Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:4]=1)=O.[H-].[Na+].[OH2:27].[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:32]([O:31][C:30](=[O:27])/[CH:29]=[CH:1]/[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]([C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:22])(=[O:23])[NH2:24])=[CH:17][CH:16]=2)[N:4]=1)[CH3:28]
Reactant: Cc1ccc(-c2cc(C=O)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C1CCOC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of aldehyde 12c (0.16 g, 0.47 mmol) and triethyl phosphonoacetate (0.12 g, 0.52 mmol) in 5 mL of THF was added 60% sodium hydride in oil (21 mg, 0.52 mmol) at 0° C. The reaction mixture was stirred for 1 hour. After adding 5 mL of water, the mixture was extracted with EtOAc. After drying with MgSO4, the solvent was removed in vacuo. The resulting white solid was filtered and washed with hexanes to give the titled compound (0.14 g, 73% yield) as a white solid. mp 166.8-171.2° C. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J=9 Hz, 2H), 7.72 (d, J=16 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.20-7.08 (m, 4H), 6.70 (s, 1H), 6.52 (d, J=16 Hz, 1H), 4.90 (s, 2H), 4.27 (q, J=7 Hz, 2H), 2.38 (s, 3H), 1.34 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([OH:23])=O)=[CH:9][CH:10]=2)[N:5]=1)=[O:3].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:21]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:2]([NH2:1])=[O:3])[CH:13]=2)=[CH:19][CH:18]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(C(=O)N3CCCC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
2-(Aminocarbonyl)-4-(4-fluorophenyl)quinoline-7-carboxylic acid (5-3, 50.0 mg, 0.161 mmol, 1.0 equiv), pyrrolidine (11.5 mg, 0.161 mmol, 1.0 equiv.), BOP (93.0 mg, 0.209 mmol, 1.3 equiv.), and TEA (0.0670 mL, 0.483 mmol, 3 equiv) were dissolved into DMF (1.0 mL) and stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-Fluorophenyl)-7-(pyrrolidin-1-ylcarbonyl)quinoline-2-carboxamide (5-4, 50.0 mg, 85.0%) as a colorless solid. 1H NMR (500 MHz, CDCl3): δ 8.324 (d, J=1.47 Hz, 1H); 8.273 (s, 1H); 8.251 (br s, 1H); 8.026 (d, J=8.78 Hz, 1H); 7.762 (dd, J1=8.54 Hz, J2=1.71 Hz, 1H); 7.501-7.529 (m, 2H); 7.246-7.286 (m, 2H); 6.750 (br s, 1H); 3.765 (tr, J=6.95 Hz, 2H); 3.567 (tr, J=6.68 Hz, 2H); 2.055 (quint, J=6.78 Hz, 2H); 1.962 (quint, J=6.65 Hz, 2H). LRMS m/z (M+H)+ 364.1 found, 364.1 required.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[N:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1)=[O:8].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[N+:26]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[N:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1)=[O:8])([O-:28])=[O:27]
Reactant: C1CCNCC1
Reactant: O=C(Nc1ncn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=C(Nc1ncn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-2-nitro-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (500 mg, 1.21 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), and piperidine (500 mg, 5.88 mmol, 4.84 equiv). The resulting solution was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 500 mg (90%) of product as white oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].[CH3:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=1)=[O:25]>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:34]3[N:33]=[C:32]([NH:31][C:30]4[CH:29]=[CH:28][S:27][C:26]=4[C:24](=[O:25])[NH:23][CH3:22])[C:37]([Cl:38])=[CH:36][N:35]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-methylcarbamoyl-thiophen-3-ylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (85 mg, 52%). LCMS (m/e) 560 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.65 (s, 1H), 9.58 (s, 1H), 8.57-8.45 (m, 1H), 8.32-8.21 (m, 2H), 7.82-7.73 (m, 1H), 7.61-7.50 (m, 1H), 7.33-7.21 (m, 1H), 7.20-7.10 (m, 1H), 4.20-3.90 (m, 5H), 7.75-3.50 (m, 2H), 2.78 (d, 3H, J=4.0 Hz), 2.22-1.85 (m, 11H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8]1)=[O:4].[N-:20]=[C:21]=[O:22]>CN(C)C=O.C(Cl)(Cl)Cl.CO>[Cl:18][C:15]1[CH:14]=[C:13]([NH:20][C:21](=[O:22])[NH:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]2[CH2:10][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[CH2:8]2)=[O:4])[CH:12]=[CH:17][CH:16]=1
Reactant: NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: [N-]=C=O
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)Nc1cccc(Cl)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 8 h

Procedure:
A solution of 2-Amino-N-[1-(3,4-dichloro-benzyl)-azetidin-3-ylmethyl]-acetamide (1 M equivalent) in dimethylformamide is treated with a solution of the isocyanate (1.5 M equivalents) in dimethylformamide and left at room temperature overnight. The reaction mixture is diluted with chloroform/methanol 50:50 and applied to a SCX-3 1 g cartridge. The cartridge is washed with chloroform methanol 50:50, and the compound eluted with a solution of 10% ammonia in methanol. The solvent is evaporated to afford the title compound.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:6][CH:5]=1.[C:19]1([CH3:29])C=CC(S(O)(=O)=O)=C[CH:20]=1>CC(C)=O.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11](/[CH:12]=[CH:20]/[C:19](=[O:1])[CH3:29])[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1cccc(Oc2ccc(Cl)cc2)c1
Reaction time: 0.08 h

Procedure:
10 N aqu. NaOH (2 ml) was added to a solution of 3-(4-chlorophenoxy)-benzaldehyde (23.3 g, Aldrich) in acetone (150 ml) and stirred vigorously. After a few minutes' stirring, the temperature rose to 32° C. The mixture was left for 5 minutes and then poured into 2 M aqu. HCl (600 ml) and extracted with ether/pet. ether (1:1, 200 ml). The extract was washed with water and satd. aqu. NaCl, dried over MgSO4, and stripped to give the aldol product. The latter was taken up in toluene (300 ml), p-toluenesulphonic acid (1 g) was added, and the mixture heated for 1 hour. The mixture was then cooled, washed with satd. aqu. NaHCO3 and satd. aqu. NaCl, dried over MgSO4 and stripped. The residue was eluted through a slice gel column using methylene chloride/40-60 pet. ether (1:1, followed by 3:1) and the eluate stripped to give the desired product (19 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccnc3ccccc23)cc1
Yield: 53.7 %

Procedure:
4-Chloroquinoline (32.3 mmoles, 5.2 g),4-nitrothiophenol (32.3 moles, 5.0 g) and potassium carbonate (32.3 moles, 4.46 g) were stirred at room temperature in 500 ml of ethanol for 16 hr. The reaction mixture was then concentrated, ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 20-40% ethyl acetate/hexane to yield 4-(4-nitrophenylthio)quinoline 4.9 g, 54%. Mass Spec (FD) 282. Calculated for C15H10N2O2S: C, 63.82 H, 3.57 N, 9.92. Found: C, 65.09; H, 3.81; N, 10.02.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:11]([O:13]C)=O)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>O1CCCC1.C(OCC)(=O)C.O>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:11](=[O:13])[N:22]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH2:2][C:3]=12
Reactant: COC(=O)c1nccc(OC)c1CBr
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2Cc3c(OC)ccnc3C2=O)cc1

Procedure:
Treat a solution of methyl 3-(bromomethyl)-4-methoxypicolinate (1.0 mmol, 1 eq) in tetrahydrofuran with 4-methoxybenzylamine (2.0 mmol, 2 eq) and stir the reaction for 16 h. After completion dilute the mixture with ethyl acetate and water and separate the layers. Wash the organic layer with 1 M hydrochloric acid and water. Concentrate the organic layer to give crude. Purify the crude by silica gel column chromatography to afford 4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[CH2:7][OH:8].[C:9](ON1C(=O)CCC1=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.C([O-])(O)=O.[Na+]>CC#N.CC(N(C)C)=O.O.CC(N(C)C)=O>[OH:8][CH2:7][C@H:2]1[NH:1][CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: OC[C@@H]1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of compound 1B (207 mg, 1.78 mmol) in CH3CN/DMA/H2O (1 mL, 0.3 mL, 0.7 mL) cooled to 0° C. was added dropwise CBZ-OSu (444 mg, 1.78 mmol) in DMA (0.5 mL). The reaction was stirred for 15 min at 0° C. then slowly warmed to RT. To the reaction was added H2O (30 mL) and sat'd NaHCO3 (5 mL), and then the product was extracted three times with EtOAc (20 mL). The combined EtOAc layers were washed twice with brine, dried over MgSO4 then concentrated in vacuo to give crude (S)-benzyl 3-(hydroxymethyl)piperazine-1-carboxylate (256 mg). HPLC RT: 1.082 min (4 min Chromolith column TFA). (M+H)+:251.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].C[O:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]#[N:10].Cl>CO>[F:12][C:11]([F:14])([F:13])[C:7]1[O:6][N:10]=[C:9]([NH2:3])[CH:8]=1.[F:12][C:11]([F:14])([F:13])[C:7]1[CH:8]=[C:9]([NH2:10])[O:4][N:3]=1
Reactant: COC(=CC#N)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1cc(C(F)(F)F)no1
Product: Nc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.3 %
Yield: 22.3 %

Procedure:
Sodium metal (0.48 g, 0.0210 mole, 1.5 eq.) was added to dry methanol (28 ml) and 97% hydroxylamine hydrochloride (1.50 g, 0.0210 mole, 1.5 eq.), obtained from Nakarai Chemicals, was then added to the resulting solution with ice cooling. After being stirred at room temperature for 15 minutes, 3-methoxy-3-(trifluromethyl)acrylonitrile (2.12 g, 0.0140 mole) was added and heated under reflux for 16 hours. To the solution was then added 36% hydrochloric acid (3.54 g, 0.0350 mole, 2.5 eq.) and it was heated under reflux for 1 hour. Methanol was distilled off at atmospheric pressure over 1 hour by using a distillation apparatus equipped with a fractionating column. Water (28 ml) was added to the residue and it was extracted with methylene chloride after pH being adjusted above 11 with 48 sodium hydroxide. The extract was dried with anhydrous sodium sulfate and it was distilled at atmospheric pressure and then under reduced pressure at room temperature by using a distillation apparatus equipped with a fractionating column to give the crude title compound (0.8968 g). This product was purified by column chromatography on silica gel to give the title compound (0.2201 g, 10.3%) and 3-trifluoromethyl-5-aminoisoxazole (0.4738 g, 22.3%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13]>C1COCC1.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of 5.82 g (30 mmol) of 2,4-dichloro-5-nitropyrimidine (N. Whittaker, J. Chem. Soc., 1951:1565–1570) in 100 mL THF at −78° C. is added dropwise over 5 minutes a solution of 3.87 g (60 mmol) of 70% aqueous ethylamine in 20 mL of 2-propanol. After being stirred at −78° C. for 15 minutes, the reaction mixture is allowed to warm to room temperature, and the solvent is removed under vacuum. The residue is worked up in EtOAc and chromatographed on silica, eluting with hexane/EtOAc (92:8), to give 4.90 g (81%) of the title compound: mp (hexane) 64–66° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].O.ON1C2C=CC=CC=2N=N1.[CH:23]1([N:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>ClCCl>[CH:23]1([N:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH:39]4[CH2:44][CH2:43][N:42]([C:7]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=5)=[O:9])[CH2:41][CH2:40]4)[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:24][CH2:25][CH2:26]1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCC(Oc3ccc4c(c3)CCN(C3CCC3)CC4)CC2)cc1
Reaction time: 16 h

Procedure:
4-Cyanobenzoic acid (147 mg, 1 mmol), 1-hydroxy benzotriazole hydrate (154 mg, 1 mmol) and N-cyclohexylcarbodiimide N′-methyl polystyrene (1.8 mmol/g, 555 mg, 1 mmol) were stirred at room temperature in dichloromethane (5 ml) for 15 minutes. 3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was added and stirring continued for 16 hours. The reaction mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethate (1:9:90) to afford the title product (E13). MS (ES+) m/e 430 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])=[CH:3]1.[NH2:19][CH2:20][C:21]1[N:26]=[CH:25][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])=[CH:23][C:22]=1[F:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:24]2[CH:23]=[C:22]([F:39])[C:21]([CH2:20][NH:19][C:16]([C@:11]3([NH:10][C:8]([C:4]4[CH:5]=[N:6][NH:7][C:2](=[O:1])[CH:3]=4)=[O:9])[CH2:15][CH2:14][O:13][CH2:12]3)=[O:18])=[N:26][CH:25]=2)=[C:29]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: NCc1ncc(Nc2ccc(Cl)cc2C(F)(F)F)cc1F
Reactant: O=C(N[C@@]1(C(=O)O)CCOC1)c1cn[nH]c(=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N[C@@]1(C(=O)NCc2ncc(Nc3ccc(Cl)cc3C(F)(F)F)cc2F)CCOC1)c1cn[nH]c(=O)c1

Procedure:
A solution of (S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (144.7 mg, 0.40 mmol), (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine (127.9 mg, 0.40 mmol), TBTU (154 mg), triethylamine (0.112 mL) and DMF (1.0 mL) in 7 mL THF was stirred for 3 hours at ambient temperature. Then the mixture was evaporated down and the crude product thus obtained was purified by column chromatography (RP, column: YMC-Pack ODS-AQ, 5 μM).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[C:11]1([CH3:17])[CH2:15][CH2:14][CH:13](C)[CH2:12]1.[I-].[Na+]>>[CH:11]1([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1CCC(C)(I)C1
Agent: [I-]
Agent: [Na+]
Product: O=Cc1ccc(OCC2CCCC2)cc1
Yield: 51 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and 1-iodo-3-methylmethylcyclopentane (344 mg, 0.98 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-(cyclopentylmethoxy)benzaldehyde (102 mg, 50% crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1([F:28])[CH2:20][CH2:19][C:18]([CH2:26]O)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>>[F:14][C:15]1([F:28])[CH2:20][CH2:19][C:18]([CH2:26][F:11])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)C1(CO)CCC(F)(F)CC1
Product: CCOC(=O)C1(CF)CCC(F)(F)CC1
Temperature: 70 °C

Procedure:
A neat stirred mixture of Deoxo-Fluor® (196 mg, 0.887 mmol) and ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (98.6 mg, 0.444 mmol) was heated at 70° C. overnight. The reaction was cooled to rt and quenched with ice and extracted with DCM, washed with satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of DCM gave a light brown oil which was purified by silica gel FCC (1:3 hexanes:DCM) to afford ethyl 4,4-difluoro-1-(fluoromethyl)cyclohexanecarboxylate as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.42 (d, J=47.2 Hz, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.33-2.19 (m, 2H), 2.15-2.01 (m, 2H), 2.01-1.81 (m, 2H), 1.69-1.56 (m, 2H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCCOCOCCCCCCCCCCCCCCCC(O)=O.[CH:51]1([N:57]=[C:58]=[N:59][CH:60]2[CH2:65][CH2:64][CH2:63]CC2)CCCCC1>O1CCCC1>[CH3:1][N:57]([C:58]1[CH:63]=[CH:64][CH:65]=[CH:60][N:59]=1)[CH3:51]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCCOCOCCCCCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 996 mg of 16-(methoxyethoxymethoxy)hexadecanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 946 mg of the title compound were obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[NH:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:27]3[CH2:26][CH2:25][CH:24]([N:23]4[C:22]5[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=5[NH:20][C:19]4=[O:18])[CH2:29][CH2:28]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CBr)Nc1ccc(C2CCCCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of N-(4-cyclohexyl-phenyl)-2-bromoacetamide (50 mg, 0.17 mmol), 4-(2-keto-1-benzimidazolinyl)-piperidine (41 mg, 0.18 mmol), and potassium carbonate (34 mg, 0.25 mmol) in dimethylsulfoxide (2 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated to give a yellow oil. The crude oil was purified on reverse phase silica gel column using 100% acetonitrile to give N-(4-cyclohexyl-phenyl)-2-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-piperidin-1-yl]-acetamide as a yellow solid (21 mg, 30%): mp 130-132° C. 1H NMR (300 MHz, CDCl3) d 9.28 (s, 1 H), 9.05 (s, 1 H), 7.53 (d, 2 H), 7.22 (d, 2 H), 7.11 (m, 4 H), 4.33 (m, 1 H), 3.22 (s, 2 H), 3.12 (d, 2 H), 2.40-2.60 (m, 5 H), 1.70-1.90 (m, 7 H), 1.20-1.60 (m, 5 H). MS m/z 433 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH2:44])=[O:43])=[C:40]([F:45])[C:39]([F:46])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH2:44])=[O:43])=[C:40]([F:45])[C:39]([F:46])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 120 °C
Yield: 76.2 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide (133 mg, 0.193 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluorobenzamide (79 mg, 0.147 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19-2.31 (m, 6 H), 3.04-3.25 (m, 4 H), 3.70-3.87 (m, 3 H), 4.18 (m, 2 H), 6.24 (d, J=0.64 Hz, 1 H), 6.95 (d, J=2.29 Hz, 2 H), 7.23-7.44 (m, 1 H), 7.54 (br. s., 1 H), 8.06-8.23 (m, 2 H), 8.24-8.38 (m, 1 H), 8.64 (br. s., 1H), 9.93 (br. s., 1 H), 11.27 (br. s., 1 H). (ESIMS (M+H)+=537)