Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH3-]C#N.[Na+].[CH2:5]([O:7][C:8](=[O:22])[C:9](=[CH:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.Cl>C(O)C>[CH2:5]([O:7][C:8](=[O:22])[CH:9]([CH2:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6]
Reactant: CCOC(=O)C(=Cc1cnc(N)s1)C(=O)OCC
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Product: CCOC(=O)C(Cc1cnc(N)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
NaCNBH3 (1.88 g; 29.9 mmol) was added to a stirred solution of 2-(2-amino-thiazol-5-ylmethylene)-malonic acid diethyl ester (1.13 g; 4.2 mmol) in ethanol at 0° C. The pH of the solution was monitored by addition of a small amount of Bromocresol Green to the solution. Concentrated HCl was added dropwise until the solution turned yellow. The ice bath was removed, and the reaction mixture was stirred at room temperature for 5 hours. Water was added and the product was extracted with CH2Cl2. The combined organic phases were dried and concentrated to yield 2-(2-amino-thiazol-5-ylmethyl)-malonic acid diethyl ester (1 g, 87.8%).
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.FC(F)(F)S(O[C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([O:30][CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=2)(=O)=O>C1COCC1.C(Cl)(Cl)Cl.[Cl-].[Cl-].[Zn+2].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>[CH:1]1([C:7]#[C:8][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([O:30][CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Reactant: C#CC1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2cc(C#CC3CCCCC3)cnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This reaction is carded out under anhydrous conditions. Cyclohexylacetylene (700 mg; 6.47 mmol) in 10 mL. THF is cooled to 0° C. To this is added 2.5M n-BuLi (3.0 mL; 7.44 mmol) and stirred for 30 min. at 0° C. under N2 atm and then 1.0M ZnCl2 (7.4 mL; 7.44 mmol). This is allowed to warm to room temperature and stirred for 3/4 hour. The reaction mixture is transferred via cannula to a flask containing 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate (500 mg; 1.48 retool) and Pd(PPh3)4 (83 mg; 0.074 mmol) in 4 mL of THF. This is then heated to 50° C. under N2 for 41/2 hours. The reaction mixture is then poured into 90 mL of 10% NH40OH, diluted with CHCl3 and stirred for 20 min. The aqueous layer is separated, and the organic layer washed with brine, dried over MgSO4, filtered, evaporated and chromatographed with 4:1 hexane: EtOAc to obtain 3-cyclohexylethynyl-6,7-dimethoxyquinoline, which is recrystallized from hexane, identified by NMR and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[I:18]Cl.BrC1C=C(C(O)=O)C=C2C=1OC(C)(C)CC2(C)C>CC(O)=O>[I:18][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13]
Reactant: ClI
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Agent: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(I)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of 2,2,4,4-tetramethyl-6-chromanoic acid (66 mg, 0.28 mmol) in 0.8 ml of AcOH was added ICl (0.07 ml, 1.4 mmol). The resulting colored solution was stirred at room temperature for overnight. Following the same procedure as for the synthesis of 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid (Compound P), the reaction gave the title compound (107 mg) as white solids.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CCO.C(OCC)C>[OH:2]/[N:1]=[C:15](\[C:16]#[N:17])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CCON=O
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: N#C/C(=N\O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A solution of isopentyl nitrite (16.00 g, 137 mmol) in EtOH (30 mL) was added dropwise to a solution of 2-phenylacetonitrile (16 g, 137 mmol) and sodium hydroxide (5.46 g, 137 mmol) while cooling in an ice bath. Once the addition was complete, the mixture was allowed to warm to room temperature. After stirring at room temperature for 2 h, the reaction was diluted with diethyl ether. The resultant precipitate was filtered and washed with diethyl ether. The solid was air dried and then vacuum dried to yield the titled compound (10 g, 68.9 mmol, 50.4% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:29]>ClCCl.O>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([F:29])=[O:6]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a stirred mixture of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (12 g, 30.5 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, in dichloromethane (70 mL) at 0° C. was added pyridine (2.5 mL, 30.8 mmol) followed by dropwise addition of cyanuric fluoride (2.8 mL, 33.6 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane (100 mL). The aqueous layer was extracted once with dichloromethane (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product as a brownish solid. Crude product was purified by flash chromatography (plug, 25% ethyl acetate in hexanes) to afford 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride as a beige solid (11.8 g, 97% yield). 1H NMR (400 MHz, CD3OD): 8.41 (s, 1H), 7.80-7.81 (m, 1H), 7.52 (dd, 1H), 7.43-7.47 (m, 1H), 6.96-7.03 (m, 1H), 6.85-6.92 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:5]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(Cl)n1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: C[C@H]1COCCN1c1nc(Cl)nc(-c2ccccc2S(C)(=O)=O)n1
Temperature: 60 °C

Procedure:
A mixture of (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine (1.25 g, 5.0 mmol), 2-methylsulfonylphenyl boronic acid (1.1 g, 5.5 mmol), sodium carbonate (1.6 g, 15.0 mmol) and bis(triphenylphosphene)palladium(II) dichloride (205 mg, 0.25 mmol) in DME/H2O/ (4:1, 10 mL) was heated in the microwave at 60° C. for 25 minutes. The mixture was then diluted with DCM (200 mL), washed with water (200 mL), the organic layer passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a dark orange/brown oil (S)-4-(4-chloro-6-(2-(methylsulfonyl)phenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine, 2.59 g, >100%, crude.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:16][CH:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:16][CH:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(NCCC2CC2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine from step 3 of this example (50 mg, 0.178 mmol) was in 0.594 mL NMP. 1-fluoro-4-(methylsulfonyl)benzene (37.2 mg, 0.2141 mol) and DBU (0.040 mL, 0.267 mmol) were sequentially added. The reaction mixture was stirred at 110° C. overnight before cooled back to room temperature. The reaction mixture was diluted with water and aqueous phase was further extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography using gradient elution (0 to 65% ethyl acetate in hexane) to give the titled compound. LRMS calc: 434.9; obs: 435 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 20 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
A solution of 2,5-dichloronicotinic acid (20 g, 0.10 mol) [OChem, 782D853] in dichloromethane (520 mL) was treated with 2 M oxalyl chloride in dichloromethane (160 mL, 310 mmol) followed by a few drops of N,N-dimethylformamide and stirred at 20° C. for 15 hours. The reaction mixture was concentrated, diluted with dichloromethane (200 mL), cooled to 0° C., treated with methanol (110 mL, 2.7 mol), and stirred at 0° C. for 5 minutes. The reaction mixture was concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0-80%) gave the desired product (19 g, 89%). LCMS calculated for C7H6Cl2NO2 (M+H)+: m/z=206.0, 208.0. found: 205.8, 207.7.
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:23]([CH3:32])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].CC(O)C>C(N(CC)CC)C>[C:26]1([C:24](=[O:25])[CH:23]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:21]=[C:10]4[N:11]=[CH:12][CH:13]=[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=5)[N:9]4[N:8]=3)[CH2:6][CH2:5]2)[CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C(=O)c1ccccc1)N1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1
Yield: 27.8 %

Procedure:
A mixture of 5.6 g (0.02 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47) and 4.2 g (0.02 moles) of α-bromopropiophenone in 100 ml of 2-propanol containing 3.6 ml (0.026 moles) of triethylamine was heated at the reflux temperature for 24 hours. The reaction mixture was evaporated to dryness in vacuo. Then 100 ml of water was added to the residue and the mixture was extracted three times with a total of 100 ml of chloroform. The combined extracts were dried over magnesium sulfate and filtered. The filtrate was passed through a pad of magnesium silicate, washing with chloroform. The filtrate was evaporated to a syrup. The syrup was dissolved in 20 ml of ethanol and 200 ml of diethyl ether was added, then hexane was added until cloudy. The mixture was evaporated by boiling to about 100 ml, then was cooled and filtered to collect the precipitate, which was washed with ether and gave 2.3 g of the desired product as yellow crystals, mp 142°-144° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:28]2[CH:36]=[C:35]3[C:31]([CH:32]=[CH:33][NH:34]3)=[CH:30][CH:29]=2)[O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[NH:34]1[C:35]2[C:31](=[CH:30][CH:29]=[C:28]([C:6]3[O:7][C:8]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]5)=[CH:13][CH:14]=4)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH:36]=2)[CH:32]=[CH:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc5cc[nH]c5c4)nc3C(N)=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2ccc3cc[nH]c3c2)oc1-c1ccc(N2CCNCC2)cc1
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-6-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.018 g, 0.04 mmol) in MeOH was loaded onto a MP-TsOH cartridge (500 mg). The cartridge was washed with MeOH and allowed to stand for 2 hours. The cartridge was then washed with 2M ammonia in MeOH and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(1H-indol-6-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.006 g, 0.02 mmol, 50%). 1H NMR (DMSO) δ 2.85 (4H, t), 3.20 (4H, t), 6.55 (1H, m), 7.04 (2H, d), 7.55 (1H, br. s), 7.56 (1H, m), 7.68 (1H, br. s), 7.71 (1H, d), 7.77 (1H, dd), 8.15 (1H, s), 8.26 (2H, d), 11.48 (1H, br. s). LCMS (2) Rt: 2.32 min; m/z (ES+) 388.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:41]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][N:15]2[CH3:41])=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 1.9 mmol) in dimethylformamide (10 ml) is placed in a 25 ml three-necked flask placed under argon, then sodium hydride (0.063 g; 2.101 mmol) is added and the mixture is left to agitate for 15 minutes. When there is no longer any gas being given off, methyl iodide (0.131 ml, 2.101 mmol) is added dropwise and the mixture is left to react at 21° C. for 2 hours. The reaction medium is run into 100 ml of distilled water, and then extracted with 2 times 100 ml of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. The evaporation compound is triturated in diisopropyl ether. The pulverulent solid compound thus obtained is filtered off and rinsed. 2-(6-Benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.888 g; 86%) is isolated in the form of a beige-colored solid, the characteristics of which are as follows:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[N:14]=[C:13]([C:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C4CCCCO4)=[CH:23][CH:22]=3)[S:17][CH:16]=2)[N:12]([CH3:34])[N:11]=1.O>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[N:14]=[C:13]([C:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[S:17][CH:16]=2)[N:12]([CH3:34])[N:11]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(OC2CCCCO2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Dilute hydrochloric acid (4 N, 2.5 mL) was added to a suspension of 3-(2-chloro-6-fluorophenyl)-5-{4-methyl-5-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]thien-3-yl}-1-methyl-1H-1,2,4-triazole (0.62 g, 1.3 mmol) in tetrahydrofuran (2.5 mL), stirred at room temperature for 30 minutes, poured into water (20 mL) and extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (100 mL) and brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure to leave the desired product (0.49 g, 96%) as a white solid. 1H NMR (CDCl3) and mass spectrometry data indicated this material to be free of impurities and to be comparable to authentic material prepared according to that in Example K.
Reaction SMILES: C(=O)=O.[CH2:4]=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[O:13].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O[Ti](OC(C)C)(Br)Br)(C)C.C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.CC(C)=O.C(Cl)Cl>[OH:13][C@@H:12]([CH2:4][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1)[C:11]([O:15][CH3:16])=[O:14]
Reactant: C=C1CCCCC1
Reactant: COC(=O)C=O
Agent: CC(C)O[Ti](Br)(Br)OC(C)C
Agent: O=C([O-])O
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)[C@@H](O)CC1=CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Into a 25-ml flask was placed 0.5 g of a powder of Molecular Sieves® 4A (manufactured by Aldrich Corp.), and the air in the flask was thoroughly displaced by argon. Then, 5 ml of methylene chloride was added thereto, and 0.16 ml (0.05 mmole) of the diisopropoxydibromotitanium solution in toluene as prepared above and 14.3 mg (0.05 mmole) of (R)-binaphthol were further added. The mixture was stirred at room temperature for 1 hour to prepare an (R)-binaphtholdibromotitanium complex. This solution was cooled to -30° C. in a bath of dry ice and acetone, and subsequently 96 mg (1 mmole) of methylenecyclohexane (manufactured by Aldrich Corp.) and 88 mg (1 mmole) of methyl glyoxylate were added to this cooled solution, followed by reaction for 3 hours. Thereafter, 10 ml of an aqueous sodium hydrogen-carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Then, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by means of silica gel column chromatography to obtain 0.16 g of methyl (S)-2- hydroxy-3-(1-cyclohexenyl)propionate. The yield was 89%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:20]([F:32])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([S:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[C:20]([F:32])[CH:19]=1
Reactant: Fc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1NSN1CCOCC1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(SN1CCOCC1)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)c1c(F)cccc1F
Reaction time: 2 h
Yield: 58.2 %

Procedure:
2,6-Difluorobenzoyl isocyanate (1.4 g) in a 1:1 (v/v) mixture of toluene and petroleum ether (10 ml) was added to a solution of the compound produced by Example 6 (3 g) in the same solvent (15 ml), at ambient temperature. The solution was stirred for two hours and placed in a freezer overnight (-5° to 0° C.). The solvent was removed by evaporation, and the residue was chromatographed twice on silica, firstly using dichloromethane as eluant and secondly using a 1:1 (v/v) mixture of diethyl ether and petroleum ether, to yield the title compound (2.5 g), m.p. 77°-80° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23](O)=[O:24])[CH:11]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:57][C:58]([F:68])([F:67])[C:59]1[N:64]=[CH:63][C:62]([CH2:65][NH2:66])=[CH:61][CH:60]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])[CH:13]=[C:12]([C:23]([NH:66][CH2:65][C:62]2[CH:63]=[N:64][C:59]([C:58]([F:68])([F:57])[F:67])=[CH:60][CH:61]=2)=[O:24])[CH:11]=1)#[N:2]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)c(C#N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)cc(C(=O)N3CCCC3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with 2′-cyano-4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (50 mg, 0.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol), 1-hydroxybenzotriazole (36 mg, 0.27 mmol), N,N-diisopropylethylamine (35 mg, 0.27 mmol), methylene chloride (4 mL), 4-dimethylaminopyridine (1 mg), and C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (47 mg, 0.27 mmol). The mixture was stirred at room temperature overnight, and then diluted with CH2Cl2, washed with aq. Na2HPO4, brine, and dried over Na2SO4, and concentrated. The residue was purified via preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccccc1Cl
Temperature: 22.5 °C
Reaction time: 20 h
Yield: 93.4 %

Procedure:
Under ice-cooling, N,O-dimethylhydroxylamine hydrochloride (3.42 g) was added to a mixture of (2-chlorophenyl)acetic acid (3.41 g) and WSCD (2.05 g) in dichloromethane (30 mL). The mixture was stirred at 0-10° C. for an hour and at 20-25° C. for 20 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel (chromatorex NH) (hexane-AcOEt 50:50 v/v) to give 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide as oil (3.99 g).