Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl>[NH2:65][C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:68][CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (300 mg, 0.66 mmol) in methylene chloride (10 mL), HATU (Aldrich, 266 mg, 0.66 mmol) was added followed by the addition of DIPEA (0.30 mL) and 4-amino-aniline (Aldrich, 143 mg, 1.32 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-85% EtOAc/hexanes) to give an off-white solid. 298 mg.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([O:17]CC)=[O:16])=[CH:4]1)[CH3:2].O.O.[OH-].[Li+].Cl>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(I)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(I)cc21
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A suspension of 2.4 g of ethyl 1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 13 g)) in 20 ml of ethanol and 6 ml of water is treated at 0° with 325 mg of lithium hydroxide monohydrate. After 3 hrs. the reaction mixture is acidified with 25% aqueous hydrochloric acid. The precipitated substance is filtered off under suction, washed with 20 ml of water, 20 ml of ethanol and 20 ml of ether and dried. 2.1 g (94%) of 1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid are obtained as a colourless solid. M.p. 237°-238°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([NH:8][OH:9])=[NH:7])[CH3:2].[CH2:14]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[C:19](O)=O)[CH3:15]>>[CH2:14]([C:16]1[CH:17]=[C:18]([C:19]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[C:11]([CH3:13])[N:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[N:7]=2)[CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[CH3:15]
Reactant: CCc1cc(C(=N)NO)cc(C)n1
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)c(O)c(CC)c3)n2)cc(C)n1

Procedure:
2-Ethyl-4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is prepared in analogy to Example 10 by coupling and cyclising 2-ethyl-N-hydroxy-6-methyl-isonicotinamidine with 3-ethyl-4-hydroxy-5-methyl-benzoic acid; LC-MS: tR=0.83 min; [M+1]+=324.15.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:21]>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:21])=[O:14])[N:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c(CO)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cn(Cc2ccccc2)c(CO)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 1-benzyl-2-hydroxymethylimidazole-4-carboxylate (described immediately above, 1 g), an aqueous ammonium hydroxide solution (specific gravity 0.88 g/ml, 60 ml) and ethanol (25 ml) was stirred at laboratory temperature for 48 hours and then heated to 50° C. for 4 hours. The mixture was evaporated to give 1-benzyl-2-hydroxymethylimidazole-4-carboxamide, m.p. 204°-207° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1.C(#N)C.C(N(CC)CC)C.[Cl:31][C:32]1[S:36][C:35]([CH:37]=[CH:38][S:39](Cl)(=[O:41])=[O:40])=[CH:34][CH:33]=1>C(OCC)(=O)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([S:39]([CH:38]=[CH:37][C:35]4[S:36][C:32]([Cl:31])=[CH:33][CH:34]=4)(=[O:41])=[O:40])[CH2:16][C:15]3=[O:20])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: O=C1CNCCN1Cc1ccc2c(Cl)cnnc2c1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1ccc2c(Cl)cnnc2c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
1-(4-chlorocinnolin-7-ylmethyl)-piperazin-2-one hydrochloride (0.14 g, 0.4 mmol), EXAMPLE 90, is treated with acetonitrile (20 mL), triethylamine (2 mL, 14 mmol) and 2-(5-chlorothiophen-2-yl)ethene-sulfonyl chloride (0.097 g, 0.4 mmol), EXAMPLE 3, at 0° C. The solution is warmed to ambient temperature over 1.5 h and diluted with ethyl acetate. The solution is washed with 10% sodium bicarbonate solution and water, dried (sodium sulfate) and concentrated to yield the title compound (0.17 g, 0.35 mmol). MS m/z: [M+H]+=483; 1H NMR (CDCl3, 300 MHz) δ9.4 (s, 1H), 8.4 (s, 1H), 8.3 (d, 1H) 7.85 (d, 1H), 7.7 (d, 1H), 7.1 (d, 1H), 6.95 (d, 1H), 6.35 (d, 1H), 4.9 (s, 2H), 4.0 (s, 2H), 3.4-3.5 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.CS([Cl:16])(=O)=O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:16])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12
Reactant: CS(=O)(=O)Cl
Reactant: [O-][n+]1ccc(Br)c2cc[nH]c21
Solvent: CN(C)C=O
Product: Clc1cc(Br)c2cc[nH]c2n1
Temperature: 75 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of the 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (27 mmol) in N,N-dimethylformamide (57 mL) at 50° C. was added methanesulfonyl chloride (67.5 mmol) under nitrogen. Upon completion of the addition, the reaction was stirred at 75° C. for 1 hour. The reaction was cooled to room temperature and quenched with water (60 mL). Then, it was cooled to 5° C. and 6N sodium hydroxide solution was added to raise the pH to 7. The ice bath was removed and the resulting slurry was stirred at room temperature for 3 h. The precipitate was filtered, washed with water (50 mL), and dried under high vacuum to give the title product as a white solid (89%). ESMS [M+H]+: 231.0
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[CH:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>C(Cl)Cl.CCN(CC)CC>[O:25]=[C:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])=[CH:15][CH:16]=1
Reactant: Nc1ccc(N2CCCC2=O)cc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)c1n[nH]c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 50 mg 1H-Indazole-3-carboxylic acid in 2 mL DCM and 0.2 mL NEt3, 108 mg 1-(4-Amino-phenyl)-pyrrolidin-2-one and 79 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent alkylation reaction without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 90 °C
Yield: 81.7 %

Procedure:
4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one (509 mg, 2.28 mmol, Eq: 1.00), tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (632 mg, 2.28 mmol, Eq: 1.00), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (198 mg, 342 μmol, Eq: 0.15) and cesium carbonate (2.6 g, 7.98 mmol, Eq: 3.5) were suspended in dioxane (20 ml) under argon. Finally tris(dibenzylideneacetone)dipalladium(0) (156 mg, 171 μmol, Eq: 0.075) was added. The reaction mixture was heated to 90° C. for 18 h. The reaction mixture was filtered over celite; washed with dioxane, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 20% to 50% EtOAc/Hex gradient) to give tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate (782 mg, 82%). LC/MS-ESI observed [M+H]+ 420.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[N:9]1[C:20](=[O:41])[CH2:21][NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([O:30]CC[Si](C)(C)C)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[N:9]1[C:20](=[O:41])[CH2:21][NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccc(F)c2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccc(F)c2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 16.5 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 1.6 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate in 5.3 cm3 of 1M tetrabutylammonium fluoride solution. The crude product is purified by chromatography on silica [eluent: ethyl acetate/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 0.22 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoic acid is thus obtained in the form of an amorphous solid ([α]D20 =+79.0°±2.0° (C=0.43%; CHCl3)) [proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, characteristic chemical shifts at 25° C.: 1.5 (bs, 9H, (CH3)3); 7.1 to 7.6 (m, 7H, aromatic); 8.0 (bs, 1H, N--C6H4 -- in position 2). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2975, 2930, 2600, 1715, 1695, 1650, 1610, 1590, 1560, 1490, 1450, 1370, 1240, 1150, 780, 755, 685].
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2=[CH:13][CH:14]=[CH:15][N:4]2[CH2:3]1.P(Br)(Br)[Br:17].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[Br:17][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2=[CH:13][CH:14]=[CH:15][N:4]2[CH2:3]1
Reactant: OC1Cn2cccc2Sc2ccccc21
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: BrC1Cn2cccc2Sc2ccccc21
Yield: 142.8 %

Procedure:
To a solution of 24a (0.26 g, 1.0 mmol) in anhydrous ethyl ether (4 ml) was added dropwise a solution of PBr3 (0.13 g, 0.5 mmol) in anhydrous ethyl ether (1 ml) and the reaction mixture was kept at reflux temperature for 2 hours under nitrogen. Anhydrous ethanol was added (0.2 ml) and the resulting solution was heated to reflux temperature for another hour. Five ml of an aqueous solution of 5% Na2CO3 were then added, the organic phase was separated, anhydrified and evaporated. The crude product was chromatographed (hexane and chloroform 1:1) to give 25a (0.2 g, 64% yield) as colourless prisms: melting point 115-116° C. (cyclohexane); 1H NMR (CDCl3) δ7.46-7.09 (m, 4H); 6.93 (m, 1H), 6.39 (m, 1H), 6.12 (m, 1H), 5.75 (dd, 1H, J=6.9, 2.6 Hz), 5.07 (dd, 1H, J=14.7, 2.6 Hz), 4.61 (dd, 1H, J=14.7, 6.9 Hz). Anal. (C12H10BrNOS): C, H, N.
Reaction SMILES: [NH2:1][C@@H:2]([CH:66]([CH3:68])[CH3:67])[C:3]([NH:5][C@@H:6]([CH3:65])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][C@H:18]3[CH:24]=[N:23][C:22]4[CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]5[C:37]([O:61][CH3:62])=[CH:38][C:39]6[C:45](=[O:46])[N:44]7[CH:47]=[C:48]([C:50]8[CH:59]=[CH:58][C:53]([C:54]([O:56]C)=[O:55])=[CH:52][CH:51]=8)[CH2:49][C@H:43]7[CH:42]=[N:41][C:40]=6[CH:60]=5)[C:27]([O:29][CH3:30])=[CH:28][C:21]=4[C:20](=[O:63])[N:19]3[CH:64]=2)=[CH:12][CH:11]=1)=[O:8])=[O:4].[OH-].[Li+]>C1COCC1.CO>[NH2:1][C@@H:2]([CH:66]([CH3:68])[CH3:67])[C:3]([NH:5][C@@H:6]([CH3:65])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:17][C@H:18]3[CH:24]=[N:23][C:22]4[CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]5[C:37]([O:61][CH3:62])=[CH:38][C:39]6[C:45](=[O:46])[N:44]7[CH:47]=[C:48]([C:50]8[CH:51]=[CH:52][C:53]([C:54]([OH:56])=[O:55])=[CH:58][CH:59]=8)[CH2:49][C@H:43]7[CH:42]=[N:41][C:40]=6[CH:60]=5)[C:27]([O:29][CH3:30])=[CH:28][C:21]=4[C:20](=[O:63])[N:19]3[CH:64]=2)=[CH:14][CH:15]=1)=[O:8])=[O:4]
Reactant: COC(=O)c1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(C(=O)O)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 9 (20 mg) in THF/CH3OH (2 mL) was added a lithium hydroxide solution (1 mL of a 0.1 M solution). The reaction mixture was stirred at an ambient temperature. At 5 hours, LC-MS revealed approximately a 30% conversion to desired product with significant decomposition. The reaction mixture was cooled to −80° C. for 16 hours. LC-MS showed a ˜1:1 mixture of 10 and 9. The reaction mixture was neutralized with 0.1N HCl (˜1 mL) and was concentrated to approximately 1 mL. DMSO (1 mL) and CH3CN (1 mL) were added, and the mixture was purified by preparatory reverse-phase HPLC. Product containing fractions were combined, frozen and lyophilized. This resulted in 1.7 mg (9%) of 10 as a yellow film: MS (ES+) m/z 938 [M+H]+.
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([N:15]=[C:16]=[S:17])[CH:12]=[CH:13][CH3:14].C(OCC)C.C(N(CC)CC)C>O1CCCC1>[N:15]([CH2:11][CH2:12][CH:13]1[O:10][N:9]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14]1)=[C:16]=[S:17]
Reactant: CC=CCN=C=S
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: S=C=NCCC1CC(c2ccccc2)=NO1
Reaction time: 24 h

Procedure:
A 23 g. portion of α-chlorobenzaldoxime, prepared as in Example 1 above, was combined with 17 g. of crotylisothiocyanate in 300 ml. of diethyl ether. The solution was cooled to 15° and 40 ml. of triethylamine in 100 ml. of tetrahydrofuran was added dropwise. The mixture was stirred for 24 hours at 15°, and was then filtered. The filtrate was washed with water, and evaporated to dryness. The residue was dissolved in chloroform, and chromatographed over a column (2.5 cm. diameter by 8 meters long) of polystyrene gel beads. The eluate was evaporated to dryness, and the residue was recrystallized from diisopropyl etherhexane. The product was identified as 10 g. of 5-(2-isothiocyanatoethyl)-3-phenyl-2-isoxazoline, m.p. 54°-56°. The microanalytical results were as follows:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][C:13]1(C)[C:17](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Cl:1][C:2]1[C:7]([C:13]([CH3:17])=[CH2:12])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Cl)c(I)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cc(N)c(OC)cc1Cl
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (1.0 g, 3.53 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (889 mg, 5.29 mmol), Pd(PPh3)4 (363 mg, 0.353 mmol), Na2CO3 (1.12 g, 10.6 mmol) in DME (10 mL) and water (3 mL) was stirred at reflux under argon for 6 h. The reaction mixture was allowed to cool to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% petroleum ether/ethyl acetate) to afford the desired product (173 mg, 25% yield) as an off-white solid. ESI-MS m/z: 198.5[M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:25])[C:15]=3[C:16]=2[CH3:17])=[CH:9][CH:8]=1.Cl[CH:29]([O:31]C)Cl.O>ClCCl>[CH:29]([C:27]1[CH:26]=[C:10]([CH:9]=[CH:8][C:7]=1[O:6][CH3:5])[CH2:11][C:12]1[O:13][C:14]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:25])[C:15]=2[C:16]=1[CH3:17])=[O:31]
Reactant: COC(Cl)Cl
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc2oc(Cc3ccc(OC)c(C=O)c3)c(C)c2c1O
Temperature: 0 °C
Yield: 37 %

Procedure:
To a suspension of aluminium chloride (214 mg; 1.6mmole) in dichloromethane (5 mL) cooled at 0° C. was added 2-(p-methoxy benzyl)-3-methyl-4-hydroxy-5-propyl benzofuran (100 mg; 0.32mmoles). A red solution resulted. To this solution was added dropwise dichloromethylmethylether (87 (1; 0.96 mmole). There was a vigorous reaction and a color change from red to green was observed. Ice and water was then added and the mixture was extracted with ethylacetate. The organic phase was dried (Na2SO4), and concentrated in vacuo and the residue was chromatographed on silica gel. Elution with 10% ethylacetate in hexane yielded 40 mg (37%) of 2-(3 formyl-4-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran.
Reaction SMILES: Cl[C:2](=[O:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[O:18].C([O-])(=O)C.[Na+]>ClCCl.O>[O:14]=[C:2]([NH:15][CH2:16][C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(=O)Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CC(=O)NCC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
The compound (3.2 g) obtained in Example 115c and 2-amino-1-[3-(trifluoromethyl)phenyl]ethanone (2.88 g) were dissolved in dichloromethane (120 mL) and water (40 ml), and an aqueous solution (40 mL) of sodium acetate (2.46 g) was added dropwise under cooling in an ice bath. The reaction mixture was stirred at room temperature overnight, and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.92 g) as a colorless solid.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:9]=2[CH:38]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([Cl:4])=[CH:38][C:9]=3[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-chloro-6-(o-chlorophenyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:3]=1[O:4][CH2:5][C@H:6]([OH:41])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH3:47][C:48](O)=[O:49]>>[CH3:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:3]=1[O:4][CH2:5][CH:6]([O:41][C:48](=[O:49])[CH3:47])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18]([N:17]=1)=[CH:19][C:20]1[CH2:21][N:22]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]3)[C:23](=[O:28])[C:24]=1[CH:25]=2
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Reactant: CC(=O)O
Product: CC(=O)OC(CNc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(CCS(C)(=O)=O)CC1)C3)COc1ccc(C)cc1C

Procedure:
A solution of 2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (65 mg, 0.1 mmol) in HOAc (20 mL) was refluxed for 32 h and was evaporated. The residue was diluted with a mixed solvent of DCM/MeOH (1:5), basified with 28% aqueous NH4OH solution and concentrated. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (110:10:1) followed by HPLC re-purification afforded the title compound in TFA salt form (8.69 mg, 11%). 1H NMR (DMSO-d6) δ 1.99-2.12 (4H), 2.05 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.15 (s, 3H, CH3), 3.25 (m, 2H), 3.52 (m, 2H), 3.60-3.78 (5H), 3.90 (s, 1H), 4.10-4.38 (4H), 4.49 (br s, 2H), 5.43 (br s, 2H, NH), 6.28 (d, J=8 Hz, 1H), 6.84 (d, J=6 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 6.99 (s, 1H), 7.40 (m, 1H), 7.80 (br s, 1H), 9.80 (br s, 1H), 11.14 (br s, NH), 11.33 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 691.7 (MH+).