Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[CH2:12][CH2:11][N:10](C(O)=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][N:6]=[C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=C1CCN(C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)ON=C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 34 ml of dichloromethane containing 0.9 g of tert-butyl ester of 4-tert-butoxyimino-piperidine-1-carboxylic acid is cooled to 0° C. 25 ml of a 4M solution of hydrochloric acid in dioxane (30 eq) is added. The reaction mixture is stirred at room temperature for 3 hours and then diluted by adding dichloromethane. A saturated solution of sodium hydrogen carbonate is then added until pH=8 is obtained. The aqueous phase is extracted three times with dichloromethane. The organic phases are then combined, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. 0.49 g of piperidin-4-one O-tert-butyl-oxime is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](Br)[CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:4][CH:3]=1.[C-:18]#[N:19].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[C:18]#[N:19])=[CH:11][CH:10]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(Br)c1ccc(C(=O)c2ccc(Cl)s2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C#N)c1ccc(C(=O)c2ccc(Cl)s2)cc1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A mixture of 9.9 parts of α-bromo-α-methyl-p-tolyl 5-chloro-2-thienyl ketone, 1.96 parts of sodium cyanide, 12 parts of water and 48 parts of dioxane is stirred for 17 hours while heating at 90° C. The reaction mixture is evaporated and 36 parts of water are added to the residue. The product is extracted with ether. The extract is dried and evaporated. The residue is purified by column-chromatography over silica gel, using chloroform as eluent. The pure fraction is collected and the eluent is evaporated. The residue is triturated in n-hexane, yielding p-(5-chloro-2-thenoyl)hydratroponitrile; mp. 90° C.
Reaction SMILES: C[Si](Cl)(C)C.Cl[C:7]([F:18])([F:17])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9].[I:19]I.O>C(#N)C.[Zn]>[F:17][C:7]([F:18])([I:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: II
Reactant: Cc1ccccc1C(=O)C(F)(F)Cl
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1C(=O)C(F)(F)I
Temperature: 55 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were added trimethylsilyl chloride (3.1 mL) and 2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone (4.0 g), and the mixture was stirred at 55° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, iodine (3.5 g) was added, and the mixture was further stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a yellow oil (yield 2.6 g, 46%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:23])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 39) (273 mg, 0.70 mmol) and N-methylmorpholine (85 μl, 0.77 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (100 μl, 0.77 mmol) and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (250 μl, 2.10 mmol) was then added and the mixture stirred under a nitrogen atmosphere for 1 hour, being allowed to warm to room temperature over this time. The mixture was then quenched with methanol (10 ml) and stirred for 10 minutes. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCa to afford the title compound as a colourless oil (187 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH2:29][C:30]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:29][C:30]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31]1
Reactant: COC(=O)C1(N)CC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1(NCc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (98.0 mg, 0.262 mmol) and methyl 1-aminocyclopropanecarboxylate hydrochloride (40 mg, 0.262 mmol) according to Reference R and the general procedure for reductive amination to give methyl 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)benzylamino)-cyclopropanecarboxylate as a tan solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc2ncccc2c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 6-aminoquinoline gave 2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.02 (dd, 1H, J=2.7 Hz), 8.00 (dd, 1H, J=2.4 Hz), 7.73 (d, 1H, J=9 Hz), 7.68 (dd, 1H, J=2.4 and 8.7 Hz), 7.28 (t, 1H, J=10.5 Hz), 6.42 (d, 1H, J=9.3 Hz); 19F NMR (CDCl3): −44344; LCMS: purity: 91%; MS (m/e): 292 (M+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
5-Trimethylsilanylethynyl-1H-pyrrolo[2,3-b]pyridine (26, 0.235 g, 1.10 mmol) was dissolved in 16 mL of methanol, and potassium carbonate (0.0152 g, 0.110 mmol) was added. The reaction was stirred for 2 hours at room temperature, then concentrated under vacuum, and the residue was dissolve in dichloromethane, dried over sodium sulfate. Solids were filtered out and the filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography, eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a solid (27, 0.155 g). MS (ESI) [M+H+]+=143.3.
Reaction SMILES: CO.[NH:3]1[CH:7]=[C:6]([CH:8]=O)[N:5]=[CH:4]1.[CH2:10]([NH2:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>Cl.[Pd].C(OCC)(=O)C>[CH2:10]([NH:20][CH2:8][C:6]1[N:5]=[CH:4][NH:3][CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1c[nH]cn1
Reactant: CCCCCCCCCCN
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCNCc1c[nH]cn1
Reaction time: 8 h

Procedure:
A 500 mL flask under a nitrogen atmosphere was charged with anhydrous methanol (150 mL), imidazole-4-carboxaldehyde (45.82 grams, 476 mmol) and decylamine (74.99 grams, 476 mmol) with stirring. Several drops of concentrated hydrochloric acid were added to the mixture and the mixture was allowed to reflux overnight under nitrogen. The mixture was taken up into ethyl acetate, washed with water and brine, dried with sodium sulfate, and evaporated to dryness. The crude product was dissolved in a 4:1 ratio of anhydrous THF and anhydrous MeOH and transferred to a hydrogenation reaction flask. To this solution was added 5 wt. % Pd/C (5 wt. %) and the resulting mixture was hydrogenated overnight at 30 psi H2. After hydrogenation was complete, the solution was filtered through Celite under vacuum to remove the Pd/C and the filtrate was evaporated to dryness. 1H NMR (CDCl3) δ 7.5-7.6 (1H), 6.8-6.9 (1H), 3.6-3.8 (2H), 2.6 (t, 2H), 1.5 (t, 2H), 1.2-1.4 (m, 14H), 0.8-0.9 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH:15](C#N)[C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH:27]([CH3:29])[CH3:28])=[C:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=[O:44])C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])=[O:44])[C:12]([CH:27]([CH3:29])[CH3:28])=[C:11]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C#N)cc(C(C#N)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C(=O)c2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 3-((2,6-bis(benzyloxy)-5-isopropylpyrimidin-4-yl)(cyano)methyl)-5-methylbenzonitrile (53.46 g, 0.0195 M) in anhydrous DMF (400 mL) in a water bath under nitrogen atmosphere, was added 60% sodium hydride (4.87 g, 0.1205 M) portionwise. After 30 min., oxygen gas was bubbled into the reaction mixture using oxygen balloon. After 3 hr., sat. aqueous ammonium chloride solution was added and the product was extracted with ether. Ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a light yellow solid. The crude product was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:9)) to afford 45.7 g (88%) of 3-(2,6-bis(benzyloxy)-5-isopropylpyrimidine-4-carbonyl)-5-methylbenzonitrile as a light yellow solid. m.p. 129-130° C. 1H NMR (300 MHz, CDCl3) δ 1.20 (3H, d, J=7.0 Hz), 1.22 (3H, d, J=7.0 Hz), 2.43 (3H, s), 2.84 (1H, m), 5.34 (2H, s), 5.51 (2H, s), 7.29-7.46 (10H, m), 7.66 (1H, s), 7.83 (1H, s), 7.90 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To 40 ml of tetrahydrofuran were dissolved 1.8 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate, 1.74 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.92 g of triphenylphosphine. At room temperature, 1.94 g of diethyl azodicarboxylate was added to the above solution, and the resulting mixture was stirred for 18 hours. After distilling off the solvent, the residue thus obtained was dissolved in ethyl acetate, and the solution was washed with water, and then dried. Thereafter, the solvent was distilled-off, and the resulting residue was purified by silica gel column chromatography using a toluene/chloroform mixture as an eluant, thereby obtaining 2.53 g of the title compound as a viscous yellow oil.
Reaction SMILES: [Na+:1].[NH:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O-:11])=[O:10])=[N:3]1.[F:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1.[N-]=C=O.O>CN(C=O)C>[Na+:1].[F:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([N:2]2[CH:6]=[CH:5][C:4]([C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([O-:11])=[O:10])=[N:3]2)=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: O=C([O-])c1cccnc1-c1cc[nH]n1
Agent: [N-]=C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C([O-])c1cccnc1-c1ccn(C(=O)Nc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 g (4.5 mM) of 2-(pyrazol-3-yl)-nicotinic acid sodium salt are stirred in 20 ml of DMF and 0.7 g (4.5 mM) of 3,5-difluorophenyl isocyanate added. After stirring for 1 hr at RT, a further 0.21 g of isocyanate in DMF are added. The DMF is stripped-off on a Kugelrohr and the resulting solid stirred with 4 ml water and filtered. The filtrate is chromatographed on a reverse phase column with 100 ml of water followed by 100 ml water-methanol. The product containing fraction was lypholized to yield the title product m.p. 165°-170° C.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16](OC)=[O:17])[N:10]=[CH:9]2)#[N:2].[BH4-].[Na+]>CO>[F:24][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[C:3]([CH:23]=1)[C:1]#[N:2]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate 77 (prepared as in Example 3) (60.0 g, 184.4 mmol) in MeOH (370 mL) was added NaBH4 (24.42 g) in five 5 gram portions over 90 minutes. The temperature rose from 25° C. to 44.7° C. at the final addition of NaBH4. The mixture was concentrated under vacuum. To the concentrate was added saturated NH4Cl (600 mL) and EtOAc (600 mL) and the mixture was vigorously stirred for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were washed with saturated NH4Cl (2×100 mL), water (200 mL), brine (500 mL), dried over MgSO4, filtered thru GF/F paper and concentrated to a bright orange solid. The crude solid was dissolved in CH2Cl2 (1 L) and hexanes (2.25 L) were added with stirring. A light brown solid formed and after stirring for 30 min the solid was collected and dried under high vacuum to yield 45.5 g. The filtrate was concentrated under reduced pressure. This material was redissolved in CH2Cl2 (100 mL) and hexanes were added (200 mL). The resulting solid (6.2 g) was collected via filtration. The two crops were combined to give 51.7 g (94.3%) of 78A. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.49 (d, 1H), 7.39-7.36 (m, 2H), 7.21-7.16 (m, 2H), 6.90 (dd, 1H), 4.49 (t, 2H), 4.17-4.13 (m, 2H), 2.81 (t, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:24])([CH3:23])[C:9]([NH:11][NH:12][C:13](=[S:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:4][C:3]=1[O:25][CH3:26].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13]([SH:22])=[N:12][N:11]=2)([CH3:24])[CH3:23])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(C)(C)c2nnc(S)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 5 °C
Yield: 99.2 %

Procedure:
A solution of 2-(2-(4-chloro-3-methoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)-hydrazine carbothioamide (8.13 g, 0.02 mol) in 3N NaOH (270 mL) was heated at reflux 4 h with mechanical stirring. The reaction mixture was cooled to 5° C. and acidified with 5N HCl to pH=4. The resulting whited solids were collected by filtration, washed with diethyl ether and dried to give 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (7.5 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.21 (d, 1H), 6.95-6.91 (t, 2H), 6.54 (d, 1H), 6.52-6.49 (dd, 1H), 6.45-6.41 (m, 2H), 3.67 (s, 3H), 1.45 (s, 6H).
Reaction SMILES: C[O:2][CH:3]1[O:7][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4]1>CO>[OH:2][CH:3]1[O:7][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4]1
Reactant: COC(=O)[C@H]1CCC(OC)O1
Solvent: CO
Product: COC(=O)[C@H]1CCC(O)O1

Procedure:
Methyl (2R)-Tetrahydro-5-hydroxy-2-furoate was prepared as for the S-isomer from methyl (2R)-tetrahydro-5-methoxy-2-furoate in similar yield: [α]D25 -9.2° (c=1.8, CH3OH); IR (neat, cm-1) 3543 (br), 2956, 1741, 1068, 1010; 1H NMR (CDCL3) for diastereomer A (58%) δ 5.62 (m, 1H), 4.67 (dd, J=6.5, 8.1 Hz, 1H), 3.78 (s, 3H), 2.46-1.93 (m, 4H); for diastereomer B (42%) δ 5.75 (m, 1H), 4.73 (dd, J=3.8, 8.5 Hz, 1H), 3.76 (s, 3H), 2.46-1.93 (m, 4H); HRMS calculated for C6H10O4 (M+), 146.0579, found 146.0577.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([CH3:13])=[CH:12][C:7]=1[CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c(Br)c(=O)n1Cc1cccnc1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CCc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a degassed solution of 3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl2(PPh3)2 (0.11 g) were added. The reaction mixture stirred at room temperature under nitrogen for 1 hour and then heated in an oil bath (65° C.) under nitrogen overnight. The solvents were distilled in vacuo and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). The extracts were concentrated to afford the desired compound (0.432 g, 69%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J=8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z 397.0361/399.0310 (M+H calculated for C20H15N2OFBr requires 397.0346/399.0328). Step 3. Preparation of 3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:18]1([C:2]2[CH:3]=[C:4]3[CH2:10][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: CCO
Product: c1ccc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)cc1
Yield: 68.5 %

Procedure:
Under a nitrogen atmosphere, 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (118 mg, 0.4 mmol), phenylboronic acid (54 mg, 0.443 mmol), and tetrakis(triphenylphosphine)palladium(0) (11 mg, 2.3 mol %) were stirred in a solution of 1,2-dimethoxyethane (3 mL) and ethanol (0.75 mL) containing 2M aqueous sodium carbonate (0.65 mL, 1.3 mmol). The mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in chloroform (15 mL), and the extract was washed with saturated aqueous sodium carbonate (5 mL). The aqueous layer was extracted with chloroform (2×15 mL), and the organic layers were combined, dried (MgSO4), filtered, and evaporated under reduced pressure. Purification by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (95:5 to 9:1), provided the title compound (80 mg, 0.274 mmol, 68%) as a tan solid: electrospray MS 293 ([MH]+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[Br:19]Br>C(O)(=O)C.Br>[Br:19][CH:9]([C:10]1[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:18]
Reactant: CSc1ccc(CC(=O)c2ccccc2C)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the ketone from Step 2 (5.92 g, 23.1 mmol) in acetic acid (50 mL) and 33% HBr in acetic acid (2 mL) was treated with a 1.1M solution of bromine in acetic acid (21.7 mL, 23.8 mmol) and stirred at room temperature for 2 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with 1N NaHSO3 and sat. aq. NaHCO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid which was used directly in the next step without further purification (5.97 g, 77%): mp 85°-89° C. 1H NMR (CDCl3) 300 MHz 7.56 (d, J=7.9 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.22 (m, 4H), 6.18 (s, 1H), 2.47 (s, 3H), 2.44 (s, 3H). Mass spectrum M+H=341.