Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:21]=[C:20]([O:22][CH:23]([C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:41])[CH2:24][CH3:25])[C:19]([F:42])=[CH:18][C:15]=1[C:16]#[N:17].O>O1CCCC1.C(O)(C)(C)C>[F:42][C:19]1[C:20]([O:22][CH:23]([C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:41])[CH2:24][CH3:25])=[CH:21][C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: CCC(Oc1cc(F)c(C#N)cc1F)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(Oc1cc(OCC(F)(F)F)c(C#N)cc1F)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 342 mg of trifluoroethanol in 2.1 mL of tetrahydrofuran at 5° C. was slowly added 4 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 1.25 g of 2,5-difluoro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile in 5.6 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 70/ethyl acetate 30) to give 1.09 g of 5-fluoro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-(2,2,2-trifluoro-ethoxy)-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]\OCC)[C:5]([F:13])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:29][C:28]1[C:23]2[N:24]([C:8]([C:6]3[C:5]([F:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:9][N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCO/C=C\c1nc(Cl)ncc1F
Reactant: Nc1ncccc1Cl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cnc(Cl)nc1-c1cnc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
25.2 g of the compound [67-1] was dissolved in a mixed solvent of 320 mL of 1,4-dioxane and 32 mL of water. Then, 22.2 g of N-bromosuccinic acid imide was added under an ice-cold condition, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, 16.0 g of 2-amino-3-chloropyridine was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The obtained organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, hexane was added, and the mixture was stirred for 30 minutes. The solid was taken by filtration, and dried under reduced pressure to obtain 20.0 g of 8-chloro-3-(2-chloro-5-fluoropyrimidin-4-yl)imidazo[1,2-a]pyridine [67-2] (hereinafter, referred to as the compound [67-2]) as a yellow solid.
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[C:6]1([OH:15])[C:5]1[CH:16]=[C:17]([CH3:21])[C:18]([CH3:20])=[CH:19][C:4]=1[O:3]2.[C:22]([OH:25])(=O)[CH3:23].N1C=CC=CC=1.C1C[O:35][CH2:34][CH2:33]1>>[C:34]([O:3][C:4]1[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:5]=1[C:6]1([O:15][C:22](=[O:25])[CH3:23])[C:7](=[O:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1])(=[O:35])[CH3:33]
Reactant: C1CCOC1
Reactant: CC(=O)O
Reactant: Cc1cc2c(cc1C)C1(O)C(=O)c3ccccc3C1(O)O2
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C)c(C)cc1C1(OC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
4b,9b-Dihydroxy-7,8-dimethyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (1.00 g, 3.5 mmol) was dissolved in anhydrous THF (50 ml). This solution was added with anhydrous acetic acid (0.67 ml, 7.1 mmol), pyridine (0.30 ml, 3.5 mmol), and 4-dimethyl aminopyridine (0.1 g), and stirred at room temperature for 3 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.55 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[CH2:18]([O:25][CH2:26][CH2:27][CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][CH2:26][CH2:27][CH2:28][O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[NH:8][C:6]1[C:5]([Cl:17])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: OCCCOCc1ccccc1
Product: Fc1cccc(OCCCOCc2ccccc2)c1Nc1nc(Cl)ncc1Cl

Procedure:
[2-(3-Benzyloxy-propoxy)-6-fluoro-phenyl]-(2,5-dichloro-pyrimidin-4-yl)-amine was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol and 3-Benzyloxy-propan-1-ol in an analogous manner to Example 1283c. Title compound was isolated as a white foam (247 mg, 46%). HPLC purity=95%. LCMS 424.13 (M+H), HNMR 8.15 (s, 1H), 7.25-7.21 (m, 1H), 6.82-6.77 (m, 2H), 6.71 (s, 1H), 6.36-6.32 (m, 5H), 4.48 (s, 2H), 4.16-4.13 (m, 2H), 3.57-3.53 (m, 2H), 2.07-2.02 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O1[CH2:18][CH2:17][O:16][CH2:15]C1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21][N:20]=1>CO.CCOC(C)=O.O.N>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH2:23][C:28]3[CH:19]=[N:20][C:17]([O:16][CH3:15])=[CH:18][CH:27]=3)=[N:21][N:20]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: c1ccc2cnncc2c1
Reactant: C1COCCO1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Under N2 atmosphere, 0.40 g (2.7 mMol) of 4-tert-butyl-aniline and 0.62 ml 4 N HCl/dioxane are added to 750 mg (2.6 mMol) of 1-chloro-4-[6-methoxy-pyridin-3-yl)methyl]phthalazine in 11 ml of methanol, and the mixture is stirred for 2 h at 65° C. After cooling, the resulting yellow solution is diluted with EtOAc, 20 ml of water and 10 ml of 2.5% NH3 solution, and the aqueous phase is removed and extracted twice with EtOAc. The organic phases are washed with water and brine, dried and partially evaporated with a RE. After addition of DIPE to the remnant, the title compound crystallizes out: FAB-MS: (M+H)+=399; HPLC(Grad20-100) tRet=11.9.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[N:20]#[C:21]Br.C(Cl)Cl>C(O)C>[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:21]#[N:20])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: N#CBr
Reactant: C1CN(C2CCOCC2)CCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: N#CN1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 131.3 %

Procedure:
A suspension of 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (600 mg, 2.467 mmol) in anhydrous Ethanol (10 mL) was added solid NaHCO3 (1555 mg, 18.51 mmol) followed by cyanic bromide (523 mg, 4.93 mmol) and the mixture was stirred at ambient temperature. The mixture was diluted by 50 mL of CH2Cl2 and the solids were filtered off. The filtrated was concentrated in vacuo to afford to give the title compound (632 mg, 3.24 mmol, >100% yield). 1H NMR (400 MHz, Chloroform-d) δ ppm=4.02 (dd, J=3.8, 11.2 Hz, 2H), 3.42-3.31 (m, 2H), 3.31-3.22 (m, 4H), 2.74-2.61 (m, 4H), 2.59-2.47 (m, 1H), 1.73 (d, J=11.5 Hz, 2H), 1.67-1.49 (m, 2H); LC/MS (m/z) ES+ (ELSD)=196.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:24])[C:10](OC)=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C(=O)C)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:25](=O)([O-])[O-:26].[K+].[K+]>CO>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([O:26][CH3:25])[CH:17]=2)[CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: COC(=Cc1ccc(OC(C)=O)cc1)C(=O)NC1CCC(C)CC1
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)NC2CCC(C)CC2)ccc1O
Yield: 83.4 %

Procedure:
Using 4.31 g of N-(4-methylcyclohexyl)-4-acetoxy-methoxycinnamamide (Example 61), 100 ml of methanol, and 10 g of potassium carbonate, a reaction similar to that conducted in Example 54 was carried out. As a result, 3.14 g of N-(4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[C:5]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[OH-:16].[Na+].Cl.[CH3:19][CH2:20][OH:21]>O>[CH3:1][C:2]1[N:7]=[C:19]([C:20]([OH:16])=[O:21])[C:5]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: [OH-]
Reactant: Cc1ccc(-c2ncccn2)c(C#N)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ncccn2)c(C(=O)O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
An alternative method to make D19 is as follows: 6-methyl-3-(2-pyrimidinyl)-2-pyridinecarbonitrile D18 (0.481 g) was suspended in EtOH (5 ml) and a solution of NaOH (0.490 g, 12.26 mmol) in water (5 ml) was added. The yellow mixture was stirred at 100° C. overnight. The yellow solution was cooled to 25° C. and HCl 6 M (1.0 ml) was added dropwise till pH=4.5. The solvent was removed to give a yellow powder that was dried at 50° C./vacuum for 1.5 hours to give the title compound D19 (1.242 g).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][CH2:5]2)[O:3]C1.C([O-])(O)=O.[Na+]>CO.Cl>[CH2:11]([O:10][CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(OCc2ccccc2)CC1

Procedure:
A solution of 4-benzyloxy cyclohexanone ethylene ketal 40 (5.0 g, 20.1 mmol) in methanol (20 mL) and 1N HCl (0.5 mL) was stirred overnight at 25° C. (Step 37). The mixture was neutralized by addition of 1N NaHCO3 (0.5 mL), solvent removed by roto-evaporation, and the residue chromatographed on silica gel using 15:85 ethyl acetate /hexane. Yield of the ketone 41 was 2.7 g ##STR8## (67%); Rf=0.35; 1H NMR (CDCl3) δ2.3 (m, 8H, ring-CH2), 3.6 (m, 1H, CH--O ), 4.6 (s, 2H, CH2 --O).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=1[CH2:22][O:23]C1CCCCO1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.O>[F:1][C:2]([F:30])([F:31])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH2:19][CH2:20][CH3:21])[C:10]=1[CH2:22][OH:23])([OH:8])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1COC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1CO
Temperature: 50 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-[4-(methoxymethoxy)-3-propyl-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl]propan-2-ol (883.2 mg, 1.92 mmol) in tetrahydrofuran (10 mL), water (5 mL), and acetic acid (20 mL) were added, and the mixture was stirred at 50° C. for 3 hours. The reaction solution was neutralized with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (678 mg, 92%) was obtained as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:14]1[C:23]2[C:18](=[C:19]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:32])[CH:15]=1>>[Cl:12][C:11]1[C:2]([NH:1][C:14]2[C:23]3[C:18](=[C:19]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[O:17][C:16](=[O:32])[CH:15]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(Cl)c1N
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Product: COC(=O)c1cccc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12

Procedure:
The title compound was prepared from methyl 2-amino-3-chlorobenzoate and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16 (30 min r×n time). 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 7.92 (m, 3H), 7.59 (t, 1H), 7.19 (d, 1H), 4.85 (m, 1H), 4.40 (s, 1H), 3.92 (s, 3H), 3.70 (s, 3H), 1.90-1.50 (m, 8H); MS (ESI): 443.9.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].Cl.N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>C(OCC)C>[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: COc1cncc(C#N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: N#Cc1cncc(O)c1
Temperature: 200 °C
Yield: 94.9 %

Procedure:
A mixture of 1 g of 5-methoxynicotinonitrile (7.46 mmol) and 8.62 g of pyridine hydrochloride is heated at 200° C. for 2 hours. The crude reaction product is diluted in a water fraction several times with diethyl ether. The aqueous phase is basified by adding sodium bicarbonate and then extracted again with diethyl ether. The organic phase is dried and then concentrated to yield 850 mg of 5-hydroxynicotinonitrile (95%) in the form of a beige solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([C:16]([F:19])([F:18])[F:17])=C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CSC.C[OH:24]>>[CH2:1]([C:3]1([CH2:13][C:14](=[O:24])[C:16]([F:19])([F:18])[F:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: C=C(CC1(CC)CCCc2ccccc21)C(F)(F)F
Reactant: CO
Solvent: CSC
Product: CCC1(CC(=O)C(F)(F)F)CCCc2ccccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
1-Ethyl-1-[2-(trifluoromethyl)-2-propen-1-yl]-1,2,3,4-tetrahydronaphthalene (Intermediate 12) (120 mg, 0.447 mmole) was dissolved in methanol (25 ml) and cooled to −78° C. Ozone was bubbled through the solution for 5 min followed by oxygen for 10 min then nitrogen for 10 min. Dimethyl sulphide (4 ml, 54 mmole) was added and the dry-ice bath was removed to bring the mixture to room temperature. Stirring was continued for 30 min then volatiles were removed in vacuo. The residue was purified on a 10 g silica SPE cartridge eluting with cyclohexane (200 ml), cyclohexane:ethyl acetate 80:20 (100 ml) and ethyl acetate (100 ml) to give the title compound (31 mg, 26%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:10]=[C:9]2[C:11]([C:14]([F:26])([F:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:12][O:13][C:8]2=[CH:7][CH:6]=1>C(O)C>[F:25][C:14]([F:26])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:11]1[C:9]2=[N:10][C:5]([N:2]([CH3:3])[CH3:1])=[CH:6][CH:7]=[C:8]2[O:13][N:12]=1
Reactant: FC(F)(c1ccc2ncccc2c1)c1noc2ccc(Cl)nc12
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2onc(C(F)(F)c3ccc4ncccc4c3)c2n1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a microwave vial was added dimethylamine (2.0 M in THF, 0.75 mL, 1.5 mmol) and, 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.30 mmol) in ethanol (3 mL). The mixture was stirred at 140° under microwave irradiation for two hours then was concentrated and purified by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) to yield the product as a light yellow solid (87 mg, 85%). MS m/z=341.2 [M+1]+ Calc'd for C18H14F2N4O: 340.3.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:16]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 30 mL 1,2-dichloroethane was treated with tert-butyl 3-oxopyrrolidine-1-carboxylate (2.94 g, 15.87 mmol) followed by sodium triacetoxyborohydride (8.4 g, 39.68 mmol) then acetic acid (2.25 mL). The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The suspension was extracted with 2×100 mL CH2Cl2. The organic layer was rinsed with brine, dried over MgSO4, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.89 g, 78.8%). 1H-NMR (CDCl3) δ 7.07 (pseudo t, J=7.2 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 6.62 (pseudo t, J=7.5 Hz, 1H), 4.44-4.40 (m, 1H), 3.63-3.20 (m, 6H), 2.75 (t, J=6.3 Hz, 2H), 2.13-2.08 (m, 2H), 1.94-1.90 (m, 2H), 1.48 (s, 9H). MS (ESI): 303.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CC(C)(C)N
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C\NC(C)(C)C)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 49 μL (0.46 mmol) tertbutylamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 58 mg (50%) product as an orange powder. MS (ESI) m/z 504 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1

Procedure:
Ethyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 3-b, (150 g, 0.46 mol) in THF (1.5 L) was treated with LiOH monohydrate (58 g, 1.39 mol) in water (60 ml) at room temperature for 3 hours. The mixture was concentrated under vacuum and diluted with water (200 ml) followed by extraction with ethyl acetate. The aqueous layer was acidified to pH=2 with 10% HCl and solid crushed out from the solution which was then filtered and washed with water to afford the compound, 3-c. (40 g, 29%).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@H:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:7][C:6]=1[Br:21])C=C.O.Cl.C(OCC)(=O)C.C(N(CC)[C:33]1[CH:38]=CC=C[CH:34]=1)C>>[CH2:38]([C:13]1[C:5]([OH:4])=[C:6]([Br:21])[CH:7]=[C:8]2[C:12]=1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:33]=[CH2:34]
Reactant: C=CCOc1cc2c(cc1Br)CC[C@H]2CCNC(=O)CC
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(O)c(Br)cc2c1[C@H](CCNC(=O)CC)CC2
Temperature: 202.5 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A suspension of (S)-N-[2-(6-allyloxy-5-bromoindan-1-yl)ethyl]propionamide (50.75 g, 144 mmol.) in N,N-diethylaniline (150 mL) was stirred for 2.5 hours at 200-205° C. under argon atmosphere. The reaction mixture was cooled, followed by distilling off N,N-diethylaniline under reduced pressure to leave an oily residue. To the residue were added water (50 mL), 2N HCl (50 mL) and ethyl acetate (100 mL). The mixture was subjected to extraction twice to extract the organic matter. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:hexane=7:3) to afford the title compound (yield 40.6 g, 80%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:23]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=1[F:21])[CH3:9]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10° C. to 15° C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0° C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25° C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%).