Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:33]([CH3:35])[CH3:34])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (60 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (235 mg, 1.70 mmol) and 2-iodopropane (0.085 mL, 0.85 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (189 mg, 1.70 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a major product (31 mg, 46% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH3:20][N:21]([CH3:35])[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:25]1([OH:28])[CH2:26][CH2:27][C:22]([N:21]([CH3:20])[CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2occc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Yield: 23.9 %

Procedure:
A solution of benzo[b]furan (1.50 g, 12.7 mmol) in dry THF (50 ml) was cooled to −8° C. under a stream of argon. Tert-butyllithium (15.2 mmol, 10.2 ml of a 1.5 molar pentane solution) was added dropwise in such a way that a reaction temperature of −5° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2½ hours at −5° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (2.76 g, 12.7 mmol) in dry THF (15 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 4 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 1.02 g 1-benzofuran-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 134–137° C. were obtained.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>ClCCl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 5.0 g of 1,2,3,4-tetrahydro-5H-1-benzazepine and 5.91 ml of triethylamine in 50 ml of dichloromethane, chilled in an ice bath, is added, dropwise, 6.32 g of 4-nitrobenzoyl chloride in 75 ml of dichloromethane. The mixture is stirred at 0° C. for 1.5 hr and then at room temperature for 18 hours. The mixture is washed with H2O, 2M HCl, 1M NaOH and dried (Na2SO4). The solvent is removed and the residue re-crystallized from ethanol with the aid of activated carbon to give 7.75 g of light yellow crystals, m.p. 148.5°-150.5° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH2:9][CH2:8]2)=[O:4].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:23])[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[N:14][CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.24 mmol), glycine (1.74 g, 23.1 mmol) and NaOMe solution (34 mL, 17.1 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 1 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 67 mg of the title compound as a white solid. MS: (+) m/z 356.11 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Br[CH2:15][C:16](=O)[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH:17]([CH3:19])[CH3:18])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: CC(C)C(=O)CBr
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(N)n2cc(C(C)C)nc12

Procedure:
The title compound was prepared according to the procedure described in the step 2 in EXAMPLE 1 (METHOD B) from methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, METHOD B, Step 1) and 1-bromo-3-methylbutan-2-one (Synthesis, 1976, 194-196) using N,N-dimethylformamide as a solvent.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:3][CH2:2]1>CO.[BH4-].[K+].ClCCl>[OH:10][CH:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:15])[N:5]1[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC1
Agent: [BH4-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C1c2ccccc2C(O)N1CC1CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
3-Hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.3 g of N-cyclopropylmethylphthalimide in 40 cm3 of methanol and 1.2 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off and the solid obtained is then taken up in dichloromethane and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 4.1 g of 3-hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder (Rf=0.38, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:25][CH2:24][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc(Nc2ncnc3c2CNCC3)cc1
Reaction time: 24 h
Yield: 101.3 %

Procedure:
6-Benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (0.64 g, 1.9 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2 (g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 0.47 g of material which was used as such for the next step.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.[CH3:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(OCC)C>[CH3:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:13](=[O:15])[C:12]([NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[O:16])[CH2:23][CH2:22]1
Reactant: Cc1ccccc1CC1CCNCC1
Reactant: O=C1Cc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: Cc1ccccc1CC1CCN(C(=O)C(=O)Nc2ccc3c(c2)CC(=O)N3)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-oxalamic acid (Example 101b) and 4-(2-methyl-benzyl)-piperidine [J. Org. Chem., 64, 3763. (1999)] according to the method described in Example 1c. Melting Point: 211-213° C. (diethylether)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)CC1
Reaction time: 1 h
Yield: 165.7 %

Procedure:
NaH (60% oil dispersion, 53 mg, 1.3 mmol) was added in portions to a solution of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (240 mg, 1.1 mmol) and benzyl bromide (0.40 mL, 0.58 g, 0.33 mmol) in DMF (2.0 mL). After 1 h, additional NaH (60% oil disperison, 15 mg, 0.38 mmol) was added. After a total of 2.25 h, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aq. NaCl, dried (Na2SO4), and evaporated. Purification by flash column chromatogaraphy on silica gel, eluting with 5-10% EtOAc in hexane gave 167 mg of 4-(benzyloxymethyl)-1-(tert-butoxycarbonyl)piperidine. A portion (160 mg, 0.55 mmol) of this intermediate was dissolved in CH3OH (2.0 mL) and a solution of HCl (2 N in ether, 2.0 mL, 4 mmol) was added. The mixture was stirred overnight at RT and evaported to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([CH3:41])[N:26]=[C:27]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=4)[CH:31]=[N:30][CH:29]=3)[C:20]=12>C(#N)C>[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([N:32]2[C:28]([C:27]3[C:20]4[C:21](=[N:22][CH:23]=[N:24][C:19]=4[N:5]4[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)[N:25]([CH3:41])[N:26]=3)=[CH:29][N:30]=[CH:31]2)=[CH:34][CH:35]=1)[CH3:40]
Reactant: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(Cl)c23)cc1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(N4CC[C@@H](N(C)C)C4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (12.4 mg, 0.109 mmol) and N,N-diisopropylethylamine (14.5 mg, 0.109 mmol) were added to a solution of 4-chloro-3-[1-(4-ethylphenyl)-1H-imidazol-5-yl]-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C22) (37 mg, 0.11 mmol) in acetonitrile (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. After removal of volatiles in vacuo, the residue was chromatographed on silica gel (Gradient: 0% to 15% ethyl acetate in methanol) to afford the product as a glass. Yield: 13 mg, 0.031 mmol, 28%. LCMS m/z 417.1 (M+1). 1H NMR (500 MHz, CDCl3), characteristic peaks: δ 1.17 (t, J=7.6 Hz, 3H), 2.49-2.65 (m, 8H), 3.51-3.61 (br m, 1H), 3.72-3.81 (br m, 1H), 4.08 (s, 3H), 7.10 (br d, J=8.3 Hz, 2H), 7.22-7.29 (m, 2H, assumed; partially obscured by solvent peak), 7.40 (br s, 1H), 7.90 (br s, 1H), 8.29 (s, 1H).
Reaction SMILES: OCCC[N:5]1[C:9]2[CH:10]=[CH:11][C:12](C(F)(F)F)=[CH:13][C:8]=2[NH:7][C:6]1=[O:18].S(Cl)(Cl)=O>ClC(Cl)Cl>[N:5]1[C:6](=[O:18])[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C1N=c2ccccc2=N1
Reaction time: 1 h

Procedure:
To a stirred mixture of 23 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one in 150 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 1 hour at a reflux temperature. After cooling, the reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane, yielding 14 parts (56%) of 1-(3-chloropropyl)-1,3-dihydro-5-trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nnc(C)s2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nnc(Sc2cnc(N)s2)s1
Yield: 30.5 %

Procedure:
A mixture of 2-acetylamino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (3.3 g) in a mixture of ethanol (70 ml), tetrahydrofuran (50 ml) and aqueous 6N-hydrochloric acid (200 ml) was refluxed for 6.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The organic solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (0.85 g, Yield: 58.2%). mp: 203°-205° C. (dec.)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]([CH2:30][C:31]([O:33][CH2:34][S:35][CH3:36])=[O:32])[N:28]=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]>>[Br:1][C:26]1[C:27]([C:37]([F:40])([F:39])[F:38])=[N:28][N:29]([CH2:30][C:31]([O:33][CH2:34][S:35][CH3:36])=[O:32])[C:25]=1[C:22]1[CH:21]=[CH:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([S:10]([CH3:9])(=[O:11])=[O:12])[CH:14]=2)=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Product: CSCOC(=O)Cn1nc(C(F)(F)F)c(Br)c1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Following bromination with N-bromosuccinimide, the title compound 42 is prepared starting from methylthiomethyl 2-(5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate 41.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]=2[N:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>ClC(Cl)C>[CH2:15]([O:14][C:12]([C:11]1[C:5]2[N:4]=[C:3]([CH2:2][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[NH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cccc2[nH]c(CCl)nc12
Reactant: C1COCCN1
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cccc2[nH]c(CN3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
To a solution of ethyl 2-chloromethyl-1H-benzimidazole-4-carboxylate (250 mg) in dichloroethane (2.5 ml) was added morpholine (183 mg) under ice bath cooling and the reaction mixture was stirred at ambient temperature for 15 hours. To the reaction mixture was added morpholine (91 mg) and stirred at 80° C. for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol:chloroform=1:9) to give ethyl-2-morpholinomethyl-1H-benzimidazole-4-carboxylate (219 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[CH3:32]OC(OC)OC>C(O)(=O)C>[CH:29]1([CH2:28][N:27]2[C:22]3[CH:21]=[C:20]([C:11]4[NH:10][C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:13][C:12]=4[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:25]=[CH:24][C:23]=3[N:26]=[CH:32]2)[CH2:30][CH2:31]1
Reactant: Nc1ccc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)cc1NCC1CC1
Reactant: COC(OC)OC
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1nc(-c2ccccc2)c(-c2ccc3ncn(CC4CC4)c3c2)[nH]1
Temperature: 25 °C

Procedure:
Heat a mixture of 2-(2,6-difluorophenyl)-4-phenyl-5-(3-(cyclopropylmethyl)amino-4-aminophenyl)imidazole (0.100 g, 0.24 mmol) and trimethylorthoformate (2 mL) in acetic acid (4 mL) at 120° C. for 1 hour. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Dilute the residue with methanol and pour over an SCX column, eluting sequentially with methanol followed by 2N ammonia in methanol. Combine the basic fractions and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 95:5 dichloromethane:methanol to provide the title compound as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:29]5[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([NH2:26])[CH:28]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: Cc1ccc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)cc1N

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-amino-4-methyl-phenylboronic acid. Mass spectrum (ESI) 421.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH:20]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H]1CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 4-chloro-aniline (0.57 g, 4.5 mmol) in methanol (18 ml) were added acetic acid (2 ml), (S)-2-formyl-azetidine-1-carboxylic acid tert.butyl ester (1.74 g, 9.4 mmol) and after 15 min stirring sodium cyanoborohydride (0.57 g, 9.0 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=9:1) to yield a colourless oil (0.99 g, 74%); MS (ISP): 297.1 ((M+H)+.); 241.3 ((M−C(CH3)3+H)+.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>>[OH:22][C:18]1[CH:17]=[C:16]([C:14]#[C:15][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCc1ccc(I)cc1
Reactant: C#Cc1cccc(O)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (100 mg, 0.34 mmol) and 3-ethynylphenol (0.025 mL, 0.38 mmol) according to the general procedure IC to give 66 mg (69%) of a light brown solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:6→1:0). Rf=0.24 (EtOAc:PE; 1:2); 1H NMR (CDCl3): δ 7.43 (d, J=8.0 Hz, 2H), 7.20-7.15 (m, 3H), 7.10-7.08 (m, 1H), 7.00-6.99 (m, 1H), 6.84-6.80 (m, 1H), 5.50 (br, 1H), 3.68 (s, 3H), 2.96 (t, J=8.0 Hz, 2H), 2.64 (t, J=8.1 Hz, 2H); 13C NMR (CDCl3): δ 173.7, 155.7, 141.0, 132.0, 129.8, 128.5, 124.7, 124.4, 121.3, 118.4, 115.9, 89.4, 89.0, 52.0, 35.6, 31.0; ESI-MS m/z 303.0 (M+Na+).
Reaction SMILES: [O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][CH:3]1[NH:25]C(=O)OCC1C=CC=CC=1.Br.CC(O)=O>CCOCC>[NH2:25][C@@H:3]1[C:2](=[O:1])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Intermediate 1A (5.24 g, 11.33 mmol) and 33% HBr/HOAc (50 mL, 11.33 mmol) were combined and stirred at room temperature for 2 h. The reaction mixture was diluted with 300 mL of ether. The resulting precipitate was collected by filtration, rinsed with ether (2×50 mL), then dried under vacuum. The solid was dissolved in 100 mL of water and made basic by the addition of solid NaHCO3. The mixture was extracted with EtOAc (2×200 mL), and the combined organic extracts were washed with water (1×40 mL) and brine (1×50 mL), then dried (MgSO4), filtered and concentrated in vacuo to give the crude racemic amine. This solid was purified by preparative SFC chromatography (Berger SFC MGII, AD-H 250×30 mm ID, 5 μm, 78/22 CO2/MeOH with 0.1% DEA, 85 mL/min). After the fractions containing product were concentrated and dried overnight under vacuum, Intermediate 1B (1.576 g, 42.4%) was obtained as a colorless solid: 1H NMR (400 MHz, DMSO-d6) δ 8.47 (1 H, dd, J=4.73, 1.65 Hz), 7.98 (1 H, td, J=7.70, 1.98 Hz), 7.62 (3 H, dd, J=14.75, 7.48 Hz), 7.45-7.57 (5 H, m), 7.26-7.43 (3 H, m), 6.92 (1 H, d, J=8.14 Hz), 4.57 (1 H, br. s.), 2.67 (1 H, br. s.); Chiral HPLC: RT=5.160 min (Berger SFC, AD-H 250×4.6 mm ID, 5 μm, 75/25 CO2/MeOH with 0.1% DEA, 2.0 mL/min); HPLC: RT=1.290 min (CHROMOLITH® ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=329.0 [M+H]+.