Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Reactant: Cn1ncc2c(F)cc(F)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 4,6-difluoro-1-methyl-1H-indazole (intermediate P) (600 mg, 3.57 mmol) in anhydrous THF (20 mL) at −78° C. was added n-BuLi (1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirred at this temperature for 1 h and then a solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (intermediate M) (698 mg, 3.57 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting solution was stirred at this temperature for 3 h and allowed to warm to it slowly and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude was purified by flash chromatography (DCM:MeOH=95:5) to give 530 mg (41%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3) ppm 8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=363.9, tR=2.15 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.C[N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]3[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=3)=[O:43])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:48]([C:47]5[CH:50]=[CH:51][C:44]([C:42](=[O:43])[NH:41][C:38]6[CH:39]=[CH:40][C:35]([N:32]7[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]7)=[CH:36][CH:37]=6)=[CH:45][CH:46]=5)=[N:1][C:4]=4[CH:5]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C=O)cc3)cc2)CC1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCNCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 251 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-piperazinylbenzamide and 4-(4-(4-methylpiperazinyl)phenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C35H36N8O2: 601.30; found: 601.19.
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:30]([O:37][CH2:38][C@H:39]1[CH2:41][O:40]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C1COCC1>[CH2:30]([O:37][CH2:38][C@H:39]([OH:40])[CH2:41][C:26]1[N:25]([C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:29]=[CH:28][N:27]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H](COCc1ccccc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In an argon atmosphere, n-butyllithium (1.6 M solution in hexane, 6.9 ml) was added drop by drop to a solution of 1-tritylimidazole (3.10 g) in THF (80 ml) under ice cooling. After stirring at the same temperature for 30 minutes, (R)-2-[(benzyloxy)methyl]oxirane (1.52 ml) was added. After stirring under ice cooling for 1.5 hours and at room temperature for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saline and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane 1:1) to yield the titled compound (1.402 g) as a pale-yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[N:21]([C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:20][CH2:19]2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 156–157° C.; 1H NMR (300 MHz, CDCl3): δ 7.25 (d, J=1.8 Hz, 1 H), 7.19 (d, J=2.9 Hz, 1 H), 6.71 (s, 1 H), 4.75–4.69 (m, 1 H), 4.27 (t, J=7.9 Hz, 2 H), 3.07 (t, J=8.1 Hz, 2 H), 1.78–1.51 (m, 4 H), 0.81 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OBrCl2 (M+H)+: 430.0089; Found m/z 430.0106.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23]([CH3:25])[CH3:24])=[C:11]([CH:14]=1)[CH2:12][OH:13]>C(#N)C.C(N(CC)CC)C>[C:1]([O:13][CH2:12][C:11]1[CH:14]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][N:23]([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CN(C)Cc1ccccc1Sc1ccc(Cl)cc1CO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OCc1cc(Cl)ccc1Sc1ccccc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
A solution of acetyl chloride (2.5 g) in 50 mL of acetonitrile was added dropwise to a solution of 9.8 g of 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol (Example 2) in 25 mL of triethylamine and 200 mL of acetonitrile. The reaction mixture was stirred for 3 hr at room temperature, filtered and concentrated in vacuo to give a yellow oil. This oil was chromatographed on silica gel with EtOAc as the eluent. Concentration of solvents afforded 3.8 g (34% yield) of 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl acetate as a light yellow oil. Upon standing, oil crystallized to a beige solid, m.p. 41°-44° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:21][CH2:22][CH3:23])([CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])=[O:5])[CH3:2].[OH-].[Li+].C1CCC(NC2CCCCC2)CC1>CCOCC.C(OC(=O)C)C>[CH2:22]([O:21][P:4]([O:3][CH2:1][CH3:2])([CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])=[O:5])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)P(=O)(OCC)OCC
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(Cc1ccc(OC)cc1)C(=O)O
Temperature: 0 °C

Procedure:
The product of stage (a) (10 g) was stirred for 4 hr with 1 M lithium hydroxide (30.5 ml). The mixture was extracted with ether, the aqueous phase cooled to 0° C. and acidified to pH 1.0 with 2 N.HCl and extracted with ethyl acetate, exhaustively. The extracts were dried after washing with brine to give a solid residue. The solid was dissolved in a mixture of ether (35 ml) and ethylacetate (35 ml) and DCHA (4.37 g) added. After refrigeration, the precipitated DCHA salt (m.p. 136°-140°) was filtered and washed with ether. The salt was partitioned between ethyl acetate and 5% citric acid solution, the ethyl acetate extract washed with brine and evaporated in vacuo to give the desired product as a crystalline solid m.p. 94°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:22]([C:20]1[CH:19]=[CH:18][C:3]([NH:4][C:5]2[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:21]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-{2-Fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (195 mg, 0.50 mmol) was dissolved/suspended in a mixture of MeOH (30 mL) and THF (20 mL) to which was added solid K2CO3 (139 mg, 1.01 mmol). This mixture was stirred for 48 h. at R.T. All solvent was then removed under reduced pressure, the residue taken up into EtOAc containing 10% MeOH (100 mL), and this solution washed with water (2×100 mL) and brine (100 mL). The combined aqueous fractions were back-extracted with EtOAc (2×100 mL). All EtOAc fractions were combined and dried with Na2SO4, the solvent removed under reduced pressure and the residue purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant). This gave 4-(4-ethynyl-2-fluoroanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (152 mg, 96%), m.p. (acetone/MeOH) 265-273° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.44 (br s, 1H), 10.41 (s, 1H), 8.49 (br t, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.45 (dd, J=11.5, 1.8 Hz, 1H), 7.33 (dd, J=8.3, 1.4 Hz, 1H), 5.62 (s, 1H), 4.72 (t, J=5.7 Hz, 1H), 4.24 (s, 1H), 3.50 (q, J=5.8 Hz, 2H), 3.31-3.23 (m, 2H). Anal. Calcd for C16H14FN3O3: C, 61.0; H, 4.5; N, 13.3. Found: C, 61.1; H, 4.3; N, 13.3.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][C:3]=1[Cl:15].CO.[OH-].[Na+]>O>[NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:15]
Reactant: CON=Cc1cc(C(=O)[O-])cc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 210 g (0.86 moles) of the previously prepared 4-amino-3-chloro-5-methoxyiminomethylbenzoate, 1.7 l of methanol and 462 g (1.73 moles) of 15% aqueous sodium hydroxide. The resulting mixture was refluxed for 3 hours, after which the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated using a rotary evaporator. The crude reaction mixture was dissolved in 2 l of water. The resulting aqueous solution was washed once with 500 mL of ethyl acetate, cooled in an ice bath and acidified to pH=2 with concentrated hydrochloric acid. The expected 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid precipitated as a light yellow solid which was separated by suction filtration. The filter cake was washed with a 1:2 mixture of ethyl ether and hexane yielding after drying 185.2 g (94% yield).
Reaction SMILES: [Mg].C(Br)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[CH:14].Br[CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21]>O1CCCC1.Cl>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[C:14][CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21]
Reactant: CCC/C=C/CBr
Reactant: C#CCOC1CCCCO1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC/C=C/CC#CCOC1CCCCO1
Yield: 73.3 %

Procedure:
To a solution of magnesium metal (8.6 g) in dry tetrahydrofuran (100 ml) was added dropwise ethyl bromide (39 g) in a nitrogen atmosphere at ambient temperature. After the mixture was stirred for an hour at the same temperature, to the mixture was added dropwise a solution of 3-(2-tetrahydropyranyloxy)-1-propyne (50 g) in dry tetrahydrofuran (75 ml) and cuprous cyanide (20 mg). The reaction mixture was stirred for 30 minutes at ambient temperature. To the mixture was added with stirring a solution of 1-bromo-trans-2-hexene (58 g) in dry tetrahydrofuran (75 ml) under ice-cooling. The reaction mixture was stirred for 30 minutes at ambient temperature and concentrated under reduced pressure to give a residue, which was dissolved in diluted hydrochloric acid and extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellowish oily residue, which was distilled under reduced pressure to give colorless oily 1-(2-tetrahydropyranyloxy)-trans-5-nonen-2-yne (58 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22].[OH-].[K+].Cl>CO.O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])/[CH:20]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])=[CH:15][C:14]=1[CH3:22]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-Formylbenzoic acid (15.0 g, 0.1 mol, Aldrich) and 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol, Indofine) was dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, filtered, washed with water (200 mL), methanol (100 mL) and dried in the air. 19 g (67%) of a solid was obtained as the desired (E)-3-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6): 13.18 (br, 1H), 10.39 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.95 (m, 4H), 7.75 (d, 1H), 7.60 (m, 1H), 6.95 (d, 1H), 2.20 (s, 3H). MS (EI) for C17H14O4: 283 (MH+).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(OC)ccc2C1(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 5.86 g of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-dimethyl-1-indanone in 100 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.64 ml of dimethyl sulfide the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichloromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 4.94 g (89%) of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-dimethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[C:12]1([CH:18]2[NH:22][C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>CCOCC.O>[C:12]1([CH:18]2[N:22]([C:27]([O:29][CH3:30])=[O:28])[C@H:21]([C:23]([OH:25])=[O:24])[CH2:20][S:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2)N1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)N1C(c2ccccc2)SC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a mixture of 60 g. of sodium carbonate in 330 ml. of water and 220 ml. of 10% sodium bicarbonate was added 62.7 g. (0.3 mole) of 2-phenyl-4-(R)-carboxythiazolidine. A solution of 23.0 ml. (28.4 g., .3 mole) of methyl chloroformate in 75 ml. of ether was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for one additional hour. The entire reaction mixture, including some solid which occasionally separated, was acidified carefully (foaming) to pH 1 by the dropwise addition of about 50 ml. of 6N HCl. The reaction was extracted 3 × 300 ml. portions of methylene chloride. The organic phases were dried over sodium sulfate and evaporated to afford 77.4 g (97%) of the 2-phenyl-3-carbomethoxy-4-(R)-carboxythiazolidine as a white crystalline solid, having a m.p. of 129°-130° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:16]1C=C[N:18]=[N:17]1>>[C:1]1([C:7]2[N:18]=[N:17][S:16][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1csnn1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Product: c1ccc(-c2nnsc2-c2ccccc2)cc1

Procedure:
The tosylhydrazone (58.0 g, 0.16 mol) was dissolved in CH2Cl2 (200 ml) and thionyl chloride (14.1 ml, 0.2 mol) in CH2Cl2 (10 ml) was added and the entire reaction was stirred at room temperature 2.25 hours. Filtration of the mixture afforded 9.0 g of solid identified by NMR as toluenesulfonylchloride. The remaining liquid was concentrated and then heated at reflux in THF (200 ml) and H2O (50 ml) for 20.5 hours. After cooling, it was brought to pH 11 with NaOH. The aqueous layer was extracted with 2×50 ml portions of Et2O. Drying and evaporation yielded 34 g of solid material. This was recrystallized from hexane to afford 3 (7.5 g, 46%), m.p. 92°-94° C. A second crop from recrystallization afforded additional amounts of 3 (6.9 g) contaminated with a-phenylacetophenone. The thiadiazole could be sublimed at 110° C. (0.2 mm).
Reaction SMILES: O.NN.[CH3:4][S:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19][O:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:10]=2[CH:38]=1>C(O)C>[NH2:21][O:20][CH2:19][C:16]1[N:15]2[C:9]3[CH:8]=[CH:7][C:6]([S:5][CH3:4])=[CH:38][C:10]=3[C:11]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:12][CH2:13][C:14]2=[N:18][N:17]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CON3C(=O)c4ccccc4C3=O)n1-2
Agent: NN
Solvent: O
Solvent: CCO
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CON)n1-2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-methylthio-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][OH:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:14][N:13]([CH3:12])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(O)C(=O)Cc1ccccc1

Procedure:
At 0° C. phenyl-acetyl chloride (11.2 mL) is added drop wise to a solution of N-methyl-hydroxylamine hydrochloride (7.07 g) and triethylamine (59 mL) in DCM (300 mL). After stirring for 90 min a sat. aqueous NaHCO3 solution is added, the layers are separated and the aqueous layer is extracted twice with DCM (2×200 mL). The solvents are removed in vacuo and the residue is purified by flash chromatography (EA/heptane 1/1) to give the desired N-hydroxy-acetamide as a colorless liquid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:12].[ClH:30]>ClCCl.CCOCC>[ClH:30].[ClH:30].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][NH:20][CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 1B (8.5 g) in dichloromethane (80 mL) was added 2N HCl in ether (80 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=4[CH:11]=3)=[CH:20][CH:19]=2)[O:29]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(COc3ccc4nc(C#N)sc4c3)cc2)OC1(C)C
Temperature: 60 °C
Reaction time: 0.79 h
Yield: 82.1 %

Procedure:
2-Cyano-6-hydroxybenzothiazole (300 mg, 1.7 mmol) and 4-(bromomethyl)benzeneboronic acid pinacol ester (505.7 mg, 1.7 mmol) were dissolved in 30 mL dry DMF prior to the addition of cesium carbonate (610.25 mg, 1.87 mmol). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with deionized water (DI H2O). The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 hexanes:ethyl acetate, dry loaded) to give 547.4 mg (82%) of the pure product. 1H NMR (400 MHz, CDCl3): δ 1.36 (1H, s), 5.21 (2H, s), 7.32 (1H, d, J=8.8 Hz), 7.40 (1H, s), 7.45 (2H, d, J=7.6 Hz), 7.86 (2H, d, J=7.2 Hz), 8.09 (1H, d, J=9.2 Hz). LRESI-MS: calculated for [C21H22BN2O3S]+393.1. found 393.1.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]1([C:7](=[N:17][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccccc1
Yield: 94.7 %

Procedure:
A solution of deoxybenzoin (407.4 g, 2.076 mol) in 2 L of absolute ethanol and 600 mL of water was treated with hydroxylamine hydrochloride (288 g, 4.15 mol) and sodium acetate trihydrate (564 g, 4.15 mol). The solution was then warmed to reflux for 2 hours. The reaction mixture was then diluted with 1000 mL of 30% aqueous ethanol and allowed to cool to room temperature whereupon crystals of pure oxime formed which were isolated by filtration and air dried to afford 415.4 g, 95%, mp 94°-96° C. of pure deoxybenzoin oxime.