Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16]C)[CH2:12][N:11]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[CH2:10][CH2:9]2>ClCCl>[BrH:2].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][N:11]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)[CH2:10][CH2:9]2
Reactant: BrB(Br)Br
Reactant: COc1cc2c(cc1F)CCN(Nc1ccncc1)C2
Solvent: ClCCl
Product: Br
Product: Oc1cc2c(cc1F)CCN(Nc1ccncc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
Boron tribromide (8.8 g) was added dropwise to a solution of 6-fluoro-7-methoxy-2-(4-pyridinylamino)-1,2,3,4-tetrahydroisoquinoline (2.9 g) in dichloromethane (200 mL) at -78° C. The dry ice bath was removed, and the suspension was stirred at ambient temperature for 3 hrs. The reaction mixture was cooled to -78° C., and methanol (100 mL) was added. The mixture was stirred at ambient temperature for 1 hr and concentrated in vacuo. The residue was washed with methanol/ethyl ether and recrystallized from 2-propanol/ethyl acetate to give 0.61 g (17%) of product, mp 244-245° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C1COCC1.CN(C=O)C.[Cu]I.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:1][C:2]1[CH:22]=[C:21]([C:26]#[C:25][CH2:24][OH:27])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 79 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (79%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.26 (s, 1H), 8.44 (t, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.38 (dd, J=11.6, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 5.70 (s, 1H), 5.35 (t, J=5.9 Hz, 1H), 4.76 (t, J=5.7 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.50 (q, J=5.8 Hz, 2H), 3.38 (s, 3H), 3.31-3.26 (m, 2H). LCMS (APCI+) calcd for C18H18FN3O4 360 (MH+), found 360.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]([F:32])([F:45])[F:44])[CH:24]=1
Reactant: CC(C)N(NC(=O)C1CCCCC1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)C1CCCCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 62.3 %

Procedure:
A solution of cyclohexanecarboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (310 mg, 0.75 mmol) in DME (3 ml)/2M Na2CO3 (1.3 ml, 2.62 mmol) was treated 2-trifluoromethoxybenzeneboronic acid (231 mg, 1.12 mmol) and Pd[PPh3]4 (172 mg, 0.15 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 30-80% ethyl acetate/hexanes gradient to afford the product as a solid (232 mg, 63%). MS m/e 497.53 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CN(C)[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[S:3][C:4]([CH:15]=[O:16])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1csc(Cl)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1C=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-chloro-4-methylthiazole (0.3 g) in tetrahydrofuran (3 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 1.52 ml) dropwise at −70° C. under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at −70° C. To the resultant mixture was added N,N-dimethylformamide (0.21 ml) at −70° C., and the mixture was stirred for 40 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (silica gel 10 g, n-hexane:ethyl acetate=10:1) to give 2-chloro-5-formyl-4-methylthiazole (231 mg).
Reaction SMILES: N1C=CN=C1[C:6]([O:8][CH:9]([N:12]1[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]([C:22](=[O:36])[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])=[N:13]1)[CH2:10][CH3:11])=[O:7].CCC([OH:42])CC.[C:43]1(C)[CH:48]=[CH:47]C=[CH:45][CH:44]=1>>[CH3:32][O:31][C:26]1[C:27]([O:29][CH3:30])=[CH:28][C:23]([C:22]([C:14]2[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:16][N:12]([CH:9]([O:8][C:6]([O:7][CH:43]([CH2:48][CH3:47])[CH2:44][CH3:45])=[O:42])[CH2:10][CH3:11])[N:13]=2)=[O:36])=[C:24]([N+:33]([O-:35])=[O:34])[CH:25]=1
Reactant: Cc1ccccc1
Reactant: CCC(O)CC
Reactant: CCOC(=O)c1nn(C(CC)OC(=O)c2ncc[nH]2)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Product: CCOC(=O)c1nn(C(CC)OC(=O)OC(CC)CC)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]

Procedure:
Ethyl 2-(1-(imidazolylcarbonyloxy)propyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (377 mg) prepared in step (19a) was dissolved in toluene (12 ml). 3-Pentanol (1.6 ml) was added to the solution. The mixture was heated under reflux for 20 hr. The mixture was post-treated by a conventional method and subjected to separation and purification to give ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-(3-pentyloxycarbonyloxy)propyl)-2H-1,2,3-triazole-4-carboxylate (280 mg) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][C@H:34]([CH2:38][OH:39])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][O:35][C@H:34]([CH2:38][OH:39])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@@H]1CNCCO1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (S)-Morpholin-2-yl-methanol following General Procedure C.
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([N+]#N)=[C:9]([CH2:17][CH3:18])[CH:8]=1.[CH3:19][OH:20]>[Cl-].[Zn+2].[Cl-]>[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:20][CH3:19])=[C:9]([CH2:17][CH3:18])[CH:8]=1
Reactant: CCc1cc(Br)cc(CC)c1[N+]#N
Reactant: CO
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1cc(Br)cc(CC)c1OC
Temperature: 25 °C
Yield: 94 %

Procedure:
A stirred solution containing 4-bromo-2,6-diethylbenzenediazonium tetrafluoroborate (17.25 g, 52.77 mmol) and freshly ground anhydrous zinc chloride (7.2 g, 52.9 mmol) in methanol (1.06 L) was refluxed for 6 h. The reaction was cooled to ambient temperature, quenched with H2O (1.2 L), saturated with solid sodium chloride and extracted with hexane. The combined organic extracts were sequentially washed with sat. aq. NaHCO3 (1×100 mL), with H2O (1×100 mL), with brine (1×100 mL), dried (Na2SO4) and concentrated to give 12.0 g (94%) of title compound. 1H NMR: consistent. mass spectrum (EI), m/z 242 (M+).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:14][C@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=O>C(Cl)Cl>[C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:19])[CH2:14][C@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(O)CN2CCN(C(=O)OCc3ccccc3)C[C@H]2CO)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S)-tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.87 g, 7.32 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (20 mL) at rt, and the resulting solution was stirred at rt for 1 h. After removing the volatile solvents, the residue was dissolved in methylene chloride (50 mL). To the above solution was added triethylamine (6.12 mL, 43.9 mmol) and benzyl chloroformate (1.1 mL, 7.3 mmol) dropwise at 0° C. The reaction solution was stirred at 0° C. for 1 h before quenching with saturated sodium bicarbonate solution (200 mL). The mixture was then extracted with methylene chloride (3×100 mL). The combined organic phase was dried over sodium sulphate and concentrated to give the title compound. LC/MS: (M+1)+: 428.18.
Reaction SMILES: C1([C@@H]([N:9]2[CH2:13][CH:12]([C:14]3([NH:18]C(OC(C)(C)C)=O)[CH2:17][CH2:16][CH2:15]3)[CH:11]([F:26])[CH2:10]2)C)C=CC=CC=1.[NH2:27][C:28]1[C:37]([F:38])=[C:36](F)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:27][C:28]1[C:37]([F:38])=[C:36]([N:9]2[CH2:13][C@H:12]([C:14]3([NH2:18])[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: C[C@@H](c1ccccc1)N1CC(F)C(C2(NC(=O)OC(C)(C)C)CCC2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(N)CCC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
Cis 1-[(1-(S)-phenylethyl]-4-(1-tert-butoxycarbonylaminocyclobutyl)-3-fluoropyrrolidine (optical isomer B; 1.13 g, 3.12 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 10% palladium-carbon catalyst (water content, 55.6%; 1.0 g) and stirred at 50° C. for 18 hours under a hydrogen atmosphere. The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (10 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (1.18 g, 3.78 mmol) and triethylamine (5 ml) and stirred at 140° C. for 4 days under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (50 ml) and washed with a 10% citric acid aqueous solution (50 ml) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with an eluant of chloroform:methanol 9:1. The eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 30 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative TLC (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1) to obtain a crude title compound, and this was recrystallized from a mixture of ethanol and ether to obtain 157 mg (17%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)CCC.CCOC(C)=O.Cl>CN(C=O)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.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:14]=1)[N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A mixture of 8-bromo-5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (126 mg, 0.28 mmol), 4-tributylstannanyl-pyridine (154 mg, 0.42 mmol) and PdCl2(PPh3)2 (39 mg, 0.056 mmol) in 6 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-100% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound. MS: (+) m/z 450.36 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 75.0 g (431 mmol) of 4-(trifluoromethyl)benzaldehyde in 750 ml of diethyl ether was slowly added dropwise to 517 ml (517 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran at RT under argon. After heating under reflux for 1 h, the reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The organic phase was dried, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 9/1) to result in 87.0 g (100% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]=[C:25]1[CH:30]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:30]([C:25]3[O:24][CH2:29][CH2:28][CH2:27][CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=CC1=CCCCO1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(C3=CCCCO3)nn12

Procedure:
The title compound, MS m/e (%): 295 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 5,6-dihydro-4H-pyran-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[N:22]=[CH:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:17]3[CH2:18][CH2:19][CH:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[O:8][C:7](=[O:12])[CH:6]=4)[CH2:15][CH2:16]3)=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: O=Cc1ccc2ocnc2c1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: O=c1cc(NC2CCN(Cc3ccc4ocnc4c3)CC2)c2cc(Cl)ccc2o1

Procedure:
6-Chloro-4-(piperidin-4-ylamino)-chromen-2-one and benzooxazole-5-carbaldehyde were allowed to react in a manner analogous to that previously described to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.66 (m, 2H) 1.91 (m, 2H) 2.14 (m, J=10.29 Hz, 2H) 2.85 (m, 2H) 3.50 (m, 1H) 3.63 (s, 2H) 5.28 (s, 1H) 7.29 (m, 1H) 7.33 (m, 1H) 7.41 (m, 1H) 7.62 (m, 1H) 7.71 (m, 2H) 8.32 (m, 1H) 8.71 (s, 1H); MS (DCI/NH3) m/z 410 [M+H9 +.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:15]
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1-methyl-1H-pyrazol-4-amine (61.7 mg, 0.64 mmol) was added in one charge to a stirred suspension of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5; 150 mg, 0.49 mmol), EDC (281 mg, 1.47 mmol) and HOBT (224 mg, 1.47 mmol) in N,N-dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. 20 ml of water was added and the mixture was extracted with ethyl acetate (20 ml×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give crude product, which was purified by prep-HPLC (Gilson GX-281; waters X-Bridge 5 μm 30*100 mm; A: 0.1NH3*H2O/Water; B: CH3CN) twice to yield the title compound as a white solid. 70 mg.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][C@H:8]([C@@H:30]([NH:38][C:39](=[O:58])[C@H:40]([CH2:54][C:55](=[O:57])[NH2:56])[NH:41][C:42]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=1)=[O:43])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:11][C:12](=[O:22])[C@H:13]([CH:19]([CH3:21])[CH3:20])[NH:14][C:15]([O:17][CH3:18])=[O:16]>CN(C1C=CN=CC=1)C.O1CCOCC1.C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:7][C@H:8]([C@@H:30]([NH:38][C:39](=[O:58])[C@H:40]([CH2:54][C:55](=[O:57])[NH2:56])[NH:41][C:42]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=1)=[O:43])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:9][N:10]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:11][C:12](=[O:22])[C@H:13]([CH:19]([CH3:20])[CH3:21])[NH:14][C:15]([O:17][CH3:18])=[O:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)O[C@@H](CN(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1

Procedure:
Under a nitrogen atmosphere, a small amount of DMAP and 0.2 ml of butyric acid chloride are added to a solution of 121 mg (0.17 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]-hydrazine (Example 109) in 3.5 ml of dioxane, 2 ml of methylene chloride and 0.4 ml of pyridine. Dilution of the reaction mixture with methylene chloride, washing with 2 portions of saturated NaHCO3 solution, water and brine, extraction of the aqueous phases with 2 portions of methylene chloride, drying of the organic phases with Na2SO4, concentration by evaporation and column chromatography (SiO2, methylene chloride/methanol 50:1→19:1) yields the title compound: TLC Rf (I')=0.5; tRet (V)=15.6 min.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([OH:20])(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:12][C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)=[O:14])(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Product: CC(=O)OCC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure of Example, 1, 5 grams of 4-phenylphenacyl bromide are reacted with 5 grams of acetic acid to obtain 4-phenylphenacyl acetate, m.p. 109°-110° C.
Reaction SMILES: O.[S:2](=[O:6])(=[O:5])([OH:4])[OH:3].S([O-])([O-])=O.[NH4+:11].[NH4+].S(=O)(O)[O-].[NH4+]>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[NH4+:11].[NH4+:11].[S:2](=[O:4])(=[O:3])([OH:6])[O-:5].[NH4+:11]
Reactant: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: O=S([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)([O-])O
Product: O=S(=O)([O-])[O-]

Procedure:
A sulfuric waste water containing 150 kmoles of sulfuric acid and 60 kmoles of metal sulfates (line 51) is treated with a sulfitic solution containing 82.5 kmoles of ammonium sulfite and 82.5 kmoles of ammonium bisulfite (line 52) in reactor (53); 165 kmoles of SO2 evolve and 97.5 kmoles of ammonium sulfate and 52.5 kmoles of ammonium bisulfate (line 55) are produced according to the reaction:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH2:19])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (0.0194 mol) of 4-benzyloxy-3-aminophenyl acetate, 3.3 ml (0.0236 mol) of triethylamine and 3.0 ml (0.0236 mol) of benzenesulphonyl chloride in 150 ml of methylene chloride is stirred at room temperature overnight. The mixture is then washed with water and the organic phase is dried, followed by purification by chromatography on a silica gel column, eluting with a 7/3 cyclohexane/ethyl acetate mixture. The compound of the title is obtained.