Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:4]3[CH:3]=[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH2:11][CH2:12]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: O=C(c1cc(Br)ccn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC1(C)OB(c2ccccn2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(c1cc(-c2ccccn2)ccn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 120 °C
Yield: 1.3 %

Procedure:
In a 5 ml microwave vial were added 1-[(4-bromo-2-pyridinyl)carbonyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 17) (150 mg, 0.314 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Description 5) (129 mg, 0.627 mmol), bis(triphenylphosphine)palladium(II) chloride (44.0 mg, 0.063 mmol), sodium carbonate (100 mg, 0.941 mmol), 1,2-dimethoxyethane (1.5 ml), ethanol (1.0 ml) and water (0.50 ml). The reaction mixture was heated for 20 minutes at 120° C. in the microwave. The crude material was diluted in EtOH and filtered through celite. The filtrate was concentrated in vacuo then diluted with MeOH and filtered through an SCX cartridge (1 g). All material came out with MeOH wash so product concentrated, diluted with MeOH and filtered through a 5 g SCX column (washed with MeOH, eluted with NH3 0.5M in MeOH). The eluted product was concentrated in vacuo then dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were combined and concentrated under vacuo to give the title compound (2 mg).
Reaction SMILES: BrC1C=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C=CC=1)N.Br[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH2:22][C:23]([O:25]CC)=[O:24].S1C=CC(C2C=C(CC(O)=S)C=CC=2)=C1.S1C=CC(C2C=C(NCC(O)=O)C=CC=2)=C1>>[S:8]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:4]1
Reactant: CCOC(=O)COc1cccc(Br)c1
Reactant: Sc1cccc(Br)c1
Agent: O=C(O)CNc1cccc(-c2ccsc2)c1
Agent: OC(=S)Cc1cccc(-c2ccsc2)c1
Solvent: Nc1cccc(Br)c1
Product: O=C(O)COc1cccc(-c2ccsc2)c1

Procedure:
When the same reactions as in Referential Example 12 are carried out using 3-bromothiophenol or 3-bromoaniline instead of the starting 3-bromophenol, 3-(3-thienyl)phenylthioacetic acid and 3-(3-thienyl)phenylaminoacetic acid are obtained.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:30])[CH2:8][S:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N[C@H](C(NCCSC(=O)C)=O)CS)(=O)C.C(Cl)Cl.CCOCC.C(Cl)(Cl)Cl>CCCCCC>[C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:30])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)C
Agent: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)N[C@@H](CS)C(=O)NCCSC(=O)C(C)C

Procedure:
This compound is obtained by the S-detritylation of 15 (2.75 mmol). The protocol used is the same as that described in example 1 for the synthesis of I-152. After the various treatments, a gum is collected, which gum is purified by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 25%). I-208 is isolated in the form of a gum which, after trituration in hexane, provides a colorless powder (Yd=69%). Rf (CH2Cl2/ether, 5/5): 0.39. M.p.=125-127° C. [α]D20=−25.7° (c 1.05, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[N:10]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)=[N:12][CH:11]=1.N1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:13]3[N:12]=[CH:11][NH:10][C:15]4=[N:16][CH:17]=[CH:18][C:14]=34)[CH2:24][CH2:23]2)=[O:8])[CH:3]=1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: C1COCCN1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-methyl-3-isoxazolecarbonyl chloride (0.029 g, 0.200 mmol) in DCM (1 mL) and DMF (0.5 mL) was added to a solution of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (0.043 g) in DMF (1.5 mL) in the presence of polymer-supported morpholine (0.279 g, 0.600 mmol, loading 2.15 mmol/g). The reaction mixture was shaken overnight at room temperature. The morpholine resin was filtered off and washed with a DCM:DMF (1:1) mixture. The unreacted acid chloride was removed by filtration on a Si—NH2 cartridge [Biotage] eluting with a DCM:DMF 1:1 mixture, and then the solvents were removed in vacuo. The crude mixture was purified by MDAP using a formic acid method to afford E16 (23.4 mg); 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.64 (1H, d), 8.14 (1H, s), 7.18 (1H, d), 6.59 (1H, d), 6.52 (1H, s), 4.71 (2H, dt), 4.12 (1H, m), 3.15 (2H, dt), 2.44 (3H, s), 1.85 (2H, m), 1.60 (2H, m), MS(ES+) 326 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:14][CH:13]3[C:15](=[O:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]3[C:15]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=4)([OH:16])[CH:13]([CH2:12][CH2:11]3)[CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2CC3CCC(C2)C3=O)cc1
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(OC)c2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 111.5 %

Procedure:
3-(4-Methoxy-benzyl)-3-aza-bicyclo[3.2.1]octan-8-one (1.09 g, 4.44 mmol) was azeotroped from THF (3×50 mL) then dissolved in anhydrous THF (20 mL) under N2 and cooled to −78° C. This was treated with 3-methoxyphenylmagnesiumbromide (4.89 mL, 4.89 mmol) dropwise and stirred at −78° C. for 5 min, then warmed to room temperature. The reaction was quenched with 1N HCl (pH 1), washed with ether (2×50 mL), then the organic layer was back extracted with water (1×50 mL). The combined aqueous layers were neutralized to pH 8 with saturated aqueous NaHCO3 solution, extracted with CH2Cl2 (3×50 mL), washed with saturated aqueous NaCl solution (1×50 mL), dried through a cotton plug, and concentrated to yield a yellow oil (1.75 g, 100%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J=7.9 Hz; 2H), 7.05 (d, J=7.4 Hz, 1H), 7.01 (s, 1H), 6.84–6.78 (m, 4H), 3.77 (s, 3H), 3.76 (s, 3H), 3.52 (s, 2H), 2.83 (d, J=10.3 Hz, 2H), 2.58 (d, J=8.3 Hz, 2H), 2.36 (s, 2H), 1.75 (d, J=7.5 Hz, 2H), 1.41 (m, 2H); GCMS m/z 353 (M)+; APCI MS m/z 354.4 (M+1)+.
Reaction SMILES: C([Mg]Br)C.C1C[O:8][CH2:7][CH2:6]1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C(Cl)(=O)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:7]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)(=[O:8])[CH3:6]
Reactant: C1CCOC1
Reactant: CSc1nc(I)n2ccsc12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CSc1nc(C(C)=O)n2ccsc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A 1 M ethylmagnesium bromide/THF solution (4.78 ml) was added in an argon atmosphere at −40° C. to a solution of 963 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 30 ml of dry THF. The mixture was stirred at the same temperature for 30 min. Acetyl chloride (0.35 ml) was added thereto. The temperature of the system was raised to −5° C. over a period of 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=2:1:1) to give 384 mg of 5-acetyl-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:20]([O-])=O)=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[F:12]>CN(C)C=O.[C].[Pd]>[F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[F:12]
Reactant: CC1Cc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(=O)O)cn1c23
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 49.8 %

Procedure:
8,9-Difluoro-2-methyl-7-nitro-6-oxo-1,2-dihyro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (6 g) is dissolved in dimethylformamide (300 ml) and thereto is added 20% palladium-carbon catalyst (0.5 g), and the mixture is subjected to a catalytic reduction under a pressure of 5 kg/cm2. After the reaction, the cartalyst is filtered off and further dimethylformamide is distilled off, and to the residue is added ethanol. The resulting precipited crystals are separated by filtration and recrystallized from dimethylformamide to give 8,9-difluoro-2-methyl-7-amino-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (2.7 g) as yellow cubic crystals. m.p. 270°-274° C. (decomp.)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N+](C1C=C(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)C=CC=1)([O-])=O.[F-].[K+]>C1COCC1>[O:25]1[CH2:26][C@H:24]1[CH2:23][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CN(C[C@@H]1CO1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of isoindoline (500 mg, 4.20 mmol) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.27 g, 5.04 mmol) in THF (100 mL) was added KF (580 mg, 10 mmol) at 0° C. The reaction mixture was warmed to 25° C., stirred for 16 h, filtered and concentrated. The crude product was used in the next step without further purification. (600 mg, yield 68%) MS (ESI+) e/z: 176.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:4].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:15][CH2:14]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC1CCc2ccccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1CCc2cc(Br)ccc2N1
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a solution of 2-methoxycarbonylmethyltetrahydroquinoline (31.5 g, 0.153 mol) in DMF (750 mL) was added dropwise a solution of N-bromosuccinimide (27.41 g, 0.154 mol) in DMF (550 mL) at 0° C. The mixture was stirred for 2 h at the same temperature, poured into water (2 L), and extracted with a mixture of toluene and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 44.72 g of the title compound (quant).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[C:18]12([CH2:28][S:29]([OH:32])(=[O:31])=[O:30])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][C:19]2=[O:20]>C(O)C>[NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[C:18]12([CH2:28][S:29]([O-:32])(=[O:30])=[O:31])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][C:19]2=[O:20]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: CCO
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2

Procedure:
In 1,400 ml of ethanol was dissolved 8.41 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 8.52 g of (+)-camphorsulfonic acid was added to the solution. The resulting salts were recrystallized from ethanol several times to obtain 5.20 g of optically active 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane·(+)-camphorsulfonate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>O.[Pt]=O.C(O)C>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1OCC(F)(F)F
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80147.1 %

Procedure:
A mixture of 1-(2,2,2-trifluoroethoxy)-2-nitrobenzene (15 g, 68 mmol), platinum oxide hydrate (100 mg) and absolute ethanol (80 mL) was hydrogenated 18 hours with stirring at 25° C. and 15 psi of pressure. The reaction mixture then was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to give 2-(2,2,2-trifluoroethoxy)aniline (10.4 g, 54.5 mol), m.p. 49°-50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COc1c(C)cc(C)cc1/C=C/C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(C)cc(C)cc1CCC(=O)O
Yield: 91.9 %

Procedure:
In acetic acid (80 mL) were suspended (E)-3-(2-methoxy-3,5-dimethylphenyl)propenoic acid (9.60 g, 46.5 mmol) and 10% palladium-on-carbon (hydrous) (0.60 g) and the suspension was stirred in a hydrogen atmosphere at 60° C. for 14 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethanol to provide 8.90 g of the title compound. Yield 91%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>C(O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Yield: 78.2 %

Procedure:
A solution of (1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol (0.091 g, 0.24 mmol), triethylamine (0.1 mL, 0.72 mmol) and (S)-1-aminoindane (0.0662 g, 0.48 mmol) in ethanol (5 mL) was refluxed at 95° C. for 14 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (0 to 60% EtOAc/DCM) to afford the title compound (0.09 g, 80%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C.Cl>C(#N)C>[CH:26]1([NH:32][C:33]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)NC4CCCCC4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.43 g, 1.16 mmol) and cyclohexylisocyanate (0.148 mL, 1.16 mmol) in acetonitrile (8 mL), was added triethylamine (0.32 mL, 2.33 mmol) at room temperature under nitrogen. After 2 h, dil. aq. HCl (10 mL) was added. The solids were collected by filtration and washed with dil. aq. HCl (20 mL) and acetonitrile (10 mL). The product was dried in vacuo to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.24 g, 52% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; 25/75 CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 5.94 min (99.50%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 0.99-1.36 (m, 5H, CH2, CH2, CH), 1.44-1.84 (m, 5H, CH2, CH2, CH), 1.92-2.06 (m, 1H, CH), 2.25-2.47 (m, 1H, CH), 2.59 (d, J=17.4 Hz, 1H, CH), 2.82-3.02 (m, 1H, CH), 3.33-3.47 (m, 1H, CH), 4.22-4.50 (m, 4H, CH2 and CH2), 5.10 (dd, J=5.0, 13.3 Hz, 1H, NCH), 5.88 (d, J=7.9 Hz, 1H, NH), 6.29 (t, J=5.9 Hz, 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.44 (s, 1H, Ar), 7.67 (d, J=7.7 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 24.49, 25.28, 31.20, 33.28, 42.86, 47.09, 47.89, 51.55, 121.76, 122.84, 126.81, 130.13, 142.30, 145.51, 157.26, 167.98, 170.99, 172.85; LCMS: MH=399; Anal Calcd for C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.30; H, 6.51; N, 13.76.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11](Cl)=[O:12])#[N:3]>O1CCCC1.O>[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11]([NH2:1])=[O:12])#[N:3]
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a stirred, ice-cold solution of 10 mL (0.15 mole) of concentrated aqueous ammonia in 15 mL of tetrahydrofuran was added dropwise a solution of 0.35 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 15 mL of tetrahydrofuran. Upon completion of the addition, the cooling bath was removed. The reaction vessel was closed by placing a rubber balloon over the open inlet of the reaction vessel. The reaction mixture was then allowed to warm to ambient temperature where it was stirred for one hour. After this time, the reaction mixture was concentrated at 45° C. under reduced pressure to a residual solid. The solid was triturated with petroleum ether and filtered, yielding a solid that did not completely melt at 212° C. The filtrate was concentrated in an air current, yielding a tan-yellow solid. Both solids were stirred in water separately. Each of the solids was then collected by filtration. The tan-yellow solid was triturated with two drops of isopropyl alcohol and petroleum ether. The suspension was cooled in a dry ice bath, and the solid was collected by filtration. The two solids were combined and dried, yielding 0.18 gram of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]-acrylamide, m.p. 208°-210° C., dec. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10](I)[N:11]=1)[CH2:7][CH2:6][O:5]2.N([Si](C)(C)C)[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:29]([NH2:27])=[O:30])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 12-bromo-4-iodo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca 1(14),2,4,10,12-pentaene (11.0 g, 28.7 mmol) in dried DMF (300 mL) was added Pd(PPh3)2Cl2 (1.0 g, 1.4 mmol) and (Me3Si)2NH (14 g, 86 mmol). The mixture was stirred at 70° C. for 4 h under carbon monoxide atmosphere. After removal of the solvent, the residue was treated with ice-water, filtered, extracted with ethyl acetate (400 ml), dried over anhydrous Na2SO4, and concentrated to give 12-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (7.2 g, 97% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 308.1 [M+H+].
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[O:26])[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[O:26])[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: O=CNc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 5 h
Yield: 21.8 %

Procedure:
A mixture of conc.hydrochloric acid (2.44 g) and methanol (10 ml) was added to a mixture of 7-[2-(2-formamido-4-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxylic acid (2.44 g) in methanol (40 ml) under ice-cooling, stirred at 20° to 22° C. for 5 hours and filtered. The filtrate was concentrated under reduced pressure, and water (100 ml) was added to the residue adjusted to pH 6.5 with sodium bicarbonate with stirring and filtered. The filtrate was washed with ethyl acetate, and adjusted to pH 3.5 with 10% hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxylic acid (0.492 g). The filtrate and washings were subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), washed with water and eluted with 15% isopropyl alcohol. The isopropyl alcohol was distilled off under reduced pressure and the remaining solution was lyophilized to give the same object compound (1.561 g). Total yield 2.053 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(F)cc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.4 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 4-fluorophenylboronic acid (59 mg, 0.423 mmol) and K3PO4 (149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude, which was purified by reverse phase HPLC to yield 5-(4′-fluorobiphenyl-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (19.23 mg). 1H NMR (Oxalate salt, CD3OD) d (ppm): 7.65-7.59 (m, 3H), 7.41 (d, 1H), 7.25 (s, 1H), 7.15 (m, 1H), 7.05-6.85 (m, 5H), 4.5-3.39 (m, 2H), 3.6-3.5 (m, 1H), 3.2-3.19 (m, 1H), 2.95 (s, 3H), 2.85-2.8 (m, 1H), 2.59-2.50 (m, 1H), 2.4 (s, 3H).