Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=1[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=2[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(Br)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1=O
Yield: 74.2 %

Procedure:
A solution of 4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (29.0 g, 107.4 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34.7 g, 118.8 mmol), and Cs2CO3 (104.7 g, 322.2 mmol) in toluene (200 mL) and water (50 mL) was degassed. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (8.5 g, 10 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 3 h and monitored for completion by TLC. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of Celite® washing with ethyl acetate. The organic layer was then washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane on 230-400 mesh silica gel (Rf=0.3) to afford 4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (31.5 g, 74.25%) as solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (d, 2H), 7.75 (d, 2H), 7.5 (d, 4H), 7.35 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (99.5%, Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (−)-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.013 g, 0.061 mmol) and triethylamine (17.1 μL, 0.122 mmol) in tetrahydrofuran (2 ml), was added iodoethane (7.3 μL, 0.091 mmol), the resulting solution was stirred at ambient temperature for 24 h. The crude mixture was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1). The solvent was evaporated and the crude product was analyzed by GCMS. Analysis showed 76% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 7), 226 (57), 211 (24), 141 (43), 71 (bp).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1N)[CH3:2].N([O-])=[O:14].[Na+].NC(N)=O.[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[OH:14])[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Yield: 57.9 %

Procedure:
A solution of 2-ethyl-5-nitroaniline (prepared as described by E. Dyszer et al, Przemysl. Chem 42 (8) 433-5 (1963)) (5 g) in concentrated sulphuric acid (27 ml) and water (160 ml) at 0° C., was treated with sodium nitrite (2.3 g) in water (5 ml) over 5 minutes with stirring. After 1/4 h at 0° C., urea (2 g) was added and the mixture heated to 80° C. for 2 h. After stirring overnight at room temperature, the pH was adjusted to pH 10-12 with 10% sodium hydroxide, and the mixture extracted into ethyl acetate. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure. Flash column chromatography on silica gel, eluting with ethyl acetate and 60°-80° C. petroleum-ether gave the title compound (2.91 g, 58%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2[O:11][CH3:12].[Li]CCCC.[CH2:19]1[O:21][CH2:20]1.O>C1COCC1>[CH3:12][O:11][CH:6]1[C:7]2[C:3](=[C:2]([CH2:19][CH2:20][OH:21])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH:5]1[CH3:13]
Reactant: COC1c2cccc(Br)c2CC1C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC1c2cccc(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 22.2 g (92.0 mmol) of 4-bromo-2-methyl-methoxyindane in 200 ml of THF 36.9 ml of 2.5 M (92.1 mmol) nBuLi in hexanes was added for 20 minutes at −80° C. This mixture was stirred for 30 minutes at this temperature, cooled to −110° C., and 4.86 g (110 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 hours at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 150 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes-ether=20:1, vol.). Yield 14.7 g (77%) of a ca. 1 to 1.1 mixture of two diastereomers. Anal. calc. for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.80; H, 8.94. 1H NMR (CDCl3): δ 7.29 (m, 2H, 6-H of both isomers), 7.23 (m, 2H, 7-H of both isomers), 7.15 (m, 2H, 5-H of both isomers), 4.58 (d, J=5.5 Hz, 1H, CHOMe of minor isomer), 4.48 (d, J=4.0 Hz, 1H, CHOMe of major isomer), 3.53 (s, 3H, OMe of major isomer), 3.48 (s, 3H, OMe of minor isomer), 3.74 (m, 4H, CH2Br of both isomers), 3.27 (dd, J=15.9 Hz, J=7.7 Hz, 1H, 3-CHH′ of major isomer), 2.97 (dd, J=15.0 Hz, J=6.8 Hz, 1H, 3-CHH′ of minor isomer), 2.82 (m, 4H, CH2CH2Br of both isomers), 2.73 (dd, J=15.0 Hz, J=7.0 Hz, 1H, 3-CHH′ of minor isomer), 2.54-2.71 (m, 4H, CHMe and OH of both isomers), 2.46 (dd, J=15.9 Hz, J=5.0 Hz, 1H, 3-CHH′ of major isomer), 1.18 (d, J=7.0 Hz, 3H, 2-Me of major isomer), 1.15 (d, J=7.9 Hz, 3H, 2-Me of minor isomer). 13C{1H} NMR (CDCl3): δ 142.6, 142.4, 141.9 (2C), 134.8, 134.6, 128.9, 128.7, 126.6, 126.2, 123.4, 123.2, 91.4, 86.1, 62.3, 62.2, 56.6, 56.2, 39.1, 38.3, 36.8, 36.5, 36.4, 36.2, 19.3, 13.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.Cl[CH2:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=2[CH:37]=1)=[O:26].CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=4[CH:37]=3)=[O:26])[CH2:19]2)=[N:14]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2c1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCC(=O)c3ccc5c(c3)NC(=O)CO5)C4)c2c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 0.8 %

Procedure:
To a solution of 2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (50 mg, 0.2 mmol) in DMF (0.5 mL) was added 6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (0.05 g, 0.22 mmol) and Et3N (0.033 mL, 0.22 mmol). The reaction was heated to 50° C. and stirred for 12 h. The crude was purified directly by basic reverse phase HPLC to afford 0.8 mg (10%) of the title compound. HPLC: Rt=5.50 min. MS (ESI): exact mass calculated for C27H25N5O4, 483.19; m/z found, 484.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.78 (d, J=4.7, 1H), 8.06 (d, J=9.1, 1H), 7.69-7.61 (m, 3H), 7.42 (d, J=2.6, 1H), 7.40 (dd, J=9.1, 2.6, 1H), 7.32 (d, J=4.7, 1H), 7.04 (d, J=8.9, 1H), 4.70 (s, 2H), 4.21 (s, 1H), 3.89 (s, 3H), 3.11-2.80 (m, 5H), 2.62-2.58 (m, 1H), 2.26-2.17 (m, 1H), 1.93-1.86 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:12])[NH:15][OH:16])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccc(C(=N)NO)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
(4-Cyano-phenyl)-acetic acid methylester (1.054 g, 6.02 mmol), hydroxylamine hydrochloride (0.690 g, 9.93 mmol) and sodium bicarbonate (0.834 g, 9.93 mmol) were dissolved in MeOH (12.03 mL) at RT. The mixture was stirred at 60° C. for 5 h, diluted with EtOAc (200 mL) and 40 ml water added. The aqueous layer was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (40 mL) and dried over sodium sulfate. Solvent was removed to yield 1.2 g (5.76 mmol) of yellow oil, which was dried on high vacuum over night. The crude mixture was used without further purification.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>CCCCCC>[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH:11]([Br:1])[CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(Br)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
bromine (32.5 g≡10.4 ml) was added over 15 minutes to a stirred mixture of (±)-1-(3-trifluoromethylphenyl)-ethanol [38 g, described by Overberger et al., Org. Synth. Coll. 3, 200 (1955)], triphenylphosphine (56 g) and dry dimethylformamide (200 ml) in an atmosphere of nitrogen. The temperature of the mixture was maintained at 40°-50° C. by ice-cooling. Further bromine was added dropwise to give a permanent orange colour and after stirring for 15 minutes the mixture was poured into a mixture of ice-water (1 liter) and hexane (500 ml). The mixture was filtered and the solid material was washed well with hexane. The hexane solutions were combined, washed with water (4×100 ml), dried over sodium sulphate and distilled to give (±)-1-(3-trifluoromethylphenyl)ethyl bromide, b.p. 98°-105° C./15 mmHg, as a clear mobile oil.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:23])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:3][C:4]([O:6]C)=[O:5].[OH-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:23])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(O)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(O)CC(=O)O

Procedure:
A solution of methyl 3-hydroxy-7,11,15-trimethylhexadeca-6,10,14-trienoate (139 mg, 430 μmol), ethanol (1 mL) and sodium hydroxide (1N, 440 μL, 440 μmol) was stirred at room temperature for two-hours. The crude mixture was purified by flash chromatography on a 20 mm ID silica gel column. Elution of the column with choloform:acetic acid (40:1/v=v) gave title compound as a colorless gum.
Reaction SMILES: C(O)(=O)CCCCCCCCCCCCCCCCC.NCCCO.C[O-].[Na+].[OH:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].[C:53]([C:57]1[CH:58]=[C:59]([CH2:68][CH2:69][C:70](O)=[O:71])[CH:60]=[C:61]([C:64]([CH3:67])([CH3:66])[CH3:65])[C:62]=1[OH:63])([CH3:56])([CH3:55])[CH3:54]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].C1(C)C(C)=CC=CC=1.CCCCCC.O>[C:64]([C:61]1[CH:60]=[C:59]([CH2:68][CH2:69][C:70]([O:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:71])[CH:58]=[C:57]([C:53]([CH3:55])([CH3:54])[CH3:56])[C:62]=1[OH:63])([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCO
Agent: [Ti+4]
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCC[O-]
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Stearic acid (56.8 g; 0.2 mole) was added to a hot (80° C.) mixture of 30 g (0.4 mole) 3-aminopropanol, 100 ml xylene and 0.5 g sodium methoxide. The mixture was heated at reflux for two hours with removal of water and was then poured into hexane, in which N-(3-hydroxypropyl)stearamide crystallized and was obtained by filtration; it melted at 83°-89° C. After the product was recrystallized from acetone, melting point rose to 94°-96° C. A 34.1 g (0.1 mole) portion of this intermediate was heated with 27.8 g (0.1 mole) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 1 g of Tyzor TBT catalyst and 100 ml xylene. After the mixture was refluxed for 3 hours, 2 ml of water was collected in the Stark and Dean trap. The xylene was distilled off under vacuum, and the residue was crystallized from acetonitrile. The title product (29 g) thus obtained melted at 50°-52° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C.[Mg].C(Br)C.C1(C#C[Mg]Br)C=CC=CC=1.[C:27]1([C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[C:27]1([C:33]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Br[Mg]C#Cc1ccccc1
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Product: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of phenylacetylene (11.2 g., 0.1 mole) in 25 ml. of anhydrous ether was added over a 45 minute period to a suspension of ethylmagnesium bromide (0.1 mole) prepared from magnesium (2.4 g., 0.1 g. atom) and ethyl bromide (10.9 g., 0.1 mole) in 100 ml. of ether. The mixture was stirred overnight. The resultant phenylethynylmagnesium bromide suspension was subsequently added dropwise through a stop-cock at the base of the flask to a solution of ethyl phenylglyoxylate (17.8 g., 0.1 mole) in 100 ml. of dry ether at 0°-5° over a two hour period. The cooling bath was removed and the mixture stirred for five hours. The reaction mixture was kept overnight, then poured on a slurry of ice and concentrated hydrochloric acid and extracted with ether. The ether extracts were dried and the solvent distilled in vacuo. The resultant oil was distilled to give 14.5 g. (52%) of product, b.p. 170°-82° (0.25 mm.). An analytical sample distilled at 156°-58° (0.08 mm.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)CCC(=O)N2
Yield: 62.9 %

Procedure:
6-Hydroxy-3,4-dihydroquinolin-2(1H)-one (18.38 mmol, 3.00 g) was treated in the presence of K2CO3 (22.98 mmol, 3.18 g) with methyl iodide (22.98 mmol, 3.26 g) in N,N-dimethylformamide (30 ml) at room temperature for 24 hours, resulting in 2.05 g of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH2:22])[N:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:8][C:9]1[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:22][C:5](=[O:7])[CH3:6])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)cc2c([N+](=O)[O-])cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2c([N+](=O)[O-])cccc2c(C)n1
Reaction time: 3.5 h
Yield: 32.6 %

Procedure:
Acetic anhydride (1.4 mL, 15 mmol) was added to a suspension of Example 141C (5 mmol) and triethylamine (0.76 mL, 5.5 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred for 3.5 hours, then the volatiles were removed under reduced pressure. The residue was chased with toluene (3×25 mL) and concentrated under reduced pressure to afford the title compound (0.40 g, 33% yield over three steps). MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>N1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)[CH:15]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3cccnc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.71 (dd, J=5.7, 4.1 Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 8.15-8.12 (d, J=7.8 Hz, 1H) 8.44-8.42 (m, 1H), 8.50 (m, 1H), 8.60-8.56 (m, 1H), 8.93-8.91 (dd, J=1.7 Hz, 1H), 9.37-9.38 (d, J=1.7 Hz, 1H) ppm; MS (DCl/NH3) m/z 249 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O:19][C:20](=O)[CH2:21][C:22]([CH3:24])=O)C>>[CH2:15]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[O:19])[CH2:21][C:22]([CH3:24])=[N:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:6])[CH3:16]
Reactant: CCN(CC)S(=O)(=O)c1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(N2N=C(C)CC2=O)cc1

Procedure:
From the reaction of N,N-diethyl-4-hydrazinobenzenesulfonamide and ethylacetoacetate gives N,N diethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide. Subsequent reaction wvith 2-ethoxyaniline yields N,N-diethyl4-(4,5-dihydro-4-(2-ethoxyanilinomethylene)-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide, Mp: 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[O:18]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]3=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0 g, 41 mmol) in dioxane (200 cm3) and SeO2 (22.8 g, 205 mmol) was brought to reflux for 2 h then cooled to RT and concentrated onto Florisil. The Florisil was washed (acetone:CHCl3 1:9) and the combined organic extracts were evaporated. The residue was purified by column chromatography (SiO2, acetone:CHCl3 1:8) to afford the subtitled compound (8 g, 31 mmol, 76%) as a tan solid: m.p. 256-258° C., 1H NMR (THF-d8) δ 6.96 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd, J=7.7, 7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz, 1H), 7.83-7.86 (m, 2H), 10.05 (br s, 1H); 13C NMR (DMSO-d6) δ 113.30 (d), 119.08 (s), 123.44, 125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47 (s), 137.25 (d), 141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256 (M−H)+; Anal. (C14H8ClNO2-0.1H2O) C, H, N.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[Sn]Cl.[OH-].[Na+]>O1CCOCC1.Cl>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1
Reactant: CN(c1cccnc1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(c1cccnc1)c1cccc(N)c1
Yield: 99 %

Procedure:
Compound 16 (330 mg, 1.44 mmol, 1.00 eq) was dissolved in dioxane (7 mL) and SnCl2 (1.37 g, 7.22 mmol, 5.00 eq) dissolved in conc HCl (3 mL) was added dropwise over 15 min. After determination of completion by LCMS, the reaction was neutralized with 1N NaOH, filtered, diluted with water and extracted with CH2Cl2 (2×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give 284 mg (99%) of a brown oil that was used subsequently without purification. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=2.3 Hz, 1H), 7.99 (dd, J=4.2, 1.6 Hz, 1H), 7.24-7.17 (m, 2H), 7.01-6.95 (m, 1H), 6.32-6.28 (m, 2H), 6.27-6.23 (m, 1H), 5.08 (s, 2H), 3.19 (s, 3H); ES-MS [M+1]+: 200.2.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:11]=1[C:22]([F:25])([F:24])[F:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:11]=2[C:22]([F:23])([F:25])[F:24])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccc(Cl)cc2)c(C(F)(F)F)c1

Procedure:
A mixture of 4-chloroaniline (127.5 g) and 2-chloro-3,5-dinitrobenzotrifluoride (270.5 g.) in toluene (2 l.) was heated under reflux for 16 hours and the hot mixture then filtered. The filtrate was concentrated in vacuo, and the true amounts of toluene removed by co-distillation with industrial methylated spirit, to give a black semi-solid. Extraction of this solid with cyclohexane gave yellow crystals of 2(4-chloroanilino)-3,5-dinitrobenzotrifluoride, melting point 104°-106° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.[NH:34]1[CH2:37][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH2:35]1>C(O)(C)C.CO>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:34]3[CH2:37][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH2:35]3)=[O:14])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCN(C2CCC2)CC1
Reactant: COC(=O)C1CNC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 85 °C
Yield: 42.9 %

Procedure:
To a stirred solution of 4-nitrophenyl 4-cyclobutyl-1,4-diazepane-1-carboxylate (2.4 g, 7.5 mmol) in isopropyl alcohol (6 ml) and methanol (3 ml) was added DIPEA (3.80 ml, 24 mmol) followed by methyl azetidine-3-carboxylate hydrochloride (1.70 g, 11 mmol) portion wise over 2 minutes. The resulting suspension was heated at 85° C. for 72 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with 1M sodium carbonate solution (3×30 ml), dried (Na2SO4), filtered and evaporated at reduced pressure. Purification by FCC on silica provided the title compound as pale yellow oil (0.95 g, 43%).