Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)=[N:8]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClC(Cl)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)=[N:8]3)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CNCc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.4 %

Procedure:
A solution of (5-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (example 80, step B) (200 mg, 0.69 mmol), 4-fluorobenzaldehyde (94 mg, 0.76 mmol) and acetic acid (166 mg, 2.76 mmol) in 1,1-dichloroethane (10 ml) was stirred at room temperature for 30 minutes. Afterwards sodium triacetoxy-boron hydride (342 mg, 1.61 mmol) was added, the reaction mixture was allowed to stir for 17 hours at room temperature, poured into ice/saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow oil (130 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[Cl:13][CH2:14][C:15](O)=O.Cl>CO.[Pd]>[Cl:13][CH2:14][C:15]1[NH:10][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[N:1]=1
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: O=C(O)CCl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc2[nH]c(CCl)nc12
Yield: 86.6 %

Procedure:
A solution of 2-amino-3-methoxy-1-nitrobenzene (0.860 g, 5.11 mmol) in MeOH (50 mL) was hydrogenated (1 atm) over palladium, 10 wt. % on activated carbon (0.163 g). The resultant crude 3-methoxy-1,2-phenylenediamine was reacted with chloroacetic acid (0.953 g, 10.08 mmol) in refluxing 4 N HCl (10 mL) overnight. After aqueous workup, 0.87 g of 2-chloromethyl-4-methoxy-1H-benzimidazole was isolated as a red-brown solid, which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 4-fluoronaphthalene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:ethyl acetate=10:1) to give the objective substance (0.65 g, 91%) as crystals.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Yield: 50 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dec-1-ynylbenzaldehyde and 4-(trifluoromethyl)aniline gave the title compound as a colorless oil (50%). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.21-7.13 (m, 2H), 6.50 (d, J=8.7 Hz, 2H), 4.28 (s, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.60-1.43 (m, 2H), 1.43-1.31 (m, 2H), 1.30-1.11 (m, 8H), 0.87-0.75 (m, 3H). M−(LC/MS(ESI)): 386.4. HPLC (Condition A), Rt: 6.43 min (HPLC purity: 82.6%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:34][CH2:33]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Clc1ccccc1N1CCNCC1
Product: Cc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 72 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: C(O)(=O)C.[CH:5](N)=[NH:6].[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[N:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]3=[CH:22][N:21]=2)=[O:19])=[CH:14][C:10]=1[C:11](O)=[O:12].[OH-].[Na+]>C(O)C>[CH:22]1[N:21]=[C:20]([C:18]([C:15]2[CH:14]=[C:10]3[C:9](=[CH:17][CH:16]=2)[N:8]=[CH:5][NH:6][C:11]3=[O:12])=[O:19])[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: Nc1ccc(C(=O)c2ncc3ccccn23)cc1C(=O)O
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(c1ccc2nc[nH]c(=O)c2c1)c1ncc2ccccn12
Temperature: 150 °C
Yield: 25.8 %

Procedure:
0.36 g (3.6 mmol) of formamidine acetate is added to 0.2 g (0.72 mmol) of 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid (described in WO 06/097625) in 7 ml of ethanol. The reaction medium is microwave-heated at 150° C. for 25 minutes. The reaction medium is hydrolysed with a 1N aqueous solution of sodium hydroxide. The aqueous phase is extracted with dichloromethane. The heterogeneous organic phase is filtered. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 54 mg of a yellow solid are obtained.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([CH3:28])=[C:15]3[CH3:29])=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:11][CH:10]=3)=[CH:20][CH:19]=2)[C:15]([CH3:29])=[C:16]1[CH3:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(C)c(C)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.230 g, 0.576 mmol) was reacted with 1N KOH (1.2 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.139 g, 0.361 mmol, 63%) as an off-white solid, mp 203-206° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.27 (s, 3H), 4.68 (s, 2H), 5.38 (s, 2H), 6.95-6.99 (m, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.25-7.29 (m, 3H), 7.37 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.62 (s, 1H), 13.00 (broad s, 1H); IR (solid) 3030, 2910, 1740, 1710, 1605, 1520, 1480, and 1240 cm−1; [ESI(−)], m/z 384 (M−H)—; Anal. Calcd. for C25H23NO3: C, 77.90; H, 6.01; N, 3.63; Found: C, 77.87; H, 5.99; N, 3.64.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[C:22]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([CH3:27])[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[C:22]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:36])[F:37])[CH:29]=2)([CH3:27])[CH2:21]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 99.5 %

Procedure:
A solution of (1RS,2RS,4RS)-4-((tert-butyldiphenylsilyloxy)methyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-2-methylcyclohexanol (1.35 g, 2.406 mmol) in dichloromethane (40 mL) was treated with Celite (1.5 g, 24.97 mmol) and pyridinium chlorochromate (0.778 g, 3.61 mmol). The resulting mixture was stirred at rt for 19.5 h, then diluted with Et2O and stirred vigorously at rt. The resulting slurry was filtered through a pad of Florisil and the solids were rinsed thoroughly with Et2O. The filtrate was concentrated under vacuum, taken up in dichloromethane and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with 0-15% ethyl acetate-hexane, to provide (2RS,4RS)-4-((tert-butyldiphenylsilyloxy)methyl)-2-(4-chloro-3-(trifluoro-methyl)phenyl)-2-methylcyclohexanone as a colorless gum (1.338 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 4 H), 7.53 (d, J=2.0 Hz, 1 H), 7.43 (m, 7 H), 7.26 (m, 1 H), 3.58 (dd, J=9.8, 5.5 Hz, 1 H), 3.48 (dd, J=9.8, 7.1 Hz, 3 H), 2.79 (dt, J=14.6, 3.0 Hz, 1 H), 2.33 (m, 2 H), 2.07 (m, 1 H), 1.93 (m, 1 H), 1.49 (dd, J=14.6, 12.6 Hz, 1 H), 1.41 (m, J=12.5, 4.9 Hz, 1 H), 1.26 (s, 3 H), 1.09 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36])[NH:31][CH2:30][CH2:29]2>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([O:25][CH3:24])=[C:34]([C:35]([F:37])([F:38])[F:36])[CH:33]=3)[CH2:29][CH2:30]2)=[O:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2cccnc2)c1)Oc1ccccc1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(Cl)c(-c3cccnc3)c1)CC2
Temperature: 120 °C
Yield: 36.2 %

Procedure:
Phenyl N-(4-Chloro-3-(pyrid-3-yl)phenyl)carbamate (D67) (0.12 g, 0.00037 mole) in dry dimethylformamide (6 ml) was treated under argon, with 5-methoxy-6-trifluoromethylindoline (D11) (0.08 g, 0.00037 mole) and heated to 120° C. for 2 hours. After cooling to ambient temperature, the solvent was removed in vacuo. The residue was partitioned between 1N aqueous sodium hydroxide solution and dichloromethane. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was triturated in diethyl ether, filtered and dried in vacuo at 60° C. to afford the title compound (0.06 g, 36%) as a grey-green solid (mp 210-213° C.)
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=O>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: COc1ccc(Br)cc1CN1CCN(c2cc(=O)[nH]cn2)CC1

Procedure:
6-[4-(5-Bromo-2-methoxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromo-2-methoxybenzaldehyde. Mass spectrum (ES) MH+=379.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1COCC1.[Cl-].[Na+].O>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[NH:4][CH2:5][C:6]1=[O:12])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (475 mg, 2.86 mmol) in THF (10 ml) was added sodium hydride (60%, 115 mg, 2.86 mg) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 30 min and cooled in an ice/water bath. tert-Butyl bromoacetate (460 μl, 2.86 mmol) was added and the mixture was allowed to warm to room temperature slowly and stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between brine and EtOAc and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc;pet. ether 40:60) to give a white solid; yield 500 mg, 62%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:7]=[C:6]2[C:22]1[N:30](S(C2C=CC(C)=CC=2)(=O)=O)[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[C:6]2[C:22]1[NH:30][C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CC(=O)OC(C)(C)C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)O)c2cc1OC
Yield: 112.1 %

Procedure:
2-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]acetic acid is prepared by following the procedure described in example 88a, but using 1 g of tert-butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}acetate and a solution of 73 ml of methanolic potassium hydroxide (0.1 g/ml; 1.78M). 0.701 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]acetic acid is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]([NH2:11])C)[CH:5]=[N:4]1)[CH3:2].[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27](O)=[O:28])[CH:23]=2)[N:18]=1)([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:11][C:27]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25]3)=[O:28])[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(c1ccc2cc(C(=O)O)ccc2n1)C(F)(F)F
Reactant: CCn1ncc(C(C)N)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1ncc(CNC(=O)c2ccc3nc(C(C)(C)C(F)(F)F)ccc3c2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a DMF (3 ml) solution of 1-(1-ethyl-5-methyl-1H-pyrazol-4-yl)ethanamine (95 mg, 0.62 mmol), (2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylic acid (176 mg, 0.62 mmol), HBTU (284 mg, 0.748 mmol) and triethylamine (0.434 ml, 3.12 mmol) were added and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with sat. NaHCO3 aq and water, and the product was extracted with EtOAc/hexane (4:1) (3×20 ml). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography, using EtOAc/hexane (2:1) to give the title product (31 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 1.27 (3H, t) 1.49 (3H, d), 1.71 (6H, s), 2.25 (3H, s), 4.01 (1H, q), 5.19 (1H, m), 7.44 (1H, s), 7.86 (1H, d), 8.06 (1H, d), 8.20 (1H, d), 8.51 (1H, d), 8.53 (1H, bs) 8.86 (1H, d). LCMS (ESI) RT=3.11 mins, m/z 417 (M−H)−, 419 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C)C=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A solution of 2.01 g (10 mmol) of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate in 20 ml of dimethylformamide is admixed with 7 g (40 mmol) of 1-bromo-4-fluorobenzene and 2.5 g (50 mmol) of sodium hydride at 50% in mineral oil. The mixture is stirred at 100° C. for 3 hours and then evaporated to dryness. The residue is taken up in 50 ml of ice-water and extracted with dichloromethane. The organic extracts are evaporated to dryness, to give 3.5 g of an oily product, which is used as it is in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)c3ncco3)cc2)cn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 496 (M++1).
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.[CH3:33][N:34]=[C:35]=[O:36]>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:35]([NH:34][CH3:33])=[O:36])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: CN=C=O
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)NC(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and methyl isocyanate. LC-MS Method 1 tR=1.45 min, m/z=492, 434; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.49 (d, 3H), 1.64 (s, 6H), 2.10-2.50 (5H), 2.81 (m, 1H), 2.82 (s, 3H), 5.66 (q, 1H), 6.88 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.527 mmol) in N,N-dimethylformamide (2.63 mLl) was added saturated aqueous bicarbonate solution (0.88 mL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 4 hours and was quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 75% ethyl acetate in hexane, to give the title compound MS ESI(+) m/z 524.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:46])[CH2:32][C@@H:33]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:36]1[CH:37]=[CH:38][C:34]([C@H:33]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:2][C:3]3[S:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[CH:41][CH:40]=2)[CH2:32][C:31]([N:26]2[C@@H:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:29][O:28][C:27]2=[O:30])=[O:46])=[N:35]1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C[C@@H](c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 61.4 (0.19 mmol), 7.5 (62 mg, 0.16 mmol), and Cs2CO3 (155 mg, 0.48 mmol) in DMF (1.6 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (25-50% EtOAc/hexane) to afford 61.5 (76 mg, 54%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 7.69 (d, 2H), 7.64 (d, 2H), 7.35 (m, 2H), 7.28 (m, 4H), 7.21 (m, 2H), 7.11 (d, 1H), 6.98 (d, 2H), 6.16 (d, 1H), 5.22 (s, 2H), 4.78 (dd, 1H), 4.64 (m, 1H), 4.16 (m, 2H), 4.05 (dd, 1H), 3.56 (dd, 1H), 3.22 (dd, 1H), 2.78 (dd, 1H).