Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([Cl:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][C:3]2[C:12]3[C:7](=[C:8]([Cl:13])[CH:9]=[CH:10][CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1cccc2c(CBr)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccnc3c(Cl)cccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
4-Bromomethyl-8-chloroquinoline (0.8 g, 3.11 mmol) was dissolved with stirring in dry THF (10 mls) and sodium hydride (0.15 g, 60% dispersion in mineral oil, 6.23 mmol) added. The mixture was stirred at room temperature for 15 minutes and 4-fluorophenol (0.52 g, 3.11 mmol) added. The mixture was stirred at room temperature overnight and worked up to provide the product (0.46 g, 51.2%) as a white solid, mp 144-5° C.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:37](=[O:49])[CH2:38][O:39][CH2:40][C:41]2[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[CH:42]=2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20](C(OCC4C=CC=CC=4)=O)[CH2:19]3)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[Cl:9].CCOCC>C(O)(=O)C>[Cl:48][C:43]1[CH:42]=[C:41]([CH2:40][O:39][CH2:38][C:37](=[O:49])[CH:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][C:16]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19]3)[CH2:17][CH2:18]2)[CH:46]=[C:45]([Cl:47])[CH:44]=1
Reactant: O=C(COCc1cc(Cl)cc(Cl)c1)C(CCN1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12)c1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(COCc1cc(Cl)cc(Cl)c1)C(CCN1CCC2(CC1)CNc1ccccc12)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add a solution of HBr (gas) in acetic acid (3.0 ml) to phenylmethyl 1'-[3-(3,4-dichlorophenyl)-5-[(3,5-dichlorophenyl)methoxy]-4-oxopentyl]-1,2-dihydro-spiro[3H-indole-3,4'-piperidine]-1-carboxylate [0.250 g, 0.34 mmoles) dissolved in glacial acetic acid (2.0 ml). Stir the solution at room temperature for 4 h, then add Et2O (30 ml). Decant the liquid and wash the resultant solid with Et2O. Suspend the solid in water (10 ml) and add 1.0M aqueous KOH (5.0 ml). Extract the mixture with Et2O (3×30 ml), combine the extracts, wash with water and dry (Na2SO4). Remove the solvent and purify the reaction mixture by preparative thin layer chromatography (SiO2), eluting the plates twice with ETOAc:hexanes:CH3OH(NH3) (15:85:3). Extract the desired product with 5% CH3OH(NH3)/EtOAc. Yield: 57 mg.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[Br:22]>>[Br:22][C:17]1[C:18]([CH3:21])=[N:19][O:20][C:16]=1[NH:15][S:2]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CCCC#Cc1ccc(S(=O)(=O)Cl)s1
Reactant: Cc1noc(N)c1Br
Product: CCCC#Cc1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1
Yield: 87.6 %

Procedure:
N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(1-pentynyl)thiophene (55 mg. 0.22 mmol) with 5-amino-4-bromo-3-methylisoxazole (43 mg, 0.22 mmol) yielded 75 mg of N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide (87% yield). A portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a light brown oil.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[F:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH2:12].C(C(Br)C1C=CC=C(OC2C=CC=CC=2)C=1)#C>>[F:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH:12][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(Br)C(=O)O
Reactant: Cc1ccc(N)c(F)c1
Agent: C#CC(Br)c1cccc(Oc2ccccc2)c1
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)c(F)c1

Procedure:
N-(2-fluoro-4-methylphenyl)valine is prepared from α-bromoisovaleric acid and 2-fluoro-4-methylaniline and then reacted with α-ethynyl-m-phenoxybenzyl bromide to yield the α-ethynyl-m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)valine, MS m/e 431 (M+, 180).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccccc1COc1cccnc1N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.19 g, 0.0056 mol), 4-chlorophenyl isothiocyanate (1.15 g, 0.0068 mol) and toluene (10 ml) was refluxed for 2.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 1.63 g (77%), m.p. 181°-183 ° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[S:10][CH:9]=1
Reactant: NCCCc1nc(Cl)nc2ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: NCCCc1nc(Cl)nc2c(Br)csc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.6 %

Procedure:
8.34 g (36.63 mmol) of (2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (IV) is dissolved in 60 mL of acetonitrile and 7.89 g (44.32 mmol) of N-bromosuccinimide is added. The reaction mixture is stirred for 16 hours at ambient temperature and for 6 hours at 50° C. Then it is concentrated by evaporation and the residue is combined with water. The precipitate formed is suction filtered, washed, and dried. 7.25 g of product V (61%) is obtained as a powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC1C=CC(OC)=CC=1)[C:5]2([CH3:22])[CH3:21].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)c3ccc(F)cc3C2(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a stirred solution of 5-fluoro-2-(4-methoxy-benzyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (3.8 g, 12.7 mmol) in MeCN (80 ml) and H2O (40 mL) was added CAN (20.9 g, 38.1 mmol) at 0° C. After stirring for 2 hours at 0° C., the reaction mixture was diluted with EtOAc and washed with brine. The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to provide a crude product, which was purified by column chromatography to give tile product (1.03 g, yield 45%) as a solid.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(Br)C#C>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:3]([C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:1]#[CH:2]
Reactant: COC(=O)C1CCCCC1
Reactant: CC(C)NC(C)C
Agent: C#CCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCC1(C(=O)OC)CCCCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
To a solution of diisopropylamine (879 μL, 6.22 mmol) in anhydrous tetrahydrofuran (12 mL) at −40° C. under nitrogen was added 1.6 M n-butyl lithium in hexane (3.9 mL, 6.22 mmol), followed by hexamethylphosphoramide (4 mL). The mixture was cooled down to −78° C. and added a solution of methyl cyclohexanecarboxylate (80 7 μL, 5.65 mmol) tetrahydrofuran (4 mL) with the temperature maintained below −70° C. throughout the addition. After 15 min, propargyl bromide (80% w/w in xylene, 2.5 mL, 22.6 mmol) was added, and the reaction mixture was allowed to warm to room temperature. After 30 min, it was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with water (×4), dried over MgSO4, filtered and concentrated to get 900 mg the title intermediate as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:15])[CH3:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid t-butyl ester (2.05 g, 8.43 mmol) in dry tetrahydrofuran (25 mL) was added 1.4M methyl magnesium bromide in diethyl ether (6.02 mL) at −78° C. The mixture was stirred at −78° C. for 30 min and then warmed to −5° C. The mixture was extracted with diethyl ether and ammonium chloride solution. The organic layer was dried and concentrated. The crude mixture was purified by ISCO flash chromatography (0 to 60% ethyl acetate/hexanes) to give two fractions. The first fraction afforded (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester as a colorless oil (870 mg): 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (d, J=6.0 Hz, 3H), 1.42-1.60 (m, 1H), 1.50 (s, 12H), 1.55 (s, 3H), 1.68-1.88 (m, 1H), 3.66 (d, J=8.8 Hz, 1H), 3.69-3.80 (m, 1H), 3.94-4.08 (m, 1H), 4.17-4.30 (m, 1H), 4.62 (br. s., 1H); The second fraction afforded (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester as a white solid (740 mg): 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (d, J=6.0 Hz, 3H), 1.49 (s, 12H), 1.58 (br. s., 3H), 1.75-1.90 (m, 2H), 2.56 (br. s., 1H), 3.75-3.93 (m, 2H), 3.95-4.05 (m, 1H), 4.03-4.20 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13](O)=O>>[NH2:9][C:10]1[CH:11]=[C:12]([C:13]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: Nc1ccccc1O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-aminophenol (720 mg, 7.0 mmol) and 3-amino-4-methylbenzoic acid (1.00 g, 7.0 mmol) the subtitle compound was obtained, 942 mg (57%). 1H NMR (DMSO) δ 7.67(m, 2H), 7.42(s, 1H), 7.31(m, 2H), 7.24(d, 1H), 7.07(d, 1H), 2.43(s, 3H). MS 225 m/z (M+H)+.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI.C(OC(C)C)(=O)C>O.CN(C)C=O>[CH3:29][O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) prepared according to Example 2 in WO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Methyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×10 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me). 1H NMR (CDCl3): 1.18 (3H), 1.41 (9H), 1.51 (1H), 1.95 (1H), 2.66 (1H), 2.85 (2H), 3.70 (3H), 3.94 (1H), 4.36 (1H), 7.25 (2H), 7.35 (1H), 7.45 (2H), 7.53 (2H), 7.59 (2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](N(OC)C)=[O:17])[N:6]=1)([CH3:4])[CH3:3].[CH2:22]([Mg]Br)[CH3:23]>O1CCCC1.C(OCC)C>[CH3:13][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([C:16](=[O:17])[CH2:22][CH3:23])[N:8]=1)([CH3:14])[CH3:15]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reaction time: 2 h

Procedure:
A solution of 8.4 g (28 mmol) of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide in 150 mL of tetrahydrofuran was cooled in ice and treated dropwise with 40 mL (120 mmol) of a 3.0M solution of ethylmagnesium bromide in diethyl ether. The mixture was stirred in ice for 2 hours, then at room temperature for an additional 16 hours. The reaction mixture was again cooled in ice, and excess Grignard reagent was destroyed by dropwise addition of 50 mL of saturated aqueous ammonium chloride solution. The reaction mixture was added to 400 mL of ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous sodium sulfate), and evaporated. Recrystallization of the residue from hexane yielded 5.0 g (67%) of the ethyl ketone product, mp 123° C.-125° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)(=[O:5])[CH3:4]>CO>[OH:5][CH:3]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)[CH3:4]
Reactant: CC(=O)c1ccc(C)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(C)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Add sodium borohydride (270 mg, 7.13 mmol) to a solution of 2-acetyl-5-methylthiophene (1.0 g, 7.13 mmol) in methanol (40 mL). Stir the mixture for 1 h at room temperature. Remove the solvent in vacuo and partition the residue between water and DCM. Separate the organic phase, dry over Na2SO4, filter and concentrate to obtain the desired intermediate as an oil (0.995 g, 98%) that was used without further purification. GC-MS m/z 142 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:19]#[C:20][Si](C)(C)C.[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[C:19]#[CH:20]
Reactant: CCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)c(F)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1ccc(C#Cc2ccc(CCC)cc2)cc1F
Yield: 98.8 %

Procedure:
22 mmol of 1-[2-fluoro-4-[2-(4-propylphenyl)-ethynyl]phenyl]-2-trimethylsilylacetylene and 10 g of potassium hydroxide were dissolved in 100 ml of ethanol and 10 ml of water, and the solution was stirred at 40° C. for 6 hours. After completion of the agitation, the reaction solution was poured into dilute hydrochloric acid and extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown oily product. This product was isolated and purified by a silica gel column chromatography to afford 5.7 g of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]phenyl acetylene as a colourless solid.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:20][C:19]([S:36][CH3:37])=[N:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[N:18]=[C:19]([S:36][CH3:37])[N:20]=2)=[CH:27][CH:28]=1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
1-Chloroethyl chloroformate (572 mg, 4 mmol) was added dropwise to the solution of 7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (860 mg, 2 mmol) and diisopropylethyl amine (516 mg, 4 mmol) in 1,2-dichloroethane (5 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed by sodium bicarbonate's aqueous solution, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated by diethyl ether to yield the product as a beige solid (454 mg, 67%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)CCC.[NH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH:42][CH2:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[CH2:2][CH2:7][CH3:6]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CCCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 33 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-butyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 33% yield: mp 109-111° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55-8.45 (m, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.24-7.19 (m, 1H), 6.45 (br s, 1H), 4.52 (d, J=5.8 Hz, 2H), 4.05-4.00 (m, 2H), 3.55-3.49 (m, 2H), 3.31-3.18 (m, 2H), 2.55 (s, 3H), 1.53-1.20 (m, 4H), 0.88 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.4, 153.6, 149.2, 148.8, 135.5, 134.0, 123.6, 116.6, 43.5, 42.1, 42.0, 41.3, 29.3, 19.8, 17.2, 13.6; MS (ES+) m/z 374.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1ccnc(O)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2c(F)cccc2F)c1
Yield: 61.7 %

Procedure:
A mixture of 5.00 g (24.2 mmol, 1.0 eq.) of 2,6-difluorobenzyl bromide [CAS No: 85118-00-9] and 3.16 g (29.0 mmol, 1.2 eq.) of 2-hydroxy-4-methylpyridine [CAS No: 13466-41-6] was dissolved in 50 ml of THF. The solution was admixed with 7.99 g (29.0 mmol, 1.2 eq.) of silver carbonate and the mixture was heated to reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr and eluted with ethyl acetate, and the filtrate was concentrated. The crude product was purified by means of Biotage Isolera (100 g silica gel cartridge, cyclohexane/ethyl acetate gradient, 0% to 10% ethyl acetate). 3.51 g of the title compound were obtained (61% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-1-Benzyl-4-methyl-3-pyrrolidinecarboxylic acid (4.04 g) was dissolved in dichloromethane (50 mL). To this solution, 1,1′-carbonylbis-1H-imidazole (3.58 g) was added and the mixture was stirred at room temperature for 1 hour. While the reaction mixture was cooled on an ice bath, a dichloromethane solution (15 mL) of cyclopropylamine (1.53 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was washed with water, was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The resulting residue was crystallized in a hexane/diisopropyl ether mixture and the formed crystal was filtrated. The collected crystal was then washed with a hexane/diisopropyl ether mixture and was dried under reduced pressure to obtain 4.07 g of trans-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide as a white crystal.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]4)=[N:6][CH:7]=3)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O[C@@H]1CCN(c2ccc(I)cn2)C1
Product: O[C@@H]1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1

Procedure:
Prepared according to general working method I from (R)-1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-ol (1.30 g, 4.48 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (957 mg, 4.48 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[CH3:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[CH2:1][CH3:2])[CH2:10][CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCc1ccccc1OC(CC)C(=O)O
Product: CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 121.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 416 mg of (2RS)-2-(2-ethylphenoxy)butyric acid and 551 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 900 mg of the title compound as a colorless foam.