Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Reactant: N#Cc1ccc(CCl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2nc3c(Br)c(-c4ccc(Cl)cc4)ccn3c2=O)nc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirred mixture of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.07 g, 3.31 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (0.91 g, 6.62 mmol) and 6-(chloromethyl)nicotinonitrile (0.63 g, 4.14 mmol). The mixture was then heated to 60° C. for 7 h, after which HPLC indicated complete reaction. The mixture was cooled to room temperature, diluted with water (100 mL), and stirred for 30 min. Solid was collected by filtration and washed with water (10 mL×5), then methanol (3 mL×3), and finally dried under vacuum. The title compound (0.98 g) was obtained as a tan solid. HPLC/MS: retention time=3.4 min, [M+H]+=442.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)=[O:2].[C-:8]#[N:9].[Na+].[O-]S([O-])=O.[Na+]>O>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH:1]([OH:2])[C:8]#[N:9]
Reactant: O=Cc1cccs1
Reactant: [C-]#N
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CC(O)c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
In this example 25.0 g of 2-formylthiophene was added to a stirred solution containing 10.93 g of sodium cyanide in 37 ml of water at room temperature. 63 ml of aqueous saturated sodium acid sulfite was then slowly added to the stirred mixture. During the addition of the sodium acid sulfite solution, small amounts (about 20 g) of ice were periodically added. The mixture was then stirred for another 15 minutes and extracted with ethyl ether. The ethyl ether extracts were combined, dried over magnesium sulfate and evaporated under vacuum affording 18.4 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH2:20][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:19]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2CCCC2=O)c1
Product: CCOC(=O)CC1=C(c2cccc(OC)c2)CCC1
Yield: 81.4 %

Procedure:
Reflux a solution of 2-(3-methoxy-phenyl)-cyclopentanone (4.34 g 22.8 mmoles), and (carboethoxymethylene)-triphenylphosphorane (14.31 g, 41.1 mmoles) in 130 ml of xylenes for 15 hours. Concentrate in vacuo at 40° C. and slurry with ether. Remove triphenyl phosphine oxide by vacuum filtration, and chromatographed on silica with 14% ethyl acetate/hexanes. to yield the 4.83 g of the titled compound. 1H NMR (CDCl3): 7.26 (m, 1H), 6.9 (m, 2H), 6.8 (m, 1H), 4.17 (q, J=7.2, 2H), 3.81 (s, 3H), 3.22 (s, 2H), 2.76 (m, 2H), 2.58 (m, 2H), 1.95 (m, 2H) 1.28 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23][C:24]2[CH:25]=[C:26]([O:40][CH2:41][CH3:42])[C:27](I)=[C:28]([O:30][S:31]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])=[O:32])[CH:29]=2)=[CH:18][N:17]=1>>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:27]2[C:26]([O:40][CH2:41][CH3:42])=[CH:25][C:24]([CH2:23][C:19]3[C:20]([NH2:22])=[N:21][C:16]([NH2:15])=[N:17][CH:18]=3)=[CH:29][C:28]=2[O:30][S:31]([CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37])(=[O:32])=[O:33])=[CH:7][CH:6]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1I
Reactant: O=C(Nc1ccc(Br)cc1)C(F)(F)F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1-c1ccc(N)cc1
Yield: 22.6 %

Procedure:
Starting from 272 mg (1.01 mmol) N-(4-bromo-phenyl)-2,2,2-trifluoro-acetamide and 265 mg (0.51 mmol) 2,2-dimethyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 56 mg of the title compound are isolated as a yellowish foam after two chromatography operations.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.[O:18]=[C:19]1[CH2:24][CH2:23][CH2:22][S:21][CH2:20]1>>[O:18]=[C:19]1[CH2:24][CH2:23][CH2:22][S:21][C:20]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: O=C1CCCSC1
Product: CC(C(=O)OC(C)(C)C)c1ccc(C=C2SCCCC2=O)cc1
Yield: 29.6 %

Procedure:
By using tert-butyl 2-(4-formylphenyl)propionate (500 mg) and 3-oxothiane (500 mg), the title compound (210 mg, 30%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[C:5]([N:7]([CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][C:10](=O)[NH:11][CH3:12])=[O:6].[N-:22]=[N+:23]=[N-:24].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[C:5]([N:7]([CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][C:10]1[N:11]([CH3:12])[N:24]=[N:23][N:22]=1)=[O:6]
Reactant: CNC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Cl)cc(C(=O)N(CCc2nnnn2C)C(C)C)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 35.9 %

Procedure:
To a stirred solution of 3-chloro-N-isopropyl-5-methoxy-N-(2-methylcarbamoyl-ethyl)-benzamide (0.312 g) in anhydrous dichloromethane (5.0 ml) was added sodium azide (0.065 g) and the mixture cooled to 0° C. Trifluoromethanesulphonic anhydride (0.200 ml) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic layer dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (4:1 v/v); to give the title compound as a white solid (0.121 g).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH2:31]1[CH:39]2[N:34]([CH2:35][CH2:36][C:37](=[O:40])[CH2:38]2)[CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[NH:4][N:3]=[C:2]([C:37]3([OH:40])[CH2:38][CH:39]4[N:34]([CH2:33][CH2:32][CH2:31]4)[CH2:35][CH2:36]3)[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Reactant: O=C1CCN2CCCC2C1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CCN2CCCC2C1
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
3-Bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (3.18 g (10 mmol), prepared as described in 1)) was dissolved in tetrahydrofuran (32 ml). To the solution was added a solution of 1.6 M butyl lithium/hexane (13.75 ml, 13.75 mmol) at −78° C., and the resulting mixture was stirred for 10 minutes. To the mixture was added 1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (1.53 g, 11 mmol) at −78° C., and the resulting mixture was stirred first at −78° C. for 2 hours, then at room temperature for 1 hour. At the end of this time, the reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=20:1:1), to give the title compound (830 mg) as a pale yellow powder (yield 22%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:27][S:26][C@@H:9]2[C@H:10]([NH:13][C:14](/[C:16](/[C:20]3[N:24]=[C:23]([NH2:25])[S:22][CH:21]=3)=[N:17]\[O:18][CH3:19])=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:28]([OH:30])=[O:29])=O.[Na].[CH3:32][C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[S:46][N:45]=[N:44][C:43]=2[SH:47])=[CH:38][CH:37]=1)([CH3:35])[CH3:34].[K]>O>[NH2:25][C:23]1[S:22][CH:21]=[C:20](/[C:16](=[N:17]/[O:18][CH3:19])/[C:14]([NH:13][CH:10]2[C:11](=[O:12])[N:8]3[CH:9]2[S:26][CH2:27][C:6]([CH2:5][S:47][C:43]2[N:44]=[N:45][S:46][C:42]=2[C:39]2[CH:40]=[CH:41][C:36]([C:33]([CH3:35])([CH3:34])[CH3:32])=[CH:37][CH:38]=2)=[C:7]3[C:28]([OH:30])=[O:29])=[O:15])[N:24]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Agent: [K]
Agent: [Na]
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnsc3-c3ccc(C(C)(C)C)cc3)CSC12)c1csc(N)n1
Temperature: 70 °C
Yield: 12.1 %

Procedure:
A mixture of 0.5 g of Cefotaxime, sodium salt, 0.4 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt and 16 ml of water was heated at 70° C. for 5.5 hours with pH adjustment to 6.8-7.2, then cooled and filtered. The filtrate was adjusted to pH 5 and extracted with 30 ml of ethyl acetate. The aqueous remainder was filtered through diatomaceous earth and adjusted to pH 2.5 with 2N hydrochloric acid. The resulting solid was collected, washed with water and dried, giving 86 mg of the desired product as a light orange solid [α]D26 =-10°+2 (0.885 DMSO): IR(KBr) 1770 cm-1 (β-lactam --C=O).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8](OC(=O)CC)(=[O:11])[CH2:9]C.C(OC(=O)CCC)(=O)CCC.C(OC(=O)CCCC)(=O)CCCC.C(OC(=O)CCCCC)(=O)CCCCC>>[CH3:6][C:5]([O:4][CH2:1][CH2:2][CH2:9][CH2:8][OH:11])=[O:7]
Reactant: CCC(=O)OC(=O)CC
Reactant: CC(=O)OC(C)=O
Agent: CCCC(=O)OC(=O)CCC
Agent: CCCCC(=O)OC(=O)CCCC
Agent: CCCCCC(=O)OC(=O)CCCCC
Product: CC(=O)OCCCCO

Procedure:
The anhydride may be, but not limited to, acetic acid anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride or hexanoic anhydride. Preferably, the anhydride is acetic acid anhydride. According to an embodiment, the esterification of 1,4-bunediol is performed with acetic acid anhydride to form CH3C(O)O—(CH2)4—OH.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[H-].[Na+].Cl[CH2:19][CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CN(C)C=O>[C:24]1([NH:23][C:21]([CH2:20][CH2:19][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:8]2)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc2c(Cc3ncc[nH]3)c[nH]c2c1
Reactant: O=C(CCCl)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCn1cc(Cc2ncc[nH]2)c2ccccc21)Nc1ccccc1
Reaction time: 18 h
Yield: 35 %

Procedure:
3-(1-Imidazolylmethyl)indole (1.97 g) was dissolved in dry N,N-dimethylformamide (50 ml) and the solution was cooled to °C. Sodium hydride (0.55 g of 50% dispersion in oil) was added portionwise with stirring and the mixture was stirred at 0° C. for 30 minutes. A solution of 3-chloropropionanilide (1.83 g) in dry N,N-dimethylformamide was added dropwise with stirring and the resulting mixture was stirred at 0° C. for 2 hours followed by 18 hours at room temperature. The mixture was evaporated and water was added to the residue. The solid product was filtered off, washed with chloroform to remove impurity and crystallised from methanol to give 1-[2-(N-phenylcarbamoyl)ethyl]-3-(1-imidazolylmethyl)indole (1.20 g), m.p. 254°-255° C. Found: C, 73.14; H, 5.82; N, 15.88. C21H20N4O requires: C, 73.23; H, 5.85; N, 16.27%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:15]=1)[C:10]([OH:12])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:45]([O:52][C:53](=[O:67])[NH:54][CH2:55][C@@H:56]([OH:66])[C@@H:57]([NH2:65])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:45]([O:52][C:53](=[O:67])[NH:54][CH2:55][C@@H:56]([OH:66])[C@@H:57]([NH:65][C:10]([C:9]1[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:15]=[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH:8]=1)=[O:12])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CCCCCOc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
To a suspension of 3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzoic acid (A13) (530 mg, 1.82 mmol, 1 equiv) in CH2Cl2 (20 ml) were added HOBT (300 mg, 2.2 mmol, 1.2 equiv) and EDAC.HCl (420 mg, 2.2 mmol, 1.2 equiv). After stirring for 5 min, 3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzoic acid hydrochloride (D104) (570 mg, 1.82 mmol, 1 equiv) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2 (20 ml) washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give [(2R,3S)-2-hydroxy-3-({1-[3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-phenyl]-methanoyl}-amino)-4-phenyl-butyl]-carbamic acid benzyl ester (D105) (510 mg, 48%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([OH:3])=[O:2].N([O-])=O.[Na+].[BrH:21]>[Pd].O>[Br:21][C:8]1[CH:7]=[CH:6][C:5]([CH2:13][C:14]([OH:16])=[O:15])=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1
Reactant: Br
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(Br)cc1C(=O)O

Procedure:
A mixture of 2-carboxy-4-nitrophenylacetic acid (described by H. E. Ungnade et al., J. Org. Chem., 10, 533 (1945), 50 g, 0.22 mol) and 5% palladium on carbon (5 g) is rapidly stirred under an atmosphere of hydrogen until the nitro group is reduced. Water (300 ml) is added and the mixture is warmed to dissolve the precipitate. The mixture is filtered through diatomaceous earth. The filtrate is evaporated and 375 ml of 2 N hydrobromic acid is added. The resulting solution is cooled in an ice-bath to 0°-5° C. Sodium nitrite (15.2 g, 0.22 mol) in 50 ml of water is added while stirring. The latter solution is added slowly to a cold (0°-5° C.) stirring freshly prepared solution of cuprous bromide (150 g, 0.105 mol) in 230 ml of 49% hydrobromic acid. The reaction is stirred at room temperature for 2 hr and the precipitate is collected by filtration. The precipitate is washed with water and dried to obtain 4-bromo-2-carboxyphenylacetic acid (53 g), mp 210°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.O1CCC[CH2:22]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([OH:19])[CH3:22])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2ccc(F)cc2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirring mixture of 2-(2-chlorophenyl)-7-fluoroquinoline-3-carbaldehyde (0.7588 g, 2.656 mmol) in tetrahydrofuran (26.56 mL, 2.656 mmol) was added methylmagnesium bromide 3 M in diethyl ether (1.328 mL, 3.984 mmol) dropwise at 0° C. (started at 4:00 pm), and the mixture was allowed to warm to room temperature with stirring over 19 h. The reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×1). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethanol as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (1 H, d, J=11.0 Hz), 8.20 (1 H, dd, J=8.6, 6.7 Hz), 7.75 (1 H, dd, J=10.6, 2.7 Hz), 7.42-7.66 (5 H, m), 5.39 (1 H, dd, J=57.5, 3.9 Hz), 4.59-4.69 (1 H, m), 1.20 (3 H, dd, J=58.7, 6.3 Hz); LC-MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9](=[O:34])[NH:10][C:11]1([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:13][CH2:12]1)[CH:6]([CH3:8])[CH3:7].[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+]>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.COCCOC.O>[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:22]3[CH:23]=[CH:24][C:19]([C:16]4[NH:15][C:14]([C:11]5([NH:10][C:9](=[O:34])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:35])[CH:6]([CH3:8])[CH3:7])[CH2:12][CH2:13]5)=[N:18][CH:17]=4)=[CH:20][CH:21]=3)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)CC1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)CC1)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
(1-{2-{[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: [2-Methyl-1-(1-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-cyclopropylcarbamoyl)-propyl]-carbamic acid methyl ester (85 mg, 0.21 mmol) and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (97 mg, 0.21 mmol) in 3:1 DME/H2O (2.5 mL) were treated with Pd(PPh3)4 (10 mg, 0.0084 mmol) and K2CO3 (2 M solution, 0.42 mL, 0.84 mmol). The mixture was stirred in a sealed tube at 80° C. for 3 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.3 mg, 2%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.93 (s, 2H), 7.84 (m, 4H), 5.20 (m, 1H), 4.23 (d, J=7.2 Hz, 2H), 4.01 (m, 2H), 3.83 (m, 4H), 3.70 (s, 3H), 3.66 (s, 3H), 3.38 (m, 2H), 2.57 (m, 2H), 2.18 (m, 4H), 2.04 (m, 4H), 1.75 (m, 4H), 1.58 (m, 4H), 0.95 (m, 12H); MS (ESI) m/z 725 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:41][N:42]1[C:46]([CH3:47])=[C:45]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[N:43]1>O1CCCC1.O>[CH3:41][N:42]1[C:46]([CH3:47])=[C:45]([S:48]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:50])=[O:49])[CH:44]=[N:43]1
Reactant: Cc1c(S(=O)(=O)Cl)cnn1C
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cnn1C
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg) at room temperature, and the mixture was stirred for 5 min. 15-Crown-5 (273 mg) was added. Then 1,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (181 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 290 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:9]=[C:10]2[C:16](I)=[N:15][N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]2=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH2:44])=[CH:41][CH:40]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:9]=[C:10]2[C:16](/[CH:44]=[CH:43]/[C:42]3[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=3)=[N:15][N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]2=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 68.2 %

Procedure:
To a solution of 400 mg of (3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl)carbamic acid tert-butyl ester and 162 mg of 4-fluorostyrene in 2.0 mL of N,N-dimethylformamide were added 15 mg of palladium acetate, 40 mg of 2-(di-tert-butylphosphino)biphenyl and 0.46 mL of triethylamine at room temperature, and stirred at 80° C. for 6 hours. After diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-dichloromethane:n-hexane=1:1-ethyl acetate:n-hexane=1:3). The resultant crystals were washed with diethyl ether, to afford 270 mg of the title compound as colorless crystals.