Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:11]=[C:12]([C:31]4[O:32][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[N:34][N:35]=4)[C:13]([N:16](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:14][CH:15]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C:13]1[N:14]=[CH:15][C:10]([N:8]2[CH2:9][C@@H:5]3[CH2:4][CH2:3][C:2](=[O:1])[C@@H:6]3[CH2:7]2)=[N:11][C:12]=1[C:31]1[O:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(=O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(N2C[C@@H]3CCC(=O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl N-[5-[(3aR,6aS)-6-oxo-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (57 mg, 0.10 mmol) in DCM (1 mL) was treated with TFA (1.5 g, 1 mL, 13 mmol) The reaction mixture was stirred at room temperature for 1 h. The solvents were evaporated and the residue was dissolved in DMF and purified by reverse phase column chromatography to obtain (3aR,6aS)-2-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-6-one. LC/MS m/z 363.1 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:11]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.O.Cl[Sn]Cl>CO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:11]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH:3]([CH2:2][OH:1])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2[N+](=O)[O-])C(CO)C(=O)OC(C)(C)C)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Yield: 53.7 %

Procedure:
A mixture of 0.60 g (1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionic acid, tert-butyl ester and 1.45 g (6.45 mmol) of SnCl2.2H2O in 20 ml of methanol was heated in an oil bath at 90° C. for 2 hours. The solvent was removed under vacuum and ethyl acetate added to the residue. The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0.30 g (53%) of a gum. Anal. for C21H28N2O6S: Calc'd: C, 57.8; H, 6.5; N, 6.4; Found: C, 57.8; H, 7.0; N, 6.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[NH:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1.[C:17]([S:20][CH2:21][CH:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:19])[CH3:18].O>CC(N(C)C)=O>[C:17]([S:20][CH2:21][CH:22]([CH3:26])[C:23]([N:12]([CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1)[CH2:13][C:14]([OH:16])=[O:15])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COc1ccc2c(c1)C(NCC(=O)O)CC2
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc2c(c1)C(N(CC(=O)O)C(=O)C(C)CSC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
N-(6-Methoxy-1-indanyl)glycine (2.0 g) is suspended in 20 ml of dimethylacetamide, then 2.2 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. After ethyl acetate is distilled off under reduced pressure, the residue is subjected to silica gel column chromatography, eluted with acetone-benzene (1:9). The oily substance obtained is crystallized from an ethyl ether-petroleum ether mixture, to give 1.8 g of N-(3-acetylthio-2-methylpropionyl)-N-(6-methoxy-1-indanyl)glycine, colorless needles showing a melting point of 106°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[C:34]([CH2:33][CH:7]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[C:8]1=[O:15])([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(=O)c2ccc(OC)c(OC)c2CC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one (5 g, 17.7 mmol, 1.0 equivalents), the product of Example 1, in 150 mL of dry THF cooled to -78° C., was added 19.5 mL of lithium bis(trimethylsilyl)amide (1M solution in THF, 19.5 mmol, 1.1 equivalent). The resultant solution was stirred at -78° C. for 1 h and then ethyl bromoacetate (2.2 mL, 19.5 mmol, 1.1 equivalent) was added in one portion. The reaction solution was then allowed to warm to ambient temperature and was stirred for 3 h. The reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. The resultant light yellow colored THF layer was separated and evaporated to an oil. The oil was taken up into 200 mL of methylene chloride and the methylene chloride solution was washed with 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate/hexane (1:6) to give 5.4 g (83% yield) of the title compound as a white solid; 1H NMR (CDCl3) δ: 1.2 (t, 3H, J=7.5 Hz), 2.45 (m, 2H), 3.03 (m, 1H), 3.30 (m, 2H), 3.43 (m, 1H), 3.78 (s, 3H), 3.93 (s, 3H), 4.07 (m, 2H), 6.92 (d, 1H, J=9.0 Hz), 7.32 (m, 5H), 7.89 (d, 1H, J=9.0 Hz). Analysis calculated for C22H24O5 : C, 71.72; H, 6.57. Found: C, 71.39; H, 6.63.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(=O)NCC(=O)O
Yield: 72.4 %

Procedure:
Glycine (1.5 g, 20 mmol) and heptanoyl chloride (22 mmol) were reacted in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 5. The crude product was recrystallized from EtOAc (30 ml) to give title compound (2.71 g, 72%), m.p. 98°-100° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])=[N:17][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:40])([CH3:41])[CH3:42])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])=[N:15][CH:14]=1)[CH3:9]
Reactant: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Trifluoroacetic acid (0.13 mL) was added to a solution of {2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-pyrimidin-5-yl}-acetic acid ethyl ester (Example 64-(1); 19.4 mg, 0.030 mmol) in dichloromethane (0.74 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (15.0 mg, 94%).
Reaction SMILES: I[C:2]([F:5])([F:4])[F:3].Br[C:7]1[C:12]([O:13][CH2:14][C:15]2[N:16]([CH3:20])[N:17]=[CH:18][N:19]=2)=[N:11][N:10]2[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:22][N:23]=[C:9]2[CH:8]=1>CN(C=O)C.ClCCl.[Cu]>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[N:10]2[N:11]=[C:12]([O:13][CH2:14][C:15]3[N:16]([CH3:20])[N:17]=[CH:18][N:19]=3)[C:7]([C:2]([F:5])([F:4])[F:3])=[CH:8][C:9]2=[N:23][N:22]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1Br
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
Iodotrifluoromethane (2.0 g, 10 mmol) was bubbled through a solution of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.10 g, 0.25 mmol) in dry DMF (2 ml) at room temperature until the required quantity of gas had dissolved. Copper powder (0.16 g, 2.5 mmol) was added and the mixture was stirred in a sealed tube at 80° C. for 18 h. The mixture was cooled, diluted with dichloromethane (50 ml) and filtered. The filtrate was washed with water (50 ml), then dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography, eluting with 3% methanol-dichloromethane, gave 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3 ylmethoxy)-7-trifluoromethyl-1,2,4-triazolo[4,3-b]pyridazine (0.0061 g, 6%) as a pale yellow solid; m.p. 123-126° C.; 1H NMR (360 MHz, CDCl3) δ3.92 (3H, s), 5.60 (2H, s), 7.31 (1H, dd, J=8 and 8 Hz), 7.40 (1H, dd, J=8 and 8 Hz), 7.56-7.64 (1H, m), 7.86-7.94 (2H, m), 8.50 (1H, s); MS (ES+) m/e 393 [mH]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][CH:39]([CH3:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:40](=[O:41])[CH:39]([CH3:43])[CH3:38])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by 2-methylpropanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 147 mg, 83%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.47-8.60 (2 H, m) 7.62-7.72 (2 H, m) 7.31 (2 H, dd, J=8.46, 5.68 Hz) 7.15 (2 H, t, J=8.97 Hz) 6.53 (1 H, s) 5.07-5.35 (2 H, m) 4.43-4.61 (0.5 H, m) 4.38 (1 H, d, J=12.88 Hz) 3.95 (3.5 H, s) 3.05-3.29 (1 H, m) 2.88-3.04 (0.5 H, m) 2.53-2.89 (4.5 H, m) 1.39-1.86 (4 H, m) 0.91-1.08 (6 H, m); m/z (APCI+) for C27H32N5O2F 478.2 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:13](OCC)=[O:14]>C1COCC1.C(OCC)(=O)C>[CH3:11][C:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:13][OH:14]
Reactant: CCOC(=O)C(C)(Cc1ccc(C)cc1)c1cccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CC(C)(CO)c2cccnc2)cc1
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride 120 ml. 120 mmol, 1.0M in THF) was added to a solution of the product of STEP 2 (11.6 g, 38.7 mmol) in 100 ml THF at 0° C. over 20 min. After 1 h, the reaction was diluted with 25 ml ethyl acetate and quenched with 75 ml H2O. The resulting mixture was filtered through a short column of Celite®, and washed with ethyl acetate. Filtrate was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate) to give a pale brown liquid in 4.1 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:4]([F:26])[C:3]=1[F:27].[C:28](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:28][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:5]4[C:4]([F:26])=[C:3]([F:27])[C:2]([Cl:1])=[C:7]([F:8])[C:6]=4[F:9])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3c(F)c(F)c(Cl)c(F)c3F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4c(F)c(F)c(Cl)c(F)c4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-chloro-2,3,5,6-tetrafluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (43 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0,022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (66%) of the title compound as an off-white solid. mp 150°-151°. FDMS: m/e=412 α[D]589 =+68.57 (c=0.12, chloroform).
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]C(O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(O)Cc1ccccn1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccn1)c1c[nH]c2ncccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (200 mg, 1.13 mmol) and 2-pyridinyl-acetic acid hydrochloride (440 mg, 2.53 mmol) in anhydrous THF (10 mL) was added LiHMDS (1.0 M in THF, 10 mL, 10.0 mmol) at −78° C. The solution was stirred at −78° C. for 30 min and was allowed to warm up to RT. After stirring at RT for another 30 min, the reaction mixture was heated under reflux for 14 h. The solvent was then evaporated, the residue was taken up to ethyl acetate (50 mL), and washed with aq. NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was used directly for the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCCBr

Procedure:
In analogy to the procedure described in example 5) (a) 2-nitrophenol was treated with sodium carbonate followed by 1,3-dibromo-propane in N,N-dimethylformamide to yield the 1-(3-bromo-propoxy)-2-nitro-benzene as slightly green solid; MS: 259, 261 (M)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)([O-:7])=[O:6]>CCOCC.CN(C=O)C>[N+:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:3])=[O:14])([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCO[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)CCCO[N+](=O)[O-]

Procedure:
Thionyl chloride (0.6 ml, 7.7 mmol) was slowly added, under stirring and under argon, to a solution of 4-(Nitrooxy)butanoic acid (1.00 g, 6.7 mmol) in anhydrous Et2O (25 ml) kept 0° C. A few drops of DMF (4-5 drops) were also added under stirring to the reaction mixture and the reaction temperature was allowed to rise to r.t. (ca. 20° C.). The reaction mixture was stirred at room temperature and under argon for 5 hours. The reaction mixture was concentrated in vacuo to provide crude 4-(nitrooxy)butanoyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH:7][CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].C(Cl)Cl.[N:19]#[C:20]Cl>O>[CH2:1]([O:3][C:4]([NH:6][N:7]([CH:8]([CH3:10])[CH3:9])[C:20]#[N:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)NNC(C)C
Reactant: N#CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NN(C#N)C(C)C
Yield: 87.7 %

Procedure:
73.0 g of 2-isopropylhydrazinecarboxylic acid ethyl ester and 42.0 g of sodium bicarbonate are stirred into 200 ml of methylene chloride and 400 ml of water. There is then introduced at room temperature in the course of 20 minutes, with continuous stirring, 30.8 g of gaseous cyanogen chloride. After an hour's stirring, the methylene chloride base is separated, dried over sodium sulphate and the solvent is distilled off in vacuo. There is obtained as residue 75.0 g (87.5% of theory) of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3=[C:24]([CH2:27][S:28][C:29](=O)[CH3:30])[CH:25]=[CH:26][N:22]3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.N#N.C[O-].[Na+].BrCC[OH:40]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3=[C:24]([CH2:27][S:28][CH2:29][CH2:30][OH:40])[CH:25]=[CH:26][N:22]3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(=O)SCc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: OCCBr
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCSCc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
A solution of thioacetic acid S-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}ester (80 mg, 0.175 mmole) in dry THF (4 mL) was sparged with N2 for 15 min. NaOMe (0.40 mL, 0.5 M in MeOH, 1.1 equiv), 2-bromoethanol (0.013 mL, 1 equiv) were added and the reaction was left stirring at RT. After 16 h, the solvents were removed and the residue was partitioned between DCM and water. The organic phase was separated, dried (Na2SO4), and the solvent removed. Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2% MeOH) afforded 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethylsulfanyl}-ethanol (35 mg, 44%): 1H NMR (CDCl3) δ 2.73 (t, 2H, J=5.9 Hz), 3.81 (t, 2H, J=5.9 Hz), 4.11 (s, 2H), 5.13 (s, 2H), 6.55 (d, 1H, J=2.6 Hz), 6.92–7.93 (m, 10H), 8.99 (s, 1H). Solid m-chloroperbenzoic acid (19 mg, 58 to 70%, 1 equiv) was added to an ice-cooled solution of the alcohol (35 mg, 0.18 mmole) in CHCl3 (4 mL). After 1 h, this was removed from the bath and washed with a 6% aq. solution of NaHSO3, sat. aq. NaHCO3 (3×) and then dried (Na2SO4). Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2, 3% MeOH) afforded the title compound (22 mg, 60%): MS: 475 (M+H)+; HPLC Ret Time: 1.66 min (YMC Xterra C18 S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:43])C.[OH-].[Na+].Cl>C(O)C>[CH3:42][S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]#[C:31][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([CH3:43])[CH:9]=3)[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=2)=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (168 mg; 0.26 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 120 mg (75%). HPLC-MS: m/z: 614.1 (M+H)+; Rt: 2.45 min.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:12]([CH2:11][CH2:10][CH2:9][OH:8])[NH:13][CH:14]=2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: Fc1ccc(-c2c[nH]c(CCCOCc3ccccc3)c2-c2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCCCc1[nH]cc(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 94.5 %

Procedure:
A solution of 2-(3-benzyloxypropyl)-4-(4-fluorophenyl)-3-(4-pyridyl)pyrrole (0.95 g, 0.0025 mol) in ethanol (125 mL) containing concentrated HCl (0.2 mL) was added to Pd on carbon (0.2 g). This mixture was placed in a hydrogen atmosphere for 16 hours on a Parr hydrogenator at 50 PSI. The mixture was filtered through Celite and triethylamine (0.5 mL) was added to the resulting solution, followed by evaporation in vacuo to give a solid. The solid was extracted into ethyl acetate (100 mL) and washed with water (3×50 mL). The organics were dried over Na2SO4 and evaporated in vacuo to give a light yellow solid (0.7 g, 96% yield). 1HNMR (DMSO-d6) δ 11.10 (1H, s, NH), 8.44 (2H, d), 7.05 (6H, m), 6.91 (1H, d), 4.53 (1H, br s, OH), 3.49 (2H, br s), 2.64 (2H, t), 1.72 (2H, m).