Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[O:1]=[C:2]1[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CCC(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
A mixture of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (2760 mg, 17.56 mmol), bromobenzene (2.034 ml, 3030 mg, 19.32 mmol), Pd2(dba)3 (402 mg, 0.439 mmol), Cs2CO3 (8580 mg, 26.3 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 254 mg, 0.439 mmol) in 70 ml of dioxane was stirred at 100° C. for 6 h under nitrogen atmosphere. Due to only partial reaction after this time additional Pd2(dba)3 (402 mg, 0.439 mmol), Cs2CO3 (2860 mg, 8.77 mmol) and Xantphos (254 mg, 0.439 mmol) were added and stiffing at 100° C. was continued for additional 6 h. The reaction mixture was then filtered via a short celite column, the solvent was removed under reduced pressure, and the remaining residue was taken up in ethyl acetate, washed successively with an aq. sat. NaHCO3 solution and an aq. citric acid solution (each 3×), then with water and brine. The organic layer was dried over Na2SO4, the solvent evaporated under reduced pressure, and the obtained residue purified by column chromatography on silica gel using dichloromethane to give (R)-ethyl 5-oxo-1-phenylpyrrolidine-2-carboxylate as a brown oil (715 mg, 3.07 mmol; yield: 17%; ESI-MS [M+H]+=234.1). Saponification to the corresponding carboxylate was achieved by stirring at room temperature overnight in a solution of 4 ml ethanol and 1.84 ml 2N NaOH (aq). Subsequent evaporation of the solvent followed by addition of water, extraction with MTBE (3×), acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane (3×), washing the combined organic layers with brine, drying over MgSO4 and removing the solvent under reduced pressure yielded the title compound as a pale brown powder (0.5 g; yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:6][N:7]=1.[H][H]>C(Cl)Cl.CO.[Pd]>[NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCC4(CC3)OCCO4)cnc2N)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
To a solution of tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (11 g, 25.7 mmol) in DCM (100 mL) and MeOH (100 mL) at room temperature was added Pd/C (5 g, 25.7 mmol) (10% in carbon, wet). The resulting mixture was vacuumed, and then refilled with hydrogen. The process was repeated three times. Then the reaction was stirred at room temperature under H2 atmosphere for 6 h. Catalyst was filtered out through Celite®, and washed with DCM. The filtrate was concentrated, and the residue was dissolved in DCM (60 mL), filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc/heptane to provide tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-2-fluorobenzoate (8.18 g, 19.04 mmol, 74%) as a light yellow solid. LCMS (m/z): 430.2 (MH+), 0.99 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-7.82 (m, 2H), 7.71-7.49 (m, 2H), 6.13 (s, 2H), 3.85 (s, 4H), 3.30 (s, 1H), 2.77-2.55 (m, 1H), 2.48 (dt, J=3.62, 1.91 Hz, 2H), 1.88-1.65 (m, 6H), 1.63-1.46 (m, 10H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 3-methoxy-1-propanol (6 g, 65.24 mmol), triethylamine (27.5 mL, 195.7 mmol) and tosylchloride (18.85 g, 97.9 mmol) in methylene chloride (50 mL) is stirred for 3 h at room temperature under nitrogen. The mixture is poured into H2O, and the aqueous layer extracted twice with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 4/1) to afford the title compound as an orange oil: MS 261.9 [M+18]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.21 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[F:19].O1CCCC1.[Cl-].[NH4+]>O.[Zn]>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1cccnc1Nc1cc(F)c(Cl)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccnc1Nc1cc(F)c(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-3,5-difluorophenyl)-3-nitropyridin-2-amine (C17) (100 mg, 0.35 mmol) in a 1:1 mixture of tetrahydrofuran and water (20 mL) was added ammonium chloride (148 mg, 2.77 mmol) followed by zinc (182 mg, 2.78 mmol), and the reaction mixture was stirred at room temperature for 2 hours. It was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow solid. This material was used directly in the following step. Yield: 80 mg, 0.31 mmol, 89%.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]([O:12]CCCCC)=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].Cl>CO>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOC(=O)c1ccc(OCCCCC)c(OCCCCC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCOc1ccc(C(=O)O)cc1OCCCCC
Yield: 69.6 %

Procedure:
Pentyl 3,4-dipentyloxybenzoate (911 mg, 2.50 mmol) was dissolved in methanol (15.0 ml). To this solution was added a 1N aqueous potassium hydroxide solution (7.5 ml, 7.5 mmol, 3 eq), and the mixture was stirred with reflux for 5 hours. A 3N aqueous hydrochloric acid solution was added to this reaction mixture to make the same acidic (pH <2). The mixture was extracted with chloroform (20 ml×3). The organic layer was washed with saturated brine (20 ml). The organic layer was d ried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure to give a colorless solid. This was recrystallized from ethyl acetate-hexane to give 3,4-dipentyloxybenzoic acid (512 mg, 70%) as colorless crystals.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].CC([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.[CH3:29][C:30]([C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][N:34]=1)([CH3:32])[CH3:31]>CCCCCC.O1CCCC1>[CH3:1][C:2]1([CH3:3])[C@@H:39]([C:36]2[CH:35]=[N:34][C:33]([C:30]([CH3:29])([CH3:31])[CH3:32])=[N:38][CH:37]=2)[C@@H:40]1[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: [Li]CCCC
Reactant: CCOC(=O)/C=C/c1cnc(C(C)(C)C)nc1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)[C@H]1[C@H](c2cnc(C(C)(C)C)nc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (10.6 cm3 of a 1.55M solution in hexane) was added slowly to a stirred solution of prop-2-yl triphenyl phosphonium iodide (7.1 g) in dry tetrahydrofuran (20 cm3) at the ambient temperature under a nitrogen atmosphere and the resultant mixture stirred for a further 15 minutes after which a solution of ethyl trans 3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]propenoate (3.2 g) in dry tetrahydrofuran (25 cm3) was added dropwise at -5° C. After stirring for a further period of 30 minutes during which time the mixture warmed to the ambient temperature it was kept at the ambient temperature for 16 hours. The mixture was partitioned between water (300 cm3) and diethyl ether (200 cm3) and the aqueous phase extracted with ether (2×200 cm3) and the extracts combined with the ethereal phase. After washing with water (2×100 cm3) and drying over anhydrous magnesium sulphate, the ether was removed by evaporation under reduced pressure to yield a residual oil which was subjected to dry column chromatography using a silica column eluted first with dichloromethane (to remove triphenyl phosphine) and then with a mixture of dichloromethane (100 parts by volume) and ethyl acetate (5 parts by volume) to yield ethyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate (2.8 g), the identity of which was confirmed by infra red and n.m.r. spectroscopy.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([I:14])=[C:12]([Cl:15])[CH:11]=[CH:10][N:9]=1)(C)(C)C.[OH-].[Na+]>Br.C1COCC1>[Cl:15][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[C:13]=1[I:14]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nccc(Cl)c1I
Temperature: 100 °C
Yield: 92 %

Procedure:
A suspension of (4-chloro-3-iodo-pyridin-2-yl)-carbamic acid tert-butyl ester (5.6 g, 15.8 mmol) in 48% hydrobromic acid was heated at 100° C. for 10 min to give a clear solution. The mixture was cooled, treated with crushed ice and made basic with 6 M NaOH. The precipitated product was collected by vacuum filtration, washed with H2O and sucked partially on the funnel to give a white solid. The product was dissolved in THF and the solution dried over MgSO4 and concentrated in vacuo to give the title compound (3.7 g, 93%) as a white solid. 1H NMR (DMSO-d6) δ 7.84 (d, 1H, J=5.1 Hz), 6.73 (d, 1H, J=5.6 Hz), 6.51 (br s, 2H); MS(ESI+): m/z 254.97 (M+H)+.
Reaction SMILES: [N:1](=[C:3]1[CH:8]([CH3:9])[N:7]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:14])[CH2:5][S:4]1)[OH:2].[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C>[CH3:15][NH:16][C:17]([O:2][N:1]=[C:3]1[CH:8]([CH3:9])[N:7]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:14])[CH2:5][S:4]1)=[O:18]
Reactant: CN=C=O
Reactant: CCCCN1C(=O)CSC(=NO)C1C
Solvent: CCN(CC)CC
Product: CCCCN1C(=O)CSC(=NOC(=O)NC)C1C

Procedure:
Utilizing the procedure of Example V, 2-oximino-3-methyl-4-butyltetrahydro-1,4-thiazin-5-one was reacted with methyl isocyanate in the presence of triethylamine to yield 7.0 of 2-[O-(methylcarbamoyl)oximino]-3-methyl-4-butyltetrahydro-1,4-thiazin-5-one, m.p. 118°-120° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Nc1ccccc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A solution of 15.0 g of 4-bromobenzoic acid (74 mmol) and 13.9 g of 2-aminothiophenol (110 mmol) in 250 mL of dry toluene was heated to 45° C. and 10.1 mL of phosphorus trichloride (110 mmol) was slowly added to the reaction mixture via syringe. The mixture was allowed to reflux for 4 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to afford a yellow solid. The solid was slowly added to 500 mL of saturated aq. NaHCO3 and the aqueous solution was extracted with 2×200 mL of ethyl acetate. The combined organic solutions were washed with water (3x), dried over sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford 6.0 g of 2-(4-bromophenyl)benzothiazole.
Reaction SMILES: O1[CH2:6][CH2:5][O:4][CH2:3]C1.CC(C)([O-])C.[K+].[Br:13][C:14]1C=C[C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][C:15]=1F>CO>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:22])=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)c(F)c1
Reactant: C1COCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(S(=O)(=O)C(C)C)ccc1Br
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To dioxane (5 mL) and MeOH (0.216 mL) was added a solution of potassium tert-butoxide (1M in THF, 5.16 mL) and the mixture stirred for 15 minutes. To the mixture was added 1-bromo-2-fluoro-4-(isopropylsulfonyl)benzene (Preparation 34, 500 mg, 1.78 mmol) and the reaction mixture stirred for 16 hours at 60° C. The cooled reaction mixture was quenched with water (15 mL), and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc/heptanes 33/67-100/0 to afford title compound as a colourless solid in 75% yield.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH3:35][N:36]([CH3:51])[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[C:42]2[S:47]([NH2:50])(=[O:49])=[O:48]>>[Cl:24][C:17]1[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:34])[NH:50][S:47]([C:42]4[C:43]5[C:38](=[C:37]([N:36]([CH3:51])[CH3:35])[CH:46]=[CH:45][CH:44]=5)[CH:39]=[CH:40][CH:41]=4)(=[O:48])=[O:49])=[CH:10][CH:9]=3)[C:15]=2[CH:16]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: CN(C)c1cccc2c(S(N)(=O)=O)cccc12
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccc3c(N(C)C)cccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 5-(dimethylamino)-1-naphthylsulfonamide.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1>C(O)(=O)C.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[NH:33][CH2:32][CH2:31][CH2:30]4)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3cccnc23)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3c2NCCC3)CC1

Procedure:
Prepared from N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-quinoline-8-sulphonamide by catalytic hydrogenation in the presence of palladium/charcoal in 50% acetic acid analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1.[Cl-].[NH4+].Cl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2ccccc2N)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1-c1ccc(C)cc1
Reaction time: 16 h
Yield: 83.6 %

Procedure:
A stirred solution of 4′-methyl-1,1′-biphenyl-2-amine (3.09 g, 16.87 mmol) in dichloromethane was treated with acetic anhydride (1.75 mL, 18.6 mmol), pyridine (3.14 mL, 38.8 mmol), and 4-(N,N-dimethylamino)pyridine (0.062 g, 0.506 mmol). After stirring under argon for 16 hours, a saturated, aqueous, ammonium chloride solution (5 mL) was added to the reaction mixture and stirring continued another 30 minutes. The reaction mixture was poured into a 0.1 N hydrochloric acid solution. The separated aqueous phase was further extracted with dichloromethane (3×). The combined organic phase was washed sequentially with a 0.1 N hydrochloric acid solution and a saturated aqueous, sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo. The crude product was purified by re-crystallization from a mixture of ethyl acetate-hexane to yield the title compound (3.17 g, 14.1 mmol, 83%) as a white, crystalline solid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (2 g, 9.4 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (2.3 g, 7.5 mmol) prepared in Example 2 in dichloromethane (30 mL) were added triethyl amine (2.8 mL, 20 mmol) and AgF (1.1 g, 8.7 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2) to give as rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white foam (1.9 g, 49%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N+:12]([O-])=[C:11]([CH3:21])[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:21][C:11]1[C:10]([CH3:22])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(c1)c(OCc1ccccc1)c(C)c(C)[n+]2[O-]
Product: CC(=O)OCc1nc2ccc(C)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.18 g) was dissolved in acetic anhydride (32 mL), followed by stirring at room temperature for 2 hours. After the solvent was evaporated under reduced pressure, water (50 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methyl acetate (1.25 g).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([NH:22][C:23]([C:25]2[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=2)=O)=[CH:10][N:9]=1)(C)(C)C.[C:35](O)(=O)C>>[CH2:15]([N:14]1[C:12]2[CH:13]=[C:8]([NH:7][C:6](=[O:5])[CH3:35])[N:9]=[CH:10][C:11]=2[N:22]=[C:23]1[C:25]1[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(C(=O)Nc2cnc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Reactant: CC(=O)O
Product: CC(=O)Nc1cc2c(cn1)nc(-c1cc(C)c(=O)n(C)c1)n2Cc1ccccc1
Temperature: 170 °C

Procedure:
{4-Benzylamino-5-[(1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-carbamic acid tert-butyl ester II-16″ (2.000 g; 4.315 mmol) is suspended in acetic acid (5.190 g; 86 mmol) in a microwave vial and heated in a CEM microwave at 170° C. for 5 h. The reaction mixture is then concentrated under reduced pressure. The residue is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH2:25]1[CH:29]2[CH2:30][NH:31][CH2:32][CH:28]2[CH2:27][N:26]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C(O)CCCC>[NH2:24][C:20]1[CH:19]=[C:18]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:30][CH:29]5[CH2:25][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][CH:28]5[CH2:32]4)[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(Cl)nn23)ccn1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCCCCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nc(-c5ccc(Cl)cc5)c(-c5ccnc(N)c5)n4n3)CC2C1
Temperature: 135 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
A mixture of 0.15 g (0.42 mmol) of 4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine and 0.36 g (1.7 mmol) of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 7 mL of pentanol is stirred at 135° C. for 20 hours. The solvent is then evaporated off under reduced pressure and the oily residue is chromatographed on a column of silica gel, eluting with a stepwise gradient of methanol and aqueous ammonia in dichloromethane (0:0:100 to 2:1:98). 0.16 g of product is isolated after trituration in diisopropyl ether, filtering off and drying under reduced pressure.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([NH:24][CH2:25][CH3:26])=[C:22]([NH2:27])[CH:21]=[N:20]1>CCOC(C)=O>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]2[N:24]([CH2:25][CH3:26])[C:2](=[O:4])[C:1](=[O:8])[NH:27][C:22]=2[CH:21]=[N:20]1
Reactant: CCNc1c(N)cnn1-c1ccc(F)cc1F
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(=O)[nH]c2cnn(-c3ccc(F)cc3F)c21
Temperature: 150 °C

Procedure:
A mixture of diethyl oxalate (5.68 mL, 4.20 mmol) and 1-(2,4-difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine (1.00 g, 4.20 mmol) were heated in an oil bath at 150° C. for 18 h. The reaction mixture was cooled to RT and treated with EtOAc (5 mL) and hexanes (15 mL). The precipitated tan solid was filtered and rinsed with 5 mL of ether to afford 1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione. MS (ES+): 293.1 (M+H)+.