxoethylcarbamate (0.36 g, 1.142 mmol) in DCM was added 4 M hydrogen chloride in dioxane (2 ml, 8.00 mmol) and some MeOH. The reaction was stirred at rt for 3 hrs. The reaction mixture was concentrated to dryness to yield 2-amino-1-HCl salf of (5-bromopyridin-2-yl)ethanone (0.32 g) as a yellow solid. LC/MS (Cond. N-1): [M+H]+ 215.13, RT=0.945 min.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[Cl:28])[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:12])=[O:11])=[CH:6][N:5]=1.ClCCl.C(OCC)(=O)C>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[Cl:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[CH:13]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([F:1])=[N:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: [F-]
Reactant: O=S(=O)(c1ccc(Cl)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 25 °C
Yield: 6.9 %

Procedure:
Potassium fluoride (94 mg, 1.60 mmol) and tetraphenylphosphonium bromide (134 mg, 0.32 mmol) were added to a solution of 2-chloro-5-[(3-chloropyridin-4-yl) (2,5-difluorophenyl)methylsulfonyl]pyridine (66 mg, 0.16 mmol) in acetonitrile (2 ml). The resulting mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature. Dichloromethane was added and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with hexane:ethyl acetate=17:3 was concentrated under reduced pressure, whereby the title compound (4.5 mg, 0.011 mmol, 7%) was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9].Br[CH:30]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])[C:31]([CH:33]1[CH2:35][CH2:34]1)=[O:32].[ClH:43]>C(N(CC)CC)C>[ClH:43].[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:31]([CH:33]2[CH2:34][CH2:35]2)=[O:32])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COC(=O)Cn1nncc1/C=C1\CNCCC1SC(C)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Yield: 50 %

Procedure:
Following a procedure similar to that described in Example 150-(g), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}piperidine hydrogen trifluoroacetate (1.06 g) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone and triethylamine and the free base that was obtained by silica gel chromatography was similarly treated with hydrogen chloride to yield the title compound (650 mg, yield: 50%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][CH3:15])=[O:13].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][CH3:15])=[O:13].[OH:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CNC(=O)Cc1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Cc1ccc(O)cc1OC
Product: CNC(=O)Cc1ccc(OC)cc1O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(2,4-dimethoxyphenyl)-N-methylacetamide (445 mg, 2.12 mmol) in CH2Cl2 (10 mL) was slowly added 1M BBr3 solution in CH2Cl2 (6.4 mL, 6.4 mmol). After addition was completed, the reaction mixture was stirred at 0° C. for 2.5 h, methanol (2 mL) was added and after 15 min the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous NaHCO3 and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-5% methanol in dichloromethane) to give the subtitled compound (16 mg) along with 2-(4-hydroxy-2-methoxyphenyl)-N-methylacetamide (30 mg).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:3](=[CH2:2])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:15][CH:16]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1c2ccccc2C(=O)C1c1ccncc1
Temperature: 25 °C

Procedure:
##STR5## 13.2 g of indanone, 15 g of pyridine-4-aldehyde and 19 g of p-toluenesulphonic acid were heated to boiling under reflux in a water separator for 5 h in 250 ml of toluene. The resulting precipitate was filtered off with suction after cooling and stirred at room temperature for 30 rain in 10% sodium carbonate solution. The resulting, pale-yellow precipitate was filtered off with suction, washed with water and dried in air. Yield: 19.3 g (87%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].[OH-].[Na+]>>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:3]1[C:2]([NH2:1])=[N:7][C:6]([C:8]2[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-c2nc3ccccc3[nH]2)ccc1-c1ccccn1
Temperature: 0 °C

Procedure:
A suspension of 6-aminopyridine-2-carboxylic acid (1.12 g, 8.2 mmol) with 1,2-diaminobenzene (1.77 mg, 16.4 mmol) was heated in 8 mL of PPA at 180 degree for 2 h. The reaction mixture was poured into 250 mL of ice-water and neutralized with 2 N NaOH (chilled) while vigorously stirred. The resulting precipitate was filtered to collect an off-white solid, which was washed with 20 mL warm water, dried and purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH (MS, M++H=211).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2cc(-c3ccc(F)cc3)nn2c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A solution of 2-(4-fluorophenyl)-6-cyanopyrazolo[1,5-a]pyridine (6.7 g, 11 mmol) and concentrated sulfuric acid (2 drops) in acetic anhydride (25 mL) was heated, and stirred, at 120° C. under N2 for 5 h. The solution was cooled to room temperature, diluted with ice water and basified to pH 11 using 2 N aqueous sodium hydroxide. The solution was extracted with chloroform (3×), and the combined organic extracts were dried and the solvent was evaporated in vacuo. Trituration with methanol afforded a light brown solid which was collected and dried to give the title compound, 1.6 g (84%). 1H NMR (d6-DMSO) δ 2.19 (s, 3H), 7.35 (t, 2H, J=8.0 Hz), 7.69 (dd, 2H, J=4.0, 8.0 Hz), 7.86 (dd, 1H, J=4.0, 16 Hz), 8.30 (d, 1H, J=12 Hz), 9.75 (s, 1H). MS (ES+) m/z 280 (M++H).