Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH2:32]/[CH:33]=[CH:34]/[C:35](Cl)=[O:36])C>CN1C(=O)CCC1.ClCCl>[O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[N:21]=[C:22]([NH:26][C:35](=[O:36])[CH:34]=[CH:33][CH3:32])[CH:23]=[CH:24][CH:25]=3)[CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: Nc1cccc(Nc2cc(Oc3ccc(Oc4ccccc4)cc3)ncn2)n1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC=CC(=O)Nc1cccc(Nc2cc(Oc3ccc(Oc4ccccc4)cc3)ncn2)n1
Reaction time: 1 h

Procedure:
To a stirred solution of N2-(6-(4-phenoxyphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (0.65 g, 1.75 mmol) in NMP (10 mL) was added dimethylaminocrotonyl chloride (1.026 g, 7 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and kept at it for 1 h. It was diluted with dichloromethane (10 mL), was washed with NaHCO3 solution (2 mL) and water (2 mL), and dried over Na2SO4. The dichloromethane solution was filtered and was concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give (E)-4-dimethylamino)-N-(6-(6-(4-phenoxyphenoxy)pyrimidin-4-ylamino)pyridin-2-yl)but-2-enamide (I-82) as an off white solid. 1H NMR (DMSO-d6) δ ppm: 2.19 (s, 6H), 3.08 (d, J=5.52 Hz, 2H), 6.50 (d, J=15.4 Hz, 1H), 6.77 (td, J=5.92 & 15.4 Hz, 1H), 7.00-7.07 (m, 5H), 7.15 (t, J=7.36 Hz, 1H), 7.21 (dd, J=2.2 & 8.92 Hz, 2H), 7.41 (t, J=7.52 Hz, 2H), 7.68 (t, J=7.96 Hz, 1H), 7.77 (d, J=7.96 Hz, 1H), 7.95 (s, 1H), 8.35 (s, 1H), 10.20 (s, 1H), 10.40 (s, 1H); LCMS: m/e 483 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:7]1([CH2:11][C:10](=O)[NH:9][C:8]1=O)[CH2:6][CH2:5]2>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:7]1([CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:6][CH2:5]2
Reactant: O=C1CC2(CCc3cc(Cl)ccc32)C(=O)N1
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)CCC21CCNC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.7 %

Procedure:
To a stirred solution of 5-chloro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]-2′,5′-dione (Prep7, 3 g, 12.7 mmol) in anhydrous THF (20 ml) at 0° C. and under a nitrogen atmosphere, BH3(CH3)2S complex in THF (1M, 50 ml) was added dropwise. The ice-bath was removed, the reaction mixture was allowed to reach room temperature and refluxed for 28 h. The mixture was then cooled to 0° C. and hydrochloric acid (2 M, 30 ml) was cautiously added monitoring gas evolution, then the ice-bath was removed and the reaction was stirred for 1 h. THF was then removed in vacuo, the residue was cooled to 0° C. DCM was added and the stirred mixture was treated with a solution of NaOH (2M) until pH=13. The mixture was extracted with additional DCM, the solvent was evaporated under vacuum to obtain the crude title compound (3 g).
Reaction SMILES: C([C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24].N1CCCCC1.Cl>N1C=CC=CC=1>[C:23](/[CH:22]=[CH:21]/[C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:25])=[O:24]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)O)cccc2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Uneyama, K. et al., Bull. Chem. Soc. Jap. 58.; 2361, (1985)) 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml of anhydrous pyridine was stirred at 100° C. for 3 hours. After cooling to 20°-25° C. the reaction mixture was poured into a mixture of 90 g of crushed ice and 33 ml of hydrochloric acid (d=1.18). The resultant precipitate was collected by suction filtration, washed with water and crystallized twice from 95% ethanol to give 5.5 g of the title compound, m.p. 226°-229° C.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11](=[O:40])[N:12]([CH3:39])[CH:13]=[C:14]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[C:16]([OH:18])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.[Cl:75][C:76]1[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=1)[CH2:79][NH2:80]>CN(C)C=O.O>[C:1]([O:9][C:10]1[C:11](=[O:40])[N:12]([CH3:39])[CH:13]=[C:14]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:15]=1[C:16](=[O:18])[NH:80][CH2:79][C:78]1[CH:81]=[CH:82][CH:83]=[C:76]([Cl:75])[CH:77]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(=O)O)c(OC(=O)c2ccccc2)c1=O
Reactant: NCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(=O)NCc2cccc(Cl)c2)c(OC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.956 g) in dimethylformamide (10 ml) were added 1-hydroxybenzotriazole hydrate (HOBT) (0.395 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, (WSC) (0.495 g) and 3-chlorobenzylamine (0.274 ml) and the mixture was stirred at room temperature for 2 hr. Water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under,reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-4-(3-chlorobenzylcarbamoyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.615 g). This compound was dissolved in tetrahydrofuran (20 ml), and acetic acid (0.259 ml) and tetrabutylammonium fluoride (0.474 g) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give 4-(3-chlorobenzylcarbamoyl)-5-(2-hydroxyethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.213 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.Cl.C[C:38]1([NH2:41])[CH2:40][CH2:39]1>N1C=CC=CC=1>[CH:38]1([NH:41][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:40][CH2:39]1
Reactant: CC1(N)CC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Temperature: 120 °C
Yield: 39.5 %

Procedure:
Phosphorus oxychloride (0.11 ml) was added to a mixture of 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), 1-methylcyclopropylamine hydrochloride (0.13 g) and pyridine (5 ml) and the resultant was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g); NMR Spectrum: (CDCl3) 0.76 (m, 4H), 1.09 (d, 6H), 2.20 (s, 3H), 2.20 (s, 3H), 2.72 (in, 5H), 3.35 (m, 4H), 6.61 (s, 1H), 7.43 (m, 2H), 7.66 (m, 3H), 7.78 (m, 2H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:30]([CH2:32][NH2:33])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:30]([CH:31]=1)[CH2:32][NH:33][C:19](=[O:20])[C@H:18]1[CH2:22][CH2:23][CH2:24][N:17]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
Prepared by procedures similar to that described above in Example 8 from 9-hydroxy-9-fluorenylcarbonyl-L-proline and 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine.
Reaction SMILES: C(=O)(O)[O-].[Na+].[N:6]1[CH:11]=[CH:10][C:9]([SH:12])=[N:8][C:7]=1[SH:13].Cl.[CH2:15]([S:23]SC(=N)N)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O.CO>[CH2:15]([S:23][S:13][C:7]1[N:8]=[C:9]([S:12][S:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=[CH:11][N:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Sc1ccnc(S)n1
Reactant: CCCCCCCCSSC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCSSc1ccnc(SSCCCCCCCC)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of sodium bicarbonate (4.30 g; 0.05 mole) in water (60 ml) was added dropwise to a stirred suspension of pyrimidine-2,4-dithiol prepared as above (2.16 g, 0.015 mole) and S-n-octylthioisothiourea hydrochloride obtained in step (A) (7.695 g, 0.03 mole) in methanol (70 ml) at 60°-65° C. over 30 minutes. The mixture was stirred at room temperature for a further hour and then extracted into naphtha (3×50 ml). The organic extracts were washed with water, dried using anhydrous MgSO4 and evaporated yielding the product as an orange oil (5.54 g; 85%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15](=[S:17])[NH2:16])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH3:14])=[O:10])=[N:6][CH:7]=1.Br[CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22]>C(#N)C>[Br:1][C:2]1[C:3]([C:15]2[S:17][CH2:19][C:20]([OH:25])([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH3:14])=[O:10])=[N:6][CH:7]=1
Reactant: CCCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CC#N
Product: CCCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 80 °C

Procedure:
A suspension of 5-bromo-2-(3-propylureido)pyridine-4-carbothioamide (Intermediate 44, 100 g, 315 mmol), 3-bromo-1,1,1-trifluoroacetone (64 mL, 630 mmol) in acetonitrile (1.5 L) was heated at 80° C. for 20 hours. The solution was then cooled down and was concentrated under reduced pressure. This gave an orange oil that was carried on without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:29][C:30]1[CH:31]=[CH:32][C:33]([OH:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([I:29])[CH:31]=[CH:32][C:33]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(I)ccc1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1ccc(I)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-iodo-2-hydroxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 611.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl>[CH3:11][O:10][C:3]1[C:2]([NH:1][C:14](=[O:15])[CH2:13][Cl:12])=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: COc1ncnc(OC)c1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: COc1ncnc(OC)c1NC(=O)CCl
Temperature: 25 °C

Procedure:
A sulphonation flask is charged with 310 g 5-amino-4,6-dimethoxypyrimidin and 3500 ml dry CH2Cl2. To this mixture is added, within 15 minutes, a solution of 248.6 g chloroacetyl chloride in 400 ml dry CH2Cl2. The reaction is exothermic, the temperature rises from 14° to 32° and a suspension is formed. The reaction mixture is heated under reflux for 2 hours, then cooled to ambient temperature and evaporated till dryness. The solid residue is suspended in 3 l ice water, the suspension adjusted at pH 7-8 with diluted NaOH, cooled to 5° and sucked-off. The precipitate is washed twice with 500 ml ice water and then dried in vacuum at 60° to give the title compound, m.p. 193°-195°.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: NCc1ccccc1
Product: OC(CCl)CNCc1ccccc1

Procedure:
reacting epichlorohydrin with benzylamine to form the addition product, N-benzyl-3-amino-1-chloropropan-2ol (I);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[S:22][CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:25]=4)=[CH:18][C:17]=3[CH:30]=1)[N:7]=[C:6]2[C:31]([OH:33])=[O:32].S(=O)(=O)(O)O.[CH3:39]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[S:22][CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:25]=4)=[CH:18][C:17]=3[CH:30]=1)[N:7]=[C:6]2[C:31]([O:33][CH3:39])=[O:32]
Reactant: CO
Reactant: COc1ccc2c(c1)c(C(=O)O)nn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1nn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylic acid (3.0 g) and concentrated sulfuric acid (0.3 ml) in methanol (30 ml) was stirred under reflux for 6 hours. After being cooled to room temperature and stored for overnight, the precipitate was collected by filtration and washed with isopropyletyl ether to give methyl 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylate.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[O:8]=[C:9]1[C@H:13](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][CH2:11][O:10]1>C1COCC1>[OH:5][CH2:4][CH2:3][CH2:2][S:1][C@H:13]1[CH2:12][CH2:11][O:10][C:9]1=[O:8]
Reactant: OCCCS
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCC[C@@H]1SCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of 3-mercaptopropan-1-ol (360 mg, 3.90 mmol) in THF (8 mL) cooled to 0° C. was treated with 60% NaH (86 mg, 2.15 mmol). After warming to room temperature and stirring for 30 minutes, a solution of (R)-toluene-4-sulfonic acid 2-oxotetrahydrofuran-3-yl ester (500 mg, 1.95 mmol) in THF (2 mL) was added. After stirring at room temperature for 60 hours, the reaction mixture was quenched with saturated NaHCO3 and diluted with EtOAc. The organic layer was washed with saturated NH4Cl, saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was chromatographed (2:1 EtOAc/hexanes) to provide the product as colorless oil (155 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CCOC(C)=O>[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](C=C(C)C)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](CC(C)C)c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred solution of (S)-ethyl 3-(4-hydroxyphenyl)-5-methylhex-4-enoate 14.3 (0.223 g, 0.9 mmol) in EtOAc (5 mL, 51 mmol) at 0° C. was added Pd/C (0.10 g, 0.9 mmol). See Example 14—it is possible that 14.3 is the R enantiomer and that 14.2 is the S enantiomer although it is believed that 14.3 is the enantiomer shown. The reaction mixture was placed under an atmosphere of hydrogen and stirred at 23° C. for 2 hours. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford (R)-ethyl 3-(4-hydroxyphenyl)-5-methylhexanoate 46.1 (0.223 g, 99% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)C(N)(CO)CO>ClC(Cl)C>[CH2:1]([N:8]1[C:19](=[O:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:10]2([CH2:11][CH2:12][N:13]([C:31]([NH:30][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:32])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2OC2(CCNCC2)CN1Cc1ccccc1
Reactant: O=C=NC1CCCC1
Agent: NC(CO)(CO)CO
Solvent: CC(Cl)Cl
Product: O=C(NC1CCCC1)N1CCC2(CC1)CN(Cc1ccccc1)C(=O)c1ccccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 30 (0.010 mmol) in dichloroethane (0.7 mL) was added cyclopentylisocyanate (0.020 mmol), the mixture was stirred overnight at 25° C. To the reaction mixture was added PS-trisamine (Argonaut, product number 800229, loading; 4.36 mmol/g) (6.9 mg). After stirring overnight at 25° C., the mixture was filtered and the filtrate was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[C:4]([CH:24]2[CH2:27][O:26][CH2:25]2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34]C(=O)OC(C)(C)C)[CH2:29]1.CN1CCOCC1>CN1CCCC1=O>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:28]5[CH2:33][CH2:32][CH2:31][C@H:30]([NH2:34])[CH2:29]5)[CH:3]=[C:4]([CH:24]5[CH2:27][O:26][CH2:25]5)[CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(C3COC3)cc(F)n2)n1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(C3COC3)cc(N3CCC[C@H](N)C3)n2)n1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of 1-[6-fluoro-4-(oxetan-3-yl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.1443 mmol; 63 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.4329 mmol, 80.7 mg), and N-Methylmorpholine (0.3607 mmol; 36.9 mg; 0.0401 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was cooled to room temperature. The solvents were removed. The residue was treated with 20% TFA in DCM at room temperature for 2 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 250 as an off-white solid (17.5 mg, 26%). 1H NMR (400 MHz, DMSO) δ 9.61-9.57 (s, 1H), 9.49-9.43 (s, 1H), 9.36-9.29 (s, 1H), 8.69-8.66 (s, 1H), 8.65-8.61 (s, 1H), 7.33-7.30 (s, 1H), 6.82-6.76 (s, 1H), 5.02-4.95 (m, 2H), 4.73-4.66 (t, J=6.3 Hz, 2H), 4.42-4.35 (d, J=13.2 Hz, 1H), 4.35-4.27 (dd, J=15.0, 7.2 Hz, 1H), 4.20-4.13 (d, J=10.7 Hz, 1H), 3.29-3.21 (m, 2H), 3.08-3.01 (m, 1H), 2.98-2.91 (s, 1H), 2.66-2.61 (s, 3H), 2.01-1.83 (m, 3H), 1.71-1.58 (d, J=13.4 Hz, 1H), 1.51-1.40 (d, J=10.8 Hz, 1H), 0.99-0.92 (t, J=7.3 Hz, 1H); MS (ESI) m/z: 443.2 [M+H]+
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([CH2:22][CH2:23][C:24]([OH:26])=O)=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH2:32]([CH2:34][NH2:35])[OH:33].Cl>>[CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([CH2:22][CH2:23][C:24]([NH:35][CH2:34][CH2:32][OH:33])=[O:26])=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2]
Reactant: NCCO
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1CCC(=O)O
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1CCC(=O)NCCO

Procedure:
The title compound is prepared by coupling 3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenyl}-propionic acid with ethanolamine as described in Example 26 omitting the treatment with HCl; LC-MS: tR=0.80 min; [M+1]+=466.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1CCCCC1.C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Temperature: 0 °C
Yield: 500.2 %

Procedure:
5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (3.32 g, 13.4 mmol) was dissolved in pyridine (16.6 ml) and piperidine (0.66 ml) was added. Malonic acid (1.67 g, 1.61 mmol) was added and the reaction mixture was refluxed for 4 h. Cooled reaction mixture was poured into a solution of ice (100 ml) water (100 ml) and conc. HCl (100 ml). The precipitate was filtered and washed with cold water and recrystallised from ethanol to afford 2.55 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (d, 1H), 7.08 (d, 1H), 7.40 (m, 1H), 7.43 (d, 1H), 7.81 (d, 1H), 8.14 (m, 1H), 8.21 (m, 1H), 12.44 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 74.7 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.27 g, 1.26 mmol) were used to afford 0.52 g of the required product. 1H NMR (DMSO-d6): δ 1.31 (4H, m), 1.45 (9H, s), 1.80 (4H, m), 3.22 (1H, m), 3.68 (1H, m), 6.78 (1H, d, J=7.8 Hz), 7.24 (2H, d, J=9.6 Hz), 7.51 (2H, d, J=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.35 (1H, d, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([Cl:12])=[O:9])[N:6]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: O=S(Cl)Cl
Product: Cc1nc(C(=O)Cl)cs1
Temperature: 80 °C

Procedure:
To 2-methyl-1,3-thiazole-4-carboxylic acid (1 g) was added thionyl chloride (5 ml). The mixture was heated at 80° C. for 8 h. Thionyl chloride (5 ml) was added and the mixture heated for 2 h at 80° C. Further thionyl chloride (5 ml) was added and the mixture heated for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound (1.12 g) as a brown solid