Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]2[CH:19]([CH2:20][NH:21][CH2:22]2)[C:18](=[O:24])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]2[CH:19]([CH2:20][N:21]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:22]2)[C:18](=[O:24])[CH2:17][CH2:16]1
Reactant: CC1(c2ccccc2)CCC(=O)C2CNCC21
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(C)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 1.66 g of 2-methoxyphenylacetic acid in 40 cm3 of dichloromethane are added, at 4° C., 1.62 g of N,N'-carbonyldiimidazole. Stirring for 30 minutes at room temperature is followed by dropwise addition of a solution containing 1.85 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-4-perhydroisoindolone hydrochloride and 0.7 g of triethylamine in 30 cm3 of dichloromethane. After stirring for 2 hours, the reaction mixture is washed twice with 50 cm3 of water and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 15 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 50 cm3 fractions. Fractions 16 to 60 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). The residue is crystallized in 30 cm3 of ethyl acetate. 1.3 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone are obtained, in the form of white crystals melting at 160° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[CH3:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:21][C:22]1[CH:23]=[N:24][N:25]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:26]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnn(-c2cnccc2-c2nc3cc(C(F)(F)F)ccc3o2)c1
Temperature: 60 °C
Yield: 73.2 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of 4-methylpyrazole, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60° C. for 1.5 hours. To the mixture, 0.05 g of 4-methylpyrazole was added and further stirred while heating at 60° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(4-methylpyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 61”).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](Cl)[N:16]=2)[CH:14]=1>CN(C=O)C>[Br:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=2)[CH:14]=1
Reactant: C1COCCN1
Reactant: Clc1nccc(-n2cnc(Br)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cn(-c2ccnc(N3CCOCC3)n2)cn1

Procedure:
To a cooled (0° C.) solution of morpholine (0.256 g, 2.94 mmol) in anhydrouse DMF (5 ml) was added NaH (0.117 g, 2.94 mmol, 60% disp' in mineral oil). The mixture was stirred at this temperature for 30 minutes before the addition of 4-(4-Bromo-imidazol-1-yl)-2-chloro-pyrimidine (0.64 g, 2.45 mmol). The reaction vessel was sealed and heated under the infuenceof microwave radiation for 7 minutes (120° C., High absorption setting). Upon cooling the mixture was diluted with water (7 ml) and the resultant yellow precipitate removed by filtration and purified by flash chromatography (SiO2) (4:1—Hexanes:EtOAc) to give the title compound as a white solid in analytically (0.76 g, 38.6%) pure form. m/z (LC-MSW, ESP):310.3 [M+H]+, R/T=3.26 mins.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])([CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=O)[CH2:7]1)[CH3:5].Cl.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[C:24]3[C:23](=[CH:22][CH:21]=[C:20]([Br:19])[CH:25]=3)[NH:26][C:8]=2[CH2:7]1)([S:13]([CH3:16])(=[O:15])=[O:14])[CH3:5]
Reactant: COC(=O)C(C)(C1CCCC(=O)C1)S(C)(=O)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Br)cc23)C1)S(C)(=O)=O

Procedure:
Analogously to example 1.2, from a racemic mixture of diastereomers of 2-methanesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester and (4-bromo-phenyl)-hydrazine hydrochloride were prepared the following 2 racemic diastereomers which could be separated by column chromatography to yield (RS,SR)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester, MS: 414 (MH+,1Br), and (RR,SS)-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-methanesulfonyl-propionic acid methyl ester, MS: 414 (MH+,1Br).
Reaction SMILES: C[O-].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][C:10]#[N:11].[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:12]1([CH2:18][N:19]2[CH2:24][CH2:23][C:22](=[C:9]([C:5]3[S:4][CH:8]=[CH:7][CH:6]=3)[C:10]#[N:11])[CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#CCc1cccs1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(=C1CCN(Cc2ccccc2)CC1)c1cccs1
Reaction time: 1 h

Procedure:
To a stirred mixture of 80 parts of sodium methoxide and 160 parts of methanol are added successively 50 parts of 2-thiopheneacetonitrile and then dropwise 66 parts of 1-(phenylmethyl)-4-piperidinone. Upon completion, the whole is heated to reflux and stirring at reflux temperature is continued for one hour. The reaction mixture is cooled and evaporated. The residue is distilled in a molecular distillation-apparatus, yielding about 70 parts of α-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile as a residue.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[C:44]1([O:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:49][CH2:48][CH2:47][CH2:46]C1)CCC.C(N(CC)CC)C>C(Cl)Cl>[CH2:51]([O:50][C:44]1([O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)[CH2:46][CH2:47][CH2:48][CH2:49]1)[CH2:52][CH2:53][CH3:54]
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
To a solution of 2-hydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-ethyl-1H-imidazole (19) (345 mg, 1 mmol) prepared in accordance with the method as described in WO 96/10019 (EXAMPLE 25) and p-toluenesulfonic acid pyridinium (264 mg, 1.05 mmol) in methylene chloride (5 ml) was added 1,1-dibutoxycyclohexane (2.14 g, 10.0 mmol), and stirred at room temperature for 20 hours. A drop of triethylamine was added to the reaction mixture , and the mixture was filtered to remove the precipitated insoluble matter. The filtrate was concentrated under reduced pressure. Hexane was added to the residue, and the mixture was filtered to remove the insoluble matter. The filtrate was purified by chromatography on an alumina column (eluate: toluene) to give the compound 20 (165 mg, 34%). Rf 0.41 (Al2O3 60, Type E, toluene).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[C:4]([F:28])[CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[F:28][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1F

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-2-fluoro-phenyl)-1-[(E)-hydroxyimino]-3-o-tolyl-propyl}-1-methyl-1H-pyridin-2-one (example 193, step 4) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as a light brown solid, MS (ESI+): m/z=485.2 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:10]=3[CH2:9][CH2:8]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>C(#N)C>[C:25]([N:2]1[CH2:3][CH2:4][C:5]2([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:7]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc2c3c([nH]c2c1)C1(CCNCC1)CC3
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCC2(CCc3c2[nH]c2ccccc32)CC1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of 1,4-dihydrospiro[cyclopent[b]indole-3(2H),4'-piperidine] hydrochloride (1.0 g) and potassium carbonate (0.8 g) in acetonitrile (10 ml) was added benzoyl chloride (0.5g), under nitrogen, with stirring. The reaction mixture was heated under reflux for 5 hrs and allowed to cool to ambient temperature. Ethyl acetate (200 ml) was added, and the mixture was washed with water and saturated sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 0.5% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 0.40 g (33%) of product, mp 231°-232° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][C:34]=1[F:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:33]5[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][C:34]=5[F:42])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(N)=O)cc1F
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10 mmol), 4-bromo-3-fluorobenzamide (24 mg, 0.11 mmol), Pd-FibreCat 1007 (10 mg), K2CO3 (1M, 240 mL), and DMF (1 mL) were combined in a scintillation vial and heated at 80° C. for 3 hr. The mixture was filtered and purified using reverse-phase preparative HPLC to provide 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2′-methylbiphenyl-4-carboxamide (ESI-MS m/z calc. 428.5, found 429.5 (M+1); retention time 3.30 min).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>[OH-].[Na+]>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of 165 g of d,l-phenylalanine in 1100 ml of 1 N sodium hydroxide was added simultaneously 1000 ml of 1 N sodium hydroxide and 146 g of benzoyl chloride over a period of 1 hr with maintenance of the temperature at 2°-5° C. After 3 hr at 5°-10° C., the solution was acidified to pH4 with 5 N hydrochloric acid. The precipitate was collected, washed with water and acetone and dried to leave 234.5 g (87%) of N-benzoyl phenylalanine, mp 185°-188° C. The material was mixed with 2000 ml of acetic anhydride and heated at 95°-100° for 45 minutes. The solvent was removed in vacuo to afford 222 g (100%) of the azlactone, m.p. 60° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][C:12](=[CH:15][O:16]C)[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2]
Reactant: CCOc1ccc2c(c1F)OC1CC(=COC)CCC21
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCOc1ccc2c(c1F)OC1CC(C=O)CCC21

Procedure:
8.0 g (28.7 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-3-[1-methoxy-methylidene]-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 200 ml of toluene and stirred vigorously at room temperature for 18 h together with 30 ml (0.80 mol) of formic acid and 0.5 ml (27.8 mmol) of water. The organic phase is separated off and washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Purification by column chromatography (SiO2, toluene:ethyl acetate=99:1) gives a mixture (64:36) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde and (±)-(3S*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[C:21]([F:32])[C:20]=1[O:33][CH3:34]>>[NH2:31][C:28]1[N:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:20]([O:33][CH3:34])[C:21]=2[F:32])=[N:26][CH:27]=1
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: COc1c(-c2ccccc2S(=O)(=O)NC(C)(C)C)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared by a method analogous to Example 461 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): mass calcd. for C21H23FN4O3S, 430.15; m/z found, 431.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.53-8.48 (m, 1H), 8.19 (dd, J=7.9, 1.4, 1H), 8.08 (d, J=1.5, 1H), 7.64-7.55 (m, 2H), 7.52 (m, 1H), 7.29 (dd, J=7.4, 1.4, 1H), 7.18 (dd, J=8.2, 1.4, 1H), 4.80 (s, 2H), 4.42 (s, 1H), 3.85 (d, J=1.8, 3H), 1.21 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:29])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH:13]=C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)=[O:32].O>O=[Os](=O)(=O)=O>[C:27]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:11]([CH2:12][CH:13]=[O:32])[C:10]([NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[O:29])=[CH:16][CH:17]=2)[CH:26]=[CH:25][CH:24]=1)#[N:28]
Reactant: C=CCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2cccc(C#N)c2)cc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: N#Cc1cccc(-c2ccc(C(CC=O)C(=O)Nc3cc(Cl)cc(Cl)c3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
To a solution of 2-(3′-cyano-biphenyl-4-yl)-pent-4-enoic acid (3,5-dichloro-phenyl)-amide (680 mg, 1.6 mmol) in 9 mL of acetone/H2O (2:1 v/v) was added OsO4 (4% in H2O, 100 L, 1 mmol %) and NaIO4 (860 mg, 4.0 mmol, 2.5 eq). The reaction mixture was stirred at r.t. for 6 h. The mixture was then partitioned between CH2Cl2 (20 mL) and 10% NaHCO3 (20 mL) and the organic layer separated. The aqueous layer was extracted with CH2Cl2 (10 mL×3) and the combined organic layer was washed with saturated brine (10 mL), dried (Na2SO4), and concentrated. Chromatography on silica gel (20% EtOAc/hexanes) gave 2-(3′-cyano-biphenyl-4-yl)-N-(3,5-dichloro-phenyl)-4-oxobutyramide as a light yellow oil (300 mg, 44%). MS(ESI): 423.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:9]=[C:8]2[CH:4]([CH2:5][C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]2)[CH2:3]1>CCO.[Pd]>[O:1]=[C:2]1[CH2:3][CH:4]2[CH:8]([CH2:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5]2)[CH2:9]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC2=CC(=O)CC2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC2CC(=O)CC2C1

Procedure:
A stirred suspension of diethyl 5-oxo-3,3a,4,5-tetrahydropentalene-2,2(1H)-dicarboxylate (322 mg, 1.209 mmol) and 10% Pd—C (129 mg, 0.121 mmol) in EtOH (40 mL) was hydrogenated under balloon pressure overnight. The suspension was filtered and the filtrate was evaporated to dryness to afford diethyl 5-oxohexahydropentalene-2,2(1H)-dicarboxylate as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([CH3:25])[C:22]([C:26](O)=[O:27])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:26]([C:22]2[C:23]([CH3:25])=[N:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[N:20][CH:21]=2)=[O:27])[CH:3]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2ncccc21
Reaction time: 1 h
Yield: 44 %

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (75% pure) (240 mg, <1.63 mmol), 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (379 mg, 1.63 mmol), HATU (744 mg, 1.96 mmol) and DIPEA (388 mg, 4.89 mmol) in DMF (5 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM. The resulting product is recrystallized with ether to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (197 mg, 44%). MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.14 (s, 1H), 8.40 (d, 1H), 8.36 (d, 1H), 8.22 (d, 1H), 7.85(d, 1H), 7.55 (q 1H), 7.47 (s, 1H), 7.25-7.34 (m, 2H), 2.83 (s, 3H), 2.42(s, 3H). IC50=2 nM.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH2:15][O:16][CH2:17][C:18](O)=[O:19])=[N:13][N:12]2[C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=[C:11]2[C:10]=1[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C)C=O>[CH2:24]([C:21]1[N:12]2[N:13]=[C:14]([CH2:15][O:16][CH2:17][C:18]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:19])[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:33])=[C:10]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:11]2=[CH:23][CH:22]=1)[CH3:25]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCCCc1c(COCC(=O)O)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(COCC(=O)N2CCOCC2)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid (55 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (34.9 mg) and 1-hydroxybenotriazole (24.6 mg) in dimethylformamide (2 mL) was added morpholine (12.7 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and methanol (50:1–20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (50 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
1-Chloro-2-nitrobenzene (3.00 mmol, 475 mg), Pd2(DBA)3 (0.060 mmol, 55 mg), S-Phos (0.18 mmol, 75 mg), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.0 mmol, 1.2 g) and K3PO4 (4.5 mmol, 1.0 g) were loaded into a Schlenk tube containing a stir bar. The tube was capped with a rubber septum, evacuated and refilled with nitrogen. Toluene (5 mL) was added through the septum via a syringe and the tube was sealed with a Teflon screw cap under a flow of nitrogen, and put into an oil bath at 100° C. The reaction was allowed to stir at this temperature for about 15 hours, then the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo and the resulting residue was purified using flash column chromatography on silica gel (eluent: 14% EtOAc in Hexane) to provide 4-(2-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a brown solid 660 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.58-7.53 (m, 1H), 7.44-7.39 (m, 1H), 7.30-7.27 (m, 1H), 5.62-5.58 (m, 1H), 4.04-4.01 (m, 2H), 3.64 (t, J=5.2 Hz, 2H), 2.36-2.30 (m, 2H), 1.49 (s, 9H).