Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:24]([O:31][CH2:32][C:33](Cl)=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH2:24]([O:31][CH2:32][C:33]([O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]=1[O:11][CH3:12])=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(OC(=O)COCc2ccccc2)c(OC)c1OC
Reaction time: 2 h

Procedure:
6-Nitro-2,3,4-trimethoxyphenol (1.25 g) and triethylamine (1.12 mL) were dissolved in dichloromethane (20 mL), benzyloxyacetyl chloride (1.1 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 2 hours as it is. The reaction mixture was extracted with chloroform, and the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound. Yield: 1.38 g (66.5%).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1)/[CH:11]=[C:12]1/[C:13](=[O:17])[NH:14][CH2:15][CH2:16]/1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:41]Br>C(OCC)(=O)C.O>[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:41][N:14]1[CH2:15][CH2:16]/[C:12](=[CH:11]\[C:10]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:8]([O:7][CH3:6])[CH:9]=2)/[C:13]1=[O:17]
Reactant: COc1cc(/C=C2\CCNC2=O)ccc1-n1cnc(C)c1
Reactant: Fc1ccc(CBr)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CCN(Cc3ccc(F)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a DMF (6.0 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)pyrrolidin-2-one (100 mg), lithium bis(trimethylsilyl)amide (1M hexane solution, 0.53 mL) was added at 0° C., and the reaction solution was agitated for 30 minutes at 0° C. 3,4-difluorobenzylbromide (0.060 mL) was added to this solution at 0° C., and that reaction solution was agitated at room temperature for 1 hour. The reaction solution was added to iced water and ethyl acetate, and the organic layer was partitioned. The obtained organic layer was washed with a saturated salt solution, and it concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 80 mg of the title compound was obtained.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]2[C:10](=[O:19])[NH:11][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:13][C:8]=2[CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:20][C:21]1[C:29]2[C:24](=[C:25]([CH3:33])[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[NH:23][N:22]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:20][C:21]1[C:29]2[C:24](=[C:25]([CH3:33])[CH:26]=[C:27]([C:30]([N:16]3[CH2:17][CH2:18][C:12]4([NH:11][C:10](=[O:19])[C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][C:8]=5[CH2:13]4)[CH2:14][CH2:15]3)=[O:31])[CH:28]=2)[NH:23][N:22]=1
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Reactant: Cc1n[nH]c2c(C)cc(C(=O)O)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c(C)cc(C(=O)N3CCC4(CC3)Cc3cnn(C(C)C)c3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one hydrochloride salt (Intermediate 2, 430 mg, 1.3 mmol) and 3,7-dimethyl-1H-indazole-5-carboxylic acid (306 mg, 1.6 mmol) in dimethylformamide (2 mL) was added triethylamine (0.75 mL, 5.4 mmol), 4-dimethylaminopyridine (33 mg, 0.37 mmol), and 1-propanephosphonic acid cyclic anhydride (0.52 mL, 1.74 mmol, 50% solution in ethyl acetate), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to a solid. The solid was purified via flash column chromatography (0-15% methanol/dichloromethane) to afford a glassy solid. The glassy solid was stirred in ethyl acetate for 16 hours and the resulting solid collected by vacuum filtration to afford the desired product as a white solid (138 mg). +ESI (M+H) 421.0; 1H NMR (400 MHz, CD3OD, δ): 7.65 (s, 1H) 7.42 (s, 1H) 7.21 (s, 1H) 5.50 (m, 1H) 3.95 (br. s., 1H) 3.50-3.62 (br. s., 3H) 2.97 (s, 2H) 2.56 (m, 6H) 1.83 (br. s., 4H) 1.44 (d, 6H).
Reaction SMILES: C1C[O:4]CC1.[C:6]1([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:22]([CH3:25])([O-:24])=[O:23]>>[N+:22]([CH2:25][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:4])[CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:24])=[O:23]
Reactant: C1CCOC1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: C[N+](=O)[O-]
Product: O=C(Cc1ccccc1)C(C[N+](=O)[O-])c1ccccc1
Reaction time: 1 h
Yield: 86 %

Procedure:
1 g of IBAF-silica (ca. 1 mmole equiv. F) is suspended in 20 ml of THF containing 6.1 g (0.1 mole) of nitromethane and 1.04 g (5 mmole) of chalcone and the resulting mixture heated with stirring. to 60° C. for 1 h. Separation (the cooled reaction mixture is filtered, the residue washed with ether and the combined filtrates evaporated to dryness) and recrystallisation of the product from ethanol gives 1.16 g (86%) of 4-nitro-1,3-diphenylbutanone, m.p. 99°-100° C. The TBAF-silica is recovered in 95% yield. The same experiment carried out at room temperature gives a 75% yield of recrystallised product and a 99% yield of recovered TBAF-silica after 6 h. On repeating the room-temperature experiment using recovered TBAF-silica, a 70% yield of recrystallised product and ca. 97% of TBAF-silica are recovered after 6 h. A control experiment carried out in which the TBAF-silica is replaced by silica along gives no detectable product (by 1H n.m.r.) after 12 h. at room temperature.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C1(C)C=CC=CC=1>[I:16][C:17]1[CH:18]=[C:19]([NH:20][CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(I)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cccc(I)c1)C(=O)OCC

Procedure:
A mixture of ethoxymethylene malonic acid diethyl ester (13.72 g, 0.068 mol) and 3-iodoaniline (15 g, 0.068 mole) in toluene (230 ml) was refluxed for 1 h. After this period of time, solvents were removed under vacuum, and the crude material was precipitated in methyl tert-butyl ether and the resulting white solid was filtered, and dried under vacuum (24.3 g, 93%).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH:37][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][CH2:6][N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C)C(C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 43.1 %

Procedure:
N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide was prepared following the procedure for Example 100, but staring from ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol) and 2M trimethylaluminium in toluene (1.875 mL, 3.75 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (0.301 g, 43.1%) as a white solid.
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([N:19]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:34])[NH:28][C:29]4[N:30]=[N:31][NH:32][N:33]=4)=[CH:23][CH:22]=3)=[O:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:50][NH2:51]>C1COCC1>[CH3:50][NH:51][C:9](=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([N:19]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:34])[NH:28][C:29]3[N:30]=[N:31][NH:32][N:33]=3)=[CH:23][CH:22]=2)=[O:18])[CH:11]=1
Reactant: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}benzoic acid pentafluorophenyl ester was added a solution of methylamine in THF (2M, 5 mL). The mixture was shaken at 25° C. overnight, filtered and washed with THF (2×10 mL), affording the resin bound title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH2:18]([O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:18]([O:25][C:26]1[C:31]([C:2]2[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([O:16][CH3:17])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
Reactant: CC1(C)OB(c2cccnc2OCc2ccccc2)OC1(C)C
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: ClCCl
Solvent: CO
Product: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 100.7 %

Procedure:
step 2—A sealed tube containing 60 (70 mg), 2-benzoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (145 mg), Na2CO3 (62 g) and Pd(PPh3)4 (27 mg) in a mixture of MeOH (4 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 115° C. for 30 min. The organic volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 95 mg of 2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-N-methyl-benzamide (62) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43](O)=[O:44])[N:41]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=2)=[O:44])[N:41]=1
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: Nc1nc(CC(=O)O)cs1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(Cc2ccc(NC(=O)Cc3csc(N)n3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
To a solution of 10 mg (5:1 mixture cis/trans, 0.02 mmol) of tert-butyl(5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-3) and (2-amino-1,3-thiazol-4-yl)acetic acid (3.18 mg, 0.02 mmol) in 0.5 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.04 mL, 0.02 mmol) followed by EDC (5.8 mg, 0.03 mmol) and DIEA (3.5 μL, 0.02 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (500 uM) eluting with 5% MeOH in dichloromethane to afforded the product (10.3 mg, 81%). m/z (ES) 637 (MH)+, 659 (MNa)+.
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C([O-])(=O)C.[Na+].C(O)C>O>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1C(=O)N(c2ccc(Cl)c(Cl)c2)N=C1C

Procedure:
The starting material is prepared as follows: The mixture of 1.3 g of diethyl α-acetyl-malonate, 1.3 g of 3,4-dichlorophenylhydrazine hydrochloride, 0.5 g of sodium acetate, 30 ml of ethanol and 10 ml of water is warmed on the steam cone for 10 minutes. It is diluted with water, extracted with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in 50 ml of xylene, the solution distilled for 10 minutes and refluxed for 85 minutes. It is evaporated and the residue triturated with diethyl ether to yield the 1-(3,4-dichlorophenyl)-3-methyl-4-carbethoxy-2-pyrazolin-5-one, melting at 147°-148°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1.[CH3:17][Si](C)(C)[N-][Si](C)(C)C.[Na+].IC>C1COCC1>[CH3:17][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: c1cncc(-c2noc(-c3ccc[nH]3)n2)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cccc1-c1nc(-c2cccnc2)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-{5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl}-pyridine (1 g; 0.5 mmol) in 15 ml of dry THF at −70° C. was added 0.18 g of sodium hexamethyl disilazide (1 mmol), the reaction mixture was stirred at −70° C. for 30 min. and at 0° C. for 1 hour. The reaction mixture was cooled to −70° C. and added 0.076 g of iodomethane (0.52 mmol). The reaction mixture was stirred at −70° C. for ½ hour, then at room temperature overnight. The product was isolated by column chromatography. Yield 0.04 g of yellow solid (37%). Mp. 108-109° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:29][C:30]([NH2:32])=[NH:31])=[N:6][CH:5]=1.[H-].[Na+].[C:35](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC=CN=1)([CH3:38])([CH3:37])[CH3:36]>COCCOC>[C:35]([O:20][C:19](=[O:21])[CH2:18][N:17]([S:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:4]([Cl:3])=[CH:5][N:6]=[C:7]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:12][CH:11]=1)(=[O:15])=[O:16])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccn1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccccn3)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(Cc1ccccn1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine dihydrochloride ##STR25## Guanidine hydrochloride (293 mg, 3.07 mmol was added in one portion to a stirred suspension of NaH (57 mg, 80% dispersion by wt in mineral oil, 1.92 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine t-butyl ester (370 mg, 0.78 mmol) in DME (10 mL) was added and the mixture heated at 90° C. for 1 h. The solvents were evaporated in vacuo, the residue was dissolved with EtOAc (200 mL), and washed with aqueous NH4Cl (150 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 20:80) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine t-butyl ester (120 mg, 0.24 mmol) as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10](C)[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CN1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reaction time: 64 h

Procedure:
A mixture of 10.26 g of trans-4-(4-chlorophenoxy)-1-methyl-3-phenylpiperidine of Example 26, 7.05 g of anhydrous potassium carbonate, 75 ml of dry benzene and 5.53 g of ethyl chloroformate is refluxed for 18 hours under nitrogen. The mixture is then partitioned between distilled water and hexane. The organic phase is washed with water, the combined aqueous extracts are extracted with hexane, the combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to afford an oil which almost completely crystallizes after standing for about 64 hours. The colorless solid is triturated with hexane, filtered and washed well with hexane to afford trans-4-(4-chlorophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine, m.p. s 80°, 81.5°-84° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:31])[CH2:15][N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH3:30])=[C:24]([C:26]([O:28]C)=[O:27])[S:25][C:19]=3[N:18]=[CH:17]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.O.[OH-].[Li+]>C1COCC1.CO>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:31])[CH2:15][N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH3:30])=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:19]=3[N:18]=[CH:17]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)c1sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of methyl 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, (3.3 g, 6.75 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.42 g, 33.8 mmol). The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.9 g of 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 59%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:18][N:14]1[CH:15]=[CH:16][C:17]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[C:26]=4[F:27])[CH:3]=3)[CH:10]=[N:11][C:12]=2[C:13]1=[O:19]
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cccc(F)c3F)c2)c1=O
Yield: 40 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 2,3-difluorobenzeneboronic acid, in the same way as in Example 1, to give 5-methyl-1-(2,2′,3′-trifluorobiphenyl-5-yl)-1,5-dihydroimidazo[4,5-c]pyridin-4-one as an off-white solid (32 mg, 40%): δH(400 MHz, d6-DMSO) 3.54 (3H, s), 6.61 (1H, d, J 7), 7.35-7.41 (1H, m), 7.48 (1H, dd, J 8 and 7), 7.55-7.67 (3H, m), 7.77-7.81 (2H, m), 8.40 (1H, s); m/z (ES+) 356 [MH+].
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[O:16])[N:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].[CH3:21][N:22]=[C:23]=S.CO>CN(C=O)C>[CH3:21][NH:22][C:23]1[C:4]2[C:5](=[O:20])[N:6]([CH2:17][CH2:18][CH3:19])[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccnc2)c1=O
Reactant: CN=C=S
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
A solution of 6-hydrazino-1-(3-pyridylmethyl)-3-propyluracil (0.7 g, 2.66 mM) and methyl isothiocyanate (0.7 ml, 10.3 mM) in DMF (10 ml) was heated at 90° C. for 14 hours and then at 110° C. for 14 hours. To the reaction solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water afforded colorless needles (0.5 g, 60%), m.p. >300° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2].[CH2:20]([O:22]CC)[CH3:21].C([CH:27]([C:31](Cl)=[O:32])[C:28](Cl)=[O:29])C.O>C(O)C.C(O)(=O)C>[CH2:20]([O:22][C:31]([C:27]1[C:28](=[O:29])[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[CH:8][C:3]=2[C:1]=1[NH2:2])=[O:32])[CH3:21]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: COCCNc1nc(-c2ccccc2)ncc1C#N
Reactant: CCOCC
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 9.3 g. (0.037 mole) of 5-cyano-4-(2-methoxyethylamino)-2-phenyl pyrimidine in 350 ml. of diethyl ether was added 2.8 g. (0.019 mole) of ethyl malonyl chloride and this mixture was stirred at room temperature for 4.5 hours. Then the solid material was filtered off and the filtrate evaporated to dryness. Ethanol was added until a solution was obtained and this solution was added to 0.85 g. (0.057 mole) of Na in ethanol and stirred 20 minutes. A little water was added and the solution was acidified with acetic acid. The solid product was collected on a suction filter and recrystallized from ethanol to give 2.0 g. of product--m.p. 245°-247° C.