Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:35]([C:27]3[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([C:24]([F:23])([F:39])[F:40])[CH:26]=3)(=[O:37])=[O:36])[C:13]=2[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2N
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of (5-amino-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (125.0 mg, 0.38 mmol) and 3,5-di-(trifluoromethyl)benzene-1-sulfonyl chloride (0.117 g, 0.38 mmol) in dry tetrahydrofuran (5 mL) was added diisopropylethylamine (0.2 mL, 0.94 mmol) at 0° C. under nitrogen. After 2 hours of stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The collected organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in hexane) gave [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (163.2 mg, 71%). MS cald. for C24H23ClF7NO5S 605, obsd. 604 [(M+H)+].
Reaction SMILES: [C:1]([C:14]1[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H][H]>N1C=CC=CC=1.[Pd]>[CH:1](/[C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: CCCCCCCCCCC/C=C\c1ccc(C=CC(=O)OC)cc1

Procedure:
A solution of methyl 4-(1-tridecynyl)cinnamate (1.020 g, 3 mmole from Example 4) in pyridine (20 ml) was hydrogenated in the presence of 5% palladium on barium sulphate (24 mg) until 1 equivalent of hydrogen was absorbed. After removal of the catalyst by filtration the solvent was removed to give the alkene as a pale yellow solid. Recrystallization from methanol gave 885 mg (87%) of pure (Z) alkene of mp 60°-62° C. indentical with that of Example 15.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: COc1ccc(B(O)O)cc1
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: CC#N
Product: COc1ccc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cc1
Yield: 29.6 %

Procedure:
General procedure D (See Example 4) was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088 mmol), 4-methoxybenzene boronic acid (16 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative hplc (CH3CN, H2O, 23:77) to furnish the title compound as a white solid (9 mg, 30%), LC-MS (ESI) Rt 1.67 min, m/z 346 (100%, [M+H]+); m/z (ESI) C18H21ClN3O2 requires 346.1317 found [M+H]+ 346.1317.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:19][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:2]([F:1])[CH:7]=1
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)cc1F
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution (150 mL) of 2′-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (14.1 g) in toluene was added phosphorus tribromide (18.7 g) at room temperature, and the mixture was stirred for 16 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (15.3 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].C(N(CC)CC)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[OH:1][CH2:2][CH:3]([CH2:14][O:15][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: O=c1ccn(CCC(CO)CO)c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(CCC(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of compound 35 (45 g, 0.213 mol) in dry DMF (225 mL) was added triethylamine (60 mL, 0.425 mol) and stirred at RT for 15 min. The above reaction mixture was cooled to 0° C., added tritylchloride (59 g, 0.213 mol) followed by addition of catalytic amount of 4-DMAP (app. 20 mg) and allowed to stir at RT for 24 h. The reaction was diluted with water (100 mL), extracted with ethyl acetate (5×200 mL), dried and concentrated under vacuum. The crude was purified by column chromatography over silica gel (6% methanol in chloroform) to give the title compound (33 g, 34%). TLC: Chloroform/Methanol, 9:1, Rf=0.5
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[C:18](Br)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29].N#N.C(N(CC)CC)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[C:18](/[CH:29]=[CH:28]/[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 80 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a solution of 12.4 (100 mg, 0.243 mmol) in DMF (1.5 ml) was added tert-butyl acrylate (0.045 ml, 0.304 mmol) and tri-o-tolylphosphine (3.7 mg, 0.0122 mmol). After the 5 min degass with N2, triethylamine (0.068 ml, 0.486 mmol) and Pd(OAc)2 (2.7 mg, 0.0122 mmol) were added, and the reaction mixture stirred at 80° C. for 17 h. Additional reagents (same molar equivalents except triethylamine (0.034 ml, 0.243 mmol) and the mixture was stirred at 100° C. for an additional 3 h. Reagent addition was repeated and the mixture again stirred at 100° C. for 17 h. The solution was partitioned between EtOAc and H2O and the organic phase washed with brine, dried (Na2SO4), concentrated, and the crude product purified by SiO2 chromatography (stepwise gradient: 30 to 50% Et2O/hexanes) to afford 67 mg (60%) of 12.5. MS (ESI) 459.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH3:21])[C:3]=1[CH3:22].OOS([O-])=O.[K+].[O-2:29].[Al+3].[O-2:31].[O-2].[Al+3]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:21])(=[O:31])=[O:29])[C:3]=1[CH3:22]
Reactant: [O-2]
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: O=S([O-])OO
Agent: [Al+3]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 65 °C

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (300 mg, 0.893 mmol) was dissolved in chloroform (8 mL) and Oxone™ (1.65 g, 2.68 mmol) and wet aluminum(III) oxide (910 mg, 8.90 mmol) was added. The heterogeneous mixture was stirred vigorously at 65° C. and refluxed for five h. Another portion of Oxone™ (1.65 g, 2.68 mmol) and aluminum(III) oxide (910 mg, 8.90 mmol) was added and the reaction was stirred vigorously overnight at 65° C. The reaction was cooled to rt and slurried in DCM and filtered. The filtrate was concentrated and the crude product was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=368.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)=[CH:19][N:18]=1>>[CH3:11][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:28][CH2:27][O:26][CH2:25]3)=[CH:19][N:18]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: Clc1ccc(OC2CCOC2)cn1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC3CCOC3)cn2)cc1

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide was reacted with 2-chloro-5-(tetrahydrofuran-3-yloxy)pyridine in analogy to example 2c.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:17][CH2:16][CH2:15][CH:8]([C:9]3[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]2=[N:18]O)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].N.Cl.C(C12C(N)C(CC3C=CC(OC)=CC=31)CCCC2)C1C=CC=CC=1>CCOCC.C(O)C.O1CCCC1>[NH2:18][CH:7]1[CH:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]1([CH2:4][OH:3])[CH2:17][CH2:16][CH2:15]2
Reactant: CCOC(=O)C12CCCC(C1=NO)c1ccccc12
Agent: COc1ccc2c(c1)C1(Cc3ccccc3)CCCCC(C2)C1N
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1C2CCCC1(CO)c1ccccc12
Reaction time: 72 h

Procedure:
A mixture of 1-ethoxycarbonyl-1,3-propano-2-indanone oxime (1.9 g.) and lithium aluminum hydride (1.6 g.) and 100 ml. of tetrahydrofuran is heated at its reflux temperature under dry nitrogen for 40 hours and allowed to stand for 3 days at room temperature. A few ml. of concentrated aqueous ammonia is added and after 15 minutes stirring the mixture is filtered. The filter cake is washed twice with isopropanol containing a little ammonia. The combined filtrates are concentrated to give 1.6 g. of oil which when treated with hydrogen chloride in ether and ethanol gives 1.2 g. of crystalline hydrochloride salt of the title product with m.p 217°-220°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:22]C(=O)C)=[C:17]([CH:21]=2)[C:18]([OH:20])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([CH:21]=2)[C:18]([OH:20])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)O)c2)=C(C)C1=O
Yield: 41.4 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.150 g, 0.401 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.055 g, 0.166 mmol, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])C[C:10]=12)=[O:4].[CH3:26]S(C1C=CC(F)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OC(C1C=C(O)C2CCOC=2C=1)=O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:8]2[CH2:14][CH2:12][O:13][C:9]=2[CH:10]=1)=[O:4])[CH3:26]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)c1cc(O)c2c(c1)OCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1cc2c(c(Oc3ccc(S(C)(=O)=O)cc3)c1)CCO2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (285 mg, 1.64 mmol), Cs2CO3 (997 mg, 3.06 mmol), and 4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid ethyl ester (8b) (315 mg, 1.51 mmol). Purification by column chromatography eluting with 10-20% EtOAC in hexanes gave a pale yellow oil (199 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.90-7.97 (m, 2 H) 7.34 (d, J=4.29 Hz, 1 H) 7.24-7.29 (m, 1 H) 7.07-7.13 (m, 2 H) 4.67 (m, 2 H) 4.32-4.39 (m, 2 H) 3.09-3.14 (m, 2 H) 3.06-3.09 (m, 3 H) 1.34-1.42 (m, 3 H); LCMS for C18H18O6S m/z 385.00 (M+Na)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)=[CH:9][C:8]=1[CH3:23].CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)=[CH:9][C:8]=1[CH3:23]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(C)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(-c2ccc(O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A 1.0 M BBr3 solution in CH2Cl2 (3.4 mL, 3.40 mmol) was added to an ice-cold solution of methyl 4′-methoxy-3′-methyl-[1,1′-biphenyl]-3-carboxylate (345 mg, 1.35 mmol) in CH2Cl2 (13 mL). The reaction mixture was stirred at 25° C. for 2 h then was cooled to 0° C. MeOH (5 mL) was added and the mixture was stirred at 0° C. for 15 min then was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexane, 10 to 15%) to yield the title compound (278 mg, 85% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>C1COCC1>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccc(Cl)cc3s2)CC1
Yield: 82 %

Procedure:
A mixture of 2,6-dichloro-benzothiazole (1.83 g, 8.97 mmol, 1.0 equiv) and ethyl 4-amino-1-piperidine carboxylate (3.09 g, 17.93 mmol, 2.0 equiv) in anhydrous THF (20 mL) was heated to reflux for 12 h. Purification with column chromatography on silica eluting with ethyl acetate/hexane (3:1) yielded 2.5 g (76%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.18 (t, J=7.2 Hz, 3H), 1.33 (br m, 2H), 1.97 (br d, 2H), 3.01 (br s, 2H), 3.90 (br d, 3H), 4.04 (q, J=7.2 Hz, 2H), 7.21 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 8.16 (d, J=7.2 Hz, 1H). MS (ISP): 340.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[O:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[NH2:32]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:32][C:22]4[N:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:24][O:25][C:21]=4[CH3:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: CC1=C(N)N(c2ccccc2)CO1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CC1=C(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)N(c2ccccc2)CO1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 5-methyl-3-phenyl-4-oxazolylamine gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.80–7.65 (m, 2H), 7.45 (bd, 1H), 7.20 (m, 1H), 7.00 (m, 1H), 6.65 (bd, 1H), 4.20 (s, 4H), 2.35 (s, 3H); LCMS: ret. time: 20.61 min.; purity: 78%; MS (m/e): 420 (MH+).
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[Na].[CH2:31]([OH:34])[CH2:32][OH:33]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]2[CH:5]=[CH:4][C:3](=[O:29])[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:7]=2[N:8]=[C:9]([O:33][CH2:32][CH2:31][OH:34])[N:10]=1
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1Cl
Reactant: OCCO
Agent: [Na]
Product: O=c1ccc2c(-c3ccccc3Cl)nc(OCCO)nc2n1-c1ccccc1Cl

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and ethylene glycol sodium salt to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-ethoxy)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.81 (m, 2H), 4.23 (m, 2H), 5.62 (m, 0.5H), 6.65 (d, 1H, J=9.6 Hz), 7.29-7.58 (9H). LC MS (m/e)=428 (MH+). Rt=1.85 min
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: O=C(O)c1cccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1cccnc1Cl
Yield: 90 %

Procedure:
2-Chloropyridine-3-carboxylic acid (7.9 g) and thionyl chloride (45 ml) were heated for 3 hours in benzene (65 ml) under reflux. The reaction mixture was concentrated to leave an oil, which was added dropwise to ethanol (40 ml). The mixture was heated for further one hour under reflux. The solvent was distilled, and the residue was dissolved in toluene. The solution was dried over anhydrous magnesium sulfate. The solvent was distilled to leave the title compound (8.4 g, 90%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15](Cl)[N:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([NH:35][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(Cc3ccccc3)nn12
Product: c1ccc(Cc2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 31.8 %

Procedure:
A solution of 4-(2-benzyl-7-chloropyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (65 mg, 0.16 mmol) in cyclopentylamine (2 mL, 20 mmol) was heated at 116° C. for 16 hours. The reaction mixture was cooled and the excess cyclopentylamine was removed in vacuo. The crude material was chromatographed (19:1 dichloromethane:acetone) to provide N-{4-[2-benzyl-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (23 mg 32%) as a pale yellow solid. Rf 0.12 (5:1 hexanes:ethyl acetate); 1H NMR δ 8.18 (d, 1H), 7.59 (d, 1H), 7.30–7.10 (m, 6H), 6.65 (d, 1H), 5.99 (d, 1H), 4.59 (s, 2H), 4.30 (m, 1H), 3.98 (m, 1H), 2.21–2.00 (m, 4H), 1.90–1.50 (m, 12H); MS m/z 453 (M+1).
Reaction SMILES: [N:1]([C@@H:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].Cl[C:19](=[CH2:22])[C:20]#[N:21]>O>[C:20]([C:19]1[N:3]=[N:2][N:1]([C@@H:4]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:22]=1)#[N:21]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N=[N+]=[N-]
Reactant: C=C(Cl)C#N
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)n1cc(C#N)nn1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of ethyl 2-azido-4-phenyl-(2S)-butyrate (2.33 g) and 2-chloroacrylonitrile (1.75 g) in water (25 ml) is stirred at about 80° C. for 23 hours. After cooling, the product is extracted with toluene and purified by column chromatography (30 g of silica gel 60; eluent toluene). The purified product is obtained as a yellowish oil (yield 1.84 g; 65% of theory) and characterized by 1H--NMR spectrum (CDCl3). δ value: 1.29 (*H; t; J=7 Hz); 2.40-2.67 (4H, m); 4.20 (2H, q, J=7 Hz); 5.39 (1H, m); 7.10 (2H, dxd, J1 =6.6 Hz, J2 =1.5 Hz); 7.24 (1H, txt, J1 =6.6 Hz, J2 ≤1.5 Hz); 7.31 (2h, m); 8.21 (1H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CNCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-fluoro-3-nitrobenzotrifluoride (1.00 g, 4.78 mmol) in THF (25 mL) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.84 mL, 5.7 mmol) and NaHCO3 (1.1 g, 13 mmol). The resulting mixture was stirred for 1 h at RT, diluted with CH2Cl2, and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound.