Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:29]=[N:30]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1[C:29]#[N:30])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
A stirred mixture of 3-acetylamino-4-(2',4'-dibromo-6'-nitrophenylazo)-N,N-diethylaniline (5.3 parts), copper (I) iodide (1.9 parts), formaldoxime trimer (1.8 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (100 parts), was heated to 90° C. for 10 hours when thin layer chromatography showed reaction to be effectively complete. The mixture was filtered, cooled, and the solvent was removed by steam distillation. Crystallisation of the solid product from ethanol gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-nitrophenylazo)-N,N-diethylaniline (Found; C, 49.5; H, 4.3; Br, 17.7; N, 18.3. C19H19BrN6O3 requires C, 49.65; H, 4.15; Br, 17.4; N, 18.3%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.[CH:17]1(/[CH:20]=[CH:21]/B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Cl:16][C:5]1[CH:4]=[CH:3][C:2](/[CH:21]=[CH:20]/[CH:17]2[CH2:19][CH2:18]2)=[CH:7][C:6]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(/C=C/C2CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(/C=C/C2CC2)ccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (from the previous step) (1.0 eq.) and (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (commercially available) (1.0 eq.) in toluene (0.2 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and water. The two phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% EtOAc/Hexanes to give (E)-tert-butyl 2-chloro-5-(2-cyclopropylvinyl)phenylcarbamate as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][Al](C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:4]1[N:3]=[C:2]([CH3:13])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc2ccccc12
Temperature: 100 °C

Procedure:
A mixture of 1,3-dichloroisoquinoline (2.0 g, 10.1 mmol), trimethylaluminum (2.0 M in heptane, 6.1 mL, 12.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (117 mg, 0.1 mmol) in THF (8 mL) was heated in a microwave reactor at 100° C. for 15 min. After quenching by addition of water (30 mL), the mixture was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.12 (dd, J=8.5, 0.5 Hz, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.10 (dt, J=8.5, 0.5 Hz, 1H), 7.62-7.60 (m, 2H); 2.97 (s, 3H). LC6: 2.85 min, (M+H): 178.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:18]=[C:17]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=O)[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:18]=[C:17]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[CH2:1])[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C1CCCN(C(=O)c2ccc(C(=O)OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (607 mg) in N,N-dimethylformamide (10 ml) was added potassium-tert-butoxide (191 mg), and the mixture was stirred at room temperature for 30 minutes. Methyl 2-methoxy-4-(2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonylbenzoate (300 mg) was added to the resulting solution, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The crude product was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give methyl 2-methoxy-4-(2,3,4,5-tetrahydro-5-methylene-1H-1-benzazepin-1-yl)carbonylbenzoate (65 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:2]=C.N1C=C[CH:22]=[CH:21][CH:20]=1.C(OC(=O)C)(=[O:27])C>O>[C:1]([O:4][C:5]1[C:10]([CH2:20][CH:21]=[CH2:22])=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:27])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: C=CCOc1ccccc1Oc1ccccc1C
Solvent: O
Product: C=CCc1cccc(Oc2ccccc2C)c1OC(C)=O
Reaction time: 0.5 h

Procedure:
o-Tolyl 2-allyloxyphenyl ether (70 g) was heated at 250° C. with stirring for 30 minutes. To the resultant substance were added pyridine (200 ml) and acetic anhydride (50 g), and the mixture was allowed to stand at room temperature for an hour. The reaction mixture was poured into water (1 l) and extracted with diethyl ether. The extract was washed with dil. hydrochloric acid and water successively, dried over magnesium sulfate and then evaporated. The oily residue (85.0 g) was subjected to distillation under reduced pressure to give colorless oil of o-tolyl 2-acetoxy-3-allylphenyl ether (60.0 g). bp 147°-150° C./0.6 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[CH3:15][C:16]1[N:22]([CH:23]2[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=2)[N:1]=1
Reactant: c1c[nH]cn1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CC(=O)Cl
Solvent: O
Product: Cc1ccc2c(=O)n(C3CCC(=O)NC3=O)c(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a stirred mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13 mmol) and imidazole (1.1 g, 16 mmol) in acetonitrile (20 mL), was added acetyl chloride (1.1 mL, 16 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13 mmol), imidazole (2.0 g, 30 mmol) and triphenyl phosphite (4.2 mL, 16 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(2,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (2.52 g, 67% yield): HPLC: Waters Symmetry C13, 5 μM, 3.9×150 mm, 1 mL/min. 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.13 min (99.9%); mp: 305° C. (decomp); 1H NMR (DMSO-d6) δ 2.08-2.24 (m, 1H, CHH), 2.45 (s, 3H, CH3), 2.56-2.75 (m, 5H, 2CHH), 2.81-2.91 (m, 1H, CHH), 5.24 (dd, J=6, 11 Hz, 1H, NCH), 7.32 (dd, J=1.8 Hz 1H, Ar), 7.43 (s, 1H, Ar), 7.91 (d, J=8 Hz, 1H, Ar), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.00, 21.35, 23.45, 30.61, 56.43, 117.94, 125.80, 126.10, 127.97, 145.21, 146.98, 154.96, 160.34, 169.56, 172.62; LCMS: MH=286; Anal Calcd for C15H15N3O3: C, 63.15; H, 5.21; N, 14.73. Found: C, 63.14; H, 5.21; N, 14.76.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:65]1([NH2:72])[C:66]([NH2:71])=[CH:67][CH:68]=[CH:69][CH:70]=1>CN(C)C=O>[NH2:71][C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=1[NH:72][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)O
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: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of N,N-dimethylformamide (5.0 mL) was added (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (709.6 mg, 1.561 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (712 mg, 1.87 mmol), and N,N-diisopropylethylamine (1.3 mL, 7.80 mmol) and premixed for 5 minutes and then 1,2-benzenediamine (253 mg, 2.34 mmol) was added and stirred at room temperature overnight. Product was concentrated and purified on preparative LCMS to give the product (690 mg, 67%). LCMS found for C27H37N4O6S (M+H)+: m/z=545.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(NCC)(C)C.[CH3:19][O:20][CH2:21]Cl.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: CCNC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCOc1ccc2ccc(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-hydroxycoumarin (100 g) and isopropylethylamine (161 ml) in anhydrous dimethylformamide (DMF; 500 ml) was added dropwise methoxymethylchloride (70.3 ml) at 0° C. under an atmosphere of argon. The mixture was stirred at room temperature for 4 hours. To the reaction mixture were added hexane/ethyl acetate (2/1, 1000 ml) and a saturated aqueous solution of sodium bicarbonate (1000 ml) and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water (twice) and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (74.1 g) having the following physical data. The obtained crude product was used to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:8](O)=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[F:26].CC([OH:32])CCC>>[ClH:1].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][C:13]([F:26])=[C:12]2[N:6]([OH:32])[C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[F:10]
Reactant: CCCC(C)O
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2ncc(F)c(Cl)c2cc1OC
Product: COc1cc2ncc(F)c(N(O)c3ccc(Cl)cc3F)c2cc1OC
Product: Cl
Yield: 37 %

Procedure:
4-Chloro-2-fluoro-5-hydroxyaniline (194 mg, 1.2 mmol), (as described in EP 61741 A2), was added to a suspension of 4-chloro-6,7-dimethoxy-3-fluoroquinoline (241 mg, 1 mmol) in 2-pentanol (5 ml). After refluxing for 15 hours, the precipitate was collected by filtration, washed with isopropanol and dried under vacuum. The solid was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol 95/5. The purified product was dissolved in methylene chloride/isopropanol and 5M hydrogen chloride in isopropanol (0.5 ml) was added. After evaporation of the methylene chloride, the precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 6,7-dimethoxy-3-fluoro-4-(4-chloro-2-fluoro-hydroxyanilino)quinoline hydrochloride (150 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 64.6 %

Procedure:
A solution of [(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.846 g, 1.83 mmol) in ethyl acetate (10 mL) was added to a suspension of platinum (IV) oxide (45 mg, 0.198 mmol) in absolute ethanol (30 mL) and the mixture hydrogenated at 10 psi of hydrogen for 100 minutes. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane afforded 0.548 g (64%) of [(2R)-8-(2.6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. HRMS: calcd for C23H20Cl2O4S+H+, 463.0532 1. found (ESI, [M+H]+), 463.0555.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:20]2[C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=[CH:27][C:19]=2[CH:18]([NH:28][CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:20]2[C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=[CH:27][C:19]=2[CH:18]([N:28]([C:1](=[O:3])[CH3:2])[CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc3c(c21)CCC3
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc1c2CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 mmol) followed by titanium isopropoxide (414 mg, 1.46 mmol) to 6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (300 mg, 1.04 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-6-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (443 mg, 83%). Add acetic anhydride (0.24 mL, 2.52 mmol) dropwise to a solution of the amine (184 mg, 0.36 mmol) and pyridine (0.25 mL, 3.06 mmol) in dichloromethane (3.1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (149 mg, 74%); MS (ES+): 557 (M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:13][CH2:14][N:15]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1
Reactant: NC1(C(=O)NCc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(C(=O)NCc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A degassed mixture of 4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamide dihydrochloride (48 mg, 0.13 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (21 mg, 0.12 mmol), triethylamine (126 uL, 0.9 mmol) and n-butanol (1.2 mL) was stirred at 100° C. for 18 h. The solvents were removed by evaporation and the crude mixture was first purified on a SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, and then by preparative TLC, eluting with 10% methanol in dichloromethane, to give 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid 4-chloro-benzylamide (37 mg, 0.096 mmol, 80%). LC-MS (LCT2) m/z 385 [M+H+], Rt 2.84 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:37]3[C:38]([O:52][CH2:53][CH3:54])=[CH:39][C:40]([Cl:51])=[C:41]([S:43]([NH:46]C(C)(C)C)(=[O:45])=[O:44])[CH:42]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58]>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:37]3[C:38]([O:52][CH2:53][CH3:54])=[CH:39][C:40]([Cl:51])=[C:41]([S:43]([NH2:46])(=[O:45])=[O:44])[CH:42]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:55][C:56]([F:61])([F:60])[C:57]([O-:59])=[O:58]
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOc1cc(Cl)c(S(N)(=O)=O)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: O=C([O-])C(F)(F)F
Temperature: 80 °C

Procedure:
5-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-N-tert-butyl-2-chloro-4-ethoxy-benzenesulfonamide (˜10 mg) was dissolved in 2 mL of trifluoroacetic acid and heated to 80° C. for 30 min. The reaction mixture was diluted with 2 mL of methylene chloride and 1.5 mL of 10% potassium carbonate solution then agitated. The organic layer was separated and concentrated in vacuo to give 5-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-4-ethoxy-benzenesulfonamide as trifluoroacetate salt. LC-MS: 763.3 [(M+H)+].
Reaction SMILES: N1C=CC=N[CH:2]=1.C([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])C.[CH:14](O)([CH3:16])[CH3:15]>>[CH:14]([N:9]([CH:10]([CH3:11])[CH3:2])[CH2:12][CH3:13])([CH3:16])[CH3:15]
Reactant: c1cncnc1
Reactant: CC(C)O
Reactant: CCN(CC)CC
Product: CCN(C(C)C)C(C)C

Procedure:
The starting pyrimidine (a) is reacted with an appropriately substituted amine and a suitable base such as diisopropylethylamine or triethylamine in a suitable solvent such as isopropanol at elevated temperature to provide compound (b).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[C:24]3[N:23]=[CH:22][N:21](C(OC(C)(C)C)=O)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>CO.[OH-].[Li+]>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[C:24]3[NH:23][CH:22]=[N:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc3c2ncn3C(=O)OC(C)(C)C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2nc[nH]c12)c1ccc(C(=O)O)c(Cl)c1
Yield: 85 %

Procedure:
A mixture of 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13; 1.40, 5.1 mmol), 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 1.62 g, 5.2 mmol), and 10% palladium on charcoal (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite. TIc indicated that the reaction was not complete so more 10% palladium on charcoal (210 mg) was added and the mixture was hydrogenated at atmospheric pressure for 3 h and then shaken at 50 psi of hydrogen for 3 h. The reaction mixture was allowed to stand under hydrogen for 12 h, then filtered through Celite, evaporated, and chromatographed (20–100% ethyl acetate/hexanes) to give 2-chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered off and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4-[[[(benzimidazol-4-yl)methyl]amino]carbonyl]-benzoic acid (925 mg, 86%).
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:23][CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:29])C>>[CH3:21][N:20]([CH3:22])[C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[C:11]([S:23][CH3:24])=[CH:10][CH:9]=[C:3]([OH:29])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N(C)C)cc1)N(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
The procedure is as in Example 4, starting with ethyl 2-dimethylamino-6-(4-dimethylaminophenyl)-5-methylthio-6-oxo-2,4-hexadienoate (5.5 g), 12N aqueous hydrochloric acid solution (38 cc) and ethanol (50 cc). The mixture is heated to boiling for 5 minutes, and is then cooled to a temperature of approximately 20° C. After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (60:40 by volume), ethyl 6-(4-dimethylaminophenyl)-2-hydroxy-5-methylthio-6-oxo-2,4-hexadienoate (3.9 g) is obtained in the form of a brown oil (Rf=0.2; support: silica gel; eluent: cyclohexane/ethyl acetate 60:40 by volume).