Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)([CH2:14][NH:15][C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][C:11]1([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a stirred solution of 4-(4-iodo-phenyl)-4-(isobutoxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (0.075 g, 0.15 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added TFA (0.5 mL). The mixture was stirred at room temperature for 3 h. TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×10 mL), diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 solution (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation and dried under high vacuum for 1 h to give [4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester as a reddish solid (0.058 g, ˜0.14 mmol). MS (ESI): 417.1/418.1(M+1).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]Br>CN(C=O)C.CCOC(C)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:22][C:8]1[O:9][C:10]2[N:11]=[CH:12][N:13]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:14](=[O:16])[C:15]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2c(-c3ccccc3)coc2ncn1CC(F)(F)F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2c(-c3ccccc3)c(Br)oc2ncn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-phenyl-3-(2,2,2-trifluoroethyl)furo[2,3-d]pyrimidin-4(3H)-one (730 mg, 2.48 mmol) in DMF (10 ml) at 0° C. was added bromine (0.153 ml, 2.98 mmol). The reaction mixture was stirred at 0° C. for 1 h and then 3 h at RT. The reaction mixture was diluted with EtOAc (50 ml) and 20% w/w aq. sodium thiosulfate solution (50 ml) and the layers were separated. The organic layer was further washed with brine (2×50 ml), dried (Na2SO4) and concentrated in vacuo affording the title compound as an orange solid. LCMS RT=1.40 min, M+H+=373/375.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reaction time: 1.25 h
Yield: 91 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (400 g, 14.7 mmol) in anhydrous acetonitrile (160 mL) under nitrogen was added Selectfluor™ reagent (5.74 g, 16.2 mmol) and the mixture was stirred for 75 min. The mixture was poured into ethyl acetate (600 mL), washed with diluted brine (300 mL), then saturated NaCl solution (100 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (alumina, 0-5% MeOH/EtOAc) to afford 2.91 g (91%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.50 (9H, s), 2.52-2.64 (2H, m), 3.22-3.38 (2H, m), 4.18 (1H, m), 4.45 (1H, m), 4.83 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH:25]=[O:26])[CH:32]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.483 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added (3-formylphenyl)boronic acid (317 mg, 1.93 mmol), and Cs2CO3 (315 mg, 0.97 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a stirred solution of [10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazol-7-yl](cyclopropyl)methanol (81.4 mg, 0.186 mmol) in acetonitrile (2.5 mL) was added Dess-Martin reagent (94.7 mg, 0.223 mmol) at room temperature. After 5 h, the reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (67.1 mg, 0.154 mmol, 83%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)NOc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)NOc1ccccc1
Yield: 57 %

Procedure:
17 (350 mg, 0.8 mmol) was suspended in 175 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The hydrogen pressure was set to 35 psi with agitation, and the process went on for 41 h. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH2Cl2 and MeOH and THF. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU to yield a white, feathery microcrystalline solid. Yield: 57%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.75 (s, 2H, —CH2—), 6.11 (t, J=7.0 Hz, 1H, Ar—H), 6.72 (d, J=7.2 Hz, 1H, Ar—H), 6.97 (m, 4H, Phenoxy-H), 7.11 (m, 2H, Ar—H, Phenoxy-H), 7.36 (t, J=7.2 Hz, 2H, Phenoxy-H), 7.58 (d, J=6.8 Hz, 2H, Phenoxy-H), 9.03 (s, 1H, —OH), 10.36 (s, 1H, —NH—). APCI-MS: m/z 336.9 [M+H]+. Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.75; H, 5.07; N, 8.49.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:7]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1nc[nH]n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(CSc2nc[nH]n2)cc1

Procedure:
A solution of 3-mercapto-1H-1,2,4-triazole (100 mg) and benzyl bromide (118 μl) in dimethylformamide (2 ml) was stirred at room temperature for 23 hours. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogencarbonate solution at room temperature, and the resultant mixture was extracted once with ethyl acetate. The organic layer was washed three times with water and subsequently once with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The residue was filtered off, and the solvent was distilled from the resulting filtrate under reduced pressure to yield the titled compound (172 mg) as white solids.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[C:17]([N+:24]([O-])=O)[CH:16]=2)[C:3]1=[O:27].[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[NH2:24][C:17]1[CH:16]=[C:15]([N:4]2[C:3](=[O:27])[C:2]([CH3:1])([CH3:28])[N:6]([CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[C:5]2=[O:14])[CH:20]=[CH:19][C:18]=1[CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
2.64 g (6.90 mmol ) 5,5-dimethyl-3-(3-nitro-4-isopropyl-phenyl)-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 50 ml acetic acid. 7.22 g zinc dust were added in portions while temperature was kept below 45° C. The mixture was stirred for 1 h at RT, then diluted with 100 ml water, made alkaline with 6N sodium hydroxide solution and extracted with methylene chloride. Separating zinc salts were removed by filtration over cellite. Evaporation of the combined organic phases yielded 1.53 g product that were used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][CH:6]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH:6]([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C=CC(NC(=O)OC(C)(C)C)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC(NC(=O)OC(C)(C)C)C1CCCCC1
Reaction time: 4 h

Procedure:
To a solution of 4-tert-butoxycarbonylamino-4-cyclohexyl-but-2-enoic acid methyl ester (9 g, 30 mmol) in MeOH (100 mL) was added Pd—C (10% on activated carbon) (1 g) under N2, and the reaction mixture was subjected to hydrogenation under 20 psi for 4 hours. The catalyst was filtered out, and the MeOH was evaporated to yield 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid methyl ester as a white solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=C[CH:13]=1>CC(C)=O>[CH3:13][C:12](=[N:11][NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH3:17]
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)=NNS(=O)(=O)c1ccccc1
Temperature: 20 °C

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 86 g (0.5 mol) of benzenesulfonohydrazide, 0.95 g (0.005 mol) of p-toluenesulfonic acid and 700 ml of acetone and then heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:35]=[C:36]=[O:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>O1CCCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1ccc(N=C=O)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3,4-dimethoxyphenyl isocyanate (0.182 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from tetrahydrofuran to give 64.6 mg (18.7%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCCOCn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 94.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (188 mg, 0.272 mmol) prepared in Example 159b, triethylsilane (0.20 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL), to yield the title compound (139 mg, 95%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 93 %

Procedure:
Using m-anisidine (2.50 g, 15.0 mmol) and 4-nitrobenzoic acid (2.03 g, 16.5 mmol), the procedure of Reference Example 16 was repeated to obtain 3.80 g (93.2%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=[CH:16][C:10]=2[C:9]=1[C:24](=[O:26])[NH2:25])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=[CH:16][C:10]=2[C:9]=1[C:24]([NH2:25])=[O:26]
Reactant: CC(C)(C)OC(=O)Nc1sc2cc(-c3ccc(F)cc3)ccc2c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(N)sc2cc(-c3ccc(F)cc3)ccc12
Yield: 54.8 %

Procedure:
A solution of 1h (20 mg, 0.051 mmol) in CH2Cl2 (5 mL) was mixed with trifluoroacetic acid (0.5 mL). The resultant solution was stirred at room temperature for 1 h, then mixed with saturated NaHCO3 solution (30 mL), and extracted with ethyl acetate (30 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) provided the title compound (8 mg, 55%) as a white solid: MS (ES) m/z 287 (M+H)+; 1H NMR (400 MHz, CD3OD) δ7.73 (s, 1H), 7.63-7.50 (m, 3H), 7.42 (m, 1H), 7.08 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:13]([C:14]#[C:15][Si](C)(C)C)[CH2:12][CH2:11][C@H:6]1[C:7]([O:9]C)=[O:8])=[O:4].O[Li].O>CO.O>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:13]([C:14]#[CH:15])[CH2:12][CH2:11][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)CCl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl (5R)-1-(chloroacetyl)-5-((trimethylsilyl)ethynyl)-L-prolinate (3.69 g, 12.2 mmol) in MeOH (24 mL) and H2O (24 mL) at room temperature was added LiOH.H2O (0.8 g, 18 mmol). The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was taken up in water and extracted with diethyl ether (2×). The aqueous layer was acidified to pH˜3 by adding 4% KHSO4 dropwise. The solution was extracted with ethyl acetate (3×). Combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 216 (M+1)+.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:19])[C:8]1=[O:20])=[O:5])C.[OH-].[Na+]>C1COCC1.O>[C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:19])[C:8]1=[O:20])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Yield: 64.7 %

Procedure:
The ester of example 21 (34 mg, 0.107 mmol) was reacted with 0.1M NaOH (3.2 ml) in a mixture of THF (2.0 ml) and water (0,5 ml) for 26 h at 45° C. The solvent was removed in vacuo and the remanens was dissolved in water (1.0 ml), cooled in an ice bath and the pH was adjusted to 2.5 with 0.5 M hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 20 mg (65%) of the title compound. 1H-NMR (DMSO-d6):δ5.0 (s, 2H), 7.2 (d, 1H), 7.41 (d, 1H), 12.33 (s, 1H), 13.18 (br.s, 1H).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2)#[CH:10]>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][NH:23][C:22]=1/[CH:21]=[C:13]1\[C:14](=[O:20])[NH:15][C:16]2[C:12]\1=[C:11]([C:9]#[C:10][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH:19]=[CH:18][CH:17]=2
Reactant: Brc1ccncc1
Reactant: C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccncc3)c21

Procedure:
Using Method J above, 4-bromopyridine hydrochloride (110 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 5) (100 mg, 0.38 mmol) using DPPFPdCl2 (15.4 mg) (Aldrich) and CuI (4 mg) (Aldrich) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent and heating at reflux for 1 day, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(4-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 70 mg, 54%).
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[K].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>CN(C=O)C>[C:4]([N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11])#[C:3][CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CC#CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C

Procedure:
32.3 g (271 mmol) 3-bromopropine are dissolved in 150 ml DMF and 50.3 g (271 mmol) phthalimide potassium salt are added under ice cooling. The suspension is warmed at 70° C. for eight hours. The mixture is concentrated under a vacuum and the residue is distributed between acetic acid ethyl ester and water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from acetic acid ethyl ester: Yield 36.4 g (72%) colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][N:23]=1>>[CH2:28]([C:25]1[CH:24]=[N:23][C:22]([N:15]2[CH2:14][CH2:13][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][C:4]=3[F:20])[CH2:17][CH2:16]2)=[N:27][CH:26]=1)[CH3:29]
Reactant: CCc1cnc(Cl)nc1
Reactant: Fc1cc(Br)ccc1COC[C@@H]1C[C@@H]1C1CCNCC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3F)CC2)nc1

Procedure:
This compound was prepared from the product of step A and 2-chloro-5-ethylpyrimidine according to the conditions outlined in intermediate 7 (step B). 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 2H), 7.33-7.31 (m, 2H), 7.26 (d, J 9.0 Hz, 1H), 4.72-4.65 (m, 2H), 4.60 (d, J 12.4 Hz, 1H), 4.52 (d, J 12.4 Hz, 1H), 3.65 (dd, J 10.1 & 6.4 Hz, 1H), 3.47 (t, J 9.6 Hz, 1H), 2.88-2.76 (m, 2H), 2.47 (q, J 7.5 Hz, 1H), 1.95 (d, J 13.0 Hz, 1H), 1.82 (d, J 13.3 Hz, 1H), 1.45-1.35 (m, 2H), 1.21 (t, J 7.5 Hz, 3H), 1.09-1.00 (m, 1H), 0.79-0.69 (m, 2H), 0.09-0.04 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[C:15]([C:22]([F:25])([F:24])[F:23])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>>[F:13][C:14]1[C:15]([C:22]([F:23])([F:24])[F:25])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: Fc1cccc(CBr)c1C(F)(F)F
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1cccc(F)c1C(F)(F)F
Yield: 54 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.051 g) was alkylated with 3-fluoro-2-(trifluoromethyl)benzyl bromide as in General Procedure 1 to give the title compound as a light brown solid (54% yield). M.p.>200° C., LCMS: m/z=451.79 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.17 (2H, s), 5.20 (2H, bs), 7.01 (1H, d, J=7.6 Hz), 7.17 (1H, s), 7.23 (1H, s), 7.42 (1H, m), 7.63 (1H, m), 7.86 (1H, m).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:20]1([S:19]([C:16]2[CH:17]=[CH:18][C:13]([N:4]3[N:3]=[C:2]([Br:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:12])=[CH:14][CH:15]=2)=[O:34])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Product: O=c1c2ccccc2c(Br)nn1-c1ccc(S(=O)c2ccccc2)cc1

Procedure:
4-Bromo-2-(4-phenylsulfanyl-phenyl)-2H-phthalazin-1-one (0.095 g, 0.23 mmol) and MCPBA (0.052 g, 0.23 mmol) were stirred at RT in DCM (1 ml) for 1 h. The title compound was obtained after evaporation of the solvent in vacuum and subsequent purification of the raw product by chromatography over silica gel with heptane:DCM (1:1 until 0:1) (0.031 g, 31% yield). 1H-NMR: (400 MHz, CDCl3) 8.49 (1H, d), 7.80-7.99 (5H, m), 7.76 (2H, d), 7.69 (2H, d), 7.48 (3H, m); MS (ESI+)=427.22 (M+H)+.