Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:22])[CH2:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[C:15]([Cl:21])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=[O:24].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:21][C:15]1[N+:14]([O-:24])=[C:13]([CH2:12][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:22])[C:18]([C:19]#[N:20])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(Cl)[n+]([O-])c1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Another batch was prepared as follows: To a suspension of (6-chloro-3-cyano-pyridin-2-yl)-acetic acid 4-nitro-phenyl ester (157 mg, 0.5 mmol) and sodium percarbonate (157 mg, 1.0 mmol) in anhydrous acetonitrile (4 mL), cooled in an ice-water bath, was added trifluoromethanesulfonic anhydride dropwise (253 μL, 1.5 mmol). The reaction mixture turned into a translucent light yellow solution. After stirring for 3 hrs in ice-water bath, the reaction mixture was poured into saturated sodium carbonate solution (30 mL) and cooled in an ice-water bath. The reaction vial was rinsed with DCM and poured into the sodium carbonate solution. After stirring for 25 min in the ice-water bath, the organic layer was separated. The aqueous layer was further extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate. After rotary evaporation of most solvent, the concentrated solution was loaded on a preparative silica TLC (2 mm, 20×20 cm) and developed with EtOAc/Hexane (1:1). The title compound was obtained as a light yellow solid (108 mg, 65%). 1H-NMR (300 MHz, CDCl3) δ 8.29 (d, 2H), 7.68 (d, 1H), 7.51 (d, 1H), 7.31 (d, 2H), 4.40 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Cl)[N:11]=1)[C:8](=[O:13])[N:7]([CH3:14])[CH:6]=[CH:5]2.[CH3:15][NH2:16]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:16][CH3:15])[N:11]=1)[C:8](=[O:13])[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: CN
Reactant: Cn1ccc2cc(Cl)nc(Cl)c2c1=O
Solvent: C1CCOC1
Product: CNc1nc(Cl)cc2ccn(C)c(=O)c12
Temperature: 95 °C

Procedure:
A mixture of 6,8-dichloro-2-methyl-2,7-naphthyridin-1(2H)-one (46 mg, 0.2 mmol) and CH3NH2 solution in THF (2.0 M, 2.5 mL) was heated at 95° C. for 5 hours and evaporated to afford the crude title compound. ESI-MS m/z 224.0 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>C(O)C.O1CCOCC1>[ClH:23].[ClH:23].[CH3:21][C:19]1[CH:18]=[C:17]([CH3:22])[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: Cc1cc(C)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(C)nc(NC2CCNCC2)n1

Procedure:
A solution of 4-(4,6-dimethyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 4.80 mmol) in ethanol (20 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 207.3 [M+H]+.
Reaction SMILES: [O:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Yield: 62.1 %

Procedure:
Reaction and post-treatment were carried out according to Reference example 12(a) using 2.81 g of diethyl phenoxymalonate, 2.59 g of 4-benzyloxybenzyl chloride and 530 mg of sodium hydride (55% oil suspension) to obtain 3.10 g of the desired compound as a syrup.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:21]([CH3:31])[CH:20]=1)=O.[OH-].[Na+]>CO.Cl>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH:9]=[CH:17][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:21]([CH3:31])[CH:20]=2)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reactant: Cc1cc(C=O)cc(C)c1CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1sc(C(=O)C=Cc2cc(C)c(CCC(=O)O)c(C)c2)c2c1CC(C)(C)CC2
Yield: 86.4 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (400 mg, 1.69 mmol), 3-(4-formyl-2,6-dimethyl-phenyl)-propionic acid (419 mg, 2.03 mmol) and NaOH (1.7 g, 42.5 mmol) in methanol (17 mL) is stirred at 75° C. for 75 min before it is diluted with 1 N aq. HCl and extracted twice with EA. The organic extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with DCM containing 6% of methanol to give 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-2,6-dimethyl-phenyl}-propionic acid (620 mg) as a pale yellow solid; LC-MS: tR=1.17 min; [M+1]=425.34; 1H NMR (CDCl3): δ 7.68 (d, J=15.8 Hz, 1H), 7.28 (s, 2H), 7.27 (d, J=15.8 Hz, 1H), 3.18 (t, J=7.0 Hz, 2H), 3.06-2.98 (m, 2H), 2.78 (q, J=7.6 Hz, 2H), 2.54-2.48 (m, 2H), 2.39 (s, 6H), 2.34 (s, 2H), 1.58 (t, J=7.0 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH2:23][CH2:24][CH3:25])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH2:23][CH2:24][CH3:25])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: CCC[C@H](N)C(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OC

Procedure:
The reaction of 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5 A, 1.34 g of (L)-norvaline methyl ester hydrochloride and 680 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-norvaline methyl ester after flash chromatography (N3). 1H-NMR (DMSO): 0.83 ppm (t, 3 H), 1.33 ppm (m, 2 H), 1.55 ppm (m, 2 H), 3.62 ppm (s, 3 H), 3.1 ppm (m, 1 H), 7.3-8 ppm aromatics.
Reaction SMILES: COCCOC.Br[C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2ccccc2CNC(=O)OC(C)(C)C)n1
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
83 ml of 1,2-dimethoxyethane were aerated with argon, and 481 mg (0.41 mmol) of Pd(PPh3)4 and 1.9 g (8.3 mmol) of ethyl 6-bromopicolinate were added. After 10 min, 3.16 g (12.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 8.3 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux under argon for 18 h, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 2.12 g (72%) of a viscous orange oil were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][CH2:2][NH:12][CH:9]1[CH2:11][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)CCBr
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC1CC1

Procedure:
14.0 ml of ethyl 3-bromopropionate are added to a solution of 15.4 ml of cyclopropylamine in 100 ml of toluene and the reaction mixture is heated to 90° for 3 hours. Subsequently, the precipitated salt is filtered and the filtrate is distilled. There are obtained 9.5 g of N-cyclopropyl-β-alanine ethyl ester, Fab-MS: 157 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: BrCc1ccccn1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Br
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ccccn1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(pyridin-2-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(bromomethyl)pyridine hydrobromide following General Procedure H.
Reaction SMILES: [C:1](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](OC)(C)(C)C>O1CCCC1>[C:1](=[N:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH3:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)C
Reactant: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CN(N=C(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 96 %

Procedure:
N-Benzhydrylidene-N′-(4-chlorophenyl)hydrazine (0.2 g, 0.65 mmol, 1 eq.) and 3.2 mL of tetrahydrofuran are placed in a predried 20 mL round-bottomed flask under argon. The solution is cooled to a temperature in the region of −10° C. and 0.5 M potassium hexamethylbis-silylamide solution (1.43 mL, 1.1 eq.) is then added. The solution darkens, and is left to react at this temperature for 30 minutes, followed by addition of a solution of methyl iodide in methyl tert-butyl ether (0.49 mL, 1.5 eq.). The mixture is then allowed to return to a temperature in the region of 25° C. and is left stirring for 4 hours. After treatment with sodium hydrogen carbonate, the mixture is extracted with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. The residual oil is purified by chromatography on silica gel, eluting with an ethyl acetate/heptane mixture (10/90 by volume). N′-Benzhydrylidene-N-(4-chlorophenyl)-N-methylhydrazine is obtained in a yield of 96% in the form of a yellow solid, which product is used directly in the following step.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cc(C(=O)OCC)c(Nc2ccc(I)cc2F)cc1=O

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and allyl bromide in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 1-allyl-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (78%), m.p. (EtOAc) 138-141° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.30 (s, 1H), 8.45 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.61 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.98-5.87 (m, 1H), 5.47 (d, J=1.3 Hz, 1H), 5.19 (ddd, J=10.4, 2.7, 1.3 Hz, 1H), 5.12 (ddd, J=17.2, 3.0, 1.5 Hz, 1H), 4.54 (br d, J=5.5 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H). Anal. Calcd for C17H16FIN2O3: C, 46.2; H, 3.7; N, 6.3. Found: C, 46.5; H, 3.6; N, 6.2.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>>[CH3:15][NH:16]/[C:17](/[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[CH:18]\[N+:19]([O-:21])=[O:20]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CNC(=C[N+](=O)[O-])SC
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 90.6 %

Procedure:
The process of Example 1 was repeated at a commercial scale, using 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (35 kg) and N-methyl-1-(methylthio)-2-nitroetheneamine (28 kg) to give crude ranitidine base (46.5 kg), m.p. 68°-70° C.; purity--99.1% (HPLC).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[Cu][C:22]#[N:23]>CN(C=O)C>[CH3:20][O:19][C:3]1[C:2]([C:22]#[N:23])=[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:6]2=[CH:5][CH:4]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2cc3c(Br)c(OC)ccc3o2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(C#N)c(OC)ccc3o2)cc1
Yield: 61.8 %

Procedure:
4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran 133 (0.258 g, 0.77 mmol) was taken into 20 mL of DMF along with copper (I) cyanide (0.173 g. 1.94 mmol) and heated at reflux for three hours. Additional copper (I) cyanide was added several times to complete the reaction. The reaction was filtered through a cotton plug that was then washed several times with ethyl acetate. The filtrate was diluted with additional ethyl acetate and then washed with water (2×), brine (1×), dried over magnesium sulfate, filtered and concentrated. The resulting material was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes as the eluent to yield the desired compound (0.133 g, 61.8%) as a white solid: Mp. 120–122° C.; 1H NMR (DMSO-d6) δ 7.96 (d, 2 H, J=8.8 Hz), 7.92 (d, 1 H, J=9.1 Hz), 7.91 (s, 1 H), 7.14 (d, 1 H, J=9.1 Hz), 7.09 (d, 2 H, J=8.9 Hz), 3.95 (s, 3 H), 3.83 (s, 3 H); MS 280 (M +H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])[CH:5]=[CH:6][C:7]=1[OH:8].[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:26]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)c(F)c2)C(O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1F

Procedure:
A solution of 0.069 g of benzyl 4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate in 5 ml of acetone is admixed with 0.034 g of potassium carbonate and 0.019 ml of dimethyl sulphate. The reaction mixture is stirred at reflux over 5 hours, cooled and filtered through Hyflo. The filtercake is washed with 2×5 ml of acetone and the filtrate is concentrated by evaporation. The residue is taken up in 30 ml of tert-butyl methyl ether, washed with 10 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=4.32.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35]=O)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl.[NH2:38][OH:39].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[N:38][OH:39])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C=NO)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (2.44 g), hydroxylamine hydrochloride (377 mg) and sodium acetate (526 mg) in acetic acid (15 ml) was stirred at room temperature for an hour to form 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate. To the reaction mixture was added acetic anhydride (1.66 g) and the mixture was stirred at room temperature for an hour and then heated at 100° C. for 3 hours with stirring. After removal of the acetic acid, the residue was adjusted to pH 7.5 with aqueous sodium bicarbonate solution and extraced twice with ethyl acetate. The extracts were washed twice with water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residual brown oil (2.6 g) was chromatographed on a column of silica-gel (78 g) and eluted with a mixture of benzene and ethyl acetate (12:1, v/v) to give an oil (1.45 g). The oil was crystallized by triturating with a small amount of mixture of diisopropyl ehter and diethyl ether, and recrystallized from a mixture of diisopropyl ether (9 ml) and ethanol (1 ml) to give pure crystals of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (840 mg), mp 114° to 115° C. An additional crop (560 mg) was recovered from the filtrate by concentrating the filtrate and allowing to stand the residue in a refrigerator.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:15][C:16]#[CH:17]>CC(C)=O.C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:17][C:16]#[CH:15])[CH2:4][CH2:3]1
Reactant: C#CCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
To a stirred, chilled suspension of 1-methylpiperazine (10.0 g, 100.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in acetone (200 mL) was added 3-bromoprop-1-yne (11.0 mL, 100 mmol) (80% in toluene). The reaction was stirred for 18 hours at room temperature under N2. The suspension was diluted with diethyl ether (200 mL) and filtered, and the filtrate was concentrated in vacuo. The resulting residue was resuspended in diethyl ether (100 mL) and refiltered. The filtrate was concentrated to an orange oil (8.2 g). The product was distilled under high vacuum. The product distilled between 95-120° C. head temperature. The product was obtained as a colorless oil (5.46 g, 32%). 1H NMR (400 MHz, CDCl3) δ 3.31 (m, 2H), 2.89 (m, 1H), 2.3-2.6 (m, 8H), 2.30 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=O)[CH:26]=[CH:27][CH:28]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:30]([CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([CH2:16][CH3:17])[NH:5]1
Reactant: CCc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
Part B: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAC, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 235-238° C. Mass Spec. 463(M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][N:14]=2)=[N:7][CH:6]=1
Reactant: Oc1ccccc1Oc1ccc(Cl)cn1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Clc1ccc(Oc2ccccc2Oc2ncc(Cl)cn2)nc1
Yield: 76.5 %

Procedure:
With stirring, 1.80 grams (0.012 mole) of 2,5-dichloropyrimidine was added to a mixture of 2.0 grams (0.009 mole) 2-(5-chloropyridin-2-yloxy)phenol, 1.5 grams potassium carbonate, and 40 ml of methyl ethyl ketone. After the addition, the mixture was heated at reflux overnight and then poured into excess H2O. After extracting with 200 ml of ethyl ether, the extract was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and evaporated to yield a yellow solid which was recrystallized from 1-chlorobutane to give 2.3 grams of product, m.p. 108°-111°; ir (Nujol): 6.35, 6.50 (C=N), 13.20 microns; NMR (CDCl3): δ6.75 (d, 1H, pyridine ring proton), 7.35 (s, 4H, ArH), 7.65 (AB quartet, 1H, pyridine ring proton), 8.10 (d, 1H, pyridine ring proton), 8.55 (s, 2H, pyrimidine ring protons).