Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:15]1[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]1=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:15]1[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]1=[O:24])=[C:5]2[C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2c(CN3C(=O)c4ccccc4C3=O)n(C)c(=O)c3ccc(Cl)cc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(O)cc2)c2cc(Cl)ccc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 2-{[6-chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (synthesized according to the method similar to that in Example 16(7)) (0.92 g, 2 mmol) in dichloromethane (10 ml) was added boron tribromide, (76 ml, 36 mmol) at 0° C. and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 2-{[6chloro-4-(4-hydroxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (0.83 g, 94.3%) as crystals.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(C#N)cc1
Yield: 92.5 %

Procedure:
A solution of tert-butyl (3-amino-2-methylpropyl)carbamate (200 mg, 1.06 mmol), 4-cyanobenzoic acid (156 mg, 1.06 mmol), HATU (525 mg, 1.38 mmol) and TEA (0.444 mL, 3.19 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanobenzamido)-2-methylpropyl)carbamate (311 mg, 0.980 mmol, 92%) as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:8][C:7]([OH:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][O:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C>CO>[OH:9][C:7]1[S:8][C:4]([CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:23]3[C:22]4[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=4[O:25][CH:24]=3)[CH2:27][CH2:28]2)=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]=1
Reactant: Oc1nc(-c2ccc(F)cc2)c(CCCl)s1
Reactant: Fc1ccc2c(C3CCNCC3)coc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nc(-c2ccc(F)cc2)c(CCN2CCC(c3coc4cc(F)ccc34)CC2)s1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 0.134 g of 5-(2-chloroethyl)-2-hydroxy-4-(4-fluorophenyl)thiazole, 0.11 g of 4-(6-fluorobenzofuran-3-yl)piperidine hydrochloride, 0.28 ml of diisopropylethylamine and 0.5 ml of methanol was stirred with heating under reflux for 15 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Merckkieselgel 60 230- to 400-mesh, eluent: hexane-ethyl acetate=2:1). The purified product was recrystallized from ethyl acetate-hexane to obtain 0.066 g of 2-hydroxy-4-(4-fluorophenyl)-5-[2-[4-(6-fluorobenzofuran-3-yl)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:6]=2[CH:34]=1.[C:35]1(=[O:46])[O:41][C:39](=[O:40])[CH:38]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:37]2[CH2:36]1>N1C=CC=CC=1>[CH2:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:6]2[CH:34]=[C:2]([NH:1][C:35]([CH2:36][CH:37]3[CH2:45][CH2:44][CH2:43][CH2:42][CH:38]3[C:39]([OH:41])=[O:40])=[O:46])[CH:3]=[CH:4][C:5]=2[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C1CC2CCCCC2C(=O)O1
Solvent: c1ccncc1
Product: CCCCc1nc2ccc(NC(=O)CC3CCCCC3C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h

Procedure:
1.3 g (2.86 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate, 0.6 g (5.35 mMol) of hexahydrohomophthalic acid anhydride and 5 ml of pyridine are refluxed with stirring for 3 hours. Then the pyridine is removed by rotary evaporation in vacuo, the residue is crystallised from acetone, washed with acetone and dried in vacuo at 70° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([OH:15])[C:7]=1[CH2:16][CH2:17][CH3:18].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:15][C:8]1[C:9]([C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])[C:7]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1OCC(=O)OC
Reaction time: 13 h
Yield: 58 %

Procedure:
A mixture of 5.0 g of 1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl]ethanone, 3.0 ml of methyl bromoacetate, and 3.3 g of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 4 hours. An additional 2.0 g of potassium carbonate was added and reflux was continued for 13 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography using 5% ethyl acetate-toluene to give 3.5 g (58%) of [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Reactant: Fc1ccc(I)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and Cul (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [CH2:1]=[C:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:5][N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:4].C(Cl)Cl.[C:22]([OH:25])(=[S:24])[CH3:23]>>[C:22]([S:24][CH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:5][N:6]1[CH2:7][CH2:8][S:9][CH2:10][CH2:11]1)=[O:4])(=[O:25])[CH3:23]
Reactant: C=C(Cc1ccccc1)C(=O)NN1CCSCC1
Reactant: CC(O)=S
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NN1CCSCC1

Procedure:
0.6 g of the product of Step A was stirred for 24 hours at ambient temperature in 10 ml of thioacetic acid and the excess of acid was eliminated under an inert atmosphere at 40°-45° C. The residue was taken up on 200 ml of methylene chloride, washed with a sodium bicarbonate solution, dried and the solvent was eliminated under reduced pressure. The residue was taken up in isopropyl ether to obtain 0.72 g of the expected product melting at 138° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1Br)CCNC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1Br)CCN(CCCCl)C(=O)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 55% sodium hydride dispersion (0.24 g, 5.5 mmol) in oil is added to 7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.35 g, 5 mmol) in dimethylsulfoxide (15 ml) and the mixture is stirred for half an hour at ambient temperature and for 10 minutes at 35°-40° C. The solution is added dropwise, with stirring, to 1-bromo-3-chloro-propane (0.79 g, 5.5 mmol) in dimethylsulfoxide (5 ml). Then the mixture is stirred for 2 hours at ambient temperature, poured into ice water and extracted (4 times) with methylene chloride. The methylene chloride extracts are washed several times with water, dried and evaporated in vacuo. The residue is purified over a silica gel column with ethyl acetate as eluant.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C@@H:10]([C:13]1[C:14]([F:28])=[C:15]([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:11][CH3:12])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]([NH:9][CH2:8][CH2:7][OH:6])[CH2:11][CH3:12])=[C:14]([F:28])[C:15]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NCCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](NCCO)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To (3-{(R)-1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-propyl}-6-chloro-2-fluoro-phenyl)-pyridin-3-yl-methanone (0.176 g, 0.39 mmol) in THF (3 ml) at 0° C. added TBAF [1M] (90.43 ml, 0.43 mmol) dropwise stirred at 0° C. for 1 hour, diluted with water, THF evaporated off and reaction mixture extracted with DCM. The organic phase was separated and dried (Na2SO4), filtered and concentrated, purified by Prep HPLC to give 2-{[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]amino}ethan-1-ol (0.129 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.C(O)C.[H][H]>C(Cl)Cl.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCCCCCCCBr)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(OCCCCCCCCBr)cc1

Procedure:
Into a glass hydrogenation vessel were added 1-(8-bromooctyloxy)-4-nitrobenzene (5.00 g, 15.1 mmol) and absolute ethanol (50 mL). Carefully, 10% Pd/C (0.5 g) was added, the vessel was charged with hydrogen (40 psi), and the mixture was shaken on a Pan hydrogenation apparatus. After 3 h the mixture was diluted with CH2Cl2 (25 mL), filtered through a Celite pad, and volatiles removed in vacuo to give 4.20 g (14.0 mmol, 93%), of as a pale pink solid, mp 61-63° C. This material was used without purification in the next reaction. 1H NMR (500 MHz, CDCl3) δ 1.27-1.44 (m, 8H), 1.75-1.84 (m, 4H), 3.39 (t, J=5.0 Hz, 2H), 3.89 (t, J=6.5 Hz, 2H), 6.77-6.88 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 22.7, 25.9, 26.0, 28.1, 28.7, 29.2, 29.4, 31.8, 32.8, 34.0, 68.5, 115.7, 118.6, 135.2, 154.1; HRMS (ESI) calculated for C14H23BrNO [M+H]+ 300.0957, observed 300.0963.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(F)ccc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(OC2CCNCC2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.6 g, 251 mmol) and di-tert-butyl azodicarboxylate (71.0 g, 308 mmol) in THF (350 mL) was added 2-bromo-5-fluorophenol (36 mL, 324 mmol). The mixture was cooled to −78° C. and a solution of triphenylphosphine (81.5 g, 311 mmol) in CH2Cl2 (130 mL) was added via a cannula. The reaction was then warmed to room temperature and stirred overnight. The solvents were removed under vacuum and the crude oil was dissolved in EtOH (200 mL). The solution was cooled to −78° C. and treated with 4 M HCl in 1,4-dioxane (450 mL). The reaction was warmed to room temperature and stirred 24 h. After this time, the solvents were removed under vacuum. The salts were neutralized with 1 N NaOH (750 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined and concentrated to dryness. The crude material was treated with heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with Et2O and treated with 4 M HCl in 1,4-dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with Et2O:hexanes (1:1). The salts were again neutralized with 1 N NaOH (500 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved in heptane (2 L), washed four times with 1 N NaOH (250 mL), brine and dried (MgSO4). The organic layer was filtered and concentrated to dryness to afford the title product as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1>>[CH3:12][C:4]1[C:5]([C:9]([N:18]2[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]2)=[O:11])=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Yield: 72.1 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96 mmol) reacted with cis-2,6-dimethylpiperazine (2.66 g, 14.36 mmol) to give 2.27 g (72%) of 3,5-dimethyl-4-[(3R,5S)-3,5-dimethyl-piperazine-1-carbonyl]-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:13]=1)=[N:7][C:8]([CH3:12])=[CH:9][C:10]=2[CH3:11])[CH3:2].[H-].[Na+].[CH2:16]([O:18][C:19](=[O:33])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:31]Br)[CH:27]=2)[CH:22]=1)[CH3:17]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:33])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:31][N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])[CH:27]=2)[CH:22]=1)[CH3:17]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCOC(=O)Cc1ccc2cc(CBr)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) (1.38 g, 6.5 mmol) in 4 ml DMF was added sodium hydride (250 mg, 6.5 mmol) and the reaction mixture was stirred 15 minutes at ambient temperature. The product of Step 2, above (51) (3.07 mmol), was dissolved in 3 ml DMF and added to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution and brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was then chromatographed on silica gel using 50% EtOAc in hexanes as the eluant to yield the title compound (52) (95 mg).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH:38]1[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1.O>CN(C=O)C>[CH3:27][N:26]([CH2:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[S:25]([N:20]1[C:21]2([CH2:23][CH2:22]2)[CH2:24][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)C1
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 45 °C
Reaction time: 16 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (1.42 mmol) and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (0.85 mmol). Stirred at 45° C. for 16 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol: 2,2,2-trifluoroethanol (3:1, 4 mL) at 150° C. for 2 h. The crude reaction mixture was concentrated on celite in vacuo and purified by standard column chromatography using methanol in DCM as eluent. The obtained compound was recrystallized in methanol:EtOAc affording the title compound as solid.
Reaction SMILES: [CH2:1]([N:10]=C=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].C1(=[O:20])NCCCCC1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:1]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1=[O:9])(=[O:20])[NH2:10]
Reactant: O=C1CCCCCN1
Reactant: O=C=NCCCCCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: NC(=O)C1CCCCNC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 817.2 %

Procedure:
To the flask were added 0.01 g of dibutyltin dilaurate and then 17.0 g of hexamethylene diisocyanate to effect reaction with the polyoxytetramethylene di-ol. After stirring for 2 hours, 12.0 g of dry ε-caprolactam was added to the reaction mixture, and the inner temperature was raised up to 80° C., at which the reaction was continued for an additional 2 hours. There was obtained 129 g of carbamoyl caprolactam-terminated polyoxytetramethylene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Fc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1F

Procedure:
Synthesized using 3,4-difluorophenylboronic acid (270 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 210 mg, 0.77 mmol, 92%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.18 (s, 2H), 6.92 (t, J=1.3 Hz, 1H), 7.13 (t, J=1.3 Hz, 1H), 7.25 (ddd, J=9.8, 8.5, 8.2 Hz, 1H), 7.49 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (s, 1H), 7.66 (dd, J=8.3, 0.6 Hz, 1H), 7.69-7.73 (m, 1H), 7.86 (ddd, J=11.4, 7.6, 2.2 Hz, 1H), 8.56 (dd, J=2.3, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 116.0 (d, J=18.2 Hz), 117.6 (d, J=17.3 Hz), 119.0, 120.2, 122.8 (dd, J=3.8, 6.7 Hz), 130.4, 130.6, 135.6 (dd, J=3.8, 5.8 Hz), 135.9, 137.3, 148.6, 150.8 (dd, J=20.2, 255.3 Hz), 151.3 (dd, J=15.4, 254.3 Hz), 155.3; MS (ESI): m/z=272.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:30][S:31]([O:34][C:35]1[CH:36]=[C:37]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:2]([NH2:1])=[O:29])=[CH:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Oc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(OS(C)(=O)=O)c3)cc2)C(N)=O)CCOCC1
Reaction time: 20 h

Procedure:
(S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg), 3-(methylsulfonyloxy)phenylboronic acid (Example 12, step (i), 125 mg) and potassium carbonate (240 mg) in acetonitrile (10 mL) and water (5 mL) were stirred and heated at 90° C. under a nitrogen atmosphere with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (11 mg). After 20 h the reaction was complete and the solvents were removed under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic phase collected and dried over magnesium sulfate. The extract was concentrated to a gum and the crude material purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled is compound (120 mg).