Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[F:28])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[F:28])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:14]
Reactant: CC(C)OC(=O)c1ccc(F)c(N)c1
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2cc(C(=O)OC(C)C)ccc2F)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Thionyl chloride (4.6 g, 0.039 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0.037 mole) and methylene chloride (50 ml). The mixture was warmed to 35°-40° C. for about 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the ice-cooled solution treated dropwise with a solution of 1-methylethyl 3-amino-4-fluorobenzoate (7.4 g, 0.037 mole) and triethylamine (3.9 g, 0.039 mole) in methylene chloride (50 ml). The reaction mixture was stirred overnight at room temperature, and then washed in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml), dried with anhydrous sodium sulfate and evaporated. Recrystallization of the solid residue from 100% ethanol (100 ml) gave light brown crystals, m.p. 132°-135° C. (7.8 g, 61% yield).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH:40]2[CH2:41][CH2:42][CH2:43][O:39]2)=[O:34])[C:15]1=[O:38]
Reactant: NCC1CCCO1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 1-(tetrahydro-2-furanyl)methanamine (0.252 mL, 2.44 mmol) for 15 min.@150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49-1.61 (m, 1H), 1.80-2.00 (m, 3H), 2.78 (t, J=6.46 Hz, 2H), 3.25-3.41 (m, 1H), 3.49-3.59 (m, 1H), 3.68 (t, J=6.81 Hz, 1H), 3.75-3.86 (m, 1H), 3.95-4.05 (m, 1H), 4.16 (s, 2H), 4.18-4.26 (m, 2H), 7.14 (ddd, J=8.95, 6.91, 1.82 Hz, 2H), 7.35-7.43 (m, 2H), 8.15 (d, J=1.40 Hz, 1H), 8.51 (s, 1H), 10.44-10.53 (m, 1H); ES+ MS: 441 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([CH3:20])=[CH2:19]>CC(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([O:8][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:7]=1
Reactant: C=C(C)CBr
Reactant: Oc1cc(Cl)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=C(C)COc1cc(Cl)ccc1I

Procedure:
To a mixture of 5-chloro-2-iodophenol (1.21 g, 4.76 mmol) and K2CO3 (723 mg, 5.23 mmol) in acetone (20 mL) was added 3-bromo-2-methyl-propene (0.53 ml, 5.23 mmol), and the reaction was heated to reflux for 16 hours. The reaction was cooled, diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organics were dried over MgSO4, filtered and concentrated to afford 4-chloro-1-iodo-2-((2-methylallyl)oxy)benzene which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[S:21]1[C:25]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:24][N:23]=[CH:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:25]3[S:21][CH:22]=[N:23][CH:24]=3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cncs2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2cncs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(thiazol-5-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 423.08 g/mol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.Cl[C:44](Cl)([O:46][C:47](=O)[O:48]C(Cl)(Cl)Cl)Cl.O1CCCC1>N1C=CC=CC=1.Cl.CO>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:14]([C:12]1[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][NH:2][C:47](=[O:48])[O:46][CH3:44])[CH2:10][CH2:9][C:8]=3[N:11]=1)=[O:15])=[O:25])=[CH:34]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
The compound (144 mg) obtained in Example 40 was dissolved in pyridine (3 mL), triethylamine (138 μl) was added, and the mixture was stirred at room temperature for 5 minutes. A solution prepared by adding triphosgene (49 mg) to tetrahydrofuran (1 mL) containing methanol (20 μl) was added dropwise to this solution at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 9:1 mixture of methylene chloride and methanol. Water was added to the solution for partitioning the mixture. The organic layer was separated and dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=100:3) to give a colorless foamy substance. This product was suspended in 1N hydrochloric acid (0.2 mL), and the suspension was concentrated under reduced pressure to give the title compound (60 mg).
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)[CH3:3].[I-].[Na+].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(N(C(C)C)C(C)C)C>C(#N)C.O>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][CH:2]([C:4]1[C:5]([NH:12][CH3:13])=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: CNc1nc(SC)ncc1C(C)Cl
Reactant: Nc1ccccc1Br
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CNc1nc(SC)ncc1C(C)Nc1ccccc1Br
Reaction time: 16 h
Yield: 38.9 %

Procedure:
0.25 g of the product from Example 11b, supra, and 34 mg sodium iodide in 10 mL acetonitrile were stirred for 15 min at RT. The resulting suspension was added drop-wise at RT to a mixture of 0.21 g 2-bromoaniline (Aldrich) and 0.33 g N-ethyl-di-isopropyl amine (Aldrich) in 5 mL acetonitrile. Stirring was continued for 16 hrs and the mixture was diluted with 20 mL water and extracted with dichloromethane. Chromatography on silica (eluent CHCl3) yielded 158 mg of the title product.
Reaction SMILES: C([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:22]#[N:23])=[CH:11][S:12][C:13]=1[NH:14][C:15](OC(C)(C)C)=[O:16])=O)(C)(C)C.C(OC(=O)C(OCC)=O)C>C(O)(=O)C>[C:22]([C:10]1[C:9]2[NH:8][C:6](=[O:5])[C:15](=[O:16])[NH:14][C:13]=2[S:12][CH:11]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1scc(C#N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: N#Cc1csc2[nH]c(=O)c(=O)[nH]c12

Procedure:
A mixture of 4-bis(t-butoxycarbonyl)amino-5-t-butoxycarbonylamino-3-thiophene carbonitrile (15.4 g, 35 mmol), diethyloxalate (100 ml, 739 mmol) and glacial acetic acid (100 ml) was refluxed for 6 h. The crystallinic product was filtered off and washed with ether to give 3.25 9 (48%) of the title compound. M.p.>250° C. 1H-NMR (DMSO-d6, δ): 8.15 (s, 1H), 12.4 (br.s, 1H), 12.5 (br.s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][CH:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:31]([CH:29]([CH3:30])[CH3:28])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CC(C)S(=O)(=O)Cl
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)C(C)C)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (80.0 mg, 0.195 mmol) was reacted with the propane-2-sulfonyl chloride (27.8 mg, 0.195 mmol) for 18 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (20 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.90 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 7.76 (d, J=8.82 Hz, 1H) 7.43-7.49 (m, 1H) 7.35-7.42 (m, 2H) 7.24-7.29 (m, 2H) 7.12-7.19 (m, 2H) 6.33 (d, J=6.99 Hz, 1H) 2.75 (s, 3H) 3.66 (m, 1) 2.39 (s, 3H) 1.40 (d, J=6.99 Hz, 6H); MS (DCI NH3+) m/z 480 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=1.[Sn](Cl)Cl.[Cl-].[NH4+].[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>[Fe].C(N(CC)CC)C>[Cl:28][CH:29]([Cl:33])[C:30]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[S:13][N:12]=2)=[CH:15][CH:16]=1)=[O:31]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3c(Cl)cccc3Cl)sn2)cc1
Agent: [Fe]
Agent: Cl[Sn]Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2cc(-c3c(Cl)cccc3Cl)sn2)cc1)C(Cl)Cl

Procedure:
By the method of Tetrahedron, 1992, 48, 8127-8142 the substance 5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)isoxazole can be treated with diphosphorus pentasulfide followed by aqueous or ethanolic ammonia quench to produce 5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)isothiazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. This aniline can then be treated with 2,2-dichloroacetyl chloride and triethylamine to yield 2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-3-isothiazolyl]phenyl]acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][O:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:12])[NH:7][O:8][CH2:9][CH2:10][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NOCCBr
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NOCCN1CCOCC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 45.6 %

Procedure:
To a solution of (2-bromo-ethoxy)-carbamic acid tert-butyl ester (252 mg, 1.05 mmol) in DMF (2 mL) at room temperature is added morpholine (0.14 mL, 1.6 mmol). The reaction mixture is stirred for 7 hours at 50° C. The reaction mixture is diluted with EtOAc, and washed with water. The organic layer is dried over MgSO4, filtered, concentrated, and purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product (118 mg, 46%): MS APCI (+) m/z 247 detected.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH2:15][CH2:14][CH2:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1>[Pd].CN(C=O)C.CO>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2cc(C3=CCCC3)sc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cnc(N)c2cc(C3CCCC3)sc12
Reaction time: 20 h
Yield: 30.9 %

Procedure:
A suspension of 4-amino-2-cyclopent-1-enyl-thieno[3,2-c]pyridine-7-carboxylic acid amide 34 (prepared in example 6 above) (0.056 g, 0.155 mmol) and 10% palladium on carbon (5 mol %) in DMF (1 mL) was stirred under H2 (1 atm) for 20 h. The suspension was diluted with MeOH (10 mL) and filtered. Solvent was removed in vacuo. To the crude solid of 35 was added concentrated H2SO4 (0.25 mL). The purple solution was stirred for 1 h followed by the addition of ice (2 g). The precipitate was filtered then purified by silica gel column chromatography (eluent: 10% MeOH, 1% NH4OH in CH2Cl2) and converted to the HCl salt to afford 12.5 mg of 36. 1H NMR (400 MHz, d6-DMSO) δ 8.76 (s, 2H), 8.45 (s, 1H), 8.29 (s, 1H), 7.75 (m, 3H), 3.37 (m, 1H), 2.14 (m,2H), 1.72 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][C:43]1[N:48]([CH2:49][C:50](O)=[O:51])[C:47]2[N:53]=[CH:54][CH:55]=[CH:56][C:46]=2[C:45](=[O:57])[N:44]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][C:43]1[N:48]([CH2:49][C:50]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH:11]2[CH2:12][CH2:13][N:8]([C:2]([CH3:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH2:10]2)=[O:51])[C:47]2[N:53]=[CH:54][CH:55]=[CH:56][C:46]=2[C:45](=[O:57])[N:44]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.3 %

Procedure:
A mixture of methyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-l piperidinyl}propanoate (Int. B6) (145 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (122 mg, 1 equiv), DIPEA (0.084 ml, 1.5 equiv) and DMF (2.0 ml) was stirred at room temperature for 5 min. The HATU (160 mg, 1.3 equiv) was added in 1 portion and stirred an additional 1 hour under nitrogen. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain methyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl} methyl)amino]-1-piperidinyl}-2-methylpropanoate (116 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:18]=[C:19]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[C:21]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:49]=2)C=CC=1OC)C1C=CC=CC=1>O=P(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:18]=[C:19]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:49])[C:21]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(NC(=O)C2CCC2)c2nccnc2Cl)cc1OCc1ccccc1
Reactant: COc1ccc(-c2nc(C3CCC3)n3ccnc(Cl)c23)cc1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1OCc1ccccc1
Temperature: 55 °C
Yield: 87 %

Procedure:
1-(3-Benzyloxy-4-methoxyphenyl)-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine: Cyclobutanecarboxylic acid [(3-benzyloxy-4-methoxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-amide (308 mg, 0.703 mmol) was dissolved in POCl3 (5 ml) and heated at 55° C. for 17 h. After that time, the excess POCl3 was removed in vacuo and the remaining mixture was basified with NH3 (2 N in iPrOH). The precipitate formed was filtered off and washed with CH2Cl2, and the filtrate was purified by chromatography on silica gel to obtain a yellow-brown solid of the title compound (87% purity by LC-MS); 1H NMR (DMSO-d6, 400 MHz) δ 2.03-2.20 (m, 2H), 2.47-2.67 (m, 4H), 3.95 (s, 3H), 5.22 (s, 2H), 7.00 (d, 1H, J=8.0 Hz), 7.25-7.47 (m, 8H); MS (ES): 420.0/422.1 (M/M+2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[C:16]([O:43][CH3:44])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:47]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1.CN(C)C=O>[NH2:47][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:15][C:16]=2[O:43][CH3:44])[N:26]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)[O-])n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.352 g, 0.672 mmol), 1-hydroxybenzotriazole (0.093 g, 0.686 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)hydrochloride (0.121 g, 0.629 mmol) in dry tetrahydrofuran (16 mL) and dimethylformamide (7 mL) was added N,N-diisopropylethylamine (0.498 mL, 2.86 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes at room temperature then ammonium carbonate (0.263 g, 2.859 mmol) was added and the resulting suspension was stirred at room temperature for 18 hours. The reaction volatiles were evaporated in vacuo and the resulting residue was diluted with ethyl acetate (15 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate) and concentrated in vacuo to give a yellow foam which was purified by flash column chromatography on silica gel (55-85% ethyl acetate/petroleum ether) to give the title compound (I8) (0.276 g, 87%) as a yellow foam; 1H NMR (300 MHz, CDCl3) δ 1.48 (d, 9H, J=1.1 Hz), 3.09 (d, 8H, J=3.9 Hz), 3.58 (brs, 4H), 3.66 (s, 2H), 3.88 (d, 3H, J=1.0 Hz), 5.48 (brs, 1H), 5.78 (brs, 1H), 6.54 (d, 1H, J=1.3 Hz), 6.57 (s, 1H), 7.23-7.25 (brs, 4H), 7.72 (s, 1H), 8.13 (d, 1H, J=8.6 Hz) and 8.48 (s, 1H). LCMS Method B: rt 8.52 min; m/z 615.4 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:37][O:36][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=5)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:2]1.I([O-])(=O)(=O)=[O:39].[Na+]>O1CCCC1.CO.O>[CH2:37]1[CH2:1][O:2][C:3]2([CH2:20][CH2:19][C@H:18]3[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][C:30]([S:33]([CH3:34])=[O:39])=[CH:31][CH:32]=5)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:36]1
Reactant: CSc1ccc(-c2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CC=C5CC6(CC[C@@H]5[C@H]43)OCCO6)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)c1ccc(-c2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CC=C5CC6(CC[C@@H]5[C@H]43)OCCO6)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
494 mg of 3,3-(ethylenedioxy)-11β-[4'-(methylthio)[1,1'-biphenyl]-4-yl]-5-estren-17-one is dissolved in a mixture of 6 ml of tetrahydrofuran, 6 ml of methanol and 2 ml of water and mixed with 924 mg of sodium periodate. The reaction mixture is stirred at room temperature overnight, then filtered on Celite and the filtrate is diluted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate, 346 mg of the title compound is obtained as white foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1>[O-2].[O-2].[Mn+4].ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentan-1-ol (100 mg), activated manganese dioxide (500 mg) and dichloromethane (100 ml) was stirred at ambient temperature for 18 hours to give, after filtration, a solution of 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentan-1-one in dichloromethane which was used in the next Example.