Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]3[O:11][CH2:12][CH2:13][CH2:14][C:6]=3[C:5]=2[C:4]([CH:15]=O)=[CH:3]1.C([O-])(=O)C.[NH4+].O.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>>[N+:23]([C:26]([CH3:27])=[CH:15][C:4]1[C:5]2[C:6]3[CH2:14][CH2:13][CH2:12][O:11][C:7]=3[CH:8]=[CH:9][C:10]=2[N:2]([CH3:1])[CH:3]=1)([O-:25])=[O:24]
Reactant: Cn1cc(C=O)c2c3c(ccc21)OCCC3
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(=Cc1cn(C)c2ccc3c(c12)CCCO3)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of 3-methyl-3,7,8,9-tetrahydro-pyrano[3,2-e]indole-1-carboxaldehyde (1.02 g, 4.74 mmol) and ammonium acetate (0.30 g, 3.90 mmol) in 12 ml of nitroethane was heated at 100° C. for 3 h, stirred at room temperature for 18 h, mixed with water (50 ml) and extracted with EtOAc (3×50 ml). The combined extracts were dried (MgSO4), filtered and evaporated to dryness. Crystallization of the residue from a mixture of dichloromethane and hexane gave an orange solid (1.10 g, 85%): mp 200-202° C.
Reaction SMILES: [Si](I)(C)(C)C.C[O:7][C:8]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:21])[CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1.CO>C(Cl)(Cl)Cl>[OH:7][C:8]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=3)=[O:21])[CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ncccc1-c1cncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cccnc2O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
TMSI (100 μL, 0.734 mmol) was added to a solution of 2′-methoxy-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 62, 79 mg, 0.203 mmol) in CHCl3 (4 mL) and the RM was stirred at 60° C. overnight. The RM was cooled to RT, poured into MeOH and the solvent was evaporated off under reduced pressure. The residue was treated with aq. 5% NH3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from hot EtOAc to afford the title compound as beige crystals. UPLC-MS (Condition 2) tR0.87 min, m/z=376.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.38 (t, J=6.65 Hz, 1H) 7.40 (d, J=8.99 Hz, 2H) 7.51 (d, J=6.26 Hz, 1H) 7.86-7.96 (m, 3H) 8.61-8.66 (m, 1H) 9.00-9.04 (m, 1H) 9.09-9.13 (m, 1H) 10.63 (s, 1H) 12.03 (br. s, 1H).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](=[NH:22])[NH2:21])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].[CH2:27]([N:31]1[CH2:36][CH2:35]N[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>>[CH2:27]([N:31]1[CH2:36][CH2:35][N:22]([C:20](=[NH:21])[C:19]2[CH:18]=[C:17]([NH:16][C:15](=[O:26])[NH:14][C:11]3[CH:10]=[CH:9][C:8]([S:5]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:6])=[O:7])=[CH:13][CH:12]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCNS(=O)(=O)c1ccc(NC(=O)Nc2cccc(C(=N)N)c2)cc1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCCC)cc3)c2)CC1
Yield: 13 %

Procedure:
The title compound was prepared from 3-(3-(4-(N-propylsulfamoyl)phenyl)ureido)benzimidamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[CH:14][C:13]=2[F:26])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]>Cl.O1CCOCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=2)=[C:13]([F:26])[CH:14]=1
Reactant: CC(=O)Nc1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Reaction time: 0.42 h
Yield: 88 %

Procedure:
A solution of tert-butyl 4-(2-acetamidopyridin-4-yloxy)-3-fluorophenylcarbamate (110 mg, 0.30 mmol) in 4 M HCl/1,4-dioxane (1.5 mL) was stirred at 0° C. for 20 min then at room temperature for 25 min. The mixture was diluted with EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL), and stirred vigorously for 5 min. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (69 mg, 87%) as a yellow solid. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.13 (d, 1H, J=5.6 Hz), 7.60 (m, 1H), 6.95 (dd, 1H, J=8.6, 9.2 Hz), 6.60 (dd, 1H, J=2.5, 5.6 Hz), 6.48 (dd, 1H, J=2.5, 13.2 Hz), 6.40 (dd, 1H, J=2.0, 8.6 Hz), 5.44 (s, 2H), 2.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+].C(O)C>[Cl-].[Na+].O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[N:20]/[OH:19])[CH:14]=[C:15]([Br:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: O=Cc1cc(Br)cc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C/c1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A mixture of 3-(benzyloxy)-5-bromobenzaldehyde (5.05 g), hydroxyl ammonium chloride (1.326 g), sodium bicarbonate (1.603 g), and ethanol (50 mL) was stirred overnight at room temperature. To the reaction mixture, water and brine were added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.48 g).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]([CH2:28][CH3:29])=[N:16][C:11]=3[CH:12]=[N:13][C:14]=2[CH:15]=1)(=[O:4])=[O:3].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:42].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]([CH2:28][CH3:29])=[N:16][C:11]=3[C:12]([NH2:42])=[N:13][C:14]=2[CH:15]=1)(=[O:3])=[O:4]
Reactant: CCc1nc2cnc3cc(OS(C)(=O)=O)ccc3c2n1CCOc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OS(C)(=O)=O)ccc3c2n1CCOc1ccccc1
Reaction time: 0.42 h

Procedure:
2-Ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl methanesulfonate (0.625 g, 1.52 mmol) was dissolved in chloroform (15 mL). 3-Chloroperoxybenzoic acid (60% pure, 0.437 g, 1.52 mmol) was added in one portion, and the reaction was stirred for 25 minutes. Ammonium hydroxide (25 mL) was added. A precipitate formed, and the reaction was stirred until the precipitate dissolved. p-Toluenesulfonyl chloride (0.290 g, 1.52 mmol) was added in one portion, and the reaction mixture was stirred for an additional 16 hours. The layers were separated, and the aqueous fraction was extracted with dichloromethane followed by chloroform. The organics were combined, washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (eluting with a chloroform:methanol:ammonium hydroxide gradient) followed by recrystallization from acetonitrile provided 0.150 g of 4-amino-2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl methanesulfonate as an orange solid, mp 213.0-214.5° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](OCC)=[O:12])[CH:6]=[CH:7][CH:8]=1.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:19][NH2:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1cccc(C(F)(F)F)c1
Yield: 80.9 %

Procedure:
A solution of ethyl 3-[3-(trifluoromethyl)phenyl]propionate (9.85 g, 40.0 mmol) and hydrazine monohydrate (9.70 mL, 200 mmol) in ethanol (50 mL) was heated under reflux overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (7.51 g, yield 81%) as colorless crystals.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:37][CH2:38][F:39]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:34])=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH2:37][CH2:38][F:39])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Reactant: FCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCN(CCF)CC1
Temperature: 55 °C
Yield: 64.5 %

Procedure:
Treat a solution of 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.67 g, 1.30 mmol) in dimethylformamide (7 mL) with 1-bromo-2-fluoroethane (0.99 g, 7.80 mmol) and heat to 55° C. for 16 hours under a nitrogen atmosphere. Cool the reaction, dilute with ethyl acetate and wash with saturated aqueous sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford 0.47 g (64%) of the title compound in its racemic form. Separate into the enantiomers by chiral HPLC (Chiralpak AD 8×33 cm column, isocratic 90:10 3 A ethanol:acetonitrile with 0.2% dimethylethylamine, 400 mL/min, 300 nM UV) to afford 286 mg of Isomer 1 (>99% ee) and 283 mg of Isomer 2 (98.9% ee): MS (m/z): 560. Check the purity of each isomer using chiral HPLC (Chiralpak AD-H 4.6×150 mm column, isocratic 90:10 3A ethanol:acetonitrile with 0.2% dimethylethylamine, 0.6 mL/min, 270 nM).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:25]1OC(O)C[O:27][CH:26]1O.CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH2:25][CH2:26][OH:27]
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: OC1COC(O)CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCO)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 56.2 %

Procedure:
A solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (350 mg, 1.05 mmol), glycolaldehyde dimer (130 mg, 1.05 mmol) and AcOH (0.15 ml, 2.1 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. Saturated aqueous sodium carbonate (10 ml) and DCM (10 ml) were added and the mixture was shaken and partitioned. The aqueous phase was extracted with DCM (2×10 ml) and the combined organics dried (K2CO3), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (223 mg, 0.59 mmol, 56%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.90 (m, 6H), 1.96 (s, 3H), 2.00 (quintet, 2H), 2.14 (m, 2H), 2.37 (t, 2H), 2.40-2.60 (m, 6H), 2.65 (t, 2H), 3.35 (t, 2H), 3.50 (m, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.89 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 377.2796 [MH]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][C:3]=1[C:36]#[C:37][C:38]([OH:41])([CH3:40])[CH3:39].[CH:42]1[C:51]2[C:46](=[CH:47][C:48](B(O)O)=[CH:49][CH:50]=2)[CH:45]=[CH:44][N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[OH:41][C:38]([CH3:40])([CH3:39])[C:37]#[C:36][C:3]1[N:4]=[C:5]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[S:6][C:2]=1[C:48]1[CH:47]=[C:46]2[C:51](=[CH:50][CH:49]=1)[CH:42]=[N:43][CH:44]=[CH:45]2
Reactant: OB(O)c1ccc2cnccc2c1
Reactant: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Temperature: 120 °C
Yield: 37 %

Procedure:
(S)-tert-butyl 1-(N-(5-bromo-4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.025 g, 0.038 mmol) was taken up in 1 mL of dioxane in a microwave safe tube. Isoquinolin-6-ylboronic acid (0.0098 g, 0.057 mmol), sodium carbonate, 2M in water (0.075 mL, 0.15 mmol), and tetrakistriphenylphosphine palladium (0) (0.0044 g, 0.0038 mmol) were added. The mixture was degassed with nitrogen and the tube was sealed. The tube was then heated to 120° C. in a Personal Chemistry microwave unit for 20 minutes. The mixture was diluted with 10 mL of EtOAc, washed with 5 mL of water and 5 mL of brine, and then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (pipette column, 25% to 70% EtOAc/hexanes), afforded (S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)-5-(isoquinolin-6-yl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.010 g, 37% yield) as a white solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:16])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=O)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CO>[Si:19]([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:16])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CSc1nc(Cl)c2c(CCOC(C)=O)c[nH]c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CO
Product: CSc1nc(Cl)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c2n1
Reaction time: 8 h

Procedure:
5-(2-Acetoxyethyl)-4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine 2.5 (750 mg, 1.66 mmol) was de-acetylated with methanol-aq ammonia (100 ml) and dried by co-evaporation with dry pyridine. The residue was dissolved in dry pyridine (80 ml) and tert-butyldimethylsilyl chloride (598 mg, 3.94 mmol) added. The solution was stirred overnight, evaporated, and residual pyridine removed by co-evaporation with water (2×20 ml). The residue was dissolved in chloroform (500 ml), washed with saturated aq. sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated. The crude product was purified by silica gel chomatography (32×400 mm) eluting with chloroform to give a white solid, 826 mg, 88%. Rf (in C) 0.43; δH(d6-DMSO) 12.10 (1 H, br s, NH), 7.28 (1 H, s, 6-H), 3.81 (2 H, t J 7.0, O—CH2), 2.96 (2 H, t J 7.0, O—CH2CH2), 2.53 (3 H, s, CH3), 0.83 (9 H, s, 3×CH3), −0.05 (6 H, s, 2×CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 40.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (39 mg, 41% over 2 steps) as a orange-red solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.22 (m, 2H), 8.09 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.71 (dd, J=9.2, 2.8 Hz, 1H), 7.15 (m, 3H), 4.51 (d, J=10.3 Hz, 1H), 4.02 (m, 1H), 3.37 (m, 1H), 2.85 (tt, J=7.7, 4.6 Hz, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.75 (m, 2H), 1.22 (m, 4H); ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC 99.0% (AUC), tR=10.81 min.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH:4]([C:8]([NH:10][C:11]1([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)=[O:9])[NH:3][CH2:2]2.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:3]1[CH:4]([C:8]([NH:10][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[CH2:12][CH2:13]2)=[O:9])[CH2:5][CH:6]2[CH:1]([CH2:7]2)[CH2:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 74.8 %

Procedure:
The title compound (D141) (53 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-(3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D100) (48 mg, 0.15 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.040 ml, 0.17 mmol). (Cs2CO3:2 eq; reaction time: 4 hrs; reaction temperature: RT.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]1[CH:40]=[CH:39][C:17]([O:18][C:19]2[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][NH:35]3)=[CH:32][C:22]3[NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:25][C:21]=3[CH:20]=2)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]2[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][N:35]3[S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][C:22]3[NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:25][C:21]=3[CH:20]=2)=[CH:39][CH:40]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.01 ml of triethylamine and 0.005 ml of methanesulfonyl chloride were added in order to an ethyl acetate (1 ml) solution of 20 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][CH:11]=[C:5]2[CH:4]=1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1.O>ClCCl>[Br:19][C:11]1[CH:10]=[N:9][N:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=12
Reactant: CCc1ccn2nccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCc1ccn2ncc(Br)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 116622.5 %

Procedure:
To a stirred solution of 5-ethylpyrazolo[1,5-a]pyridine (1.1 g, 0.008 mmol) in dichloromethane (10 mL) at 0° C. was added NBS (1.75 g, 0.009 mmol) and reaction mixture was stirred at room temperature for 5 min. Subsequently, water was added and the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layer was washed with water (1×30 mL), sat. NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and concentrated to afford 2.1 g (84%) of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17) as a brownish highly viscous liquid. The crude was progressed to next step without any further purification. ESI-LC/MS (m/z): [M+H]+ 225.0, [(M+2)+H]+227.0, RT 2.50 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>CCOCC>[OH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:19]([OH:21])=[O:20])=[CH:13][C:6]=2[C:7]=1[CH3:12]
Reactant: Cc1c(CO)oc2ccc(Br)cc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(CO)oc2ccc(C(=O)O)cc12
Reaction time: 2 h

Procedure:
A solution of 5-bromo-2-hydroxymethyl-3-methylbenzofuran (Annalen, 1112, 1973) (1.93 g) in dry ether (50 ml) was added dropwise to a stirred solution of n-butyl-lithium (12.90 ml of 1.55M solution in hexane) in dry ether (50 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was stirred at 0° for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water. The aqueous layer was separated, washed with ether and acidified with concentrated hydrochloric acid. The solid was filtered off, washed with water, dried and crystallised from isopropanol/petrol (b.p. 80°-100°) to give 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid (0.50 g), m.p. 220°-222°.
Reaction SMILES: [OH-].[K+].C(OC(=O)[NH:7][CH:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)C>C(O)C.O>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:14]1[CH2:15][CH2:16][C:10]3([CH2:9][CH:8]([NH2:7])[CH2:11]3)[CH2:12][CH2:13]1)[CH:26]=[CH:25]2
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc4cc(Cl)ccc4n3)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1CC2(CCN(c3ccc4cc(Cl)ccc4n3)CC2)C1
Temperature: 110 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
0.726 g (12.95 mmol) of potassium hydroxide is added, at room temperature, to a solution of 0.242 g (0.65 mmol) of ethyl[7-(6-chloroquinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate, obtained in step 12.5., in 3.25 mL of ethanol/water (1/1). The mixture is then heated at 110° C. for 12 hours. 0.363 g (6.47 mmol) of potassium hydroxide is added and the mixture is left stirring for 3 hours. The resulting mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. The residue is taken up in dichloromethane and 1N hydrochloric acid solution. The acidic aqueous phase is washed with dichloromethane and then basified with aqueous 1N sodium hydroxide solution, which is extracted several times with dichloromethane. The combined organic phases are then dried over sodium sulfate and the filtrate is concentrated under reduced pressure. 0.188 g of expected product is thus obtained in the form of an oil.