Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[N-:25]=[N+:26]=[N-:27].[Na+].CN(C=O)C>O>[N:25]([C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:22])[F:21])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:26]=[N-:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1N=[N+]=[N-]
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of 15.13 g (0.040 mol) of product of Example 27, 2.85 g (0.040 mol) of sodium azide and 175 ml of DMF was stirred for 1 hour and poured into 500 ml of water. The mixture was extracted with ether. The ether extract was washed several times with water, dried (MgSO4) and concentrated to give 14.4 g (93.7%) of product; mp 46°-47° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[CH:8][C:9]=2[CH2:11][OH:12])[S:4][C:3]=1[C:14]([NH2:16])=[O:15].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(OCC)(=O)C>C(O)(=O)C>[OH:12][CH2:11][C:9]1[C:10]2[C:2]3[NH:1][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:16][C:14](=[O:15])[C:3]=3[S:4][C:5]=2[N:6]=[C:7]([CH3:13])[CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(CO)c2c3c(sc2n1)C(=O)NC(c1ccccc1)N3
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxamide (100 mg, 0.42 mmol) in acetic acid (2 mL) was added benzaldehyde (53 mg, 0.50 mmol) and the mixture was heated to reflux for 16 h. After cooling to room temperature, water (2 mL) and ethyl acetate (2 mL) were added to it. The reaction was further extracted with ethyl acetate (2 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound, 4-hydroxymethyl-2-methyl-6-phenyl-6,7-dihydro-5H-9-thia-1,5,7-triaza-fluoren-8-one (16 mg, 12%).
Reaction SMILES: [C:1](=[O:3])=O.[CH:4]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:4]1([N:10]=[C:1]=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C=O
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C=NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (20 mL) solution containing cyclohexylamine (0.02 mol, 1.98 g), triethylamine (0.06 mol, 6.0 g) at -10° C. (ice and salt bath) for 30 min at a pressure of 0 psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.02 mol, 3.2 g) in 20 mL dichloromethane. After stirring ca. 30 min at -10° C. a white ppt formed. The ppt was filtered off and the filtrate concentrated in vacuo. The residue was extracted with 3×20 mL diethyl ether. The ether layers (light yellow) were 20 concentrated and the residue was distilled under vacuum collecting product, cyclohexyl isocyanate, at 31°-33° C. (1.45 g, 58%) of 97% purity as judged by GC. IR (neat) 2261 cm-1. 1H NMR (CDCl3) δ 3.44-3.39 (m, 1H), 1.90-1.85 (m, 2H), 1.72-1.68 (m, 2H), 1.50-1.41 (m, 2H), 1.33-1.20 (m, 3H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([O:23][CH3:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-[5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 82, 0.090 g, 0.208 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 1.9 M solution of lithium hydroxide (1.5 mL, 2.8 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 5–10% methanol in ethyl acetate as the eluent to afford the title product as a white amorphous solid (0.062 g, 60%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][C:8]=2[CH3:16])=[O:6])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[C:20]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:21]2[N:25]=[CH:24][NH:23][C:22]=2[CH:26]=1.[N+]1([O-])C=CC=CC=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2].O>[Br:17][C:18]1[CH:19]=[C:20]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:21]2[N:25]=[CH:24][N:23]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[C:8]([CH3:16])[CH:9]=3)[C:22]=2[CH:26]=1
Reactant: FC(F)(F)CCNc1cc(Br)cc2[nH]cnc12
Reactant: Cc1cc(B(O)O)ccc1C(=O)NC1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(-n2cnc3c(NCCC(F)(F)F)cc(Br)cc32)ccc1C(=O)NC1CC1
Temperature: 23 °C
Reaction time: 48 h
Yield: 22.8 %

Procedure:
To a solution of 751 mg [4-(cyclopropylcarbamoyl)-3-methylphenyl]boronic acid in 68.6 mL dichloromethane were added 528 mg (1.71 mmol) 6-bromo-N-(3,3,3-trifluoropropyl)-1H-benzimidazol-4-amine which was prepared according to intermediate example 1b, 623 mg copper(II)diacetate, 179 mg pyridine 1-oxide and 416 μL pyridine. The mixture was stirred at 23° C. for two days. Water was added and the mixture was extracted with dichloromethane and methanol. The organic layer was washed with water and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 188 mg (22%) of the title compound.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:18][O:17][CH2:16][CH2:15][N:11]3[CH2:12][C:13]=2[CH:14]=1)([O-])=O.Cl.[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[CH2:18]1[CH:10]2[N:11]([CH2:12][C:13]3[CH:14]=[C:5]([NH2:2])[CH:6]=[CH:7][C:8]=3[CH2:9]2)[CH2:15][CH2:16][O:17]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCOCC1C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCOCC1C2
Yield: 235.6 %

Procedure:
To 8-nitro-3,4,5,6,11,11a-hexahydro-1H-[1,4]oxazino[4,3-b]isoquinoline hydrochloride (0.4 g) in methanol (50 ml) was added 6N hydrochloric acid (0.3 ml) and 5% Pd-C (100 mg). The mixture was treated with hydrogen at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 2.0 h. The catalyst was filtered off and the solvent removed under reduced pressure to yield the title product as a solid (0.4824 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1=[CH:25][C:26]2[C:27]([CH:32]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:34]1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2=[CH:25][C:26]3[C:27]([CH:32]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:45])[CH3:44])[CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:34]2)=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OC1CCC(OS(=O)(=O)C(F)(F)F)=Cc2cccnc21)(C(C)C)C(C)C
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCC(c2ccc(F)c(F)c2)=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C

Procedure:
The mixture of 3,4-difluorophenylboronic acid (0.083 g, 0.527 mmol), sodium carbonate (0.406 mL, 0.813 mmol), (E)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl trifluoromethanesulfonate (0.2045 g, 0.439 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) in Toluene (5 mL) and MeOH (1 mL) was heat to 80° C. under N2 for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed with water one time. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated to give the crude product. The Crude was used as it is. MS (ESI)[M+H+]=430.36.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: OCCCc1cccc(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(CCCBr)c1Cl
Yield: 93.2 %

Procedure:
Compound 60-2 (2.67 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.76 g) and N-bromosuccinimide (2.55 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.25 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[N:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:11])[N:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[CH3:20][CH:21](O)[CH3:22]>Cl>[ClH:19].[NH2:1][C:2](=[N:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:11])[N:3]([CH3:8])[CH2:4][C:5]([O:7][CH:21]([CH3:22])[CH3:20])=[O:6]
Reactant: CN(CC(=O)O)C(N)=NC(=O)Nc1cccc(Cl)c1
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)CN(C)C(N)=NC(=O)Nc1cccc(Cl)c1
Reaction time: 24 h
Yield: 55 %

Procedure:
A 5.0 g sample of N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine was stirred in 200 ml of 4% hydrogen chloride in 2-propanol for 30 minutes. The undissolved solid was removed by filtration. The filtrate was stirred for 24 hours at 25°. The solution was cooled and the precipitated white crystalline 2-propyl N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate, 3.5 g (55% yield), was collected and dried, m.p. 185° C. (d).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:35][CH2:36][CH3:37])[CH2:22][C:23]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[O:24])[C:13]3=[O:38])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.IC.[C:41](=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>O.CN(C=O)C>[CH3:41][N:25]([C:23](=[O:24])[CH2:22][CH:21]([N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:38])[CH2:35][CH2:36][CH3:37])[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: CCCC(CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCCC(CC(=O)N(C)S(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 65 °C
Yield: 70 %

Procedure:
N-{3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoyl}-benzenesulfonamide (33 mg, 0.061 mmol) and Iodomethane (0.015 mL, 0.24 mmol) are added into DMF (1.0 mL) at room temperature. Then cesium carbonate (80 mg, 0.24 mmol) is added and the mixture is warmed up to 65° C. for 10 min. Then it is cooled down to room temperature for 16 hrs. Saturated NH4Cl solution (3.0 mL) and water (10 mL) are added and the mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried (MgSO4) and concentrated to give crude product. Purification by flash column chromatography using EtOAc in hexanes (from 0% to 30%) affords 24 mg (71%) of N-Methyl-N-{3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoyl}-benzenesulfonamide. LCMS (ESMS): m/z 562.19 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>C1COCC1.C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCOCCCCOCCCN
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOCCCCOCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(tert-Butoxycarbonylamino)-4,9-dioxa-12-dodecanamine (5.0 g, 16.45 mmol) was dissolved in THF (30 mL), succinic anhydride (1.81 g, 18.1 mmol) in acetonitrile (10 mL) was added and the mixture was heated to 60 C for 4 h, and subsequently stirred at RT overnight.
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:37]1([CH2:40][N:41]2[C:49]([N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)=[N:48][C:47]3[C:42]2=[N:43][C:44]([C:62]2[CH:63]=[N:64][C:65]([NH2:68])=[N:66][CH:67]=2)=[N:45][C:46]=3[N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:39][CH2:38]1>C(Cl)Cl.CO.CN(C)C=O>[NH2:68][C:65]1[N:64]=[CH:63][C:62]([C:44]2[N:43]=[C:42]3[C:47]([N:48]=[C:49]([N:50]4[CH2:51][CH2:52][N:53]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[CH2:54][CH2:55]4)[N:41]3[CH2:40][CH:37]3[CH2:38][CH2:39]3)=[C:46]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)[N:45]=2)=[CH:67][N:66]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C[C@H](O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Reaction time: 17 h
Yield: 65.6 %

Procedure:
L-Lactic acid (25.2 μl, 0.29 mmol), 1-hydroxybenzotriazole monohydrate (36.7 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (68.8 mg, 0.36 mmol), and triethylamine (50.1 μl, 0.36 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (104.5 mg, 0.24 mmol) at room temperature. The resulting mixture was stirred for 17 hours and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (80.1 mg, 66%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].C([BH3-])#N.[Na+].CO.C(Cl)(Cl)Cl>CO.C(O)(=O)C>[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][N:22]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CCCCC1(N(C)C)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 113 %

Procedure:
A solution of 4.73 g (1 equiv.) of tert-butyl methyl(2-oxoethyl)carbamate in 20 ml of methanol was added at room temperature to a solution of 7 g (1 equiv.) of 4-butyl-N,N-dimethylpiperidine-4-amine bis hydrochloride in 50 ml of methanol, and the resulting reaction mixture was stirred for 50 minutes at room temperature. 3.43 g (2 equiv.) of sodium cyanoborohydride were added in portions to this reaction mixture, and stirring was then carried out for 12 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, the reaction mixture was cooled to 0° C. and adjusted to a pH of ˜5 with acetic acid. 2 g of tert-butyl formylmethyl-methylcarbamate and 1.7 g of sodium cyanoborohydride were then added, and the reaction mixture was stirred for a further 60 minutes at room temperature. Finally, the methanol was distilled off, 100 ml of saturated NaHCO3 solution were added, the resulting mixture was extracted with ethyl acetate (2×200 ml), and the combined organic phases were dried over Na2SO4. After removal of the solvent under reduced pressure, 10.5 g of crude product were obtained in the form of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][S:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[CH:19][CH:18]=3)[N:14]=2)=[C:4]([F:32])[CH:3]=1.ClC1C=C(C(OO)=[O:41])C=CC=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][S:22]([CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[O:41])=[CH:19][CH:18]=3)[N:14]=2)=[C:4]([F:32])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(CSCCn3ccnn3)cc2)co1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 320 mg (0.68 mmol) 1-[2-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 9 ml dichloromethane at −30° C. were added dropwise during 20 min 197 mg (0.88 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 9 ml ethyl acetate. After 1 hour stirring at 30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 20:1 furnished as the second fraction 171 mg (51%) title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Clc1ccc2ccccc2n1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3ccccc3n2)C1=O
Yield: 40.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 2-chloro-quinoline (138.4 mg, 0.84650 mmol), 1,4-dioxane (30 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 105 mg of the product (40.8% yield).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:19])[C:12](=[O:20])[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10]2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu]Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)=[N:7][CH:6]=1)[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2=[O:20]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2c(Cl)cccc2c1=O
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(-c3ccc(C)nc3)nc2)c2c(Cl)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-8-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate (0.21 g, 0.49 mmol) was combined with (6-methylpyridin-3-yl) boronic acid (0.19 g, 1.2 mmol, 2.5 equiv), copper(I)chloride (48 mg, 0.49 mmol, 1 equiv), cesium carbonate (0.32 g, 0.97 mmol, 2 equiv), palladium(II)acetate (11 mg, 0.049 mmol, 0.1 equiv), and bis(diphenylphosphino)ferrocene (27 mg, 0.049 mmol, 0.1 equiv) in degassed N,N-dimethylformamide (3 mL). The mixture was placed into an oil bath preheated at 95° C. for 15 minutes, cooled to ambient temperature, diluted with water (5 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[C:25]([O:40][CH3:41])=[N:26][C:27]([O:38][CH3:39])=[C:28]([Cl:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Cl:37][C:28]1[C:27]([O:38][CH3:39])=[N:26][C:25]([O:40][CH3:41])=[C:24]([Cl:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: COCCO
Product: COc1nc(OC)c(Cl)c(-c2nc3cnc(Nc4ccc(N5CCOCC5)cc4)nc3n(C)c2=O)c1Cl
Yield: 50.5 %

Procedure:
A mixture of 0.60 g (2 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 1.23 g (4 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate, and 1 mL HOAc in 20 mL 2-methoxyethanol is heated under reflux for 16 hours. Workup in EtOAc, followed by chromatography on silica, eluting with hexane-EtOAc (3:2), gives 0.55 g (51%) of the title compound (Compound 18): mp (EtOH) 275–276° C.