Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[C:4]2[C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]2
Reactant: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCCCC2)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=c1ccc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]1
Temperature: 125 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)cinnamamide (436 mg, 1.1 mmol, 1 eq.) was placed in chlorobenzene (2.1 mL), in the presence of aluminium trichloride (906 mg, 1.5 mmol, 6 eq.). The reaction mixture was heated at 125° C. and stirred for 2 hours. After cooling down to room temperature, it was diluted with a water and ice mixture and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 8-chloro-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (225 mg, 67%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[NH:18][C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:22][C:21]([F:23])([F:24])[CH2:20][C:19]([NH:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH2:9][OH:8])=[O:25]
Reactant: COc1ccc(NC(=O)CC(F)(F)F)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CC(F)(F)F)c(CO)c1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-((tert-butyldimethylsilyloxy)methyl)-4-methoxyphenyl)-3,3,3-trifluoropropanamide (20.0 g) in anhydrous THF (200 mL) was added a solution of TBAF (16.6 g, 63.6 mmol) in anhydrous THF (60 mL). The mixture was stirred at 35° C. for 30 minutes. The mixture was quenched with ice-water. An aqueous/EtOAc workup was followed by removal of volatiles in vacuo. The crude product was purified by column chromatography on silica gel (PE/EtOAc=½) to give the product. 1H NMR (CDCl3 400 MHz): δ 8.60 (brs, 1H), 7.82 (d, J=8.8 Hz, 1H), 6.85 (dd, J=9.2, 3.2 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.65 (s, 2H), 3.80 (s, 3H), 3.23 (q, J=10.4 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].Cl.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N1C=CC=CC=1C1OC2C=C(O)C=CC=2N=1>C(N(CC)CC)C>[N:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(O)cc1O
Reactant: ClCc1ccncc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: Oc1ccc2nc(-c3ccccn3)oc2c1
Solvent: CCN(CC)CC
Product: Oc1ccc2nc(-c3ccncc3)oc2c1

Procedure:
2-Pyridin-4-yl-benzoxazol-6-ol was prepared using 4-aminoresorcinol hydrochloride (1.5 g, 9.3 mM), isonicotinyl chloride hydrochloride (1.8 g, 10.2 mM), triethylamine (3.0 g, 30.0 mM) and pyridinium-p-toluenesulfonate (PPTS, 800 mg, 3.2 mM) were refluxed in xylenes (50 mL) for about 24 hours as described for 2-pyridin-2-yl-benzoxazol-6-ol; m.p., 139-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=S.[F:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:27][C:26]([CH2:25][CH2:24][C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:31]=[CH:32][C:33]([F:34])=[C:12]([F:11])[CH:13]=3)[CH2:17][CH2:18]2)=[O:30])=[N:28][N:29]=1
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC(=O)CCC(=O)NC1CCN(Cc2ccc(F)c(F)c2)CC1
Solvent: CN(C)C=O
Product: O=C(CCc1nnc(Nc2ccccc2Cl)o1)NC1CCN(Cc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-isothiocyanato-benzene (0.125 g) and N-[1-(3,4-difluorobenzyl)-piperidin-4-yl]-3-hydrazinocarbonyl-propionamide (0.20 g) were stirred together in dimethylformamide (2 ml) at ambient temperature for 2 hours. AM resin (0.35 g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 16 hours. N-cyclohexylcarbodiimide N-methyl polystyrene HL (0.682 g, Novabiochem, 1.69 mmol/g) was added and the resulting mixture was stirred at 80° C. for 24 hours, then allowed to cool. The reaction mixture was then filtered, washing with dimethylformamide (2×2 ml). The combined filtrates were evaporated and the residue was purified by reverse phase HPLC to give the title compound as a white solid. (0.094 g, m.pt. 162-163° C., MS [M+H]+ (APCI+) 476/8).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine and 280 mg of 4-(trifluoromethyl)benzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride, then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. In this way 375 mg of expected product is obtained.
Reaction SMILES: C(OC(NCCCO[C:13]1[CH:46]=[CH:45][CH:44]=[CH:43][C:14]=1[C:15]([NH:17][C:18]1C=CC(C(N(C2C=CC(C)=CC=2OCCCCN)C)=O)=CC=1OC)=[O:16])=O)(C)(C)C.C(=O)(OC1C=CC=CC=1)OCCCN(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:18][NH:17][C:15](=[O:16])[C:14]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:13]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: CN(C)CCCOC(=O)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 250.5 %

Procedure:
A mixture of 4-[2-[3-(tert-butoxycarbonylamino)prop-1-yl]oxybenzoyl]amino-3-methoxy-N-[2-(4-aminobut-1-yl)oxy-4-methylphenyl]-N-methylbenzamide (120 mg) and 3-(dimethylamino)prop-1-yl phenyl carbonate (127 mg) in N,N-dimethylformamide (5 ml) was stirred at 50° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (15 ml) and the solution was washed successively with saturated aqueous sodium bicarbonate solution and brine. The solution was dried over potassium carbonate. The solvent was evaporated and the residue was purified on silica gel column chromatography (SiO2 20 g, 3-15% methanol in chloroform) to give 4-[2-[3-(tert-butoxycarbonylamino)prop-1-yl]oxybenzoyl]amino-3-methoxy-N-[2-(3-dimethylaminoprop-1-yl)oxycarbonylamino]but-1-yl]oxy-4-methylphenyl]-N-methylbenzamide (64 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([C:11](O)=[O:12])[CH2:5]2.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2
Reactant: O=C(O)[C@H]1Cc2ccc(Br)cc2C1
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1Cc2ccc(Br)cc2C1
Temperature: 1 °C
Yield: 99.2 %

Procedure:
(S)-5-Bromo-indan-2-carboxylic acid (12.65 mmol) was dissolved in dry THF (75 mL). The mixture was cooled with stirring to 0-2° C. under argon. 1M BH3 in THF (18.4 mL; 18.4 mmol) was added via syringe at a rapid dropwise rate. The mixture was stirred at 0° C. for 30 minutes then allowed to warm to rt and stir for 90 minutes. The reaction mixture was cooled again to 0° C. and treated carefully with 10 mL of water. Volatiles were removed under reduced pressure and the residue partitioned between diethyl ether (100 mL) and brine (50 mL). The aqueous phase was extracted with 100 mL ethyl ether and each extract washed with brine. The combined extracts were dried over Na2SO4, filtered and volatiles were removed under reduced pressure to give 2.85 g of ((S)-5-bromo-indan-2-yl)-methanol as a crystalline white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:19]3[C:27]4[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)([CH3:18])[CH2:12][C:13](OCC)=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:19]3[C:27]4[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)([CH3:18])[CH2:12][CH2:13][OH:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(C)(c1ccc2c(c1)OCCO2)c1c[nH]c2c(CSC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CSCc1cccc2c(C(C)(CCO)c3ccc4c(c3)OCCO4)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 625 mg (1.47 mmol) of the compound from Example 106A in 3 ml of tetrahydrofuran was added dropwise to 5.14 ml (5.14 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 6 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then mixed with water and acetonitrile, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 491 mg (87% of theory) of the title compound were obtained.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=O)[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CCO>[CH3:2][CH:3]1[C:8](=[N:13][OH:14])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2
Reactant: CC1C(=O)C2CCN1CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1C(=NO)C2CCN1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
2-Methylquinuclidin-3-one hydrochloride from Step L (5.3 g, 30.2 mmol, 1 eq), hydroxylamine hydrochloride (2.5 g, 36.4 mmol, 1.2 eq) and sodium acetate trihydrate (12.4 g, 90.9 mmol, 3 eq) are suspended in 70 mL EtOH and stirred at room temperature. After 24 h, the mixture is concentrated in vacuo. The residue is suspended in CHCl3 and the solids are filtered. The solids are rinsed with excess CH3CN. The combined organic washes are concentrated in vacuo to give 4.65 g (100%) of 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime. MS (ESI) for C8H14N2O m/z 155.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:4]1[CH:3]=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]2)[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: CC(C)N1CCNCC1
Reactant: FC(F)(F)Oc1cc(Br)cc(C2OCCO2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2cc(OC(F)(F)F)cc(C3OCCO3)c2)CC1
Temperature: 100 °C
Yield: 69.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (363 mg, 0.396 mmol) was added to a suspension of 2-(3-bromo-5-(trifluoromethoxy)phenyl)-1,3-dioxolane (21, 1.24 g, 3.96 mmol), isopropylpiperazine (610 mg, 4.75 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (rac-BINAP, 345 mg, 0.554 mmol), cesium carbonate (2.58 g, 7.92 mmol) and anhydrous toluene (50 mL). The mixture was placed under nitrogen and heated to 100° C. for 17 h. The solvent was removed in vacuo and methanol (30 mL) and silica gel (30 g) were added. After removing the methanol the adsorbed crude product was purified by silica gel chromatography eluting with 0-60% EtOAc in hexanes to afford the title compound (996 mg, 70%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 6.93 (s, 1H), 6.78 (s, 1H), 6.68 (s, 1H), 5.77 (s, 1H), 4.17-3.99 (m, 4H), 3.26-3.22 (m, 4H), 2.72 (sept, 1H), 2.68-2.62 (m, 4H), 1.08 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][NH:4][C:3]1=[O:8].BrBr.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:18][O:17][C:11]1[CH:16]=[CH:15][C:14]([CH:5]2[NH:4][C:3](=[O:8])[N:2]([CH3:1])[C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: CN1C(=O)CNC1=O
Reactant: COc1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2NC(=O)N(C)C2=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
4.56 g (40 mmol) of 3-methyl-hydantoin, 30 ml of acetic acid, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 40° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature. To the reaction mixture was then added 60 mmol of anisole. The reaction mixture was then allowed to undergo reaction at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.22 g (yield: 48%) of 5-(p-methoxyphenyl)-3-methyl-hydantoin.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:5](=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[Cl:13]C1SC2C=CC(F)=C(F)C=2N=1>>[Cl:13][C:2]1[S:3][C:4]2[C:5](=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: Fc1ccc2sc(Cl)nc2c1F
Reactant: N#Cc1cccc2sc(N)nc12
Product: N#Cc1cccc2sc(Cl)nc12

Procedure:
The title compound was prepared from 2-amino-1,3-benzothiazole-4-carbonitrile as described for 2-chloro-4,5-difluoro-1,3-benzothiazole.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.C[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39]4([CH3:44])OCC[O:40]4)=[CH:35][C:29]=3[C:30](=O)[O:31]2)=[CH:26][CH:25]=1.[Li]>C1COCC1.O>[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39](=[O:40])[CH3:44])=[CH:35][C:29]=3[CH:30]([C:2]3[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)[O:31]2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2c(c1)oc(=O)c1cc(C3(C)OCCO3)ccc12
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)Oc1cc(O)ccc1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
1-[2-(4-bromo-phenoxy)-ethyl]-piperidine (0.76 g, 2.7 mmol) from Step F was dissolved in THF (15 ml) under Ar and cooled to −78° C. n-Butyl lithium (10.0 M, 0.26 ml, 2.6 mmol) was added and the mixture was stirred at −78° C. for 1 hour. The compound from Step E (1.11 g, 3.56 mmol) was dissolved in THF (35 ml) under Ar and cooled to −78° C. to which the freshly prepared lithium salt of 1-(2-(4-bromo-phenoxy)-ethyl)-piperidine was transferred via a cannula. The reaction was stirred for 2 h. Water (150 ml) was added and the reaction extracted three times with ethyl acetate (150 ml). After removing the solvent the crude product was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to yield 0.56 g (48%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.44 (2H, m, NCH2CH2CH2), 1.59 (4H, m, NCH2CH2CH2) 1.61 (3H, s, CH3), 2.25 (4H, m, NCH2CH2CH2), 2.83 (2H, m, NCH2CH2O), 3.78 (2H, m, OCH2), 3.85 (3H, s, OCH3), 4.01 (2H, m, OCH2), 4.18 (2H, m, NCH2CH2O), 6.69 (1H, s, ArH), 6.73 (1H, d, ArH), 6.96 (2H, d, ArH), 7.17 (1H, s, ArH), 7.56 (1H, m, ArH), 7.60 (2H, d, ArH), 7.76 (2H, m, ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O1CCCC1>[S:25]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.6 %

Procedure:
To a solution of 2-benzyloxybenzyl alcohol (2.1 g, 9.42 mmol) in tetrahydrofuran (10 mL), triethylamine (1.38 mL, 9.89 mmol) and methanesulfonyl chloride (0.766 mL, 9.89 mmol) were added under ice cooling and stirred at room temperature for 30 minutes. After filtration to remove the insoluble materials, the filtrate was concentrated to give (2-benzyloxyphenyl)methyl mesylate (3.24 g). To a suspension of methyl isobutyrylacetate (1.43 g, 9.89 mmol), sodium hydride (60% in oil; 396 mg, 9.89 mmol) and dimethoxyethane (10 mL), a solution of (2-benzyloxyphenyl)methyl mesylate (3.24 g) in dimethoxyethane (10 mL) was added and stirred at 70° C. overnight. After addition of 0.5 M HCl, the reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oil. To this oil, toluene (20 mL) and hydrazine monohydrate (317 mg, 9.89 mmol) were added and the resulting mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 8:1) to give the titled compound (750 mg, 25%) as a light-yellow amorphous substance.
Reaction SMILES: [CH2:1]=O.[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH2:10][CH:9]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20].Cl>C(O)=O>[ClH:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH3:1])[CH2:10][CH:9]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]
Reactant: C=O
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Agent: Cl
Solvent: O=CO
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(C)C2
Temperature: 80 °C

Procedure:
Formic acid (0.55 ml) and 37% formaldehyde (0.6 ml) are added at 0° C. to the compound obtained in Example 4 (1.8 g; 7.2 mmol) in the form of a base. The reaction mixture is heated at 80° C. for 24 hours with stirring. After having cooled the reaction mixture to 0° C., 10 ml of 6N HCl are added. The mixture is then washed with ether, rendered alkaline with 2N NaOH and extracted with ether. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The yellow oil so obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached). The purified oil is taken up in ether saturated with HCl(g) and stirred until a precipitate is obtained, which precipitate is then suction-filtered off and placed under a vacuum in a dessicator to yield the title product in the form of a very hygroscopic white solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH3:28])[CH2:23]1>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=3[N:6]=2)[CH:24]([CH3:28])[CH2:23]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: CC(=O)NCc1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Solvent: CCO
Product: CC(=O)NCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)ccc4[nH]3)C(C)C2)c(Cl)c1

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (88 mg, 0.4 mmol, Example 1c) and N-{5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-ylmethyl}-acetamide from step (e) above (141 mg, 0.5 mmol) in ethanol (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 467 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][C:12]=1[CH3:30])=[O:8])C.O.[OH-].[Li+]>C1COCC1.O>[C:4]([CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][C:12]=1[CH3:30])=[O:8])([OH:31])=[O:3]
Reactant: CCOC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the ethyl ester from Example 5 (0.050 g, 0.10 mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.020 g, 0.45 mmol). The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue diluted with water then washed with diethyl ether. The aqueous layer was acidified to pH 1 by addition of 1M HCl and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a white solid; yield 0.046 g (99%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:30](=[O:37])[C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2I)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:31](=[C:32](\[C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)/[C:33]([CH3:36])([CH3:35])[CH3:34])/[C:30]2=[O:37])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)C)c2ccccc2I)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C#N)cc3)C(C)(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-cyano-phenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.35 (s, 9H) 3.84 (s, 3H) 5.07 (s, 2H) 5.19 (d, J=7.83 Hz, 1H) 6.56 (t, J=7.71 Hz, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H) 7.42 (d, J=8.08 Hz, 2H) 7.50 (t, J=7.71 Hz, 1H) 7.59 (d, J=7.58 Hz, 1H) 7.87 (d, J=7.58 Hz, 1H) 7.95-8.05 (m, 3H).