Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccccc2Cl)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Under argon, 500 mg (1.83 mmol) of dimethyl 5-bromoisophthalate together with 429 mg (2.75 mmol) of 2-chlorophenylboronic acid were dissolved in 8 ml of toluene, and 72 mg (0.18 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 84 mg (0.09 mmol) of tris(dibenzylideneacetone)dipalladium and 777 mg (3.66 mmol) of potassium phosphate were added successively. The mixture was heated to 110° C. and stirred at this temperature for 20 h. For work-up, the reaction mixture was allowed to cool to RT and diluted with 20 ml of ethyl acetate. The solid was filtered off with suction and the residue was washed three times with in each case 10 ml of ethyl acetate. The combined filtrates were washed twice with in each case 10 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically [Method 19]. This gave 305 mg (55% of theory) of the target compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([N:9]1[CH2:18][CH:17]3[CH2:19][CH2:20][CH2:21][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]1=[O:22])[CH2:2]2.Br>C(O)C>[CH:13]1[CH:12]=[C:11]2[C:10]([N:9]([C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)[CH2:18][C@H:17]3[CH2:19][CH2:20][CH2:21][C:15](=[C:16]23)[CH:14]=1)=[O:22]
Reactant: O=C1c2cccc3c2C(CCC3)CN1C1CN2CCC1CC2
Agent: Br
Solvent: CCO
Product: O=C1c2cccc3c2[C@H](CCC3)CN1[C@@H]1CN2CCC1CC2
Temperature: 10 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
2-(1-azabicyclo-[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one base (30.2 gram, 0.102 mol) was mixed with absolute ethanol (200 ml). The mixture was cooled to about 10° C. and 40% hydrobromic acid (HBr) was added dropwise (23 ml, 0.111 mol). The mixture was stirred at 10° C. for one hour, then concentrated in vacuo. The residue was diluted with ethanol (50 ml) and stirred at 10° C. for one hour. The resulting solid was filtered and dried under reduced pressure to afford 23.1 g of the hydrobromide salt of palonosetron (61% yield) having A/B isomer ratio of 77/22 and purity of 99.2% (as determined by HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([Cl:26])[CH:5]=[CH:4][C:3]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=[O:33].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([CH3:20])[CH:16]=[C:15]3[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([Cl:26])[CH:5]=[CH:4][C:3]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][OH:33]
Reactant: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C=O)c3Cl)c2n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4CO)c3Cl)c2n1
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To a solution of 1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]-2-formylpyrrole (23 mg) in methanol (0.5 ml) was added sodium borohydride (1.91 mg) udner ice-cooling, and the mixture was stirred for 2 hours. To the mixture was dropwise added aqueous solution of ammonium chloride under ice-cooling, and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo, and ethyl acetate and water were added thereto. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]-2-hydroxymethylpyrrole (11 mg) as amorphous powder.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[NH2:20][CH2:21][CH2:22][SH:23].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:23]1[CH2:22][CH2:21][NH:20][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCCS
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1NCCS1
Yield: 73.8 %

Procedure:
In 20 ml of methanol was dissolved 2.0 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 800 mg of 2-aminoethanethiol, 1.0 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.8 g of the titled compound as a colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-hydroxyindole in DCM (0.3 M) was added imidazole (2.0 eq). The mixture was cooled to 0° C. and treated with tert-butyldimethylsilyl chloride (1.0 eq). The resulting mixture was stirred at room temperature for 12 h, diluted with DCM, washed sequentially with H2O, 1N HCl (aq) and finally with brine. The combined organic fractions were dried over Na2SO4. The crude was purified by column chromatography on silica gel (Petroleum ether:Diethyl ether 90/10) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH:22]=[CH2:23].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]([S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: C=CCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CNCc1ccc(-n2cncn2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)Cc2ccc(-n3cncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 g (7.683 mmol) of (4-[1,2,4] triazol-1-yl-benzylamino)-acetic acid ethyl ester in 15 ml of dioxane and 15 ml of H 20, 2.3 g (9.22 mmol) of 4-but-3-enyloxy-benzenesulfonyl chloride and 1.3 ml (9.22 mmol) of triethyl amine are successively added at 0–5° C. After being stirred for 18 h at r.t., the reaction mixture is diluted with H 20 and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.17 (t, 3H, J=7.04 Hz), 2.55–2.65 (m, 2H), 3.95 (s, 2H), 4.07 (t, 2H, J=7.04 Hz), 4.09 (t, 2H, J=6.56 Hz), 4.53 (s, 2H), 5.10–5.25 (m, 2H), 5.85–5.95 (m, 1H), 6.99 (d, 2H, J=8.04 Hz), 7.44 (d, 2H, J=7.56 Hz), 7.64 (d, 2H, J=8.04 Hz), 7.82 (d, 2H, J=7.56 Hz), 8.11 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([OH:20])[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1.C1(C)C=CC=CC=1.O[CH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[C:32]([CH3:38])[CH:31]=1>O.C(OCC)(=O)C>[OH:20][C:12]1[CH:13]=[C:14]([CH3:19])[C:15]([CH3:18])=[CH:16][C:17]=1[CH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[C:32]([CH3:38])[CH:31]=1
Reactant: Cc1ccc(O)cc1C
Reactant: Cc1cc(CO)c(C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(Cc2cc(C)c(O)cc2C)cc1C
Temperature: 20 °C
Yield: 68.8 %

Procedure:
Into a 1 liter of four-necked flask were charged 1.90 g of para-toluene sulfonic acid, 24.43 g of 3,4-xylenol and 48.87 g of toluene. Further, keeping the temperature at 30° C., 7.61 g of 4-hydroxymethyl-2,5-dimethylphenol was added in ten portions over 1 hour. The mixture was stirred at the same temperature for 2 more hours. After completion of the reaction, 50 g of toluene and 50 g of ethyl acetate was added. Thereafter, 50 g of deionized water was added and the resulting mixture was stirred and a phase separation was carried out. Then, metal content was removed by adding 50 g of 1% aqueous oxalic acid solution, followed by stirring the mixture and by carrying out a phase separation. Thereafter, washing with 50 g of deionized water was repeated four times, and the oil phase was concentrated. To the concentrated mass, 100 g of toluene was added and the resulting solution was cooled to 20° C. and filtered. The filter cake was rinsed with 200 g of toluene and dissolved in 50 g of ethyl acetate. After adding 200 g of toluene thereto,the resulting mixture was concentrated. To the concentrated mass, 100 g of toluene was added and the resulting mass was cooled to 20° C. and filtered. The filter cake was rinsed with 100 g of toluene and dried a whole day and night under reduced pressure at 45 ° C. to obtain 8.82 g of 4-(2-hydroxy-4,5-dimethylbenzyl)-2,5-dimethylphenol.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C@H:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=[CH:25][N:26]=4)=[CH:18][CH:17]=3)=[C:9]2[N:8]=1)[CH2:4][OH:5].CCN(CC)CC>ClCCl.CS(C)=O.[Cl-].[Na+].O>[CH3:1][CH:2]([CH3:35])[C@H:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH:24]=[CH:25][N:26]=4)=[CH:20][CH:21]=3)=[C:9]2[N:8]=1)[CH:4]=[O:5]
Reactant: CC(C)[C@@H](CO)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](C=O)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of (S)-3-methyl-2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)butan-1-ol (0.41 g, 0.83 mmol) in dichloromethane (6 mL) was added Et3N (0.58 mL, 4.2 mmol) at −15° C. A solution of pyridine-sulfur trioxide complex (0.66 g, 4.2 mmol) in DMSO (6 mL) was added in one portion. After stirring at −15° C. for 30 minutes, the mixture was poured into cold brine solution and extracted with ether. The combined organic extracts were washed with brine, dried and concentrated. The residue was purified by column chromatography (5% MeOH in dichloromethane) to give (S)-3-methyl-2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)butanal (0.36 g, 88%). LCMS (APCI+) m/z 491 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[C:11]#[N:12].O.[NH2:19][NH2:20]>C(O)C>[NH2:12][C:11]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:13]([CH2:17][CH2:16][CH2:15][OH:14])[NH:19][N:20]=1
Reactant: N#CC(=C1CCCO1)c1nc2ccccc2s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c(CCCO)c1-c1nc2ccccc2s1
Yield: 59.1 %

Procedure:
The benzothiazol-2-yl-(dihydrofuran-2-ylidene)-acetonitrile (90 mg, 0.37 mmol) prepared above and hydrazine hydrate (25 mg, 0.5 mmol) were refluxed in ethanol (15 mL) for 10 hours. The solvent was evaporated and the resulting residue was triturated with dichloromethane. The solid was isolated by filtration and was then washed with dichloromethane and methanol to yield 60 mg (67%) of the title compound as a cream coloured solid. MS (m/z, ES+): 275.1 (M+1, 100). 1H NMR (300 MHz, ppm, DMSO-d6): δ (ppm), 11.5-12.2 (br s, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.77 (t, 2H), 7.29 (t, 1H), 7.00-5.20 (br m, 2H), 4.55 (s, 1H), 3.52 (q, 2H), 2.83 (br s, 2H), 1.84 (q, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:20][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:15]
Reactant: O=C(O)C1CCCN1Cc1ccccc1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(CNC(=O)C1CCCN1Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-Benzyl-pyrrolidine-2-carboxylic acid (474) (Belokon, Y. N. at al; Tetrahedron Asymmetry 1998, 9, 4249-4252) in CH2Cl2 (20 mL) was added 2,2-dimethoxy-ethylamine (614 mg, 5.84 mmol), EDCl (1.12 g, 5.84 mmol), HOBT (658 mg, 4.87 mmol), and NMM (1.08 mL, 9.8 mmol). The reaction mixture was stirred overnight at 25° C. Saturated aqueous NaHCO3 solution (50 mL) was added. The aqueous layer was extracted with CH2Cl2 (50 mL×3). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, and concentrated by rotary evaporator to give 1-benzyl-pyrrolidine-2-carboxylic acid (2,2-dimethoxy-ethyl)-amide as yellow oil. To 1-benzyl-pyrrolidine-2-carboxylic acid (2,2-dimethoxy-ethyl)-amide was added acetic acid (10 mL) and ammonium acetate (11 g). The reaction mixture was heated to 140° C. overnight. After it was cooled down, it was poured into 100 mL ice-water with stirring. Solid NaHCO3 was added in small portion with stirring to adjust the pH of the solution to 8-9. The aqueous solution was extracted with EtOAc (100 mL×2). The combined organic layers was washed with brine, dried over Na2SO4, and concentrated with rotary evaporator. Compound 475 (110 mg) was isolated by SiO2 chromatography (CH2Cl2/MeOH/NH3: 40:1:0.1 to 20:1:0.1). MS: m/z 228.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16](O)[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].P(Br)(Br)[Br:20].O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:20])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: CC(O)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(Br)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reaction time: 1 h

Procedure:
Forty (40) grams of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethanol were dissolved in 300 ml of carbon tetrachloride and then incorporated dropwise with 44.7 g of phosphorus tribromide at a temperature of -15° to -10° C., after which the whole was stirred at said temperature for 30 minutes, withdrawn from the ice bath and then further stirred for one hour. After the completion of the reaction, the reaction mixture was water washed, dried and then freed of the solvent at a reduced pressure to obtain a residue. The residue was adhered to a silica gel-packed column and then eluted with isopropyl ether-hexane (1/2), after which the eluate was freed of the solvent thereby to obtain 46.5 g of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethylbromide.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=2)[CH2:2]1.[ClH:16].[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1.O>CON[C@H](C(O)=O)CC1N=CNC=1.[OH-].[K+].CO>[ClH:16].[OH:1][CH:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH2:2][NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][CH:24]=1
Reactant: COCCc1ccc(OCC2CO2)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1
Agent: CON[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCc1ccc(OCC(O)CNCc2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
1,2-epoxy-3-[4-(2-methoxyethyl)phenoxy]propane (63.7 mmol) in 15 mL of MeOHis added dropwise to a solution of N-[4-(aminomethyl)phenyl]methanesulfonamide hydrochloride (62.4 mmol) in 1M KOH in MeOH (65 mL) at room temperature. H2O (5 mL) is added ad the mixture is refluxed overnight. Methanol is removed from the cooled mixture under reduced pressure, and the residue is partitioned between H2O and CH2Cl2, and the combined organic portions are washed with brine and dried with anhydrous Na2SO4. After removal of the solvent under reduced pressure the hydrochloride salt is formed and recrystallized with CH3CN/MeOH to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]#[CH:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]#[CH:26])[C:17]([OH:19])=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: C#CCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: C#CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
288 mg (0.7 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 295 mg (purity 85%, quant.)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.N1C=CC=CC=1.[OH-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.8 g (40 mmol) of 2-bromofluorene, 40 mL of pyridine, and 1.5 mL of tetrabutylammonium hydroxide (1.0 mol/1 methanol solution) were put into a 200 mL three-neck flask. This solution was stirred under air at room temperature for 24 hours. After completion of a reaction, 40 m/L of glacial acetic acid was added to the reaction solution and stirred for 1 hour. Then, the reaction solution was washed with water and a water layer was extracted with ethyl acetate. The extracted solution and an organic layer were combined and washed with saturated saline, and then dried with magnesium sulfate. After drying, this mixture was subjected to suction filtration, and a filtrate was concentrated. When an obtained solid was recrystallized with ethanol, 7.9 g of a yellow, powdery solid of 2-bromo-9-fluorenone that was a target matter was obtained with the yield of 76%.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([O:20][CH3:21])[CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[C:13]([O:20][CH3:21])[CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ncccc1C#N
Yield: 85 %

Procedure:
Prepared in 85% yield from 2-chloronicotinonitrile and 4-fluoro-2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 6.75-6.84 (m, 2H), 7.37 (dd, J=8.0, 4.9 Hz, 1H), 7.44 (dd, J=8.5, 6.8 Hz, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H), 8.86 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:10][C:9]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][O:40]C2CCCCO2)=[CH:32][CH:31]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:10][C:9]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:31]=1
Reactant: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCOC4CCCCO4)cc3)c(-c3ccccc3Cl)s2)CC1
Agent: Cl
Solvent: CO
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCO)cc3)c(-c3ccccc3Cl)s2)CC1
Reaction time: 2 h

Procedure:
0.45 g of the compound obtained in stage 23H) and 2 ml of 2N ethereal hydrochloric acid are added to 10 ml of methanol. After 2 hours at AT, the expected compound is filtered off 0.26 g of the expected compound is obtained.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[O:2].[Cl:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[F:22]>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:1]([OH:2])[C@H:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Fc1ccc([Mg]Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)c2ccc(F)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate (67)(367.3 mg, 1.843 mmol) in THF (9.2 mL, 0.2 M) under nitrogen atmosphere cooled to 0° C. and degassed with N2 was added dropwise a THF solution of (3-chloro-4-fluorophenyl)magnesium bromide (4056 μL, 2.028 mmol) and the solution stirred at 0° C. for 3 h. The reaction was then quenched by addition of water (3 mL) THF was removed by rotovap, and the mixture was extracted with EtOAc (2×30 mL). The combined organics were washed with water (2×30 mL) and brine (1×30 mL). The organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by chromatography eluting a DCM/acetone gradient (2 to 45% acetone) to afford 364 mg (60%) of 69a/69b as an approximate 1:1 mixture of diastereomers as a clear oil which was used without additional purification.