Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([S:17]([O-:20])(=[O:19])=[O:18])[CH:3]([O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[C:42](Cl)(=[O:46])[C:43]([CH3:45])=[CH2:44].C(N(CC)CC)C.Cl>ClCCl>[F:21][C:2]([F:1])([S:17]([O-:20])(=[O:18])=[O:19])[CH:3]([O:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:5])([F:7])[F:6].[C:42]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:46])[C:43]([CH3:45])=[CH2:44]
Reactant: C=C(C)C(=O)Cl
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1

Procedure:
In 15 g of dichloromethane was dissolved 3 g of (4-hydroxyphenyl)diphenylsulfonium 1,1,3,3,3-pentafluoro-2-benzoyloxypropane-1-sulfonate (PAG29) prepared in Synthesis Example 45. Methacryloyl chloride, 1 g, was added to the solution, which was cooled in an ice bath, and 0.9 ml of triethylamine was added dropwise. 30 g of 3N dilute hydrochloric acid was added, after which the organic layer was separated, washed with 30 g of water three times, and concentrated. The concentrate was purified by silica gel column chromatography (elute: dichloromethane/methanol 20/1 in weight ratio), after which diethyl ether was added to the concentrate for crystallization. The crystals were filtered and dried, obtaining the target compound in an amount of 3.5 g.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14](O)[C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]3([C:37]#[N:38])[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]3([C:37]#[N:38])[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:41])[CH3:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)[C@@H]3C(O)C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)C3=CC[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of 3β-benzoyloxy-14α-cyano-4,4-dimethyl-5α-cholestan-7-ol (4.5 g, 8 mmole) in pyridine (100 mL) cooled to 0° C. was added methanesulfonyl chloride (2 mL). The reaction mixture was then stirred at 25° C. for 3 hours, poured into ice water, extracted with 4:1 ether/methylene chloride and washed with water The dried, concentrated mesylate was dissolved in collidine (150 mL) and refluxed for 18 hours under argon. The reaction was partitioned between iced HCl and ether/methylene chloride, and the organic extracts were washed with dilute HCl, water, aqueous sodium bicarbonate solution and brine The 6-ene impurity was removed by dissolving the product in methylene chloride, cooling to -78° C. and passing a stream of ozone through the solution until a faint blue color persists The solution was purged with argon and dimethyl sulfide was added and the solution was concentrated in vacuo. The dried, concentrated product was chromatographed over silica gel with 25/1 to 10/1 hexanes in ethyl acetate to afford 3β-benzoyloxy-14α-cyano-4,4-dimethyl-5α-cholest-7-ene (2.1 g, 48%).
Reaction SMILES: [NH2:1]OS(C1C(C)=CC(C)=CC=1C)(=O)=O.[Cl:15][C:16]1[C:21]2[CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:23][O:24][C:20]=2[C:19]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[NH:33][C:32]2=[O:42])=[C:18]([F:43])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:15][C:16]1[C:21]2[CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:23][O:24][C:20]=2[C:19]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([NH2:1])[C:32]2=[O:42])=[C:18]([F:43])[CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c2c1ONC2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2ONC3c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
1-Aminooxysulfonyl-2,4,6-trimethylbenzene (0.5 g, 0.002 mole) was added all at once to a stirred solution of 3-[4-chloro-6-fluoro-3-phenyl-1,2(2H)-benzisoxazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.8 g, 0.002 mole) and potassium carbonate (0.4 g, 0.003 mole) in THF (50 mL). Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was filtered and the filtrate was concentrated to a residue. The residue was subjected to silica gel column chromatography using 4:1 hexane and ethyl acetate. The product-containing fractions were combined and concentrated, yielding 0.6 gram of Compound 34, m.p. 171-173° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OCC)(=O)C.C(O)(C)C.[CH:11]1([NH:14][C:15](=[O:30])[C@@H:16]([OH:29])[C@@H:17]([NH:21]C(OC(C)(C)C)=O)[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]1.[ClH:31].C(O)(C)C>CCCCCC>[ClH:31].[CH:11]1([NH:14][C:15](=[O:30])[C@@H:16]([OH:29])[C@@H:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
The ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (46.1 g, 10.8 wt. %) obtained in the above Example 2 was used. The solvent was changed from ethyl acetate to isopropyl alcohol, thereby to prepare an isopropyl alcohol solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (34.82 g). Hexane (20 g) was added to the solution and the mixture was heated up to 60° C., and 10.5 wt % hydrogen chloride/isopropyl alcohol solution (9.1 g) was dropwise added, taking 1 hour. Then, after stirred for 8 hours, the reaction solution was cooled down to 0° C. at a constant rate, taking about 6 hours. The slurry had no solid aggregation therein, and had good flowability. The precipitated crystals were collected by filtration under reduced pressure, using a kiriyama funnel (diameter 4 cm, filter pore size 4 μm). At the time, the filterability was good, and the time taken for separation of the crystals from the mother liquid was about 30 seconds. The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (15 mL). Next, the washed wet crystals were dried in vacuum at 60° C., to obtain (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (3.48 g, yield: 90 mol %, chemical purity: 100.0 area %, optical purity: 100% ee).
Reaction SMILES: C[C@@:2]1([S:13]([NH2:16])(=[O:15])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1CCCCBr.[S-]CC.[Na+]>O1CCCC1>[C:2]1([S:13]([NH2:16])(=[O:15])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(S(N)(=O)=O)C=CC=CC1CCCCBr
Agent: CC[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-bromobutyl-benzenesulfonamide (0.650 g, 1.24 mmol) in tetrahydrofuran (2 mL) was added sodium thioethoxide (0.115 g, 1.36 mmol) under nitrogen at 0° C. The mixture was stirred overnight at 22° C. The mixture was quenched with 2M NaOH (3 mL), extracted with ethyl ether (2×20 mL), dried over Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) afforded 0.500 g of 4-chloro-N-[5-chloro-2-(hydroxymethyl)phenyl]-N-[4-(ethylthio)]-1-(R)-methylbutyl]benzenesulfonamide as a yellow oil in 87% yield. MS (ESI+), 462 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:8])[CH3:2].Cl.[NH2:19]O>CO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:8][N:19]=1)=[O:17])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Yield: 67.3 %

Procedure:
A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in MeOH (60 mL) was heated at 80° C. for 4 h. After cooling, the mixture was filtered and washed with cold MeOH to afford the title compound (2.0 g, 71%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of commercially available (R)-tert-butoxycarbonylamino-phenyl-acetic acid (1.00 g, 3.98 mmol), dimethyl-pyridin-4-yl-amine (0.49 g, 3.98 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (0.84 g, 4.38 mmol) in anhydrous dichloromethane (30 mL), a solution of 2-aminobenzoic acid (0.55 g, 3.98 mmol) and triethylamine (0.56 mL, 4.38 mmol) in anhydrous dichloromethane (6 mL) was added drop wise at 0-5° C. The reaction was stirred at room temperature for 4 h, then the resulting solution was washed with 1N HCl solution, water and brine After drying over Na2SO4, the solvent was removed to give the intermediate 2-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-benzoic acid. To a solution of this intermediate in dry dichloromethane (20 mL), dimethyl-pyridin-4-yl-amine (0.19 g, 1.59 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (0.84 g, 4.38 mmol) were added. The mixture was stirred at room temperature for 2 h, then washed with 1N HCl solution, then with water and brine, dried over Na2SO4 and evaporated to dryiness. The intermediate [(R)-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl-methyl]-carbamic acid tert-butyl ester was dissolved in dry pyridine (5 mL) and aminoguanidine hydrogencarbonate (0.60 g, 4.38 mmol) was added. The mixture was heated under microwave condition at 180° C. for 30 minutes, the solvent was then evaporated and the crude purified by flash column chromatography on silica gel eluting with DCM/CH3OH 96/4, to afford title compound (0.16 g, 10% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 139.2 %

Procedure:
p-Anisidine (12.3 g) was dissolved in CH2C 12(30 ml) and the solution was cooled to 5° C. Aqueous NaOH (6.6 g in 13 ml water) and 3-chloro-propionyl-chloride (19.05 g) were simultaneous added to the above solution over 40 minutes. The two phase mixture was stirred at 5° C. for another 30 min. Water (250 ml) and concentrated HCl (3 ml) were then added . The product was isolated by filtration, washed with water and dried to a constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (29.7 g, 94.6 %) in 99.3% purity by HPLC analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccnc(F)c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of (2-Fluoro-pyridin-4-yl)-methanol (37) (381 mg, 3 mmol) in chloroform (30 ml) at 0° C. (ice bath), was added triethylamine (630 μl, 4.5 mmol) followed by methanesulfonyl chloride (270 μl, 3.6 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo to provide Methanesulfonic acid 2-fluoro-pyridin-4-ylmethyl ester (38). A flask was charged with Methanesulfonic acid 2-fluoro-pyridin-4-ylmethyl ester (38) from above, 3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (32) (891 mg, 3 mmol), anhydrous powdered potassium carbonate (408 mg, 3 mmol), and lithium iodide (402 mg, 3 mmol). Anhydrous DMF (15 ml) was then added into the mixture and stirred for 5.5 hr at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and evaporated in vacuo to give a pale yellow foam. The crude product was purified by silica gel column chromatography (eluent, methanol:chloroform (2:98)) to afford 366 mg (30%) of Example H as a pale yellow foam, which was recrystallized from chloroform-ether to give a white solid; 1H NMR (200 MHz, CDCl3) δ: 1.12 (3H, d, J=6.8 Hz), 1.23 (3H, d, J=6.8 Hz), 2.25 (1H, m), 2.42 (3H, s), 4.66 (1H, d, J=16.7 Hz), 4.93 (1H, d, J=16.7 Hz), 6.61 (1H, s), 6.90 (1H, d, J=5.3 Hz), 7.71 (2H, s), 7.91 (1H, s), 8.04 (1H, d, J=5.3 Hz), 9.44 (1H, s); m/z (EI): 406 (M+); HRMS (EI) Calcd. 406.144104, Found 406.144119.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]([NH2:21])=O)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)C(C)C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]#[N:21])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=O)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C#N)s1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
2-(N-BOC-Aminomethyl)-4-trifluoromethylthiazole-5-carboxamide [sic] (4.6 g, 14.14 mmol) was dissolved in dichloromethane (30 ml) and cooled to −5° C. Ethyldiisopropylamine (4.6 g, 35.35 mmol) and a solution of trifluoroacetic anhydride (3.4 g, 16.26 mmol) in dichloromethane (10 ml) were added at this temperature. Then, the mixture was stirred for a further 2 hours at 0° C. It was washed in succession with saturated sodium hydrogen carbonate solution and 5% strength citric acid solution. After drying (MgSO4), the solvent was removed on a rotary evaporator. The crude product was extracted by stirring with diethyl ether/petroleum ether. The supernatant was separated from the oil and concentrated on a rotary evaporator. Yield: 1.9 g (6.18 mmol, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.O>[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cnc2[nH]c3c(c2c1)CN(CCN1CCOCC1)CC3
Yield: 42.9 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (100 mg, 0.48 mmol), 4-(2-chloroethyl)morpholine hydrochloride (99 mg, 0.53 mmol), K2CO3 (0.08 mL, 1.44 mmol), and NaI (0.02 mL; 0.53 mmol) were suspended in DMF (2 mL). The reaction solution was diluted with H2O, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to provide 66 (66 mg, 43% yield) as a yellow solid. LC-MS (M+H=321, obsd.=321).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:3][C:4]#[N:5]>C1COCC1>[NH2:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[OH:1]
Reactant: N#CCC(O)c1cccc(O)c1
Solvent: C1CCOC1
Product: NCCC(O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the nitrile 21.16 (25.0 g, 153 mmol) in THF, cooled to 0° C., was added BH3-DMS (49.5 mL, 460 mmol), following which the cooling bath was removed. The resulting mixture was boiled under reflux overnight, cooled in an ice-bath and quenched by the slow addition of large excess of MeOH. After stirring at room temperature for 2 h, the excess solvent was removed under reduced pressure. The residue was again treated with MeOH and evaporated. The process was repeated three times. The brown oil was then applied onto a flash silica gel column and eluted (0 to 15% (9:1 MeOH—NH3)-DCM gradient) to give 3-(3-amino-1-hydroxypropyl)phenol (21.17) as a brown solid. Yield (25.0 g, 97%); 1H NMR (400 MHz, DMSO-d6) δ 7.04-7.09 (m, 1H), 6.74 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.58 (dd, J=8.0, 2.0 Hz, 1H), 4.55 (dd, J=7.2, 5.6 Hz, 1H), 2.57-2.66 (m, 2H), 1.56-1.62 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[NH:4]1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O.Br[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1>[Cu]I.O1CCOCC1>[CH2:1]([N:3]1[C:7]([O:8][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:6][C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:4]1)[CH3:2]
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Reactant: CC(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C(C)C)cc1
Temperature: 110 °C
Yield: 21.2 %

Procedure:
Dioxane (4.7 mL) was added to a mixture of 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (500 mg, 2.35 mmol, 1 equiv), cesium carbonate (1.53 g, 4.69 mmol, 2.00 equiv), copper (I) iodide (112 mg, 0.586 mmol, 0.250 equiv) and N,N-dimethylglycine hydrochloride (164 mg, 1.17 mmol, 0.50 equiv). The reaction flask was sealed, and nitrogen gas was bubbled through the reaction mixture for 5 minutes with a needle. The needle was removed, and 1-bromo-4-isopropylbenzene (934 mg, 4.69 mmol, 2.00 equiv) was added. The reaction flask was sealed and heated to 110° C. for 16 hours. The crude reaction mixture was loaded directly onto a silica gel column and purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford 3-[1-ethyl-5-(4-isopropylphenoxy)-1H-pyrazol-3-yl]benzonitrile (165 mg, 21%). Calcd (M+1)+: 332.2. Found: 332.1.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1C
Temperature: 25 °C
Yield: 67.6 %

Procedure:
MeOH (200 mL) was added to a flask containing 4-[1-(cyclohexylmethyl-amino)-ethylidene]-pent-2-enedioic acid dimethyl ester (6.3 g, 21.4 mmol). NaOMe solution (4.9 mL, 21.4 mmol, 4.375 M in MeOH) and N-bromosuccinimide (4.56 g, 25.6 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (20% EtOAc/hexanes) to give 4.95 g of the title compound. MS: (+) m/z 364.21, 366.16 (M+Na, 79/81Br).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC#C)C=CC=CC=1.[N:22]([C:25]1[S:26][C:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]([CH3:30])[N:29]=1)=[N+:23]=[N-:24]>>[CH3:30][C:28]1[N:29]=[C:25]([N:22]2[CH:10]=[C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:24]=[N:23]2)[S:26][C:27]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: C#CCCCc1ccccc1
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Agent: C#CCCc1ccccc1
Product: CCOC(=O)c1sc(-n2cc(CCc3ccccc3)nn2)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 12, making variations as necessary to replace 5-phenyl-1-pentyne with 4-phenyl-1-butyne to react with ethyl 2-azido-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 62% yield: 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.33-7.19 (m, 5H), 4.34 (q, J=7.1 Hz, 2H), 3.17-3.03 (m, 4H), 2.71 (s, 3H), 1.39 (t, J=7.1 Hz, 3H); MS (ES+) m/z 343.3 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)C>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(CO)cc1)OCc1ccccc1
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
2.52 g (23.8 mmol) of sodium carbonate and 8.13 g (47.6 mmol) of benzyl bromide were added to a solution of 3.95 g (23.8 mmol) of 4-Hydroxymethylphenylacetic acid [prepared as described in step (i) above] in 40 ml of N,N-dimethylformamide, and the resulting mixture was stirred for 3.5 hours. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted mixture was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by column chromatography through 200 g of silica gel, using a gradient elution method, with mixtures of methylene chloride and ethyl acetate in ratios ranging from 100:5 to 100:10 by volume as the eluent, to give 5.03 g (yield 82%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH:13]([OH:19])[CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[CH2:22]([Zn]CC)C.ICI.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:18][CH:16]([NH:15][CH2:14][CH:13]([OH:19])[CH2:12][O:11][C:10]1[CH:20]=[CH:21][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[CH3:17]
Reactant: CC[Zn]CC
Reactant: C=CCOCCc1ccc(OCC(O)CNC(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound of formula (1) (1 g, 0.003 mol) in dry toluene (5 ml), diethylzinc (1.1 M solution in toluene, 14 ml, 0.017 mol) was added at 0° C. under nitrogen atmosphere followed by diiodomethane (1.38 ml, 0.017 mol). The reaction was stirred for 16 h at 0° C. and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with toluene. The combined organic layer was washed with a solution of sodium thiosulphate, dried over anhydrous sodium sulphate, filtered and concentrated to yield racemic betaxolol of formula (2) 1.6 g (84%) mp 70 –72° C. as a white solid.