Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28]>CN(C)C=O>[F:28][CH2:27][CH2:26][CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=1
Reactant: FCCCBr
Reactant: Oc1ccc(-c2cn3cc(O)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cn3cc(OCCCF)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 0 %

Procedure:
560 mg (corresponding to 2.48 mmol) of 2-(4′-hydroxyphenyl)-6-hydroxyimidazo[1,2-a]pyridine was dissolved in 21 mL of N,N-dimethylformamide, and 1.37 g (corresponding to 9.90 mmol) of potassium carbonate and 349 mg (corresponding to 2.48 mmol) of 1-bromo-3-fluoropropane were added thereto. The solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and then supplemented with 10 mL of chloroform and 10 mL of methanol to obtain slurry. The slurry was filtered and filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform/methanol=20/1), to obtain 151 mg (corresponding to 0.527 μmol) of 6-(3′-fluoropropoxy)-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 5, Step 7).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH2:8][C:9](=O)C(O)=O>C(O)C>[NH:3]1[C:2]2=[N:1][CH:7]=[CH:8][CH:9]=[C:6]2[CH:5]=[N:4]1
Reactant: CCC(=O)C(=O)O
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: c1cnc2[nH]ncc2c1
Temperature: 80 °C

Procedure:
In an alternative route, R2-aldehyde (II), 3-aminopyrazole (III) and R3-containing methyl pyruvic acid (V) are mixed in ethanol and heated to 50-120° C., preferably 60-100° C. Subsequent oxidization, preferably by exposure to air yields the 1H-Pyrazolo[3,4-b]pyridine acid derivative (VII).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[O:6][CH:7]=1)=[O:2].I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[O:6][CH:7]=[C:3]([CH:1]=[O:2])[CH:4]=3)[C:20]=12
Reactant: O=Cc1coc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cc(C=O)co2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 38.3 %

Procedure:
A solution of 4-Formylfuran-2-boronic acid (20 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA35 (13.5 mg, 39% yield). ESI-MS (M+H)+ m/z calcd 272.1, found 272.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([OH:12])=O.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:12]
Reactant: O=C(O)C#Cc1ccccc1F
Reactant: CCOC(=O)CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 0° C. slurry of 3-(2-fluorophenyl)prop-2-ynoic acid (151 g, 0.92 mol) in CH2Cl2 (3L) was added DMAP (118 g, 0.96 mol, 1.05 equiv), followed by sarcosine ethyl ester hydrochloride (148 g, 0.96 mol, 1.05 equiv), and NMM (233 g, 2.3 mol, 2.5 equiv). The resulting clear solution was allowed to warm to room temperature and was maintained for 17 h. The reaction mixture was washed with a 2N HCl solution (4×500 mL). The aqueous layers were combined and the mixture was adjusted to pH 2 using conc. H2SO4, then back-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with a 10% H2SO4 solution (2×500 mL), dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (174 g, 72%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.61; 1H NMR (CDCl3; of rotomeric mixture) δ 1.27 (t, J=7.2 Hz, 3H), 3.07 (s, 1.4H, N—CH3), 3.36 (s, 1.6H, N—CH3), 4.17-4.27 (m, 3.2H), 4.41 (s, 0.8H, N—CH2), 7.06-7.17 (m, 2H), 7.37-7.58 (m, 2H); 13C NMR (CDCl3; of rotomeric mixture) δ 14.00, 14.03, 33.5, 37.2, 48.0, 52.5, 61.3, 61.5, 83.6, 84.3, 85.7 (d, JC−F=9.9 Hz, 1C), 108.9 (d, JC−F=15.5 Hz, 1C), 109.1, (d, JC−F=15.5 Hz, 1C), 115. (d, JC−F=10.4 Hz, 1C), 115.6 (d, JC−F=10.4 Hz, 1C), 124.2, 132.0 (d, JC−F=7.8 Hz, 1C), 132.1 (d, JC−F=7.8 Hz, 1C), 134.10, 134.15, 154.6, 163.3 (d, JC−F=254.4 Hz, 1C), 168.1, 168.5; HPLC ES-MS m/z (rel abundance) 264 (MH+, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: Clc1ccc2cc[nH]c2c1
Product: O=[N+]([O-])c1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-4-nitrobenzene: ESMS m/e: 272.6 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20].CON(C)[C:24]([C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1)=[O:25]>C1COCC1>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([C:24](=[O:25])[CH2:20][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[N:13]=3)=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Reactant: Cc1cccc(C)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 87.5 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 13.8 mL, 34.4 mmol) was added slowly to a solution of diisopropylamine (4.53 mL, 32.3 mmol) in anhydrous THF (50 mL) at −78° C. After being stirred for 0.1 hour, the mixture was allowed to warm up to 0° C. Stirring continued for 0.5 hour. The mixture was then cooled to −78° C. and 2,6-lutidine (3.76 mL, 32.3 mmol) was added slowly. The mixture was allowed to warm up to 0° C. and stirred for 0.5 hour. The mixture was then cooled to −78° C. before the slow addition of benzo[1,3]dioxole-5-carboxylic acid methoxy-methyl-amide (4.5 g, 21.5 mmol; see Example 2 above) in anhydrous THF (10 mL). The mixture was stirred at −78° C. for 0.5 hour, at 0° C. for 0.5 hour, and at room temperature for 2 hours. The mixture was then quenched with ammonium chloride aqueous solution and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. After purification using column chromatography on silica gel (eluent: ethyl acetate (2): hexanes (8)), 4.8 g (87%) of 1-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone as a yellow solid was obtained. MS (ESP+) m/z 256.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.56 (t, 1H, J=7.5 Hz), 7.39 (dd, 1H, J=1.8 Hz, 8.3 Hz), 7.30 (dd, 1H, J=0.5 Hz, 1.8 Hz), 6.93 (m, 1H), 6.83 (m, 2H), 5.98 (s, 2H), 4.87 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([F:30])([F:29])[F:18])[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3C(F)(F)F)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-(2-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) under conditions analogous to Example 7(a) using 2-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.376 (d, 1H), 7.783-7.295 (m, 6H), 4.024 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([O:48][CH3:49])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([O:48][CH3:49])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: COc1ccc(F)c(F)c1B(O)O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: COc1ccc(F)c(F)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluoro-6-methoxyphenyl)boronic acid gave 277. 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.84 (s, 1H), 7.47 (t, J=9.4 Hz, 1H), 7.39 (s, 2H), 7.01 (ddd, J=9.4, 4.0, 1.9 Hz, 1H), 5.02-4.76 (m, 2H), 4.18-3.93 (m, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 2.23-2.13 (m, 1H), 1.90-1.60 (m, 4H). LCMS (ES+) m/z 497 (M+1).
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:19][C@H:20]([CH2:24][OH:25])[C:21]([OH:23])=O)(=[O:18])[CH3:17].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:16]([NH:19][C@H:20]([CH2:24][OH:25])[C:21]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])(=[O:18])[CH3:17]
Reactant: NCc1ccccc1
Reactant: CC(=O)N[C@H](CO)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 32.5 °C
Reaction time: 0.5 h

Procedure:
4-methylmorpholine (7.3 ml) followed by isobutylchloroformate (12.35 ml) was added to a suspension of (R)-2-acetamido-3-hydroxypropanoic acid (7 grams) in tetrahydrofuran (147 ml) at −78 to −75° C., benzylamine (10.4 ml) was added to it and the reaction mixture temperature was raised to 30-35° C. then stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (35 ml) and washed with aqueous hydrochloric acid followed by sodium carbonate and then with water. The solvent from the methylene chloride layer was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)(C)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[N:5]=[CH:4][CH:3]=[C:2]3[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2cccc3c(Cl)ccnc23)cc1
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: COc1ccc(COc2cccc3c(N4CCNCC4)ccnc23)cc1
Yield: 97.1 %

Procedure:
A mixture of compound 23 (4.70 g, 15.68 mmol) and piperazine (13.63 g, 158.23 mmol) in isopropanol (30 mL) was refluxed for 46 hours with stirring. Isopropanol was evaporated under vacuo and the reaction mixture was made alkaline using saturated NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3×100 mL), dried over Na2SO4, concentrated under vacuo to afford 5.32 g (97%) of compound 24, which was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.73 (bs, 1H), 2.80-3.44 (m, 8H), 3.80 (s, 3H), 5.36 (s, 2H), 6.82-6.94 (m, 2H), 6.99 (d, 1H, J=8 Hz), 7.23-7.35 (m, 1H), 7.44 (d, 2H, J=8.4 Hz), 7.58 (d, 1H, J=8 Hz), 8.76-8.82 (m, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([CH2:7][C:6]1[CH:19]=[CH:20][CH:21]=[C:4]([Cl:3])[CH:5]=1)[C:14]([OH:16])=[O:15])[CH3:13]
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of potassium hydroxide (26 g) in absolute ethanol (375 ml) is added during 30 minutes to an ice-cold solution of diethyl 3-chlorobenzylmalonate (112 g) in absolute ethanol (375 ml). The solution is stirred at room temperature for 18 hours, and the solvent removed under reduced pressure. The residue is dissolved in water (1200 ml) and the solution cooled in an ice-bath. Concentrated hydrochloric acid (29 ml) is added, and the solution extracted with ether (2×350 ml). The combined ether solutions are washed with water (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give as an oil, 3-chlorobenzylmalonic acid monoethyl ester; NMR (CDCl3)δ: 10.13 (s, 1H), 7.2 (m, 4H), 4.15 (q, 2H), 3.5 (m, 3H), 1.21 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[CH3:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[C:30]([F:29])[CH:31]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1F
Yield: 38 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-fluoro-4-methylphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (38%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH:10]1C(=O)CCCC1=O>>[OH:7][CH:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:9]=[CH2:10]
Reactant: CC1C(=O)CCCC1=O
Reactant: O=C1CCCC(=O)C1
Product: C=CC(=O)CCCC(C)O

Procedure:
Employing procedures similar to those described in Example 1, except that cyclohexane-1,3-dione is substituted for 2-methylcyclohexane-1,3-dione, 7-hydroxyoct-1-en-3-one is produced.
Reaction SMILES: [NH2:1][C@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3]O.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH:5]([C@@H:2]1[CH2:3][CH2:8][S:9](=[O:11])(=[O:10])[NH:1]1)([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@@H](N)CO
Product: CC(C)[C@@H]1CCS(=O)(=O)N1

Procedure:
Using (R)-2-amino-3-methyl-1-butanol (5.0 g) and methanesulfonyl chloride (7.7 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (3.48 g) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH3:11][C:12]([CH3:16])=[CH:13][CH2:14]Br>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:14][CH:13]=[C:12]([CH3:16])[CH3:11]
Reactant: CC(C)=CCBr
Reactant: Oc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCOc1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 2-iodophenol (3.69 g, 16.8 mmol) in THF (50 mL) is added NaH (804 mg, 33.5 mmol) portion wise and stirred for 30 min at room temperature. 3,3-Dimethylallylbromide (3.9 mL, 33.5 mmol) was added and the reaction was stirred over night at room temperature. The reaction is quenched with water (20 mL) and extracted with diethyl ether (3×25 mL), the organic layers are dried over magnesium sulfate, filtered and concentrated. The compound was purified on silica gel using 100% hexanes as the eluent to yield 4.78 g (98%) of the title compound as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=6.0 Hz, 1H), 7.35 (t, J=9.0 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 6.74 (t, J=9.0 Hz, 1H), 5.45 (m, 1H), 4.60 (d, J=6.0 Hz, 2H), 1.75 (2s, 6H)
Reaction SMILES: [CH3:1][C:2](=[CH2:18])[CH2:3][C:4]1[C:5]([OH:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]2.[Br:19]N1C(=O)CCC1=O>>[Br:19][CH2:18][C:2]1([CH3:1])[O:17][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:3]1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]3
Reactant: C=C(C)Cc1cc(C)c2[nH]c(=O)c(C)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Yield: 90.1 %

Procedure:
Reaction, past-process, and recrystallization (chloroform-methanol-ether) were performed in a manner similar to that described in Example 277 using 6-(2-methyl-2-propenyl)-5-hydroxy-3,8-dimethylcarbostyril (3.29 g, 13.54 mmol) and N-bromsuccinimide (2.41 g, 13.54 mmol). As a result, 3.93 g of the title compound was obtained as pale yellow prisms (90.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Li]CCCC.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:21])[CH2:14]2>O1CCCC1>[OH:21][C:15]1([CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: Cc1cc(C)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(CC2(O)CN3CCC2CC3)on1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3,5-dimethylisoxazole (9.71 g, 100 mmol) in dry tetrahydrofuran (30 ml) cooled to -78° C. was added n-BuLi (2.5M in hexane, 100 mmol). The reaction mixture was stirred at -78° C. for 1 h. A solution of 3-quinuclidinone (6.25 g, 50 mmol) dissolved in dry tetrahydrofuran (50 ml) was added. The reaction mixture was stirred for 2 h at -78° C., then quenched with water (100 ml) and acidified with concentrated hydrochloric acid. The water phase was extracted with ether (2×50 ml), then basified with solid potassium carbonate and extracted with methylene chloride (4×100 ml). The methylene chloride phases were collected and dried over magnesium sulfate. After evaporation of the solvent the title compound was isolated in 10.04 g. 90% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42]O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCCCO
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 6 h
Yield: 45.4 %

Procedure:
A mixture of methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoate (300 mg, 11.28 mmol) (D41), polystyrene bound triphenylphosphine (1.71 g of loading 1.12 mmol/g, 1.92 mmol), and 4-methoxybutan-1-ol (200 mg, 1.92 mmol) in THF (5 ml) was treated dropwise with diethyl azodicarboxylate (0.302 ml, 1.92 mmol). The mixture was stiffed at room temperature for 6 hrs and then filtered. The resin was washed with THF and the filtrate was concentrated and chromatographed on silica gel (elution with ethyl acetate/hexane) to give methyl 3-(4-methoxybutoxy)-5-(2-oxopyrrolidin-1-yl)benzoate (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].Br[CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][N:6]([CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:5]2=[O:14]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CSc1cc2nc[nH]c(=O)c2cc1Cl
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(SC)c(Cl)cc2c1=O

Procedure:
In the manner of Example 4, 0.679 g (0.003 mol) of 6-chloro-7-methylthioquinazolin-4(3H)-one and 1.0 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.56 g (39%). 1H-NMR(CDCl3) 1.4-2.2 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.4 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH-N), 8.2 (singlet, 1H, aromatic H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([C:36](Cl)=[O:37])[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([C:36]([N:10]([CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:37])[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=1)#[N:25]
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 300 mg, 1.55 mmol) was dissolved in CH2Cl2 (30 m]L) and to the resultant solution were added DIPEA (440 mg, 3.40 mmol) together with 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 341 mg, 1.55 mmol). The mixture was stirred for 2 h at room temperature, diluted with CH2Cl2 (20 mL) and then washed with water, aqueous KHSO4 solution and finally with brine. The solution was dried over Na2SO4 and then the solvent was evaporated. The residue was chromatographed on silica gel using a mixture of heptane and ethyl acetate as eluent (7:3) and there was obtained 460 mg (78%) of 3-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (400 MHz, CDCl3): 0.8-4.2 (cm, 16H), 4.8-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.7-7.4 (cm, 6H); LCMS: m/z 377 (M+1)+.