Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:23][CH2:22]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCC2)CC1

Procedure:
Example 135 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, 1H, J=8.7, 6.3 Hz), 7.32 (s, 1H), 7.22–7.15 (m, 2H), 7.06 (dd, 1H, J=8.7, 3.0 Hz), 7.05–6.95 (m, 2H), 5.90–5.84 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.59–2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz), 2.41–2.40 (m, 2H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.04–1.96 (m, 2H), 1.93–1.85 (m, 2H), 1.82–1.71 (m, 3H), 1.64–1.48 (m, 7H), 1.17 (d, 6H, J=6.5 Hz); ESMS m/e: 542.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17](O)(=O)[CH:18]([CH3:20])[OH:19].C>Cl>[CH3:17][CH:18]([C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:19]
Reactant: CC(O)C(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: Cl
Product: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21
Temperature: 140 °C

Procedure:
3-Amino-4-(2-methylpropylamino) quinoline (29.0 g; 0.135 mol) and lactic acid (36 mL; 0.48 mol) were mixed and heated at 140° C. for 6 hr. The mixture was then dissolved in dilute hydrochloric acid and treated with charcoal. The solids were filtered from the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as an oil. The oil was extracted into ethyl acetate. The ethyl acetate solution was treated with decolorizing carbon and the solids were filtered from the mixture. The filtrate was evaporated to dryness to yield a greenish oil which was pure enough for further reactions. A small sample was triturated with hexane to obtain a solid which was recrystallized from ethyl acetate for analysis. m.p. 152-166° C. Analysis: Calculated: C, 71.4; H, 7.11; N, 15.6. Found: C, 71.1; H, 7.33; N, 15.4.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1.[CH:14](Cl)(Cl)Cl>O>[CH3:1][N:2]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1)[CH3:14]
Reactant: CNCc1nc(CSCCN)cs1
Reactant: ClC(Cl)Cl
Solvent: O
Product: CN(C)Cc1nc(CSCCN)cs1

Procedure:
Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:26]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1ncn2ccccc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncn2ccccc12
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-iodo-imidazo[1,5-a]pyridine (150 mg, 0.62 mmol) in THF (3 mL) at −10° C. (ice/acetone) was added isopropylmagnesium chloride (2.0 M in THF, 37 mL, 0.74 mmol). The reaction mixture was stirred at −10° C. for 20 min then tributylchlorostannane (0.20 mL, 0.74 mmol) was added. The reaction was stirred at −10° C. for 30 min then warmed to room temperature and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 1-tributylstannanyl-imidazo[1,5-a]pyridine as a yellow oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Yield: 66.1 %

Procedure:
In the same manner as in Reference Example 33 and using tert-butyl (3-hydroxyphenyl)carbamate (18.9 g, 90.3 mmol), 5-bromo-2-nitropyridine (15.3 g, 75.3 mmol), cesium carbonate (36.9 g, 113 mmol) and N,N-dimethylformamide (150 mL) as starting materials, the title compound (16.5 g, 66%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:6])[C:4]#[N:5].[CH3:7][NH:8][CH3:9]>C1COCC1>[OH:1][CH2:2][CH:3]([CH2:6][N:8]([CH3:9])[CH3:7])[C:4]#[N:5]
Reactant: CNC
Reactant: C=C(C#N)CO
Solvent: C1CCOC1
Product: CN(C)CC(C#N)CO
Temperature: 45 °C

Procedure:
2-hydroxymethyl-acrylonitrile (37 mmol, 3.1 g, prepared as per procedure described by Csuk et al. in Tetrahedron, 1996, 52, 9759-9776) was treated with dimethylamine (25 mL of a 2M solution in THF) and the reaction was heated in a sealed vessel at 45° C. for 14 h. The reaction was cooled to room temperature and all the volatiles were removed by concentration under vacuum. The crude 2-hydroxymethyl-3-dimethylaminopropionitrile thus obtained was dissolved in dry THF (50-60 mL) and this solution was added dropwise to a cold (−78° C.) suspension of LAH (6 g) in THF (300 mL). The reaction was gradually warmed to room temperature and stirred for an additional 12 h at room temperature. The reaction was then cooled in an ice bath and very carefully quenched by the sequential addition of H2O (6 mL), 4M NaOH (6 mL) and H2O (18 mL). The white slurry thus obtained was filtered through celite and the filter bed was washed with additional CH2Cl2. The entire filtrate was then concentrated under vacuum to provide crude amine 23.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.OS(O)(=O)=O>CO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH2:18][C:2]([CH2:6][CH3:7])([OH:1])[C:3]([OH:5])=[O:4])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CCC(=O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)(CC(=O)c1cccc(Cl)c1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A RBF was charged with 2-oxobutanoic acid (2.50 g, 24.5 mmol) and 3.2 mL of water and the mixture was cooled to 0° C. The acid was neutralized by slow addition of 20% aqueous KOH. 3′-chloroacetophenone (3.79 g, 24.5 mmol) was added, followed by a 1.3 M solution of KOH (2.20 g, 39.2 mmol) in MeOH. The reaction mixture was stirred at 0° C. for 48 h. The mixture was brought to pH 2 by dropwise addition of conc. H2SO4. The MeOH was removed in vacuo, and 25 mL of water was added. The heterogeneous mixture was filtered through Celite, and the filter cake was washed with water and CH2Cl2. The layers of the filtrate were separated, and the aqueous portion was extracted with additional CH2Cl2. The combined organics were dried with MgSO4, filtered and concentrated to a volume of ˜25 mL. Hexane was added until the mixture became cloudy, and upon standing a white crystalline solid formed. The mother liquor was decanted and the solids were washed with hexane and dried to provide 4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid as a white crystalline solid. MS m/z=279 [M+Na]+. Calc'd for C12H13ClO4: 256.69.
Reaction SMILES: [OH2:1].S(=O)(=O)(O)O.C=O.[NH2:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[C:13](Cl)=[CH:12][C:11]=1[Cl:27]>O>[NH2:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[C:13]([OH:1])=[CH:12][C:11]=1[Cl:27]
Reactant: Nc1c(Cl)cc(Cl)c2c1C(=O)c1ccccc1C2=O
Reactant: O
Agent: C=O
Agent: O=S(=O)(O)O
Product: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A stirred reactor is charged with 184 parts of sulfuric acid monohydrate and 4.8 parts (1 equivalent) of paraformaldehyde are added, with stirring, over about 15 minutes. Stirring is continued until a solution is obtained. This solution is then heated to 60°-65° C. and 46.5 parts of 98% 1-amino-2,4-dichloroanthraquinone are added. The reaction mixture is heated for 1 hour to 110° C. and this temperature is maintained for 3 hours. The mixture is cooled to 100° C. and 870 parts of water are added. The resultant suspension is heated to 90°-95° C. and stirred for 2 hours at this temperature, then cooled and filtered. The filter cake is washed with hot water and the product is dried in vacuo at 80°-90° C., affording 43.3 parts (95% yield) of 1-amino-2-chloro-4-hydroxyanthraquinone. Rf =0.29 (eluant: concentrated formic acid, saturated with 1-bromonaphthalene).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])=[CH:27][CH:28]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 1-bromo-4-fluorobenzene
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Cc1ccc(-c2nc3ccccc3o2)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1-c1nc2ccccc2o1

Procedure:
To a solution of 5.0 gm. of 2-(2-fluoro-4-methylphenyl)benzoxazole in 200 cc. of carbon tetrachloride is added 4.5 gm. of N-bromosuccinimide and 50 mg. of dibenzoyl peroxide. The mixture is refluxed for 2 hours, filtered to remove succinimide and concentrated in vacuo. The residue is recrystallized from toluene to give 2-(4-bromomethyl-2-fluorophenyl)benzoxazole, m.p. 170°-173° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][O:9][C:10](=[O:31])[C@H:11]([OH:30])[CH2:12][C@H:13]([NH2:29])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:17][CH:16]=1.[OH:32][N:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[N:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][O:9][C:10](=[O:31])[C@H:11]([OH:30])[CH2:12][C@H:13]([NH:29][C:38]([C:36]1[N:35]=[N:34][N:33]([OH:32])[CH:37]=1)=[O:39])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:19][CH:20]=1
Reactant: O=C(O)c1cn(O)nn1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
(2R,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (30.7 mg, 68.3 μmol), 1-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid (10.6 mg, 82 μmol) and HATU (39.0 mg, 102 μmol) were stirred in DMF (1.0 mL, 12.9 mmol) for 10 minutes. DIPEA (35.7 μL, 205 μmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and to yield a clear yellow liquids, which was purified using preparative scale C18 column chromatography (small column; 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (27.1 mg). MS m/z [M+H]+ calc'd for C25H22ClFN4O8, 561.11. found 561.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5](=O)[CH2:6][CH2:7][CH:8]=O.[Cl-].[NH4+:14]>C(O)C.C(OCC)(=O)C>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]1[NH:14][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=CCCC(=O)CCC(F)(F)F
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)CCc1ccc[nH]1
Yield: 14.5 %

Procedure:
Crude 7,7,7-trifluoro-4-oxo-heptanal (10 g, prepared above) in ethanol (100 ml) was treated with ammonium chloride (400 mmol, 21 g), then heated to reflux for 1 h. The resulting solution was diluted with ethyl acetate (300 ml) and washed with brine (2×50 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 1.3 g (21% overall from 4,4,4-trifluorobutyric acid) of 2-(3,3,3-trifluoro-propyl)-1H-pyrrole. 1H NMR (CDCl3) δ 7.98 (1H, br s), 6.71 (1H, dd, J=4.1, 2.6), 6.15 (1H, dd, J=5.9, 2.8), 5.99-5.94 (1H, m), 2.92-2.85 (2H, m), 2.52-2.35 (2H, m).
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])[C@H:8]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:37])[NH2:36])[NH:9][C:10](=[O:30])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([O:6][CH:7]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])[C@H:8]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:36])[NH2:37])[NH:9][C:10](=[O:30])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)Cc1ccccc1
Yield: 96.1 %

Procedure:
After N-benzyloxycarbonyl-L-phenylalanyl-L-argininal dibutylacetal hydrochloride (1.24 g, 2.05 mmols) was dissolved in methanol (100 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 0.93 g (96%) of L-phenylalanyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C@@:5]([OH:18])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7].[OH-].[Li+]>CO.O>[OH:18][C@:5]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([CH:6]([CH3:7])[CH3:8])[CH2:4][C:3]([OH:19])=[O:2]
Reactant: COC(=O)C[C@@](O)(CCc1ccc(O)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@](O)(CCc1ccc(O)cc1)CC(=O)O

Procedure:
The title compound was prepared by dissolving (S)-3-hydroxy-3-[2-(4-hydroxy-phenyl)-ethyl]-4-methyl-pentanoic acid methyl ester (0.57 g, 2.15 mmol) from Example TTTT in MeOH (30 mL). Lithium hydroxide (0.18 g, 4.29 mmol) in water (10 mL) was added and the reaction heated to reflux for 1 hour, cooled and pumped to dryness under vacuum. The product was partitioned between water and Et2O. The aqueous layer was decanted, acidified with 1N HCl and extracted with Et2O. The solution was dried (MgSO4) and concentrated to give the title compound (m.p. 137°-140° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: BrCC1CCCCO1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(CC2CCCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.28 g, 1.0 mmol), 2-(bromomethyl)tetrahydro-2H-pyran (0.36 g, 2.0 mmol) and cesium carbonate (1.00 g, 3.0 mmol) was stirred in butanone at 80° C. for 3 h. Upon cooling to ambient temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography with ethyl acetate-hexanes (1:5-1:1) to afford 1′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.31 g, 82%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.38-6.94 (m, 4H), 6.47 (d, J=2.9 Hz, 1H), 6.38 (s, 1H), 4.79 (ABq, 2H), 4.50 (t, J=8.6 Hz, 2H), 4.01-3.61 (m, 4H), 3.37 (t, J=11.1 Hz, 1H), 2.97 (t, J=8.4 Hz, 2H), 1.97-1.27 (m, 6H); 13C NMR (75 MHz, CDCl3) δ178.1 (2C), 161.7 (2C), 161.3, 161.2, 143.2, 143.1, 132.8, 132.7, 128.6 (2C), 123.5, 123.1, 123.1, 120.6, 120.5, 119.8 (2C), 119.0, 118.9, 109.7, 93.2, 93.1, 80.6, 75.7, 75.5, 72.3, 68.4 (2C), 57.7, 57.6, 45.8, 45.7, 29.6, 29.5, 29.1, 25.8, 23.0; MS (ES+) m/z 378.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14])[N:3]=[C:2]2[NH:28][C:25]1[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2cc(F)ccc2n1
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccc(F)cc23)n[nH]1
Yield: 84.9 %

Procedure:
(6-Fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone was prepared from (4-chloro-6-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (306 mg, 1 mmol) and 5-methyl-1H-pyrazol-3-amine (194 mg, 2 mmol) using a procedure analogous to that described in Example 48 Step A. The crude product was triturated with MeOH to afford (6-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone (310 mg, 85%). 1H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.71 (s, 1H), 8.64 (d, J=9.6 Hz, 1H), 7.95-8.09 (m, 2H), 7.93-7.95 (m, 1H), 7.80-7.86 (m, 1H), 7.39 (t, J=8.6 Hz, 2H), 6.53 (s, 1H), 1.91 (s, 3H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmoles in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH:12]1([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NNC(=O)C1CCCCC1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)C2CCCCC2)c2ccccc21
Yield: 45 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and cyclohexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 45%. 1H NMR (DMSO-d6): δ δ 0.85 (t, J=6.8 Hz, 3H), 1.24-1.83 (m, 19H), 3.74 (t, J=6.9 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.59 (d, 3H), 12.34 (br s, isomer 1: 50%, 0.5; H), 13.00 (br s, isomer 2: 50%, 0.5; H), both isomer are in the same proportion. 13C NMR (DMSO-d6): δ 14.33(CH3), 22.42 (CH2), 25.48 (CH2), 26.34 (CH2), 25.83 (CH2), 27.37 (CH2), 31.29 (CH2), 39.64 (CH2), 110.52 (CH), 119.78 (C), 123.48 (CH), 131.79 (CH), 143.27 (C═N), (C═O). HRMS (ES+) calcd for C21H30N3O2 (M+H+), m/e, 356.2328. found, 356.2333.