Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>>[Cl:28][CH:29]([Cl:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C(Cl)Cl
Product: C[C@H](NC(=O)C(Cl)Cl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and dichloroacetyl chloride (22 mg, 150 μmol). Yield 20 mg (83%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[CH:11]3[O:13][CH:12]3[C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23].[H-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[C@@H:11]([OH:13])[C@H:12]([N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 6 h

Procedure:
6-Carbomethoxy-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (2.42 g, the preparation of which is described in Example 4 of U.K. Pat. No. 1,511,187) and 2-pyrrolidone (0.88 g), were stirred in dimethyl sulphoxide (40 ml) under nitrogen at room temperature. Sodium hydride (0.31 g, 81% dispersion in mineral oil) was added during 5 mins. and the reaction stirred for a further 6 hours. Addition of water, extraction with ethyl acetate, drying or the organic phase with magnesium sulphate, filtration, evaporation and recrystallisation from ethyl acetate-pentane gave 6-carbomethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]-pyran-3-ol of m.p. 190°-192°.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH:6]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([C:21]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:22])[CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)O)c3)nc12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzoic acid (75 mg, 0.22 mmol 0 in DMF (3 mL) was added EDCI (46 mg, 0.24 mmol), HOBt (33 mg, 0.24 mmol), and morpholine (21 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed 1× with saturated sodium bicarbonate, 2× with brine, dried over MgSO4, filtered and evaporated to dryness to provide 92 mg of 7-(cyclopropylamino)-5-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=410)
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C=O.[C:19](O)(C(F)(F)F)=O>ClCCCl>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:10]1[CH2:19][N:13]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][C:9]=1[S:8]2
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)NCCc1cc2c(O)ncnc2s1
Agent: C=O
Solvent: ClCCCl
Product: CC(=O)N1CCc2sc3ncnc(O)c3c2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)acetamide (300 mg, 1.26 mmol, 1.00 equiv) and paraformaldehyde (300 mg, 10.00 mmol, 7.91 equiv) in 50 mL of 1,2-dichloroethane at 0° C. was added CF3COOH (6 mL). The solution was stirred for 12 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to afford the desired 1-[3-hydroxy-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2,4,6-tetraen-12-yl]ethan-1-one (200 mg, 63%) as a light yellow solid. MS (ES): m/z 250 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:26])[CH2:14][CH2:15][C:16]2[C:21](Br)=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[Br:25])[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:4].BrC1C=C(OC)C=C2C=1CCC(=O)N2C1C(Cl)=CC=CC=1Cl>>[Br:25][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][C:13](=[O:26])[N:12]2[C:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: COC(=O)c1ccc(C)c(NC(=O)CCc2c(Br)cc(OC)cc2Br)c1
Agent: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1

Procedure:
5-Bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from N-(3-methoxycarbonyl-6-methylphenyl)-3-(2,6-dibromo-4-methoxyphenyl)-propionamide by a procedure analogous to that described in INTERMEDIATE 1, Step E. Mass spectrum (ESI) 374.0 (M-OMe). 1H NMR (500 MHz, CDCl3): δ 8.02 (dd, J=2.0, 8.0 Hz, 1H); 7.80 (d, J=8.5 Hz, 1H); 6.80 (d, J=2.5 Hz, 1H); 5.73 (d, J=2.5 Hz, 1H); 3.89 (s, 3H); 3.63 (s, 3H); 3.16 (m, 2H); 2.80 (m, 2H); 2.13 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([OH:5])=[O:3]
Reactant: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)O

Procedure:
1-(7-Ethoxycarbonylheptyl)-2-heptyl-4,5-diphenylimidazole (1 g) was reacted with sodium hydroxide in a method similar to Example 10 to give, after column chromatography on silica gel (dichloromethane/methanol) and recrystallisation from hexane, 1-(7-carboxyheptyl)-2-heptyl-4,5-diphenylimidazole (0.26 g, 28%) as a white solid, m.p. 75°-6°. Found: C, 78.04; H, 8.85; N, 6.10%; C30H40N2O2 requires: C, 78.22; H, 8.75; N, 6.08%;
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[NH:11][N:12]=[C:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:14]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C.O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:13]2[CH:14]=[C:10]([NH:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:27])=[CH:26][CH:25]=3)=[O:8])[NH:11][N:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C#N)cc3)[nH]n2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(C(N)=O)cc3)[nH]n2)c1
Temperature: 80 °C
Yield: 9.5 %

Procedure:
4-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide (Example 23) (0.2 g, 0.58 mmol) and NaOH (69 mg, 1.73 mmol) were added to a solution of ethanol/water (20 ml, 3:1) and heated at 80° C. until complete consumption of starting material was observed. Care was required as the amide further hydrolysed to the carboxylic acid. The reaction was extracted with DCM (3×50 ml), dried and the solvent was removed in vacuo to yield a white solid. This was triturated with DCM to afford a white solid (20 mg, 10%); 1H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.75 (s, 3H), 6.42 (s, 1H), 6.82-6.75 (m, 3H), 7.20 (t, 1H), 7.46 (s, 1H), 7.95 (d, 2H), 8.16-8.03 (m, 3H), 10.82 (s, 1H), 12.18 (s, 1H); MH+ 366.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:4]=2[O:3]1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (1.0 eq) was slurried in toluene (10 vol). Vitride® (2 eq) was added via addition funnel at a rate to maintain the temperature at 15 to 25° C. At the end of the addition, the temperature was increased to 40° C. for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40 to 50° C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40° C. The organic phase was cooled to 20° C., then washed with water (2×1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:17]=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:7]1[CH2:6][CH:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:19][C:2]=2[CH3:1])[CH2:8]1
Reactant: Cc1cc(CN2CCN(C)CC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CN2CCN(C)CC2)ccc1OC1CNC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 9B (2.18 g, 5.81 mmol) in DCM (40 mL) was treated with TFA (10 g, 88 mmol) and stirred at 0° C. for 3 h. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 (sat.) and extracted several times with DCM. The organic solutions were filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by column chromatography on SiO2 using 10% triethylamine and 10% MeOH in EtOAc as eluent. There was obtained 1.44 g (90%) of 9C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.22 (s, 3H), 2.28 (s, 3H), 2.27-2.70 (bm, 8H), 3.40 (s, 2H), 3.75-3.85 (m, 2H), 3.88-3.98 (m, 2H), 4.92-5.02 (m, 1H), 6.43 (d, 1H), 7.01 (d, 1H), 7.09 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[CH2:55][CH2:54][CH:53]([CH2:56][NH2:57])[CH2:52][CH2:51]1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:57][CH2:56][CH:53]3[CH2:54][CH2:55][O:50][CH2:51][CH2:52]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 58.8 %

Procedure:
A solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (60 mg, 0.17 mmol), HATU (76 mg, 0.20 mmol), DEIA (0.035 mL, 0.20 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.023 mL, 0.20 mmol) in DMF (1 mL) was stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→100% ethyl acetate/hexane0→5% methanol/ethyl acetate) to give the title compound (44 mg, 0.100 mmol, 60%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:29]=[C:30]4[C:35]([CH3:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1cc(Br)cnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 130 °C
Yield: 17.2 %

Procedure:
1.25 g (2.81 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 631.4 mg (3.38 mmol) 2-amino-5-bromo-3-methyl-pyridine, 2.15 g molecular sieves (4 Å, dried over night at 120° C. in a drying oven), 363.5 mg (2.81 mmol) N,N-diisopropylethylamine in 12 mL 2-propanol (degassed for 15′) in a microwave vial, sealed with a microwave cap, were heated at 130° C. for 17 hours in a heating block. The reaction mixture was sucked off via a glass fibre filter and the filter was washed with dichloromethane. After evaporation to dryness, the residue was redissolved in dichloromethane (200 mL), washed with an 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate (50 mL) and brine (100 mL) and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 256.7 mg (17.1%) of the title compound.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:7][CH2:1][CH:2]1[CH2:3][CH2:4][O:5][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6]1
Reactant: O=Cc1ccccc1
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1CCOC(c2ccccc2)O1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture of 1,2,4-butanetriol (3.0 g, 28.3 mmol) and benzaldehyde (11.48 ml, 113 mmol) in dry toluene (50 mL) with p-toluenesulfonic acid monohydrate (0.269 g, 1.413 mmol) was heated under reflux in a Dean-Stark apparatus. After ˜1 h, the solution was washed with sat. aq NaHCO3, dried and concentrated under high vac to remove most of the benzaldehyde. Chromatography gave syrupy title compound (2.88 g, 14.83 mmol, 52.5% yield). The NMR's were the same as reported (Tetrahedron Asymm. 1996, 7, 3209-3246).
Reaction SMILES: [C:1]([N:8]([C:13]12[CH2:22][C:17]3([CH3:23])[CH2:18][CH:19]([CH2:21][C:15]([CH3:24])([CH2:16]3)[CH2:14]1)[CH2:20]2)[CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-:25][Mn](=O)(=O)=O.[K+].Cl>[OH-].[K+].O.CCOC(C)=O>[C:1]([N:8]([C:13]12[CH2:14][C:15]3([CH3:24])[CH2:16][C:17]([CH3:23])([CH2:18][C:19]([OH:25])([CH2:21]3)[CH2:20]1)[CH2:22]2)[CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC12CC3CC(C)(C1)CC(N(CC(=O)O)C(=O)OC(C)(C)C)(C3)C2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC12CC3(C)CC(O)(C1)CC(N(CC(=O)O)C(=O)OC(C)(C)C)(C2)C3
Temperature: 90 °C
Yield: 102 %

Procedure:
To a solution of N-BOC-(3,5-dimethyladamantan-1-yl)-glycine (1.79 g, 5.3 mmol) in 2% KOH/water (75 mL) at rt was added KMnO4 (1.0 g, 6.3 mmol). The reaction was heated to 90° C. for 2 h. An additional portion of KMnO4 (0.3 g, 1.9 mmol) was added and the reaction was heated at 90° C. for an additional 1.5 h. The reaction was then diluted with EtOAc (150 mL) and with vigorous mixing the pH was addjusted to ˜3 with 1N HCl. The EtOAc layer was separated and set aside. The aqueous layer was then extracted once more with EtOAc and twice with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated to give N-BOC-(3-hydroxy-5,7-dimethyladamant-1-yl)-glycine (1.91 g). MS m/e (M+H)+=354.2
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH2:38][CH2:39][CH3:40])C.O>C(#N)C>[CH3:25][O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:33][C:32]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1cc(O)ccc1OCC(=O)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCc1cc(OCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC
Reaction time: 6 h
Yield: 77.9 %

Procedure:
To a suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.10 g, 0.36 mmol) and Cs2CO3 (0.24 g, 0.72 mmol) in 2 mL acetonitrile is added (4-hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester (0.09 g, 0.38 mmol). The solution is stirred for 6 hrs and poured into water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organics are washed with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified using flash column chromatography (20% ethyl acetate/hexanes) to afford 0.13 g (85%) desired {4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-propyl-phenoxy}-acetic acid methyl ester. This ester is hydrolyzed in the usual way using 0.14 g ester and 3 eq. 1M LiOH in 3 mL 3:2:1 THF:MeOH:H2O to afford 0.16 g (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OCC1CCCCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCC4CCCCC4)cc3C)c2cc1OC
Yield: 86.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclohexylmethanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 83%).
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO.C(Cl)Cl>O.C(Cl)Cl>[C:15]1([S:21]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)N1CC2CC(C1)CN(S(=O)(=O)c1ccccc1)C2
Reaction time: 17.5 h
Yield: 28.6 %

Procedure:
A 50-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, an ice bath, a 10-mL addition funnel, and a glass stopper. To a stirred, ice cold (5° C.) mixture of the amine (31, 1.03 g, 6.12 mmol) and NaOH pellets (97%, 0.76 g, 18.4 mmol) in H2O (7 mL) and CH2Cl2 (5 mL) was added dropwise a solution of benzenesulfonyl chloride (2.16 g, 12.2 mmol) in CH2Cl2 (5 mL) over 30 min. Stirring of the mixture was continued for an additional 17.5 h at RT. The reaction mixture was then partitioned between H2O (30 mL) and CH2Cl2 (30 mL) followed by basification (pH~12) of the aqueous phase. Extracts (CH2Cl2, 3×30 mL) of the remaining water layer were combined with the initial organic layer. The solution was washed with 10% NaOH (30 mL) and then saturated NaCl (30 mL); it was dried (Na2SO4, overnight), filtered, and concentrated to give an orange viscous oil. Chromatography of the oil was performed on silica gel (39 g, 1.6 cm×62 cm) using 10% CH3OH/CH2Cl2. Fractions (Rf =0.44) were saved, concentrated, and reeluted on neutral alumina (90 g, 2.5 cm×18 cm) employing ethyl acetate as eluant. Fractions (Rf =0.53) were saved and concentrated. A colored impurity persisted which was removed by again eluting over silica gel (21 g, 1.6 cm×33 cm) using 5% CH3OH/CH2Cl2 as eluant. Fractions (Rf=0.34) were combined and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.54 g (28.6%) of white solid (36); mp 85.5°-86.5° C. IR (KBr) cm-1 3060 (Ar C--H), 2960, 2910, 2890, 2865, 2820 (C--H), 1585 (C=C), 1340, 1170 (S=O), 760, 720 (C--H out of plane, mono); 1H NMR (DMSO-d6) δ0.88 (d, 6 H, CH3, J=6.5 Hz), 1.40 [bs, 2 H, H(9)], 1.94 [bs, 2 H, H(1,5)], 2.35 [bd, 2 H, H(6,8)ax, J=10.3 Hz], 2.53 [heptet, 1 H, CH(CH3)2, J=6.5 Hz], 2.69 [bd, 2 H, H(6,8)eq, J=10.3 Hz], 2.89 [dd, 2 H, H(2,4)ax, J=11.2 Hz, J'=4.5 Hz], 3.36 [d, 2 H, H(2,4)eq, J=10.9 Hz], 7.58-7.75 (m, 5 H, Ar--H); 13C NMR (DMSO-d 6) ppm 17.57 (CH3), 27.39 [C(1,5)], 28.95 [C(9)], 48.88 [C(2.4)], 52.66 [C,(6,8)], 53.42 [CH(CH3)2 ], 126.90, 129.01, 132.36, 136.79 (Ar--C). Anal. Calcd. for C16H24N2O2S: C, 62.31; H, 7.85. Found: C, 62.48; H, 7.69.
Reaction SMILES: Br.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][C:3]1=[O:11].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:35][CH3:36])=[C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1>C1COCC1.CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:35][CH3:36])=[C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:3]1=[O:11]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3C(=O)Nc4ncccc43)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.9 %

Procedure:
7-Azaoxindole hydrobromide (269 mg, 1.25 mmol), (Tet.Let. 1987, 28, 4027), was added to a suspension of sodium hydride (100 mg, 2.5 mmol, prewashed with hexane) in a mixture of THF (3 ml) and DMF (3 ml). After stirring for 40 minutes at ambient temperature, 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (169 mg, 0.5 mmol) was added. After heating for 1 hour at 75° C., the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and adjusted to pH8 with 2M hydrochloric acid. After extraction with methylene chloride, the organic layer was dried (MgSO4), filtered and the volatiles removed by evaporation. The residue was dissolved in methylene chloride/methanol and 3M hydrogen chloride in ether (0.5 ml) was added. After dilution with ether, the solid was collected by filtration and dried under vacuum to give 4-(7-azaoxindol-3-yl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (150 mg, 59%).