Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][C:15]([NH:17][NH2:18])=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=N)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[N:18][NH:17][C:15](=[O:16])[CH2:14][CH2:13][C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH3:20]
Reactant: CCOC(=N)c1cccs1
Reactant: NNC(=O)CCc1nc(-c2cccc(Cl)c2)no1
Solvent: CCO
Product: CCOC(=NNC(=O)CCc1nc(-c2cccc(Cl)c2)no1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide (266.69 mg, 1 mmol) was mixed with thiophene-2-carboximidic acid ethyl ester (191.6 mg, 1 mmol) in ethanol (6 ml) and stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate, dried and concentrated in vacuo. The crude product was triturated with hexane to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid (ethoxy-thiophen-2-yl-methylene)-hydrazide as a white solid (305 mg, 75%). 1H-NMR(CDCl3) d(ppm): 8.99 (ws, 1H), 8.09 (s, 1H), 7.98 (d, 1H), 7.41(m, 4H), 7.08 (dd, 1H), 4.27 (q, 2H), 3.34 (m, 4H) and 1.41 (t, 3H). Step 2: 3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole: 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid (ethoxy-thiophen-2-yl-methylene)-hydrazide (81 mg, 0.2 mmol) was mixed with 2M methylamine (0.3 ml in THF) in ethanol (2 ml) at 70˜80° C. overnight. The reaction mixture was concentrated with silica gel and purified by column chromatography with 0.5˜2.0% methanol in ethyl acetate to give 54 mg (72.5%) of 3-(3-chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole. 1H-NMR(CDCl3) d (ppm): 8.08 (s, 1H), 7.97 (d, 1H), 7.41 (m, 4H), 7.20 (dd, 1H), 3.80 (s, 3H), 3.68 (dd, 2H), 3.38 (dd, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: CC(=O)N1CCC(=O)CC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NC1CCN(C(C)=O)CC1

Procedure:
The title compound, light yellow solid, MS: m/e=510.4 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1-acetyl-4-piperidone.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18](OC)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:33])[F:32])[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:36])=O>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([Cl:36])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:32])[F:33])[C:26]([F:28])([F:29])[F:27])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Product: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 100 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
A mixture of 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (Example 185, 2.10 g, 4.27 mmol) and phosphoryl chloride (11 mL) was stirred at 100° C. for 5 hr. The mixture was concentrated in vacuo, diluted with water, neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether/n-hexane to give the title compound as a colorless powder (889 mg, 1.79 mmol, 42%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.[NH:37]1[CH2:40][CH2:39][CH2:38]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[N:37]1([C:33](=[O:34])[CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:5])=[O:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[N:31][CH:30]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetic acid (0.200 g) in N,N-dimethylformamide (5 mL) were added azetidine hydrochloride (57 mg), triethylamine (0.169 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (116 mg) and 1-hydroxybenzotriazole (93 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, 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:methanol=100:0-80:20, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.115 g, yield 53%) as colorless crystals. MS: 534 (MH+). melting point 94-98° C.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]([CH3:31])[CH2:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[N:20]=[C:19]([Cl:32])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO>[Cl:32][C:19]1[N:20]=[C:21]([N:24]([CH3:31])[CH2:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(Cc1nccs1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CO
Product: CN(Cc1nccs1)c1nc(Cl)nc(NN)c1F
Reaction time: 96 h

Procedure:
Tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[methyl (1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (1.51 g, 2.57 mmol) was dissolved in MeOH (25 mL) and HCl (4M in 1,4-dioxane) (25 mL) at room temperature. The reaction mixture was left to stir over 4 days and then evaporated to provide 2-chloro-5-fluoro-6-hydrazino-N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine, assumed dihydrochloride, as a beige solid (0.9034 g, 98%). LCMS: (M+H−2HCl)+=289.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH2:24]>CO.C(Cl)Cl>[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:24][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and L-histidine methyl ester dihydrochloride (Sigma), the title compound was prepared as a solid (mp=195-197° C.). The reaction was monitored by tlc (Rf=0.29 in 10% CH3OH/CH2Cl2).
Reaction SMILES: [CH:1]([C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1)=[CH2:2].CO.[Br:14]Br.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:14][CH2:2][CH2:1][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: C=CC1(CC(=O)OCC)CC1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC1(CCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 30.86 ml (30.86 mmol) of borane/THF complex solution (1 M in THF) are added dropwise at 0° C. to a solution of 14.00 g (90.79 mmol) of ethyl (1-vinylcyclopropyl)acetate (Example 2A) in 80 ml of anhydrous THF. After 30 min at 0° C., the mixture is stirred at room temperature for a further 30 min, and 0.20 ml (5.00 mmol) of methanol is then added. At −5° C., 5.61 ml (108.94 mmol) of bromine and 26.98 g (150.0 mmol) of sodium methoxide solution (30% strength in methanol) are then successively added dropwise to the reaction mixture. After the mixture has reached room temperature, 30 ml of saturated sodium bicarbonate solution are added. The reaction mixture is extracted three times with tert-butyl methyl ether. The combined organic phases are washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent and kugelrohr distillation of the residue at 180° C. and 0.04 mbar gives 12.90 g (60% of theory) of the title compound as a yellow oil which, on storage in a fridge, turns very dark over a period of a few hours.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[O:20])=[CH:13][CH:14]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1

Procedure:
Using a procedure similar to Example 1B except starting with 2-nitroaniline and p-anisoyl chloride, the title compound was obtained as a solid (98%); MS(FD): 272.0.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][NH:6][C:7](=[O:25])[C:8]1[CH2:24][CH2:23][CH2:22][CH2:21][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[F:20])=[O:11])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH2:5][NH:6][C:7](=[O:25])[C:8]1[CH2:24][CH2:23][CH2:22][CH2:21][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[F:20])=[O:11])=[O:34])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCCNC(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Solvent: ClC(Cl)Cl
Product: CCS(=O)CCNC(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 3 h

Procedure:
In chloroform (30 ml) was dissolved N-(2-ethylthioethyl)-N'-(2-fluoro-4-chlorophenyl)-3,4,5,6-tetrahydrophthalamide (1.9 g), and with stirring at a constant temperature of 3°-8° C. m-Chloroperbenzoic acid (1.0 g) was added in small portions over an hour. The mixture was stirred at the same temperature for 3 hours and, then, allowed to stand at room temperature overnight. The solution was washed twice with a 10% aqueous solution of sodium nitrite (20 ml each), washed with water and dried over anhydrous sodium sulfate. The chloroform layer was concentrated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate. Yield 1.8 g; m.p. 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[N:25][CH:26]=1.Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:27][C:23]2[CH:24]=[N:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)=[O:16])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: CC(Nc1cncc(Cl)n1)c1cccc(C(=O)O)c1
Reactant: Cc1cncc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cncc(NC(=O)c2cccc(C(C)Nc3cncc(Cl)n3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.2 %

Procedure:
A mixture of 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}benzoic acid (11 mg, 0.04 mmol), 5-methylpyridin-3-amine (5 mg, 0.048 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (11 mg, 0.059 mmol), 4-pyrrolidinopyridine (1.2 mg, 0.008 mmol) and triethylamine (0.013 mL, 0.095 mmol) in dichloromethane (1 mL) was stirred at room temperature for 17 hours. After this time the mixture was diluted with dichloromethane (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}-N-(5-methylpyridin-3-yl)benzamide (9 mg, 61%) as a pale yellow oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][C:6]=1[F:16])C>C1COCC1.O>[F:11][C:10]1[CH:9]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:7]=[C:6]([F:16])[C:5]=1[CH:4]=[O:3]
Reactant: CCOC(OCC)c1c(F)cc(C(C)(C)O)cc1F
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amberlist-15(wet) (0.64 g, 6.56 mmol) was added to a solution of 2-[4-(diethoxymethyl)-3,5-difluorophenyl]propan-2-ol (1.8 g, 6.56 mmol) in THF (33 mL) and water (5.3 mL). The mixture was vigorously stirred under argon at room temperature overnight. The reaction was then filtered through a fritted funnel. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 7.05 (d, 2H), 5.23 (s, 1H), 1.50 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.C(OCC)(=[O:47])C>O>[OH2:8].[OH2:47].[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
In 24 L of dimethyl sulfoxide were suspended 14.5 kg (44.68 mol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 8.0 kg (29.88 mol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, 6.3 kg (59.43 mol) of sodium carbonate and 300 g (2.92 mol) of sodium bromide, which were then heated to 145±5° C. under a nitrogen atmosphere and stirred for 7 hours. After cooling to room temperature, 80 L of ethyl acetate and 80 L of water were added, followed by separation into two layers. The organic layer was washed with 40 L of water twice and concentrated under reduced pressure. To the residue was added 60 L of ethanol and concentrated until the total volume became 40 L under reduced pressure to yield a solution of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate in ethanol. To the ethanol solution was added 2.4 kg of sodium hydroxide dissolved in 8 L of water. The reaction mixture was heated to 60±5° C. and stirred for 1 hour. The reaction mixture was cooled to 30±5° C. and adjusted to pH 10 or lower by the addition of 13 L of 3N hydrochloric acid, followed by the addition of 56 L of ethyl acetate. The mixture was adjusted to pH 6-7 by the addition of 13 L of 3N hydrochloric acid and 6 L of water was added thereto. The crystals formed were collected by filtration, washed with 40 L of a mixed solvent of water:ethanol:ethyl acetate (1:1:1), and dried to yield 13.5 kg of the title compound. HPLC purity area percentage 98.0%, Yield 80.1%.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][CH:11]([S:14][C@@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[CH:17]([C:18](=O)[CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][CH2:23][C:24]3=[O:34])[CH2:16]2)[CH2:10]1.Cl.[NH2:37][OH:38]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][CH:11]([S:14][C@@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[CH:17](/[C:18](=[N:37]/[OH:38])/[CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][CH2:23][C:24]3=[O:34])[CH2:16]2)[CH2:10]1
Reactant: C[C@]12CC[C@@H](SC3CCNC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@]12CC[C@@H](SC3CCNC3)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The title compound was prepared following the procedure described in Example 1 and starting from 3α-[3-(RS)-pyrrolidinylthio]androstane-6,17-dione fumarate (I-dc, Example 81, 115 mg) and hydroxylamine hydrochloride (20 mg). The crude product was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3 9/1/0.1). To the concentrated fractions the stoichiometric amount of fumaric acid in MeOH was added. After addition of EtOAc, the precipitate was filtered to give the title compound I-dd as a white solid in 65% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.72 (1H, bs), 6.42 (1H, m), 4.69 (1H, m), 3.57 (1H, m), 3.30-3.10 (6H, m), 2.40-0.95 (20H, m), 0.76 (3H, s), 0.63 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=1>>[C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:33]3[CH:32]=[C:31]([CH2:30][C:29]([OH:39])=[O:28])[CH:36]=[CH:35][CH:34]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(Cl)cccc23)c1
Product: O=C(O)Cc1cccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-chloro-quinolin-3-yl]-phenyl-methanone and (3-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 507.
Reaction SMILES: C([Si]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:31])[CH:20]([O:29][CH3:30])[CH2:21][C@@H:22]([CH3:28])[C:23]([O:26][CH3:27])([CH3:25])[CH3:24])(C)C)(C)(C)C>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:30][O:29][CH:20]([CH2:21][C@@H:22]([CH3:28])[C:23]([O:26][CH3:27])([CH3:25])[CH3:24])[C@H:19]([C@@H:13]1[C@:14]2([CH3:18])[C@H:10]([C@@H:9]([OH:8])[CH2:17][CH2:16][CH2:15]2)[CH2:11][CH2:12]1)[CH3:31]
Reactant: COC(C[C@@H](C)C(C)(C)OC)[C@@H](C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(C[C@@H](C)C(C)(C)OC)[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 80 °C
Yield: 85.3 %

Procedure:
The compound of Example 10G (42 mg, 0.093 mmol) was dissolved in 1.5 mL of 1 N tetra-n-butylammonium fluoride in tetrahydrofuran, and warmed overnight at 80° C. The reaction mixture was partitioned between ethyl acetate and water; the organic phase was washed with brine and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 0% to 25% ethyl acetate in hexanes to provide the titled compound (27 mg, 86%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:21].[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:21]
Reactant: Cc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1-c1cc2ccccc2o1
Temperature: 100 °C
Reaction time: 6 h
Yield: 36.4 %

Procedure:
A solution of 4-N-[5-bromo-6-methylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (300 mg, 0.81 mmol, 1.00 equiv) in anhydrous toluene (6 mL) was added (1-benzofuran-2-yl)boronic acid (292 mg, 1.80 mmol, 2.30 equiv), sodium carbonate (286 mg, 2.70 mmol, 3.40 equiv), PPh3 (79 mg, 0.30 mmol, 0.35 equiv), Pd(OAc)2 (22 mg, 0.10 mmol, 0.12 equiv) and water (2 mL) at room temperature under nitrogen. The resulting mixture was stirred for 6 h at 100° C. in an oil bath. After cooled to room temperature, the reaction was then quenched water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (8:1) to give the desired 4-N-[5-(1-benzofuran-2-yl)-6-methylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (120 mg, 36%) as a off-white solid. MS (ES, m/z): 407 [M+H+]. 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.71 (d, 1H), 7.57 (m, 2H), 6.86 (s, 1H), 5.62 (d, 1H), 4.00 (m, 1H), 2.59 (s, 3H), 2.33 (s, 6H), 2.13 (m, 3H), 1.94 (m, 2H), 1.44 (dd, 2H), 0.98 (dd, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.C([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][F:23])C1C=CC=CC=1>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:24][C@@H:21]([CH2:22][F:23])[CH2:20][OH:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O[C@@H](CF)COCc1ccccc1
Product: Nc1ccc(F)cc1O[C@H](CO)CF

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-1-benzyloxy-3-fluoro-propan-2-ol.