Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN.[CH3:3][N:4](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]=1[CH2:37][OH:38]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([NH:4][CH3:3])=[O:35])=[CH:28][C:27]=1[CH2:37][OH:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CCc1ccc(Cl)c(CO)c1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CNC(=O)CCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.6 %

Procedure:
MeNH2 (2M in THF, 28.0 mL, 56.1 mmol) and TBTU (1.98 g, 6.17 mmol) were added to a sol. of 3-(4-chloro-3-hydroxymethyl-phenyl)-propionic acid (1.20 g, 5.59 mmol) in CH2Cl2 (42 mL). The mixture was stirred at rt for 2.5 h, and CH2Cl2 (150 mL) was added. The mixture was washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:9) yielded the title compound (250 mg, 20%). LC-MS: tR=0.67 min; ES+: 269.34.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[Cl:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Cl:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:12][C:10]1[S:11][C:7]2[C:6]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:25]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
2-Chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide was prepared from 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and and 2-chloromethyl-isonicotinic acid in exact the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide. Light yellow solid (60% yield). MS: m/e=419(M+H+).
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@H:25]([NH:28][C:29]5[N:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=5)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>O1CCOCC1.O.CCO>[C:20]1([C@@H:23]2[CH2:27][CH2:26][C@H:25]([NH:28][C:29]3[N:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=3)[CH2:24]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](Nc5cnc(C#N)cn5)C4)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1cnc(N[C@H]2CC[C@@H](c3nnc4cnc5[nH]ccc5n34)C2)cn1
Temperature: 60 °C
Yield: 67.6 %

Procedure:
A mixture of 5-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile (0.426 g, 0.853 mmol) and aqueous NaOH (1 N, 1.71 mL, 1.71 mmol) in 1,4-dioxane (4.4 mL) was heated at about 60° C. for about 80 min. The mixture was cooled to ambient temperature and diluted with water (40 mL). A solid precipitated and was collected by vacuum filtration and washed with water to give an off-white solid. The material was dissolved in hot EtOH and allowed to cool to ambient temperature. The precipitate was collected by filtration and dried under vacuum to give an off-white solid that was dried in a vacuum oven at about 70° C. to give an off-white solid (0.199 g). The material was taken up in EtOAc (10 mL) and heated at about 70° C. for about 1.5 h. The solid was collected by vacuum filtration, while rinsing with EtOAc. This material was dried under vacuum to give 54(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile (0.19 g, 64%) as an off-white solid: LC/MS (Table 2, Method a) Rt=1.55 min; MS m/z: 346 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[C:10]([C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:12]=2)=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1>C(O)C.[Ni]>[NH2:8][CH2:7][C:6]1[CH:9]=[C:10]([C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)[N:12]=2)[C:3]([CH:2]([F:27])[F:1])=[N:4][CH:5]=1
Reactant: N#Cc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: [Ni]
Solvent: CCO
Product: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 998.2 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-16 by using 6-(difluoromethyl)-5-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)nicotinonitrile (Example-183, 0.050 g, 0.13 mmol), Raney Ni (catalytic amount), TEA (0.040 g, 0.39 mmol) in ethanol (20 mL) to afford 0.50 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]3)=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:35])[CH:3]=1.[F-].[K+].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[F:12][C:11]([F:14])([F:13])[CH2:10][CH2:9][CH:8]([NH:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([C:43]2[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[CH:3][C:4]=1[CH3:35]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(Br)cc3C)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ccc(OC)cc4)cc3C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A reaction mixture of ethyl (3R)-1-(4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoyl)piperidine-3-carboxylate (200 mg), palladium acetate (4.0 mg), potassium fluoride (62.8 mg), 4-methoxyphenylboronic acid (109 mg), 2-(di-tert-butylphosphino)biphenyl (10.7 mg) and tetrahydrofuran (2 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.173 g).
Reaction SMILES: [Na].[CH2:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]2)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:34])C=CC=CC=1>C1COCC1>[CH3:26][O:25][C:23]([C:20]1([OH:34])[CH2:21][CH2:22][N:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)[CH2:19]1)=[O:24]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCCCCCCCCc1ccc(CN2CCC(C(=O)OC)C2)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(CN2CCC(O)(C(=O)OC)C2)cc1
Temperature: -72 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
To a solution of 0.52 mL (0.52 mmol) of 1.0M sodium hexamethylsilazide in THF at −78° C. was added 153 mg (0.44 mmol) of (R/S)-1-(4-nonylphenyl)methyl-pyrrolidin-3-yl carboxylic acid, methyl ester (from EXAMPLE 34, Step C) in 1 mL of THF while maintaining the internal temperature at less −72° C. After 20 min, 172 mg (0.65 mmol) of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis Reagent) in 1 mL of THF was added while maintaining the internal temperature at less −69° C. After stirring for 1.25 h at −78° C., the reaction was quenched with 1N NaHCO3 and warmed to rt. After removing volatiles under reduced pressure, the reaction mixture was diluted with 50 mL of 1N NaHCO3 and 50 mL of sat'd NaCl. The aqueous phase was extracted with 3×50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 4:1 v/v hexane/EtOAc and 4:1 v/v hexane/acetone as the gradient to afford 11 mg (7%) of the title compound as a colorless film: RF: 0.39 (4:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 0.90 (t, J=6.8, 3H), 1.28-1.33 (m, 12H), 1.59-1.64 (m, 2H), 2.02 (m, 1H), 2.42 (m, 1H), 2.60 (t, J=7.8, 2H), 2.67 (m, 1H), 2.86 (ABq, J=10.1, 2H), 2.97 (m, 1H), 3.69 (s, 2H), 3.82 (s, 3H), 7.14 (d, J=7.9, 2H), 7.26 (d, J=7.9, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[S:13](=[O:17])(=[O:16])([OH:15])O>OS(O)(=O)=O.O=S(=O)=O>[N:1]1[CH:6]=[CH:5][C:4]([S:13]([OH:15])(=[O:17])=[O:16])=[C:3]([S:13]([OH:17])(=[O:16])=[O:15])[C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(-c2ccccn2)nc1
Agent: O=S(=O)=O
Product: O=S(=O)(O)c1ccnc(-c2ccccn2)c1S(=O)(=O)O
Temperature: 20 °C

Procedure:
2 g of 2,2′Bipyridine was charged into a reactor, and 20 cc of concentrated sulfuric acid was added to it. This mixture was stirred until the amine dissolved. 20 cc of oleum 65% was added to this mixture under rapid stirring, and the reactor was cooled to about 20° C. After the solution of oleum, the reactants and contents were heated to 50° C. and maintained at this temperature for 48 hours. The reactor and its contents were cooled, and distilled water (10 cc) was added to the reaction mixture to quench the oleum. 50% NaOH solution was added to this solution, under cooling (10° C.) until the sulfuric acid solution was neutralized. The solution was concentrated and then methanol was added to extract the water-soluble ligand from the sodium sulfate powder. The methanol was evaporated to yield the water-soluble sodium salt of 2,2′bipyridine di sulfonic acid. [1.2 g] The product consists of mixtures of the bis sulfonation products as indicated by elemental analysis and 1h NMR. These can be used as such in synthesis of metal complexes for catalysis.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([NH2:16])[O:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(OCC)OCC.C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([N:16]=[CH:15][O:14][CH2:13][CH3:12])[O:14][CH:15]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2coc(N)c2C#N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=Nc1occ(-c2ccc(NC(C)=O)cc2)c1C#N
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To a suspension of 4-(4-acetamidophenyl)-2-amino-3-cyanofurane 5 (7.64 g, 39 mmol) in triethyl orthoformate (306 mL), acetic anhydride (15 mL) was added at room temperature. The mixture was heated (inner temp: 100° C.) in an oil bath for 1 h. The black material was precipitated in the mixture and then filtrated. The filtrated material was purified on a silica gel column (eluted by n-hexane-EtOAc 1:3) to afford 473 mg of 6 as a yellow solid. The filtered solution was concentrated in vacuo to afford 6 (7.44 g) as a dark orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12]([O:14][CH3:15])=[O:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (25 mg) was stirred in trifluoroacetic acid (50% in dichloromethane, 1.5 mL) for 4 h and concentrated. The residue was loaded onto a strong cation exchange cartridge and washed with several volumes of methanol. The product was eluted with 2M ammonia in methanol and concentrated. The crude piperidine was dissolved in dichloromethane (1 mL) and treated with di-tert-butyldicarbonate (17 mg). After 15 min, the reaction was quenched by addition of 2 M ammonia in methanol and concentrated. Column chromatography (ethyl acetate/n-hexane) gave the title compound. 1H-NMR (CDCl3, 500 MHz) δ 10.14 (bs, 1H), 7.93 (s, 1H), 7.66 (d, J=1.8, 1H), 7.29 (dd, J=8.2, 5.2, 2H), 7.07 (dd, J=8.9, 8.5, 2H), 4.85 (s, 1H), 3.50-3.80 (m, 6H), 3.36 (d, J=8.5, 1H), 3.02 (m, 2H), 2.15 (m, 2H), 1.81 (m, 2H), 1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 169.8, 161.7 (d, J=247 Hz), 155.0, 137.82, 137.79, 136.0, 133.7, 128.8 (d, J=7.7 Hz), 126.2, 126.1, 125.0, 120.8, 119.5, 115.7 (d,J=21 Hz), 80.7, 79.6, 79.0, 52.7, 41.3, 39.9 (br), 32.3, 32.2, 28.5.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[C:27]([O:31][C:32](=O)[O-:33])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[C:27]([O:31][C:32]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([Cl:2])=[N:4][CH:5]=[CH:6]3)[CH2:15][CH2:16]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: Clc1nccc2cc(OC3CCNCC3)ccc12
Reactant: CC(C)(C)OC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Reaction time: 8 h
Yield: 73.8 %

Procedure:
1.23 g (4.11 mmol) of 1-Chloro-6-(piperidin-4-yloxy)-isoquinoline hydrochloride (161) were dissolved in 50 ml of dichloromethane and 0.85 ml (6.15 mmol) of triethylamine were added. At 0° C. a solution of 1.09 g (5.0 mmol) of tert-butyl-carbonate in 10 ml dichloromethane was added dropwise and the mixture was allowed to stand at room temperature overnight. For working up, the mixture was washed twice with H2O, dried over magnesium sulfate and evaporated, to yield 1.1 g of the desired product, which could be used without further purification. Rt=1.86 min (Method #4). Detected mass: 363.1/365.2 (M+H+).
Reaction SMILES: C([N:8]1[CH2:12][C@:11]2([O:23][CH3:24])[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:24][O:23][C@@:11]12[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]1[CH2:9][NH:8][CH2:12]2
Reactant: CO[C@]12CN(Cc3ccccc3)C[C@H]1CN(C(=O)OC(C)(C)C)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CO[C@]12CNC[C@H]1CN(C(=O)OC(C)(C)C)C2
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of tert-butyl(cis)-5-benzyl-3a-methoxyhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (185 mg, 0.556 mmol) in EtOH (5.5 mL) purged with nitrogen was added Pd(OH)2/C (78 mg) and stirred under H2 (balloon) for 18 hrs. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (128 mg, 95% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.83-4.02 (m, 1H) 3.38-3.80 (m, 5H) 3.34 (s, 3H) 3.14-3.33 (m, 2H) 2.78-3.05 (m, 2H) 1.47 (s, J=2.57 Hz, 9H); m/z (APCI+) for C12H22N2O3 243.20 (M+H)+.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Na]>CC(C)=O>[O:25]=[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][C:5](=[O:10])[CH3:6]
Reactant: CCCCCCCCCCCCCCOc1ccccc1C(=O)OC
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccccc1C(=O)CC(C)=O

Procedure:
1,3-dioxo-1(2-tetradecyloxyphenyl)-butane was prepared by reacting 2-tetradecyloxybenzoic acid methyl ester and acetone in the presence of sodium ions as described by Bloch and v.Konstanecki in Ber. 33, 1998.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C=O.[C:30](=O)([O-])[O-:31].O>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH2:30][OH:31])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: O=C([O-])[O-]
Agent: C=O
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCO
Yield: 93.3 %

Procedure:
In a solution of 7.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 in 70 mL of 1,4-dioxane, 1.82 g of 37% formalin, 7.00 g of potasiium carbonate and 15 mL of water were added at room temperature with stirring, and stirred at the same temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted by adding 200 mL of ethyl acetate, washed with water (50 mL×1), and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, filtered through silica gel, and the solvent was distilled off under reduced pressure to obtain 7.00 g of the crude product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH2:31][CH2:32][NH2:33]>>[NH2:30][CH2:31][CH2:32][NH:33][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=1
Reactant: NCCN
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: NCCNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
The product of Example 47, and 1,2-diaminoethane were reacted by the procedure of Example 60 to afford the title compound 2-(2-amino-ethylamino)-4,8-bis-(2-chloro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 2.59 (m, 2H), 3.11 (m, 2H), 5.91 (br s, 1H), 6.40 (d, 1H, J=9.6 Hz), 7.25-7.61 (m, 9H). LC MS (m/e)=426 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[C:8]([F:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[C:8]([F:22])[CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3F)nc2c1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3F)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (118 mg) and piperidine (1.5 mL) were heated at 100° C. for 2.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (130 mg). 1H-NMR (CD3OD) δ8.22 (d, J=8.0 Hz, 1H), 7.98 (m, 2H), 7.27 (s, 1H), 6.76 (m, 3H), 4.00 (t, J=6.0 Hz, 2H), 2.48 (m, 6H), 2.38 (s, 3H), 1.96 (m, 2H), 1.61 (m, 4H), 1.47 (m, 2H)
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:27]CCl>FC(F)(F)C(O)=O>[Cl:27][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:7]=[CH:8][CH:3]=1
Reactant: ClCCl
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(N2CCNCC2)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of t-butyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (1.3 g, 4.39 mmol, 1.00 equiv) in dichloromethane (11 mL) and trifluoroacetic acid (6 mL) was placed in a 50-mL round bottom flask and stirred for 3 h at 20° C. in an oil bath. The solution was adjusted to a pH value of 7-8 with a saturated aqueous solution of sodium bicarbonate, and extracted with 6×15 mL of dichloromethane. The organic layers combined and dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under vacuum yielding 430 mg (50%) of 1-(3-chlorophenyl)piperazine as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16]Cl>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[N:2]([CH3:12])[CH3:1]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CN(C)c1ncnc2nc[nH]c12
Product: CN(C)c1ncnc2c1ncn2Cc1c(F)cccc1Cl

Procedure:
Employing N6,N6 -dimethyladenine prepared in Example 17 and 2-chloro-6-fluorobenzyl chloride, the same procedures as in Example 39, (1) were repeated to give a crude 9-(2-chloro-6-fluorobenzyl)-N6, N6 -dimethyladenine, in which the purity was 73.1% by weight and the content of the 3-isomer was 26.9% by weight.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.[H-].[Na+].[CH3:12]I>C1COCC1>[CH3:12][N:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: CI
Reactant: COC(=O)c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ncn(C)n1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (1 g) and sodium hydride (0.315 g) in anhydrous THF (30 ml) was heated at reflux for 7 h under nitrogen. The reaction was cooled to RT and methyl iodide (1.12 g) was added. The reaction was heated at reflux overnight. The solvent was evaporated and water (10 ml) was added. This was extracted with DCM, the organic layer collected and evaporated to dryness. The residue was dissolved in methanol:DMSO (6 ml, 1:1) and purified by mass directed preparative HPLC (Method A) to give title compound (0.290 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:2])=[CH:5][CH:6]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:23])[F:22])[O:18][N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 49 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (40 mg, 49%) which was obtained as a white solid. MS: m/e=481.0 [M+H]+.