Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:24][C:25]([N:11]1[C:12]([CH:13]([CH3:14])[CH3:15])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:16])[NH:10]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was dissolved in N,N-dimethylformamide (5 mL) at room temperature. N-(Benzyloxycarbonyloxy)succinimide (2.42 g) was added to the solution. The mixture was heated to 50° C. and then stirred for 16 hours. After the addition of water (20 mL) and ethyl acetate (20 mL) to the reaction mixture, the aqueous layer was separated, and the organic layer was washed with water. The obtained organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/dichloromethane=1/3 to 1/1) to give 1-benzyloxycarbonyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]C)[C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:5][N:4]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:38]>C1COCC1.C(OCC)(=O)C>[I:38][C:11]1[C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[O:9][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: [IH2+]
Reactant: COc1ccc(C#Cc2cnc(OC)cc2OC)cc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2oc3cc(OC)ncc3c2I)cc1

Procedure:
Compound S (0.019 g; 0.0705 mmol) and bis(pyridine)iodonium tetrafluoroborate (0.0524 g; 0.14 mmol) in THF (3 ml) was refluxed for 30 min., then diluted to 50 ml with ethyl acetate, washed with saturated Na2S2O5 (3 ml), saturated NaHCO3, dried over anhydrous MgSO4, filtered off and filtrate evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2) to give pure T (0.0175 g; 65%) 1HNMR (CDCl3) δ 8.2 (s, 1H); 8.04 (d, J=9.0 Hz, 2H); 7.0 (d, J=9.0 Hz, 2H); 6.75 (s, 1H); 3.99 (s, 3H): 3.86 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Br:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[F:24]>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([S:25]([N:5]2[CH2:6][C:3]([F:7])([F:2])[CH2:4]2)(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: FC1(F)CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a suspension of 3,3-difluoroazetidine hydrochloric acid (0.947 g, 7.31 mmol) in 20 mL dichloromethane at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (2.80 mL, 16.1 mmol) followed by the addition of a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.0 g, 7.3 mmol) in 4 mL dichloromethane. The mixture was stirred at room temperature overnight and then heated at 55° C. for 5 hours, diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10-50% ethyl acetate/heptanes gradient) to give the title compound (1.5 g, 62.1% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[I:15]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)Cl>[I:15][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2c(c1)CCC(=O)N2C
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1I)N(C)C(=O)CC2
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Silver trifluoroacetate (2.32 g, 10.48 mmol) was added to a dry methylene chloride (100 ml) solution of 6-Methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (1.0 g, 5.24 mmol) followed by the dropwise addition of methylene chloride (100 ml) solution of iodine (1.33 g, 10.48 mmol) over 15 minutes. The reaction mixture was stirred overnight and the precipitated silver iodide salts were filtered off. The filtrate was concentrated down to a residue which was chromatographed using 50% ethylacetate/hexane to yield the title compound (795 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 2.57–2.61 (2H, m), 2.81–2.85 (2H, m), 3.27 (3H, s), 3.82 (3H, s), 6.62 (1H, s), 7.31 (1H, s). m/z (APCI+) 318 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.959 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=4[F:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS([C:40]1[CH:45]=CC(N2C=CC(OC3CCN(C(OC4C=CC(Br)=CC=4C)=O)CC3)=CC2=O)=C[CH:41]=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:41][CH2:40][CH3:45])=[CH:29][C:28]=4[F:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(C(=O)Oc4ccc(Br)cc4F)CC3)cc2=O)cc1
Reactant: Cc1cc(Br)ccc1OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CCCc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)c(F)c1

Procedure:
Example 149 was prepared according to procedures described in Example 148 substituting 4-bromo-2-fluorophenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate for 4-bromo-2-methylphenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate at Step A. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.80 Hz, 2 H), 7.62 (d, J=8.25 Hz, 2 H), 7.32 (d, J=7.70 Hz, 1 H), 7.07 (t, J=8.25 Hz, 1 H), 6.91-7.00 (m, 2 H), 6.31 (d, J=2.47 Hz, 2 H), 6.22 (dd, J=7.70, 2.20 Hz, 1 H), 4.60-4.72 (m, 1 H), 3.88-3.99 (m, 1 H), 3.83 (app brs, 1 H), 3.68 (app brs, 1 H), 3.57 (app brs, 1 H), 3.11 (s, 3 H), 2.50-2.61 (m, 2 H), 2.11 (app brs, 2 H), 1.94 (app brs, 2 H), 1.57-1.69 (m, 2 H), 0.94 (t, J=7.15 Hz, 3 H). MS (ESI) 529 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:22](=[O:24])[CH3:23])=[CH:16][CH:15]=1.[Br-:33].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(OCC)C.C1COCC1.CCOC(C)=O.O>[Br:33][CH2:23][C:22](=[O:24])[CH:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(Cc2ccc(Br)cc2)C(C)=O)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)CBr)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Diisopropylamine (0.084 g, 0.83 mmol) was dissolved in anhydrous diethyl ether (7.5 mL) under argon atmosphere and cooled to −78° C. BuLi (0.52 mL, 0.83 mmol) was added dropwise to the solution and the resulting solution was allowed to warm to 0° C. for 10 min, then recooled to −78° C. TMS-Cl (freshly distilled over calcium hydride, 0.11 mL, 0.83 mmol) was added dropwise to the solution at −78° C., after addition, the reaction was allowed to stir for an additional 10 min. The solution was then cooled to −90° C., and 4-(4-bromophenyl)-3-(4-methoxyphenyl)butan-2-one (0.25 g, 0.75 mmol) was added dropwise as a solution in anhydrous diethyl ether. After addition was complete, the solution was allowed to stir for an additional 40 min. The reaction was then warmed to 0° C. and phenyltrimethylammonium tribromide (0.31 mg, 0.83 mmol) was slowly added dropwise as a solution in anhydrous THF (4 mL). The resulting solution was allowed to stir at 25° C. for 1 hour. The mixture was diluted with EtOAc and water, washed with NaCl (×3), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel chromatography (0-30% EtOAc in hexanes gradient) to afford 256 mg of 1-bromo-4-(4-bromophenyl)-3-(4-methoxyphenyl)butan-2-one as a viscous oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>O1CCCC1>[Si:15]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 7-bromoheptanol (50 g, 25.6 mmole) and imidazole (4.2 g, 61.5 mmole) in dry tetrahydrofuran (80 ml) was added t-butyldimethylsilyl chloride (4.6 g, 30.8 mmole) dropwise during 1 hour at room temperature. Then the reaction mixture was stirred overnight at room temperature. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=20:1) to give 5.7 g (yield: 72%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30](O)=[O:31])[CH:3]=1.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]([NH:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=2)=[O:31])[CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)O)cccc34)cc(Cl)nc21
Product: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)Nc5cccc(C(F)(F)F)c5)cccc34)cc(Cl)nc21
Yield: 88.4 %

Procedure:
5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide (92 mg, 88% yield) was prepared as described for Example 11-D starting from 5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-1-naphthoic acid (80 mg, 0.17 mmol) and 3-(trifluoromethyl)benzenamine (55 mg, 0.34 mmol). MS m/z: 612 [M+1].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[C:30]([Sn](CCCC)(CCCC)CCCC)#[C:31][CH2:32][CH2:33][CH3:34].[Cl-].[Li+]>O1CCOCC1.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>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:30]#[C:31][CH2:32][CH2:33][CH3:34])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Reactant: CCCC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (1.01 g), 1-pentynyl(tributyl)stannane (1.02 g), lithium chloride (0.29 g) and tetrakis(triphenylphosphine)palladium (80 mg) in dioxane (24 ml) was heated at 100° C. for 2 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (4:1) to give methyl 3-benzyloxycarbonylamino-4-(1-pentynyl)benzoate (536 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([OH:25])=O)=[CH:14]3)=[O:10])[CH2:4]1.[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:26][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[O:25])=[CH:14]3)=[O:10])[CH2:4]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, thiomorpholine 1,1-dioxide and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (15%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)=[O:9])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:25]=[CH:24][CH:23]=1)[CH:1]=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cccc(OCC(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-(2-(3-formylphenoxy)acetyl)piperazine-1-carboxylate (49)/(5.55 mmol) was taken in DCM and cooled to 0° C. when TFA (5 ml) was added drop wise and then stirred at rt for 16 h when TLC confirmed completion of reaction. The reaction mixture was concentrated and neutralized with satd NaHCO3 solution followed by extraction with DCM. The combined organic extracts was dried, concentrated and used directly for the next step (86%). LCMS: 98.12% (M++1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:19]([O:21][CH2:22][CH:23]([CH2:25][O:26][C:27](=[O:40])[C@H:28]([CH:37]([CH3:39])[CH3:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[OH:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:24][CH:23]([CH2:25][O:26][C:27](=[O:40])[C@H:28]([CH:37]([CH3:39])[CH3:38])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][O:21][C:19](=[O:20])[C@H:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:12]([O:11][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:13])=[O:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
Chloromethyl chloroformate (2.70 mL, 30 mmol) was added to a solution of 1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (7.27 g, 14.8 mmol) and pyridine (7.2 mL, 89 mmol) in 60 mL dry CH2Cl2, in an ice bath, under N2. After stirring for 1 h 45 min, the reaction mixture was diluted with 100 mL CH2Cl2 and washed with 40 mL water. The aqueous phase was reextracted with 20 mL H2O. The organic phases were combined, washed with 40 mL saturated NaHCO3, followed by 2×50 mL brine, dried over Na2SO4, and concentrated under vacuum. Flash column chromatography on silica gel with 2/1 hexane-EtOAc gave 8.03 g (93%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl chloromethyl carbonate).
Reaction SMILES: Br([O-])(=O)=O.[Na+].[Br:6]Br.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH3:9].Cl>O.ClCCl.BrBr>[Br:6][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
4.3 ml of alkaline (lime) bromine (containing 0.242 g bromide and 0.051 g bromate per ml of solution) and 0.52 g sodium bromate in 10 ml water were taken in a round bottom flask with total bromine content of 19.135 mmol. Into this was added 2.5 g (18.517 mmol) of acetanilide in 12.5 ml dichloromethane. 25 ml of 3.6 N hydrochloric acid was added over a period of 13 min under stirring at room temperature. Stirring was continued for another 30 min. The precipitate was filtered, washed with water and dried to give 3.689 g (92.7%) of p-bromoacetanilide (m.p. 164-168° C.) characterized through spectroscopic techniques.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.Cl.[N:48]1[CH:53]=[CH:52][C:51]([NH:54][NH2:55])=[CH:50][CH:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:51]3[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1ccncc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccncc2)n1

Procedure:
1.10 g (2.40 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 656 mg (3.61 mmol) of 4-pyridylhydrazine dihydrochloride. After hydrolysis, 23 mg (2% of theory) of the title compound is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)=[N:2]1.NN>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Agent: NN
Product: NCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 98.5 %

Procedure:
The compound prepared in Example 1 (13.00 g, 28.2 mmol) was converted to the freebase by washing a methylene chloride solution of the compound with saturated aqueous sodium bicarbonate. After drying over Na2SO4, filtration, and evaporation in vacuo, the residue was dissolved in 400 mL of methanol. To this solution was added 4 mL of hydrazine (124 mmol) and the reaction was refluxed overnight. The resulting solution was evaporated in vacuo. The residue was redissolved in methylene chloride and washed with aqueous sodium carbonate. The aqueous layer was re-extracted with 2 additional portions of methylene chloride. The combined organic layers were dried with Na2SO4, filtered and evaporated to yield 8.07 g of free base. A 1 g sample of free base was crystallized from isopropanol with the addition of 4N HCl in isopropanol to yield 500 mg of the title compound as the dihydrochloride hydrate, m.p. 262°-265° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>Cl.C(OC(=O)C)C>[ClH:1].[NH2:17][CH2:16][CH2:15][C:13]1[O:12][N:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1cc(-c2ccc(C#N)c(Cl)c2)no1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(CCN)on2)cc1Cl
Yield: 166.5 %

Procedure:
tert-Butyl (2-(3-(3-chloro-4-cyanophenyl)isoxazol-5-yl)ethyl)carbamate (078 g, 2.24 mmol) was stirred with 13 w-% ethylacetate HCl solution (20 ml) for 2 h at RT. The mixture was filtered and the precipitate was washed with EtOAc, dried in vacuo at 30° C. overnight. The title compound 0.53 g was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 3.21 (m, 4H), 7.22 (s, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.20 (s, 1H), 8.27 (bs, 3H).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]([C:36]2[CH:46]=[C:45]([O:47][CH3:48])[C:39]3[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=3[C:37]=2[F:49])[C:21]2[NH:25][C:24](=[O:26])[N:23]([C:27]3[N:35]=[CH:34][CH:33]=[CH:32][C:28]=3[C:29]([OH:31])=[O:30])[N:22]=2)=[CH:15][CH:14]=1)#[N:12]>CO>[F:49][C:37]1[C:38]2[O:44][CH2:43][CH2:42][CH2:41][O:40][C:39]=2[C:45]([O:47][CH3:48])=[CH:46][C:36]=1[CH:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:11](=[NH:12])[NH:3][OH:2])=[CH:18][CH:17]=1)[C:21]1[NH:25][C:24](=[O:26])[N:23]([C:27]2[N:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])[N:22]=1
Reactant: [NH3+]O
Reactant: COc1cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C(Nc2ccc(C(=N)NO)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 60 °C
Yield: 39.3 %

Procedure:
After adding 114 mg of hydroxylammonium chloride and 267 μl of triethylamine to a solution of 146 mg of 2-{3-[(4-cyanophenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}nicotinic acid in 10 ml of methanol, the mixture was heated for 28 hours at 60° C. After cooling the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (61 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[O:23][CH3:24])(=[O:13])=[O:12])[C:6](=[O:25])[C:5]2([N:35]1[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:36]1[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34].O>C(O)(=O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([N:35]3[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:36]3[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])[C:6]2=[O:25])(=[O:12])=[O:13])=[C:15]([O:23][CH3:24])[CH:16]=1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)c2ccc(Cl)cc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc(N)cc2OC)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A suspension of 450 mg of the compound obtained in Example 185 and 381 mg of iron in acetic acid (5 ml) was stirred at 80° C. for one hour. Water was added to the solution and the resulting mixture was extracted with EtOAc; the organic layer was washed with a saturated aqueous solution of NaHCO3 and with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 10/1; v/v) to obtain 301 mg of the title compound (amorphous).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][C:3]1=2.Br[C:19]1[CH:20]=[C:21]([CH:24]=[O:25])[NH:22][CH:23]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:19]3[CH:20]=[C:21]([CH:24]=[O:25])[NH:22][CH:23]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3c[nH]c(C=O)c3)ccc21
Yield: 21.7 %

Procedure:
In a similar manner to Example 3(b), by reaction of 5.9 g (25.6 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylboronic acid with 3.7 g (21.3 mmol) of 4-bromo-2-pyrrolecarboxaldehyde, 1.3 g (21.6%) of the expected product are obtained, with a melting point of 211-2° C.