Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[C:31](#[N:35])[CH2:32][CH2:33][CH3:34]>Cl[Cu].C(O)C>[NH:35]=[C:31]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][N:15]([CH3:16])[C:8]2[N:7]=[C:6]([NH2:30])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCC#N
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Agent: Cl[Cu]
Solvent: CCO
Product: CCCC(=N)N1CCC(CN(C)c2nc(N)c3cc(OC)c(OC)cc3n2)(c2ccccc2)CC1
Temperature: 90 °C

Procedure:
To 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (129.8 mg) was added CuCl (31.8 mg), butyronitrile (84 μl), and ethanol (1.0 ml). The reaction mixture was heated in a 90° C. block for one day. Additional CuCl (31.8 mg) and butyronitrile (84 μl) were added and the reaction heated for an additional day. This was chromatographed on silica gel to provide N2-[1-(1-imino-butyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 17 as indicated by 1HNMR and MS: 477 ([M+H]+). This material was further purified by preparative HPLC to afford the corresponding trifluoroacetic acid salt.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH2:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:51]([C:53]1[N:54]=[C:55]([C:66]([O-])=[O:67])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=1)#[N:52].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:25][C:66]([C:55]2[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=[C:53]([C:51]#[N:52])[N:54]=2)=[O:67])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(C3=CCCCC3)c2)C[C@H](C)N1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)C[C@H](C)N1
Temperature: 0 °C
Yield: 63 %

Procedure:
A solution of 153 mg (0.422 mmol) of 2-cyclohex-1-enyl-4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 295 mg (0.633 mmol) of PyBroP and 142 mg (0.464 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) to form a slurry, which was cooled to 0° C., treated with 184 μL (1.06 mmol) of DIEA, and warmed to RT for 6.5 h. The mixture was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (1×15 mL) and brine (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 163 mg (63%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C30H44N6O4SSi, 613.3 (M+H). found 612.9.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:24])[CH2:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([OH:20])[C@@H:11]([NH2:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH3:4].[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26]([C:34]([NH:36][C@H:37]([C:44](O)=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([NH:5][C:6]([CH2:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([OH:20])[C@@H:11]([NH:19][C:44]([C@@H:37]([NH:36][C:34]([C@@H:26]([NH:25][C:47](=[O:48])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:45])[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: CCCCNC(=O)C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
In an analogous manner to that described in Example 9, by reacting (3R,5S,6S)-6-amino-7-cyclohexyl-5-hydroxy-3-isopropylheptanoic acid butylamide with Boc-Phe-His-OH there is obtained t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4R)-4-[(butylcarbamoyl)methyl]-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 725 (M+H)+.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20].N(OC(C)(C)C)=O.ClCCl.C(Br)(Br)[Br:37]>>[Br:37][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20]
Reactant: BrC(Br)Br
Reactant: Nc1c(S(=O)(=O)C(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: O=S(=O)(c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 43 %

Procedure:
A suspension of 28 g (0.065 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylsulphonyl-pyrazole in 70 ml of bromoform are added to a solution of 15.5 ml (0.13 mole) of t-butyl nitrite in 30 ml of bromoform at 20° C. to 25° C. The temperature rises to 40° C. The mixture is then stirred for 15 hours at room temperature, 200 ml of dichloromethane are added, the mixture is washed in sequence with aqueous sodium hydrogen carbonate, sodium thiosulphate and sodium chloride solution, the organic phase is dried over magnesium sulphate and the solvent is removed in vacuo. The oil remaining is purified by chromatography (silica gel, eluent: dichloromethane). 13.8 g (43% of theory) of 5-bromo-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylsulphonylpyrazole of melting point 90° C. to 91° C. are obtained.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[O:25][CH2:24]3)=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28]>CN(C=O)C.CCO>[CH3:26][N:27]([CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:10]2[N:9]=[C:8]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=[CH:12][N:11]=2)=[CH:20][CH:19]=1)[CH3:28]
Reactant: CNC
Reactant: c1ccc(Nc2ccnc(Nc3ccc(OCC4CO4)cc3)n2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
4-Anilino-2-(4-(2,3-epoxypropoxy)anilino)pyrimidine (Reference Example I-1, 0.61 g, 1.84 mmol) was dissolved in DMF (2 ml) and treated with dimethylamine (6 mmol, 3 ml of a 2M solution in EtOH). After stirring overnight at ambient temperature the reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water, dried over MgSO4 and evaporated at reduced pressure. The residue was purified by chromatography (0.1%NH3 (aq), 3–10% MeOH in DCM as eluent). Upon evaporation of the fractions, an oily product was obtained,this was triturated with ether to give the title product as a white solid (0.126 g, 18%). NMR (300 MHz): 2.2 (s, 6H), 2.3–2.8 (m, 2H), 3.75–3.95 (m, 3H(, 4.82 (brs, 1H), 6.17 (d, 1H), 6.82 (d, 2H), 6.97 (t, 1H), 7.27 (t, 2H), 7.58 (d, 2H), 7.66 (d, 2H), 7.95 (d, 1H), 8.95 (s, 1H), 9.25 (s, 1H); m/z: (ES+) 380.4 (MH+).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[C:12]=2[F:29])[CH:8]=[CH:9][CH:10]=1>[Fe].O>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=3)[C:12]=2[F:29])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Cc2ccc([N+](=O)[O-])cc2)c(F)c1-c1cccc(Cl)c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
In an 18 mL vial equipped with a stir bar was placed iron powder (179 mg, 3.20 mmol), ethanol (5.0 mL) and water (1.2 mL). The mixture was heated to 85° C. in an oil bath and then the above product 3′-Chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (6) (340 mg, 0.914 mmol) was added and the reaction was continued at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. To the filtrate was added water (50 mL) and extractions were performed with ethyl acetate (2×60 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated to produce 245 mg of 4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-35) as a yellow, viscous oil in 79% yield. MS (APCI+): 342.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[C:13]([CH3:16])=[CH:14][S:15][C:3]=12.[CH3:17]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:16][C:13]1[C:4]2[N:5]([CH3:17])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2](=[O:1])[C:3]=2[S:15][CH:14]=1
Reactant: CCOC(=O)c1cnc2c(C)csc2c1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2c(C)csc2c1=O
Temperature: 0 °C

Procedure:
A 500 mL three-necked flask fitted with an overhead stirrer and argon inlet is charged with 21.9 g of ethyl 7-hydroxy-3-methylthieno[3,2-b]pyridine-6-carboxylate and 150 mL of DMF. The mixture is stirred while 25.5 g of powdered potassium carbonate is added in portions, then is cooled to 0° C. Iodomethane (15 mL) is added dropwise over 45 min, and the completed mixture is stirred vigorously and allowed to warm slowly as the ice in the bath melts. The following day, the mixture is diluted slowly with water to a final volume of 800 ml, and the resulting solid is filtered, washed well with water, and dried under vacuum to provide 17.2 g of the title compound as a brown crystalline solid. Flash chromatography of 12.2 g using 2-4% MeOH in CH2Cl2 affords 11.43 g of tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[N:10][C:5]2=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]3[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[N:10][C:5]3=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)cc(Cl)nc21
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)cc(-c3cncc(F)c3)nc21

Procedure:
Following the procedure of Example 161d, 4-(2-(5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-7-ylamino)ethyl)phenol (c) (15 mg, 0.047 mmol) was reacted with 5-fluoropyridin-3-ylboronic acid. The crude residue was purified preparative TLC (1:1 hexanes/ethyl acetate eluant) to afford the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[C:12]([O:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([N+:18]([O-:20])=[O:19])=[C:13]([OH:15])[C:12]([O:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc2cc(OC)c(O)cc2o1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OC)c(O)c([N+](=O)[O-])c2o1
Temperature: -20 °C

Procedure:
6-Hydroxy-5-methoxybenzofuran-2-carboxylic acid ethyl ester (1.5 g) was dissolved to dichloromethane (30 ml) and the solution cooled to −20° C. 1 M HNO3 in dichloromethane (6.4 ml) was added and after 10 minutes the mixture poured in ice water. The dichloromethane layer was separated and the water phase extracted with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated to dryness.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].[OH:37]OS([O-])=O.[K+]>CC(C)=O.O.CCOC(C)=O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:14][C:15]([S:18]([CH3:19])=[O:37])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2]
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)o1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)o1
Reaction time: 2 h
Yield: 22.5 %

Procedure:
A solution of tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (805 mg, 1.561 mmol) in acetone (16 mL) was added oxone (1.920 g, 3.12 mmol) in water (16.00 mL) and stirred for 2 hrs. The reaction mixture was diluted with 150 mL of EtOAc which was washed with 50 mL of 10% LiCl solution, 50 mL of brine and dried over Na2SO4. Filtration and concentration yielded a crude product which was purified on silica gel column with EtOAc to give tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (186.6 mg, 23% yield). HPLC retention time=2.993 min. LC-MS: M+1 532.3. 1H-NMR (400 MHz, methanol-d4) δ 8.30 (d, J=1.8 Hz, 1H), 8.26 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 4.50 (d, J=9.0 Hz, 1H), 3.31 (s, 3H, under MeOH peak), 2.51-2.32 (m, 1H), 2.29-2.13 (m, 1H), 2.12-1.95 (m, 1H), 1.83-1.63 (m, 1H), 1.49 (s, 3H), 1.46 (s, 9H), 1.13 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-chlorophenylbenzene (7.02 g, 37.2 mmol) in 70 mL of dichloromethane is treated with chlorosulfonic acid (4.55 g, 39.1 mmol) at RT. The reaction is stirred for 2 h further, and the formed precipitate is collected by vacuum filtration, washed with dichloromethane and dried to afford 9.6 g (96%) of 4′-chlorobiphenyl-4-sulfonic acid as a white solid.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:25][CH3:26])=[C:9]([O:23][CH3:24])[CH:10]=2)[N:5]=1>C(O)(C)C.C(OCC)(=O)C>[CH:9]([O:23][C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:25][CH3:26])=[C:9]([O:23][CH3:24])[CH:10]=2)[N:5]=1)([CH3:10])[CH3:8]
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(OC(C)C)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 mg (0.44 mmol) NaH is dissolved in 2 ml isopropanol and stirred for 2 h at rt. After that time 30 mg (0.088 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline is added and the solution is stirred at 55° C. overnight. The reaction mixture is diluted with ethyl acetate and extracted with brine. The organic layer is dried and evaporated. After chromatography (hexane/ethyl acetate) the product is obtained as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].Br[C:34]1[N:39]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:41]([NH:40][C:38]1[N:39]=[C:34]([C:21]2[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([CH:20]=2)[C:4]([NH:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=2)=[O:5])[CH:35]=[CH:36][CH:37]=1)(=[O:43])[CH3:42]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)OC1(C)C
Reactant: CC(=O)Nc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Temperature: 100 °C
Yield: 45.5 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Preparation 7, 0.5 mmol) in dioxane (5 mL) was added N-(6-bromopyridin-2-yl)acetamide (118 mg, 0.55 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05 mmol), sodium carbonate (183 mg, 1.72 mmol) and water (1 mL). The reaction was heated to 100° C. for 18 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (10 mL) and water (10 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 40-50% ethyl acetate in heptanes to afford the title compound as a yellow solid (104 mg, 46%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[F:31])[CH2:9][C:10]1[N:14]2[CH:15]=[CH:16][C:17]3[C:22]([C:13]2=[N:12][N:11]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[ClH:33].[F:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[CH2:23][C@@H:8]([NH2:7])[CH2:9][C:10]1[N:14]2[CH:15]=[CH:16][C:17]3[C:22]([C:13]2=[N:12][N:11]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2c3ccccc3ccn12
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1cc(F)ccc1F)Cc1nnc2c3ccccc3ccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 43.9 mg (0.1 mmol) of tert-butyl[(1R)-1-(2,5-difluorobenzyl)-2-[1,2,4]triazolo[3,4-a]isoquinolin-3-ylethyl]carbamate and 2 mL of 4M HCl in anhydrous dioxane was stirred at room temperature in a stoppered flask. After 2 h, the solvent was evaporated, and the residue was stirred with diethyl ether. The solid was collected on a filter, washed with diethyl ether, and dried to give the title compound as an off-white powder. LC-MS 339 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:20][CH:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [H-]
Agent: [Na+]
Product: C[C@]12CCC(OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
3β-Benzyloxyandrost-5-en-17β-thiol is obtained starting from dehydroepiandrosterone. The dehydroepiandrosterone is reacted with one equivalent of sodium hydride and benzyl chloride by standard procedures for making benzyl ethers to give 3-benzyloxyandrost-5-en-17-one. This benzyloxy compound is then reacted with Lawesson's reagent (4-methoxyphenylthiophosphine sulfide dimer) according to the procedure described in M. Feiser, "Feiser and Feiser's Reagents for Organic Synthesis", John Wiley & Sons, New York, 1980, p. 327; also B. S. Pedersen et al., Bull. Soc. Chim. Belg., 87, 223 (1978). This gives 3β-benzyloxyandrost-5-ene-17-thione and this thione is then reduced with lithium aluminum hydride by standard procedures to give the desired 17β-thiol. Then, to a solution of cyclopropanone in dichloromethane under nitrogen at -50° C., there is added rapidly 1.1 equivalent of the above thiol in dichloromethane. The temperature is allowed to rise to -30° C. and, after 16 hours, most of the solvent is evaporated. Dry ether is added to precipitate by-product polyketene. The by-product is removed by filtration, the solvent is distilled from the filtrate, and the residue is purified by flash chromatography to give 3β-benzyloxy-17β-(1-hydroxycyclopropylthio)androst-5-ene.
Reaction SMILES: IC.[CH3:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:7][CH:8]=1.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][O:16][C:13]1[CH:12]=[C:11]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH3:3])[N:5]=2)=[N:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1csc(Nc2ncc(O)cc2Oc2ccccc2)n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.0362 g, 0.255 mmol) is added to a mixture of 6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ol (0.255 mmol) and potassium carbonate (0.0794 g, 0.574 mmol) in DMF (3 mL) and stirred overnight at room temperature. The reaction mixture is partitioned between water and ether. The organic layer is washed with water, dried, and concentrated. The residue is purified by silica gel chromatography, eluting with 15-20% EtOAc in hexanes, to afford the title compound.
Reaction SMILES: C1(CC[CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:9][NH:10][C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: NCCCc1ccccc1
Reactant: O=C(O)CCCCCNC(=O)N1Cc2ccccc2C1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: CNC(=O)CCCCCNC(=O)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting methylamine for 3-phenylpropan-1-amine and 6-[(1,3-dihydro-2H-isoindol-2-ylcarbonyl)amino]hexanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.60-7.72 (m, 1H), 7.25-7.33 (m, 4H), 6.24-6.29 (m, 1H), 4.57 (s, 4H), 2.94-3.09 (m, 2H), 2.54 (d, J=4.6 Hz, 3H), 2.30 (t, J=7.3 Hz, 1H), 2.04 (t, J=7.4 Hz, 1H), 1.37-1.58 (m, 4H), 1.18-1.35 (m, 2H); MS (ESI(+)) m/e 290 (M+H)+.