Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:51]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O-:58])=O.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:61]([O:60][C:51](=[O:59])[CH2:52][CH2:53][CH2:54][CH2:55][C:56]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])=[O:58])[CH3:62]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(CC)CC
Yield: 81.6 %

Procedure:
By using 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 60 mg of monoethyl adipate, and 0.10 mL of N-ethyl-N-isopropylpropan-2-amine as starting materials, and using 142 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as a condensing agent, the reaction similar to Preparation Example 27 was performed, thereby obtaining 200 mg of methyl 4-(2-{4-[({2-[(3-{[{2-[(6-ethoxy-6-oxohexanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[NH2:15][C:10]1[N:11]=[C:12]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH:13]=[C:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[N:9]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(C#N)cc2)nc(N)n1
Yield: 72 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-amino-benzonitrile provided the title compound (72% yield). 1H NMR (CD3OD) δ 2.40 (s, 3H, CH3), 6.38 (s, 1H, Ar), 7.39 (d, 1H, J=8.9 Hz, Ar), 7.68-7.69 (m, 2H, Ar), 7.78-7.80 (m, 2H, Ar), 8.07 (d, 2H, J=7.6 Hz, Ar).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO.CC(O)=O>[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)c(F)n1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cc1ccc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)c(F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A solution of 3-[5-(2-fluoro-6-methyl-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep117, 0.46 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 104 mg, 0.46 mmol), and AcOH (32 μl) in dichloroethane-MeOH (10-0.5, 4 ml) was cooled to 0° C. NaBH(AcO)3 (102 mg, 0.48 mmol) was added portionwise. The mixture was stirred at 0° C. for one hour and then basified with 1N NaOH. The product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in the presence of PS-isocyanate (300 mg). The mixture was filtered and the solvent evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) and then SCX cartridge to give 90 mg of the title compound (40% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1)=[O:6])[CH:2]=[CH2:3].[I:39][CH3:40]>CC(C)=O>[I-:39].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][CH2+:33]1[N:37]([CH3:40])[CH:36]=[CH:35][N:34]1[CH3:38])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCc3nccn3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CI
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[CH2+]3N(C)C=CN3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(1-methylimidazol-2-yl)ethyl}-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (3.58 g) in acetone (17 ml) was added iodomethane (2.05 ml) with stirring at ambient temperature and then allowed to stand overnight. The reaction mixture was evaporated in vacuo and dried in vacuo for 1 hour to give allyl (4R,5S,6S)-3[(2R,4S)-1-allyloxycarbonyl-2-{2-(1,3-dimethyl-2-imidazolio)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (3.68 g).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][C:33](=[O:35])[CH3:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:40][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:37])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][C:33]([OH:35])([CH3:40])[CH3:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[Mg]Br
Reactant: CC(=O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCC(C)(C)O)cc1-c1ccccc1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 100 mg (0.175 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml tetrahydrofuran was added a 3 N solution of methylmagnesium bromide in diethyl ether at room temperature. The reaction mixture was stirred at room temperature for 1 h and at 65° C. for 3 h. After cooling to room temperature few drops of a 1 N aqueous solution of hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane and washing with saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 51 mg (50%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]=[O:29])[CH:9]=1.[CH2:40]1COCC1.C[Mg]Br.CCOCC>O>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([OH:29])[CH3:40])[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (11.0 g, 19.4 mmol) in anhydrous THF (200 mL, 2 mol) under nitrogen at 0° C. was added 3M methylmagnesium bromide in ether (9.69 mL, 29.0 mmol) dropwise. After 1 hour the reaction was complete by HPLC. Water (10 mL) was added over a 15 minute period to quench the reaction. Removed the flask from the ice bath and concentrated in vacuo. Dissolved the remaining residue in ethyl acetate, washed three times with water and then twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified the remaining crude material by flash chromatography (5-40% EtOAc/hex) to afford 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol (6.8 g; 60% yield) as a yellow solid. HPLC: 7.54 min (Method C). LCMS: ESI+ m/z of 584 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)[N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCCOCCOC)n[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCOCCOC)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1 g 5-[2-(2-Methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml of DMF and 154 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 5 min at room temperature, 966 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 2 h. Then 50 ml of water were added and the mixture was extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was used in the next reaction step without further purification. Yield: 1.2 g.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[C:13]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:12]=[CH:11]3)=[CH:7][C:6]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:5][CH:4]=2.[H-].C([Al+][CH2:41][CH:42]([CH3:44])[CH3:43])C(C)C.[C:45]1([CH3:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[C:3]1([C:44]([C:42]2[CH:41]=[CH:22][CH:21]=[CH:20][CH:43]=2)=[CH:51][C:45]2[CH:50]=[CH:49][C:48]([C:2]3[C:3]4[C:8]([C:9]([C:48]5[CH:49]=[CH:50][C:45]([CH:51]=[C:44]([C:14]6[CH:15]=[CH:10][CH:11]=[CH:12][CH:13]=6)[C:42]6[CH:41]=[CH:17][CH:18]=[CH:19][CH:43]=6)=[CH:46][CH:47]=5)=[C:10]5[C:11]=3[CH:12]=[C:13]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:15]5)=[CH:7][C:6]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:5][CH:4]=4)=[CH:47][CH:46]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: Cc1ccccc1
Reactant: CCCCC(CC)COc1ccc2c(Br)c3cc(OCC(CC)CCCC)ccc3c(Br)c2c1
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc2c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3cc(OCC(CC)CCCC)ccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 1187.3 %

Procedure:
Added into a 500 ml three-necked flask equipped with a condenser under a gaseous stream of argon were 9,10-dibromo-2,6-di(2-ethylhexyloxy) anthracene 0.6 g (1 mmole), dichlorobis(triphenylphosphine) palladium 0.04 g (5 mole %), diisobutylaluminum hydride/toluene solution 0.1 ml (1 M, 0.1 mmole) and THF 10 ml. After the above-mentioned Grignard reagent was added dropwise to them at room temperature, they were heated and stirred overnight. After the completion of the reaction, the reaction solution was cooled with ice water, the precipitates were filtered and washed with methanol 50 ml followed by acetone 50 ml to give the yellow powder 0.56 g. This was identified as Compound 10 by NMR, IR and field desorption mass spectra measurements (FD-MS) (yield 60%).
Reaction SMILES: C([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH:15]2[C:31](=[O:32])[N:19]3[C:20]4[C:25]([C:26]([CH2:27]N(C)C)=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C.O.O1CCCC1>[CH3:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]2[C:31](=[O:32])[CH:15]([CH2:14][C:11]3[N:10]=[CH:9][NH:8][C:12]=3[CH3:13])[CH2:16][CH2:17][C:18]=12
Reactant: Cc1c(CC2CCc3c(CN(C)C)c4ccccc4n3C2=O)ncn1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
A mixture of 7-[(1-benzyl-5-methyl-1H-imidazol-4-yl)methyl]-10-[(dimethylamino)methyl]-8,9-dihydropyrido-[1,2-a]indol-6(7H)-one (215 mg), ammonium formate (318 mg), 10% palladium on carbon (107 mg), water (1 ml), ethanol (2 ml), and tetrahydrofuran (1 ml) was heated at 75° C. for 40 minutes and then cooled. Ammonium formate (300 mg), 10% palladium on carbon (110 mg), water (1 ml), and ethanol (2 ml) were added successively to the reaction mixture. Heating at 75° C. was continued for further 1 hour 20 minutes. After cooling, the reaction mixture was filtered and the residue was washed with 10% methanol-chloroform. The filtrate was evaporated in vacuo. The residue was diluted with water and extracted three times with 10% methanol-chloroform. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfte, and evaporated in vacuo. Silica gel column chromatography of the residue using 5% methanol-chloroform as eluent gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (108 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:28]([N:27]([CH3:33])[CH3:26])[CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C1CCNC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(N(C)C)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-dimethylaminopyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.69 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][C:7]1C=N[CH:10]=[C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=12.[H-].[Na+].[Cl:25][C:26]1[C:27]([CH3:48])=[C:28]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[N:41][CH:42]=2)[C:29]([O:35][CH3:36])=[C:30]([CH:32](Cl)[CH3:33])[CH:31]=1.[CH3:49][N:50](C)C=O>O>[Cl:25][C:26]1[C:27]([CH3:48])=[C:28]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[N:41][CH:42]=2)[C:29]([O:35][CH3:36])=[C:30]([CH:32]([N:15]2[C:11]3[CH:10]=[CH:49][N:50]=[C:7]([NH:6][CH2:5][C:4]4[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=4[O:2][CH3:1])[C:12]=3[C:13]([CH3:16])=[N:14]2)[CH3:33])[CH:31]=1
Reactant: CN(C)C=O
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: COc1ccc(CNc2cncc3[nH]nc(C)c23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CNc2nccc3c2c(C)nn3C(C)c2cc(Cl)c(C)c(-c3ccc(C(=O)N(C)C)nc3)c2OC)c(OC)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-3-methyl-1H-pyrazolo[4,3-d]pyridin-4-amine (110 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was treated with sodium hydride (30 mg, 0.75 mmol) and stirred at 20° C. for 30 minutes. The reaction mixture was treated with a solution of 5-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]N,N-dimethylpyridine-2-carboxamide (130 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL) and heated at 50° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (110 mg, 49%). LCMS for C34H38ClN6O4 (M+H)+: m/z=629.3; Found: 629.1.
Reaction SMILES: O1CCC[CH2:2]1.[Si]([O:13][C:14]([NH:16][CH:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15])(C(C)(C)C)(C)C.CI.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:2][O:13][C:14]([NH:16][CH:17]([CH2:22][CH:23]=[CH2:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15]
Reactant: C=CCC(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: O
Product: C=CCC(NC(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (3.0 ml) of the compound prepared in Example 3 (170 mg, 0.59 mmol), were successively added dropwise at 0° C. in a nitrogen atmosphere methyl iodide (0.074 ml, 1.18 mmol) and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.59 ml, 0.59 mmol). The mixture was agitated for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under vacuum. The resulting reaction mixture was subjected to column chromatography and eluted with a 1:4 mixture of ether and hexane to give 93 mg of the titled compound (yield, 84% based on the starting materials used in Example 3).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[S:24]([NH2:34])(=[O:33])([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)=[O:25]>>[NH2:34][S:24]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:30][CH:31]=1)(=[O:25])=[O:33]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(S(N)(=O)=O)cc3)(CC1)CC2
Yield: 24.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and sulfanilamide (59.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-aminosulfonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (18.2 mg).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2Oc2ccccn2)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 63 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (209 mg) in dimethylformamide (2.5ml), were added 2-fluoropyridine (109 mg) and sodium hydride (60% in mineral oil, 25 mg). The mixture was then stirred at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (162 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1C(OC)=O.[CH3:12][Mg+].[Br-].Cl.CCO[C:19]([CH3:21])=[O:20]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:19]([OH:20])([CH3:21])[CH3:12]
Reactant: COC(=O)c1ccccc1Br
Reactant: C[Mg+]
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1Br
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirring solution of methyl 2-bromobenzoate (XCIV) (5 g, 0.0233 mol) in THF (30 mL) under argon at 0° C. was added dropwise MeMgBr (19.4 mL, 0.058 mol), maintaining the temperature in the range of −5 to 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was cooled to 0° C. and 1M aqueous HCl (35 mL) was added, maintaining the temperature below 5° C., after which it was allowed to reach room temperature and was stirred for 30 minutes. To this mixture EtOAc (35 mL) was added and after stirring for 5 minutes a white precipitate was removed by filtration through a Celite pad. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic fractions were concentrated, washed with brine and dried over MgSO4. Crude XCV was purified by silica gel chromatography using DCM then DCM/MeOH 300/1 to give 2-(2-bromophenyl)propan-2-ol (XCV) as a light yellow oil (4.55 g; 21.2 mmol, 91% yield). 1H NMR (CDCl3) δ ppm 1.75 (s, 6H), 2.85 (brs, 1H), 7.09 (td, J=7 Hz, J=2 Hz, 1H), 7.29 (td, J=7 Hz, J=1 Hz, 1H), 7.58 (dd, J=7, J=1, 1H), 7.67 (dd J=7, J=2, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-hydroxyphenyl)butanoic acid (2.00 g) in N,N-dimethylformamide (28.0 mL) were added potassium carbonate (1.61 g) and benzyl bromide (1.46 mL), followed by stirring at room temperature overnight. The reaction suspension was concentrated under reduced pressure, and then to the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl 4-(4-hydroxyphenyl)butanoate (2.64 g).