Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17]>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:17][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCO
Reactant: Nc1ccnc(Cl)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1nccc(N)n1
Temperature: 180 °C
Yield: 26.3 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), sodium ethoxide (189 mg, 2.78 mmol) and 2-(dimethylamino)ethanol (349 μl, 3.47 mmol) in N,N-dimethylformamide (DMF) (2.9 mL) was heated to 180° C. via a microwave reactor for min. The reaction was purified by RP-HPLC to yield 2-{[2-(dimethylamino)ethyl]oxy}-4-pyrimidinamine (111 mg, 0.609 mmol, 26% yield). MS (ES+) m/z 183.0 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:5]1[CH:4]=[CH:3][C:2](=[O:1])[CH:7]=[CH:6]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1ccc(=O)cc1
Product: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-oxopyridin-1(4H)-yl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.1 Hz, 3H) 2.86 (br. s, 6H) 4.06 (q, J=7.1 Hz, 2H) 6.01-6.11 (m, 2H) 7.43-7.47 (m, 2H) 7.48 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20]([CH:21]([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC([Cl:30])=O.CO>C1(C)C=CC=CC=1>[ClH:30].[F:23][CH:21]([F:22])[C:20]1[C:13]2[CH2:12][CH2:11][C@@:10]3([CH3:24])[C@H:15]([CH2:16][NH:8][CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C[C@]12CCc3c(C(F)F)cccc3[C@H]1CN(Cc1ccccc1)C2
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@]12CCc3c(C(F)F)cccc3[C@H]1CNC2
Product: Cl
Temperature: 160 °C

Procedure:
cis-2-Benzyl-6-(difluoromethyl)-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.070 mmol, 23 mg) was dissolved in toluene (1 ml) and ACE-Cl (0.492 mmol, 0.054 ml, 70.3 mg) was added. The reaction mixture was heated to 160° C. for 15 minutes in a microwave reactor. MeOH (1 ml) was added and the reaction mixture was heated for a further 5 minutes at 160° C. in a microwave reactor and then the resulting solution was passed through an SCX cartridge. The fractions containing the desired product were concentrated in vacuo and then purified by silica column chromatography (eluting with DCM then 2-16% MeOH(NH3) in DCM) to give a crude residue that was dissolved in DCM and 2N HCl in ether (1 ml) was added. The solvent was removed in vacuo to afford cis-6-(difluoromethyl)3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (13 mg), m/z: 238.3 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][NH:9][O:10][CH3:11].C1(C)C=CC=CC=1.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>O>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CNOC
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)N(C)OC

Procedure:
Potassium carbonate (62.4 g) was added in portions at 0° C. over 10 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (250 g) in water (250 ml), then toluene (250 ml) was added and the mixture was stirred until the internal temperature reached 2° C. Butyryl chloride (26 ml) was added dropwise over 10 minutes, then the mixture was stirred at 0° C. for 5 minutes and at ambient temperature for 1 hour. The aqueous phase was separated and shaken with toluene (2×100 ml), then the combined toluene solutions were dried (Na2SO4) and the solvent was removed in vacuo to give N-methoxy-N-methylbutyramide (21.0 g) as a pale-yellow oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2Cl)=[CH:7][C:6]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:51][CH2:50][C:49]2[CH:52]=[CH:53][C:46]([F:45])=[CH:47][CH:48]=2)=[CH:7][C:6]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(NC(=O)c3cccnc3Cl)ccc2C(C)(C)C)CC1
Reactant: NCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc2C(C)(C)C)CC1
Temperature: 125 °C

Procedure:
N-[4-tert-Butyl-3-(1-Boc-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide (200 mg), DIEA (145 μL), IpOH (3 mL) and 4-fluorobenzylamine (184 μL) were combined in a sealed tube and heated to 125° C. for 2 days. The mixture was purified by flash chromatography (EtOAc) to provide the product. M+Na 619; Calc'd for C34H43FN4O4: 590.33.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24](=[O:26])[CH3:25])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:40]([Si:37]([CH3:39])([CH3:38])[O:26][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:27]=[CH:28][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=3)=[N:10][C:11]=2[CH:17]=1)=[CH2:25])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-ethanone (0.215 g, 0.524 mmol) in CH2Cl2 (8 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (0.304 g, 1.15 mmol) and triethylamine (0.29 mL, 2.10 mmol). After stirring 2 h, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.242 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]([NH:15][CH2:16][C:17]2([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C1CCN2[C:34](=[N:35][CH2:36]CC2)[CH2:33][CH2:32]1.C1C[O:45]CC1>>[CH2:34]([NH:35][C:36]([N:20]1[CH2:19][CH2:18][C:17]([CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:21]1)=[O:45])[CH2:33][CH3:32]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C1CCOC1
Reactant: N=C(NCC1(CCc2ccccc2)CCNCC1)NC(=O)c1nc(Cl)c(N)nc1N
Product: CCCNC(=O)N1CCC(CCc2ccccc2)(CNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 100 mg (0.198 mmol) N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N′-(4-phenethyl-piperidin-4-ylmethyl)-guanidine (example 2) and 29 μl DBU in 5 ml THF 12 μM (0.2 mmol) N-propylisocyanat is dropwise added and stirred at room temperature for 2 h. Then the mixture is concentrated under reduced pressure. The residue is purified via preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[N:27]1([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C.O>CN(C)C=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:17]([CH3:26])[S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:29][CH2:28]1)[CH3:38]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.700 g) in N,N-dimethylformamide (16 ml) were-added ethyl piperazin-1-ylacetate (0.568 g) and triethylamine (0.46 ml), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=50:50-100:0), and recrystallized from ethyl acetate-hexane to give the title compound (0.531 g, yield 57%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10](C(N=[N+]=[N-])=O)[N:11]=2)[CH:2]=1.[N-:17]=[C:18]=[O:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])[NH:27][CH2:26][CH2:25]2>C1(C)C=CC=CC=1.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([NH:17][C:18]([N:27]3[C:28]4[C:24](=[CH:23][C:22]([O:21][CH3:20])=[C:30]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[CH2:25][CH2:26]3)=[O:19])[N:11]=2)[CH:2]=1
Reactant: [N-]=[N+]=NC(=O)c1csc(-c2cccnc2)n1
Reactant: [N-]=C=O
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1csc(-c3cccnc3)n1)CC2
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of acyl azide (D15) (370 mg, 1.6 mmol) in toluene (5 ml) was heated to reflux for 0.25 h. After cooling to room temperature, the solution of the isocyanate was added to a solution of 5-methoxy-6-trifluoromethyl indoline (0.35 g, 1.6 mmol) in dichloromethane (10 ml). Filtration and drying afforded the title compound as a white solid (100 mg, 15%), m.p.>200° C.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH:17]([CH3:30])[C:18](=[O:29])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=O.[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)(Cl)Cl>[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[N:35]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:19][C:18](=[O:29])[C:17]([CH3:30])=[C:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: Nc1ccccc1Cl
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2Cl)c(-c2ccccc2Cl)cc1=O
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To 200 ml of xylene were added 6.9 g (0.020 mole) of 1,5-bis(2-chlorophenyl)-2-methyl-1,3,5-pentanetrione, 25.5 g (0.20 mole) of 2-chloroaniline and 20.0 g of Molecular Sieves 5A. After heating the reaction mixture under reflux for 2 hours, the reaction mixture was poured into ice water, followed by addition of 200 ml of chloroform thereto and vigorous stirring of the resultant mixture. One hour later, the reaction mixture was filtered to remove solid matter. The organic layer was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) and then recrystallization from acetone to give 1.4 g of 1,2,6-tris(2-chlorophenyl)-3-methyl-4(1H)-pyridinone having a melting point of 205°-207° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])=[N:9][C:10]2[N:11]([C:17](=[O:32])[NH:18][C:19]3[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]([C:30]#[N:31])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:38][NH2:39]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:30]([C:22]1[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][NH:39][CH3:38])=[C:8]([CH:33]([O:34][CH3:35])[O:36][CH3:37])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:32])=[N:20][CH:21]=1)#[N:31]
Reactant: CN
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 170, 363 mg, 0.679 mmol) in THF (8 ml) was added methylamine 2 M in THF (5 ml, 10.00 mmol) at room temperature and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (3×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (including 3% NH3, 10-20%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.70 min, ESI-MS 470.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 13.60 (s, 1H), 8.27 (s, 1H), 7.74 (s, 1H), 7.53 (s, 1H), 6.92 (t, 1H), 5.50 (s, 1H), 3.96-3.91 (m, 2H), 3.73 (s, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.42-3.34 (m, 8H), 3.30 (s, 3H), 2.84 (t, 2H), 2.28 (s, 3H), 1.95-1.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].CN.[CH:13]([N:16](C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:16][CH3:13])[C:5]#[N:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: CN
Solvent: CO
Product: CNc1ccc(C#N)cc1Cl

Procedure:
A solution of 3-chloro-4-fluorobenzonitrile (1.0 g), methylamine (16 mL of a 2 M solution in methanol) and diisopropylethylamine was reacted in the microwave at 120° C. for 15 min. The mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 3-chloro-4-methylamino-benzonitrile. A suspension of 3-chloro-4-methylamino-benzonitrile (900 mg) in 2 M aqueous sodium hydroxide solution (30 mL) was heated at reflux for 3 h. After cooling to room temperature, the solution was acidified with 2 M aqueous hydrochloric acid and the resulting solid collected by filtration and air-dried to give 3-chloro-4-methylamino-benzoic acid. To a solution of 3-chloro-4-methylamino-benzoic acid (860 mg) in DMF (20 mL) was added carbonyl diimidazole (630 mg) and the reaction stirred at room temperature for 1 h. Then, methylamine hydrochloride (262 mg) and triethylamine (1.62 mL) were added and the reaction stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (3×40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-chloro-N-methyl-4-methylamino-benzamide.
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)=[O:10].[OH:31][C:32]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=2)=[CH:36][C:33]=1[CH:34]=O.CO>ClCCl>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]([C:8]3[CH:27]=[CH:28][C:29]4[NH:30][C:34]([C:33]5[CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=6)[CH:38]=[CH:39][C:32]=5[OH:31])=[N:5][C:6]=4[CH:7]=3)=[O:10])=[CH:17][CH:16]=2)[CH2:21][CH2:22]1
Reactant: COc1cccc(-c2ccc(O)c(C=O)c2)n1
Reactant: CN1CCN(CCc2ccc(NC(=O)c3ccc(N)c(N)c3)cc2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COc1cccc(-c2ccc(O)c(-c3nc4cc(C(=O)Nc5ccc(CCN6CCN(C)CC6)cc5)ccc4[nH]3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a suspension of silica gel (0.8 g) in dichloromethane (5 mL) was added SOCl2 (0.6 mL) and the mixture was stirred at the room temperature for 1 h (gas was released from the reaction mixture). 3,4-Diamino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-benzamide (178.2 mg, 0.5 mmol), 2-hydroxy-5-(6-methoxy-pyridin-2-yl)-benzaldehyde (114.6 mg, 0.5 mmol) and 2 mL dichloromethane were added, and the resulting reaction mixture was stirred at the room temperature for 4 h. After methanol (5 mL) was added, the reaction mixture was stirred at room temperature for another 1 h and was evaporated under reduced pressure. The residue on silica gel was purified by chromatography (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (190 mg, 68%). 1H NMR (MeOH-d4) δ 2.26 (s, 3H), 2.37-2.72 (12H), 4.01 (s, 3H), 6.62 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 7.12 (d, J=9 Hz, 2H), 7.37 (d, J=6 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.54-7.63 (2H), 7.76 (d, J=6 Hz, 1H), 8.04 (d, J=6 Hz, 1H), 8.13 (s, 1H), 8.53 (s, 1H). ESI-MS m/z 563 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:6]2[CH:5]=[CH:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:58][C@@H:59]([CH3:76])[CH2:60][N:61]1[CH:65]=[CH:64][C:63]([C:66]2[CH:73]=[C:72]([F:74])[C:69]([C:70]#[N:71])=[C:68]([Cl:75])[CH:67]=2)=[N:62]1>CN(C=O)C.CCOC(C)=O>[Cl:75][C:68]1[CH:67]=[C:66]([C:63]2[CH:64]=[CH:65][N:61]([CH2:60][C@@H:59]([NH:58][C:11]([C:9]3[N:10]=[C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:1])[N:7]4[CH:8]=3)=[O:13])[CH3:76])[N:62]=2)[CH:73]=[C:72]([F:74])[C:69]=1[C:70]#[N:71]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2c(=O)[nH]ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(=O)[nH]ccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.1 %

Procedure:
5-Oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (0.323 mmol, 0.058 g), HBTU (0.027 mmol, 10.21 mg), DIPEA (0.323 mmol, 0.042 g) and EDCI (0.323 mmol, 0.062 g) were suspended in DMF (2 ml) and the resulting mixture was stirred at RT for 10 min. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.269 mmol, 0.1 g) dissolved in DMF (2 ml) was added and the resulting mixture was stirred for 17 h at RT. At this point more starting materials were added so that the amount of every starting material was raised by half of the original amount. The amount of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile was not changed. The reaction was continued for another 22 h after which the temperature was raised to 80° C. for 4.5 h. The reaction mixture was diluted with EtOAc and washed with 1M Na2CO3, brine and water. The organic phase was dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.006 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.25 (d, 3H), 4.30-4.37 (m, 1H), 4.42-4.49 (m, 1H), 4.54-4.65 (m, 1H), 6.61 (dd, 1H), 6.70 (d, 1H), 7.18 (d, 1H), 7.63 (d, 1H), 7.75-7.82 (m, 2H), 8.26 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)(=[O:12])=[O:11].[C:27]1([CH:37]=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)[CH2:37][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1)(=[O:12])=[O:11]
Reactant: O=Cc1nccc2ccccc12
Reactant: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCS(=O)(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Yield: 50 %

Procedure:
Using General Procedure B: Reaction of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine and isoquinoline-1-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave COMPOUND 177 as a white foam (50% yield). 1H NMR (CDCl3) δ 1.51-1.63 (m, 4H), 2.10 (s, 3H), 2.27 (s, 3H), 2.42-2.45 (m, 2H), 3.26-3.30 (m, 2H), 3.81 (s, 2H), 4.17 (s, 2H), 7.12 (t, 1H, J=8 Hz), 7.27 (s, 1H), 7.37-7.42 (m, 2H), 7.50-7.55 (m, 2H), 7.69-7.74 (m, 3H), 8.05 (d, 1H, J=8 Hz), 8.28 (br s, 1H), 8.40 (d, 1H, J=6 Hz); 13C NMR (CDCl3) δ 17.9, 18.3, 21.4, 23.7, 53.1, 54.4, 57.7, 58.7, 117.2, 120.8, 124.8, 125.9, 126.9, 127.6, 130.2, 132.4, 133.1, 136.3, 139.5, 140.9, 146.2, 148.0, 153.1, 158.2; ES-MS m/z 514 [M+H]+. Anal. Calcd. for C29H31N5O2S.1.3CH3OH: C, 65.54; H, 6.57; N, 12.61; S, 5.77. Found: C, 65.67; H, 6.41; N, 12.23; S, 5.43.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=O)[CH2:15][CH2:16]1)[CH2:11][C@H:10]3[CH3:22].Cl.[NH2:24][OH:25].O>N1C=CC=CC=1>[OH:25]/[N:24]=[C:14]1/[CH:13]=[C:12]2[C@H:17]([CH2:16][CH2:15]/1)[C@@H:18]1[C@H:9]([C@@H:6]3[C@@:4]([CH2:20][CH2:19]1)([CH3:5])[C@H:3]([CH2:2][OH:1])[CH2:8][CH2:7]3)[C@H:10]([CH3:22])[CH2:11]2.[OH:25]/[N:24]=[C:14]1\[CH:13]=[C:12]2[C@H:17]([CH2:16][CH2:15]\1)[C@@H:18]1[C@H:9]([C@@H:6]3[C@@:4]([CH2:20][CH2:19]1)([CH3:5])[C@H:3]([CH2:2][OH:1])[CH2:8][CH2:7]3)[C@H:10]([CH3:22])[CH2:11]2
Reactant: NO
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@@H]3[C@@H]21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H]1CC2=C/C(=N/O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@@H]3[C@@H]21
Product: C[C@@H]1CC2=C/C(=N\O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)CC[C@@H]3[C@@H]21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of (7α,14β,17α)-17-(hydroxymethyl)-7-methylestr4-en-3-one (Example 4; 1.0 g) in pyridine (6 ml) was added hydroxylamine hydrochloride (2.65 g). The reaction mixture was stirred at 80° C. for 1.5 h. After cooling, the mixture was poured into water. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (3E,7α,14β,17α)-3-(hydroxyimino)-7-methylestr-4-ene-17-methanol (0.54 g), [α]D20=+95.5 ° (c=1.41, dioxane), and (3Z,7α,14β,17α)-3-(hydroxyimino)-7-methylestr-4-ene-17-methanol(0.28 g), [α]D20=+87.4 (c=1.0, dioxane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: C1CCCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCCCCC2)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and hexahydro-1H-azepine (0.34 mL, 3.05 mmol) in CH3OH (10 mL). Triethylamine (0.47 mL, 3.35 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 5 hours at 50° C. The reaction was cooled to room temperature and concentrated. The resulting yellow solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (600 mg, 82%) as a yellow solid. LC-MS (ES) m/z=227 [M+H]+.