Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]([C@@H:12]1[CH2:16][C@H:15](OS(C(F)(F)F)(=O)=O)[CH:14]([O:25][CH3:26])[O:13]1)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[C:1]([O:9][CH:10]([C@@H:12]1[CH2:16][C@@H:15]([N:27]=[N+:28]=[N-:29])[CH:14]([O:25][CH3:26])[O:13]1)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1O[C@H](C(C)OC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1O[C@H](C(C)OC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 206 %

Procedure:
To a solution of 1-[(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]ethyl benzoate (compound 25j, 400 mg, 1 mmol) in DMF (2 mL) was added sodium azide (65 mg, 1.05 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and H2O, the organic layer was separated and the aqueous layer was extracted with EtOAc twice. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 600 mg crude product of 1-[(2S,4R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]ethyl benzoate (compound 25k), which was used in next step without further purification.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(O)(Cc2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C(=Cc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (10 g, 53.5 mmol) and Mg turnings (1.32 g, 54.3 mg-atom) in 25 mL Et2O was added deoxybenzoin (9.81 g, 50 mmol) in 75 mL Et2O dropwise under reflux. After stirring at reflux 3 h, the mixture was carefully poured onto 1N H2SO4 and ice. The layers were allowed to separate and the aqueous layer was extracted with 25 mL Et2O. The ether layers were combined, washed with H2O (2×80 mL), dried (Na2SO4), and concentrated to give a yellow oil which solidified at room temperature (14.2 g, 93.3% crude yield). Recrystallization from 95% EtOH gave 1,2-diphenyl-1-(4-methoxyphenyl)ethanol as a white powder mp: 111°-112° C. (lit. 112°-113° C.); NMR δ 7.2 (m, 14H, ArH), 3.75 (s, 3H, OCH3), 3.63 (s, 2H, CH2), 2.35 (brs, 1H, OH). The tertiary carbinol (14 g, 46 mmol) and p-TsOH.H2O (1 g, 5.31 mmol) were dissolved in 40 mL dry C6H6, heated to reflux, and stirred 2 h. The red mixture was cooled to room temperature and washed with 5% NaHCO3 (2×75 mL). The combined aqueous layers were extracted with 25 mL C6H6. The organic layers were combined, washed with 100 mL H2O, dried (Na2SO4), and concentrated to give a yellow oil. The (E)- and (Z)-olefin mixture was purified on 60 g flash SiO2 (petroleum ether) and 1,2-Diphenyl-1-(4-methoxyphenyl)ethene was obtained as a clear oil (8 g, 61%); NMR δ 7.15 (m, 10H, ArH), 6.9 (s, 1H, C=CH), 6.8 (AA'BB', c, 4H, MeOC6H 4), 3.71 (d, 3H, (E)- & (Z)-OCH3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccncc2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
1.121 g of 4-pyridylboronic acid, 2.35 g of methyl 3-bromobenzoate, 7.5 g of cesium carbonate and 530 mg of tetrakistriphenyl phosphine palladium were dissolved in 40 ml of N,N-dimethylformamide, and the mixture was stirred at 120° C. overnight in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column, to give 1.325 g of the title compound in the 4:3 hexane-ethyl acetate fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[CH:11]=[N:10]1.C(N(CC)CC)C.CCOC(C)=O.[Br:41][CH2:42][CH2:43]Br>>[Br:41][CH2:42][CH2:43][N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[CH:11][C:12]=2[CH:25]([CH3:27])[CH3:26])=[CH:17][C:18]=1[CH3:24])[CH3:23]
Reactant: CNc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Reactant: BrCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)CCBr
Temperature: 90 °C
Yield: 37 %

Procedure:
To an ambient temperature solution of {4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amine (1.12 g, 2.77 mmol) in 1,2-dibromoethane (5 mL) is added triethylamine (1.54 mL, 11.08 mmol). The reaction is heated to 90° C. overnight. EtOAc is added to the reaction mixture. The resultant mixture is washed with brine, dried (MgSO4), and chromatographed (0% to 20% EtOAc/Hex) to yield the title compound (520 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.43-7.40 (m, 2H), 7.31 (dd, 1H, J=9.0, 7.1 Hz), 6.93 (d, 1H, J=7.3 Hz), 6.61-6.54 (m, 2H), 4.77 (s, 2H), 3.34 (t, 2H, J=6.5 Hz), 3.26 (t, 2H, J=6.7 Hz), 2.99 (sept, 1H, J=7.0 Hz), 2.65 (s, 3H), 2.26 (s, 3H), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[CH2:15]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[CH2:16][CH3:17]>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:21]2([OH:24])[CH2:22][CH2:23][CH:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)=[C:9]([F:14])[CH:8]=1
Reactant: CCCC1CCC(=O)CC1
Reactant: Fc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1CCC(O)(c2ccc(Br)cc2F)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (108.0 mL, 174.0 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (300 mL) solution of 4-bromo-2-fluoro-1-iodobenzene (67) (50.0 g, 166.0 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then 4-propylcyclohexanone (66) (24.5 g, 174.0 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 200 mL of 1N hydrochloric acid aqueous solution, and extracted with 100 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 1-(4-bromo-2-fluorophenyl)-4-propylcyclohexanol (68) (42.0 g, yield 80.2%) was obtained.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]3[CH3:25])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1>CO>[ClH:1].[ClH:1].[Br:2][C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH3:25])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CO
Product: CC1CNCCN1c1ccc2ncc(Br)n2n1

Procedure:
Concentrated hydrochloric acid (3.0 mL) was added to a solution of tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-3-methylpiperazine-1-carboxylate (1.2 g, 3.1 mmol) in methanol (60 mL) and allowed to stir at ambient temperature under N2 blanket for 3d. The solution was then evaporated to dryness to provide 1.1 g of light brown solid. LRMS (ESI) m/z 295.9/297.9 [(M+H)]+, calc'd for C11H14BrN5. 296.17.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:22]=[C:21]([OH:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:32])(=O)=O.CCCCCC>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:22]=[C:21]([O:23][CH3:32])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(O)c2c1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cc(-c2ccc(C3CCCCC3)cc2)nc2ccc(NC(C)=O)cc12
Temperature: 70 °C
Yield: 96.6 %

Procedure:
Into a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet was added 35.7 g (0.099 moles) of N-[2-(4-cyclohexylphenyl)-4-hydroxy-quinolin-6-yl]-acetamide. The material was suspended in 250 mL of toluene with stirring and then 20.6 mL (0.21 moles) of dimethyl sulfate was added. The resulting suspension was heated with a silicone oil heating bath, to gentle a reflux for 18 hr. After this time the reaction was allowed to cool and hexane was added. The solids were collected by vacuum filtration and washed with hexane. After drying, the solids were suspended in a 2 L Erlenmeyer flask with 1 L of 5% sodium hydroxide solution. The vigorously stirred suspension was then heated to 70° C. for 30 min. This step converted the salt form of the material to the free base and removed some impurities. After cooling the solids were collected by vacuum filtration and then washed with water. The product was dried in a vacuum oven to give 35.8 g (96%) of a material which contained approximately 30% of side products, with the N-methylated material constituting the major impurity. This material was used in the following procedure without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)[O:14]C1.O>C(O)COCCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Reactant: Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1c(O)cccc1Cl

Procedure:
16.1 g (0.1 mol) of 2,6-dichlorotoluene, 19.8 g (0.3 mol) of potassium hydroxide (85%) and 0.3 g of dibenzo-18-crown-6 are heated in 30 ml of diethylene glycol at a bath temperature of 190° C. with reflux for 16 hours. The water released during the reaction is distilled off. After cooling, the reaction mixture is stirred with 100 ml of water until a solution is obtained and extracted three times with 50 ml of dichloromethane. The aqueous phase is admixed with 35 ml of 30% hydrochloric acid and extracted three times with 70 ml of dichloromethane. The organic phases are dried and concentrated under reduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (11.5 g, content by HPLC: 97%, 78% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([NH2:15])[CH:14]=1)=[O:8])[CH3:5].[N:23]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:12]=[C:13]([NH:15][NH2:23])[CH:14]=1)=[O:8])[CH3:5]
Reactant: O=N[O-]
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COCC(C)NC(=O)c1cc(NN)cc(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (596 mg, 2 mmol) was dissolved in 6 mL of concentrated HCl and stirred for 15 minutes at 0° C. To the reaction mixture was added a solution of NaNO2 (138 mg, 2 mmol) in water (1.5 mL) dropwise at 0° C. The mixture was stirred for 30 minutes, and then a solution of SnCl2 (4.5 mmol, 189.6 mg) in 2 mL of concentrated HCl was added dropwise. A precipitate began to form immediately. After stirring for another 30 minutes, the resulting 5-hydrazino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was isolated as a hydrochloride salt by filtration and immediately used in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][N:17]=1>>[CH2:22]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:21]=1)[CH3:23]
Reactant: CCc1ccnc(Br)c1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: CCc1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Yield: 51 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-ethylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 74 mg, 51%) which was obtained as a yellow oil. MS: m/e=289.1 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[C:6][N:7]1[C:12]([OH:13])=[C:11]2[CH:14]=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[N:16]=[C:10]2[N:9]=[CH:8]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:6]([N:7]1[C:12]([OH:13])=[C:11]2[CH:14]=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[N:16]=[C:10]2[N:9]=[CH:8]1)#[CH:5]
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(C#C[Si](C)(C)C)cnc-2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cn1cnc2nc(NC(=O)C(C)(C)C)cc-2c1O
Reaction time: 0.08 h

Procedure:
To a solution of 1.5 g of 3-trimethylsilylethynyl--4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 100 mL of anhydrous tetrahydrofuran cooled to 0° C. are added under nitrogen 4.75 mL of 1M tetrabutylammonium fluoride in anhydrous tetrahydrofuran. After 5 minutes, the reaction mixture is allowed to attain room temperature and is then stirred for 2 hours. The solvent is removed under reduced pressure and the residue purified by chromatography over silica gel to yield 3-ethynyl-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:29]([Cl:31])=[O:30].O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:29]([Cl:31])=[O:30])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3)CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3C(=O)Cl)CC2)CC1
Temperature: 0 °C

Procedure:
Solution prepared by dissolving 25.5 g of (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene in 200 ml of methylene chloride was cooled to 0° C., and 24 g of aluminum chloride was added to the solution and stirred. To the solution was added dropwise little by little 21.5 g of oxalyl chloride, and its temperature was raised to room temperature and stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 200 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 18 g of (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzoylchloride.
Reaction SMILES: CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH:45]([CH2:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[C:46]([NH:48][C:49]2[S:50][C:51]([C:54](O)=[O:55])=[CH:52][N:53]=2)=[O:47])=[CH:41][CH:40]=1)(=[O:38])=[O:37].Cl.[CH3:65][NH:66][O:67][CH3:68]>CN(C=O)C>[CH3:68][O:67][N:66]([CH3:65])[C:54]([C:51]1[S:50][C:49]([NH:48][C:46](=[O:47])[CH:45]([C:42]2[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:44][CH:43]=2)[CH2:57][CH:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:53][CH:52]=1)=[O:55]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
NEt3 (647 μL, 4.64 mmol) and BOP (976 mg, 2.21 mmol) were added to a stirred solution of 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylic acid (EXAMPLE 127, 968 mg, 2.21 mmol) in anhydrous DMF (30 mL). After 5 min, N,O-dimethylhydroxylamine hydrochloride (237 mg, 2.43 mmol) was added, then the mixture was stirred at 20° C. for 18 h. The solvents were removed in vacuo, then the residue was dissolved in EtOAc (75 mL). The EtOAc solution was washed with saturated aqueous Na2CO3 (40 mL), 2M HCl (40 mL), and brine (40 mL), before being dried (MgSO4). Filtration and solvent evaporation provided the title compound: RTB=1.27 min; m/z (ES+)=482.0 [M+H]+.
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[N:15][C:22]([CH:18]1[C:19]([CH3:21])([CH3:20])[C:17]1([CH3:25])[CH3:16])=[O:23]
Reactant: COCCn1c2c(sc1=N)CCCC2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c2c(sc1=NC(=O)C1C(C)(C)C1(C)C)CCCC2

Procedure:
A mixture of the product of Example 121A (156 mg, 0.55 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (94 mg, 0.66 mmol), HATU (479 mg, 0.83 mmol) and triethylamine (0.46 mL, 3.30 mmol) in 10 mL of DMF was processed according to the method of Example 2B to provide the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.16 (s, 6H) 1.23 (s, 6H) 1.45 (s, 1H) 1.69-1.82 (m, 4H) 2.43-2.48 (m, 2H) 2.54-2.59 (m, 2H) 3.24 (s, 3H) 3.60 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.3 Hz, 2H); MS (DCI/NH3) m/z 337 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]([NH2:42])=[O:41])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert. butyl 4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product as a yellow solid 2-[4-(4-fluoro-phenyl) 2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (74.3 mg, 65%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[C:18]1[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[C:16]([NH:30][CH:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH:17]=1
Reactant: Clc1nccc2c(Br)cccc12
Reactant: CC1(C)OB(c2ccc(C#N)c(NC3CCC(O)CC3)c2)OC1(C)C
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
Product: N#Cc1ccc(-c2nccc3c(Br)cccc23)cc1NC1CCC(O)CC1
Yield: 153.8 %

Procedure:
Pd(PPh3)4 (1.39 g) was added to a solution of compound (1b) (5.83 g), 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester (7.80 g), and an aqueous sodium carbonate solution (2 M, 40 mL) in ethylene glycol dimethyl ether (80 mL) in a nitrogen atmosphere, and the mixture was stirred at 85° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (2a) (14.8 g, yield: 62%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E.MS (ESI): predicted mass calcd. for C21H18FN5O2, 391.1