Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:22])[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[O:20][CH3:21])([CH3:5])[CH3:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:21][O:20][C:9]1[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:7]1[O:22][CH2:4][C:3]([CH3:2])([CH3:5])[N:6]=1
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)NC(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OC)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 5.66 g (17.62 mmol) N-(2-hydroxy-1,1-dimethyl-ethyl)-2,6-dimethoxy-4-trifluoromethyl-benzamide in 60 ml dichloromethane was cooled to 10° C. 3.8 ml (52.85 mmol) thionylchloride was added drop-wise. The temperature rose to 15° C. The mixture was stirred at room temperature for 1 hour. The solution was added drop-wise to 130 ml of a cooled 2M sodium carbonate solution. The emulsion was diluted with water and filtered, to remove the white solid. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude light yellow solid (5.27 g) was purified with flash column chromatography on silica (70 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 50%) to provide 4.8 g (yield: 89.8%) of the title compound as a white solid. MS (m/e): 304.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[CH:13]=O.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:13][C:3]3[CH:4]=[N:5][N:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]=3[CH3:1])[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Product: Cc1c(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cnn1-c1ccccc1

Procedure:
Prepared by Procedure F and Scheme R using 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 417.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[NH2:23][C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=[C:26]([C:37](=[N:39]O)[NH2:38])[N:25]=1>N1C=CC=CC=1>[F:1][C:2]1[C:3]([C:8]2[O:10][N:39]=[C:37]([C:26]3[N:27]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:29]=[C:24]([NH2:23])[N:25]=3)[N:38]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=NO)c1nc(N)nc(Nc2ccccc2)n1
Reactant: O=C(O)c1ncccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ncccc3F)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
3-Fluoropyridine-2-carboxylic acid (1.75 g, 12.38 mmol) was dissolved in pyridine (15 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.74 g, 14.28 mmol) was added. The mixture was stirred at room temperature for 2 h. 4-Amino-N′-hydroxy-6-(phenylamino)-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 4, 2.33 g, 9.52 mmol) was added and the mixture stirred at room temperature for 16 h. LCMS showed incomplete conversion, so further N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.30 g, 6.8 mmol) was added and the mixture stirred at room temperature for 3 h, before being heated to 60 C under nitrogen for 16 h. Pyridine was removed under vacuum and water (100 mL) was added to the residue. The mixture was extracted with EtOAc (100 mL), with the addition of brine (100 mL) to aid separation of an emulsion. The aqueous phase was then extracted with DCM (100 mL), which also formed an emulsion. After separation the aqueous phase was filtered to remove an insoluble gum. The aqueous phase was then further extracted with DCM (2×100 mL). The combined DCM and EtOAc layers were dried over sodium sulfate and concentrated under vacuum to yield a pale orange solid. This was purified by FCC using a gradient of 0-8% MeOH in DCM. The crude product was further purified by trituration with DCM to afford the title compound as a white solid (0.425 g, 13%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:13][C:14](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:15]>O>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:15])[CH3:13]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC(C)=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
17.0 g of 3-Hydroxy-4-methoxy-benzoic acid were added to 51.6 g of acetic ahydride and the mixture stirred at 140° C. for 3 h. The mixture was then allowed to cool to 100° C., 50 ml of water added dropwise and the temperature kept at 100° C. Then, 200 ml of water were added and the mixture was stirred at 100° C. for 30 minutes. The mixture was then cooled and stirred at 0° C. for 1 h. The product was then isolated by filtration, washed with 50 ml of water and dried under reduced pressure to yield 18.8 g of the title compound that was used without further purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(C)=O)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (5.56 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated at reflux for 5 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate:acetone) to give (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 93%) as a colored syrup: 1H NMR (CDCl3): δ 7.96–7.59 (m, 3H), 7.53 (d, 1H), 7.23 (dd, 1H), 6.93 (d, 2H), 5.97–5.94 (m, 2H), 5.07 (d, 1H), 3.95 (m, 1H), 3.81 (s, 3H), 3.0–2.3 (m, 6H), 2.07 (m, 2H), 1.76–1.60 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C>CO.[OH-].[Na+]>[Br:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:14])[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccccc1Br)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(C)(Cc2ccccc2Br)C(=O)O)cc1

Procedure:
3-(2-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid was prepared starting from 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.7 g, 63%. Waxy solid; MS: 414 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[CH:12]([CH3:13])[C:11](=[O:14])[N:10]([C:15]2[CH:20]=[C:19]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25](=[O:32])[NH:24][N:23]=3)[CH:18]=[CH:17][C:16]=2[F:33])[C:9]1=[O:34])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:33][C:16]1[CH:17]=[CH:18][C:19]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)=[CH:20][C:15]=1[N:10]1[C:11](=[O:14])[CH:12]([CH3:13])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]1=[O:34]
Reactant: CC1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)O
Reaction time: 8 h

Procedure:
To a solution of {3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5-methyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid tert-butyl ester (35A)(1.3 g, 2.7 mmol) in dry DCM (20 ml) was added trifluoroacetic acid (2 mL, ca 27 mmol) dropwise over 2 minutes. After overnight stirring the reaction mixture was concentrated to dryness and subjected to flash chromatography. Eluent 1% acetic acid in ethyl acetate. The title compound was isolated as a white solid. Single peak in LC-MS analysis, (0.680 mg, 100% purity) and required no further purification; m/z (LC-MS, ESN), RT=2.95 mins (M−H) 423
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16].[Li]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1](=[O:13])[CH2:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:3]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: [Li]
Product: COC(=O)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Dimethyl isophthalate (67.9 g) was treated with lithium tert.-butyl acetate according to general procedure K (method b) to give crude 3-tert-butoxycarbonylacetyl-benzoic acid methyl ester (74.5 g) as a pale-yellow oil.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.C(=O)([O-])[O-:13].[K+].[K+].OO>CO>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:13])=[O:6])[O:2]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc2c1OCO2
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc2c1OCO2
Yield: 96.5 %

Procedure:
A solution of 2,3-(methylenedioxy)benzaldehyde (160mg, 1.06mmol), potassium carbonate (960 mg, 6.9 mmol) and 2.4mL of hydrogen peroxide (30-32 wt.% solution in water) in 10 mL of methanol was stirred for 16 hours at room temperature. The mixture was washed with diethyl ether. The water layer was acidified with 1 N aq. HCl to pH>1, then extracted with ethyl acetate. The organic layer was dried over MgSO4, then concentrated to give the desired product (170mg, 96%). EI-MS (m/z) 164.8 (M−).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NC1CCCCC1
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with cyclohexylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(=O)CC>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:18][C:3]1[C:2]([Br:1])=[CH:17][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:8][O:9][C:5]=2[CH:4]=1)[CH3:31]
Reactant: Oc1cc2onc(-c3ccccc3F)c2cc1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Br

Procedure:
A mixture of 12 g of 5-bromo-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, 10.8 g of potassium carbonate and 7.8 g of ethyl bromoacetate in 200 ml of 2-butanone is stirred at reflux for 6hours. The reaction mixture is filtered and the solvent removed from the filtrate under vacuum. Recrystallization of the residue from ether-chloroform-hexane gives ethyl{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 130°-132° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:19]([N:32]1[CH2:35][C:34](=[O:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH:19]([N:32]1[CH2:35][C:34]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])([OH:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1coc2ccccc12
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A solution of 3-methylbenzofuran (550 mg, 4.16 mmol) in dry THF (17 mL) was cooled to −78° C. and LDA (1.8 M in THF/heptane/ethylbenzene) (2.8 mL, 5.04 mmol) was added dropwise under N2 over 5 min. After stirring for 30 min, 1-benzhydrylazetidin-3-one (1.61 g, 6.78 mmol) was added portionwise over 10 min. The reaction was stirred under N2 at −78° C. for 15 min, and was then allowed to warm to rt and stirred for 1.5 h. The reaction was quenched with 0.5N HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried on Na2SO4 and concentrated. The residue was purified by flash chromatography (heptane/EtOAc, 5%→35%), yielding the product (472 mg, 31%) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:11]=1[OH:12])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:11]=1[OH:12])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2c(-c3ccc(C(C)(C)c4ccccc4)cc3)cnn2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(c1ccccc1)c1ccc(-c2cnn3c(O)c(C(=O)O)cnc23)cc1
Yield: 89.6 %

Procedure:
To a solution of 6-ethoxycarbonyl-7-hydroxy-3-[4-(2-phenylpropan-2-yl)phenyl]pyrazolo[1,5-a]pyrimidine (1.2 g) in ethanol (20 ml) was added 5N sodium hydroxide solution (3.0 ml), and the mixture was heated and refluxed for 20 hours. The solvent was distilled away under reduced pressure, and thereto was added water (100 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtraltion, washed with water to give the title compound (1.0 g, 89.6%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CS(C)=O>[CH:34]1([NH:40][C:7]2[C:8]3[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCCC1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC3CCCCC3)c2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol) in DMSO (1 mL) was dispensed in a library plate. Cyclohexanamine (6.94 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at 80° C. before it was filtered and purified by preparative HPLC to give 1-(4-(cyclohexylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (11.2 mg, 36%).
Reaction SMILES: [Br:1][CH:2]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)C(O)=O>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1
Reactant: O=C(O)C(Br)c1noc2ccccc12
Solvent: Cc1ccccc1
Product: BrCc1noc2ccccc12

Procedure:
Alpha-bromo-1,2-benzisoxazole-3-acetic acid (58.0 g, 0.23 mole) is suspended in toluene (350 mL) and the mixture is stirred at reflux for 18 hours. The solvent is evaporated and the residue is taken up in methylene chloride (250 mL). This solution is washed with saturated aqueous sodium bicarbonate (2×50 mL), water (50 mL) and dried over anhydrous magnesium sulfate. The solution is filtered and evaporated to afford 3-bromomethyl-1,2-benzisoxazole, m.p. 60°-62° C. The compound is purified by recrystallisation from ether-hexane, m.p. 64°-66° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.C([N:15](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1c(F)cc(Br)cc1F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
To a stirred solution of the above benzoic acid intermediate (18 g, 76 mmol) in THF (150 mL)), at −20° C., was added triethylamine (7.6 g, 76 mmol) and ethyl chloroformate (9.8 g, 91 mmol. The reaction was stirred at −20° C. for 20 min. Then it was warmed up to room temperature and an ammonia solution (0.5 M in dioxane, 150 mL, 76 mmol) was added. The reaction was stirred at room temperature overnight. It was then concentrated, diluted with dichloromethane, washed with 1 N HCl and brine, and dried over Na2SO4. The solvent was removed to give the crude product as a solid. It was washed with dichloromethane to give 4-bromo-2,6-difluorobenzamide (9.4 g, 52.4%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(O)[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([F:39])[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-4-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (5.20 g, 11.17 mmol) in CH2Cl2 (100 mL) at −78° C. was added DAST (2.21 mL, 16.75 mmol). The solution was stirred for 16 hours at RT then was washed with sat NaHCO3 (2×100 mL). The organic layer was dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 9:1). MS (UPLC/MS): 468 [M+H]+, 512 [M+HCOO]−; tR (HPLC conditions f): 3.00 min.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][O:8]CC)(=[O:5])[OH:4])[CH3:2].[OH-:11].[Na+].C>O>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:8])=[O:11])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCOCCP(=O)(O)CC
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CC(=O)O
Temperature: 70 °C
Yield: 78 %

Procedure:
16.6 g (0.1 mol) of ethyl(2-ethoxyethyl)phosphinic acid (produced as in Example 8) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.45 g of charcoal with 5% Pt and 1% Bi is added, the suspension is heated to 70° C. and air is passed through the suspension at 10 l/h. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, which is washed, and made acidic with hydrochloric acid and the water is distilled off in vacua. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off to leave 11.9 g (78% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as a colorless solid material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C@H:8]3[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[C@@H:9]3[CH2:17][O:18][C:4]=2[C:3]=1[O:19][CH3:20].C([Li])CCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[OH:29][CH2:28][C:2]1[CH:7]=[CH:6][C:5]2[C@H:8]3[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[C@@H:9]3[CH2:17][O:18][C:4]=2[C:3]=1[O:19][CH3:20]
Reactant: CCCN1CCC[C@@H]2c3ccc(Br)c(OC)c3OC[C@H]21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN1CCC[C@@H]2c3ccc(CO)c(OC)c3OC[C@H]21
Reaction time: 0.17 h

Procedure:
A solution of 600 mg of trans-8-bromo-7-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 10 ml of tetrahydrofuran is treated with 1.68 ml of 2.1M n-butyllithium at -78°. After 10 minutes, 27 ml of dimethylformamide is added. After 30 minutes at 0°, the reaction mixture is poured onto water and the products are extracted with ether. After drying the solvent is removed. The residue is treated with 35 mg of sodium borohydride in 5 ml of methanol. After 10 minutes the solvent is removed and the residue is chromatographed on 10 g silica gel with acetone/hexane 1:2 as the eluent to afford trans-8-hydroxymethyl-7-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.C(OC(C)C)(=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-n2cncn2)cc1
Temperature: 105 °C
Reaction time: 3.5 h

Procedure:
4-Fluorobenzaldehyde (12.0 mL, 112 mmol) was added dropwise by syringe to a stirring, heterogeneous mixture of 1,2,4-triazole (11.6 g, 168 mmol) and potassium carbonate (24.7 g, 179 mmol) in dimethyl formamide (220 mL) at 23° C. The mixture was heated to 105° C. After 3.5 hours, the mixture was allowed to cool to 23° C. The cooled solution was transferred to a 2 L Erlenmeyer flask and diluted with water (500 mL) and ethyl acetate (1200 mL). The biphasic mixture was stirred until the layers cleanly separated. The layers were separated. The organic layer was washed with half-saturated aqueous sodium chloride solution (3×100 mL). The washed solution was dried with sodium sulfate, and the dried solution was filtered. The filtrate was concentrated to provide an off-white solid. The solid was suspended in a mixture of heptanes and isopropyl acetate (5:1, 600 mL). The mixture was filtered and the filter cake was washed with heptanes-isopropyl acetate (5:1). The solids were collected and dried under vacuum to afford the titled compound as a white solid.