Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[CH2:1]([NH:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)=[O:24])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCNc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCNc1ccc(NC(=O)N2CCN(C)CC2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 282.9 %

Procedure:
To a 100 mL flask was added 4-ethylamino-3-nitroaniline (625 mg, 3.45 mmol), chloroform (30 mL), and triphosgene (341 mg, 1.15 mmol). To the solution was added satd NaHCO3 (30 mL), and the biphasic mixture was stirred for 30 min. The organic phase was partitioned, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (16 mL), and 4-methylpiperizine (291 mg, 2.90 mmol) was added. The solution was stirred at 40° C. for 1 h, cooled and concentrated under reduced pressure to provide the title compound (1.0 g, 94%) as a red solid. 1H-NMR (CDCl3): δ 7.91 (1H, d), 7.84 (1H, t), 7.61 (1H, dd), 6.95 (1H, s), 6.73 (1H, d) 3.52 (4H, t), 3.31 (2H, m), 2.42 (4H, t), 2.32 (3H, s), 1.34 (3H, t); MS(ESI): 308 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([OH:20])=O)[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:28].[Cl-]>>[NH2:28][C:18]([CH:17]1[N:12]2[N:11]=[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:13]2[C:14](=[O:22])[N:15]([CH3:21])[CH2:16]1)=[O:20]
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Reactant: [NH4+]
Agent: [Cl-]
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(N)=O
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-benzyloxy-2-ethoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid using a procedure similar to that described in Example 2, Step 5 except that NH4Cl was used in place of 4-fluorobenzylamine, and the reaction time totaled 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3, and the aqueous layer was extracted twice more into EtOAc. The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and azeotroped with toluene to afford the title product as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.50-7.49 (m, 2H), 7.29-7.32 (m, 3H), 5.19 (dd, J=10.8, 24.4 Hz, 2H), 4.28-4.24 (m, 3H), 4.16 (dd, J=5.2, 13.6 Hz, 1H), 3.86-3.83 (m, 1H), 2.99 (s, 3H), 1.27 (t, J=6.8 Hz, 3H); ES MS (M+H)=373.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)(=O)=O.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C.O[Li].O>C1COCC1.O>[CH2:36]([NH:43][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=3)[NH:13][CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: NCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(NCc2ccccc2)nc1-c1c[nH]c2ncc(C(F)(F)F)cc12
Reaction time: 1 h

Procedure:
2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (50 mg, 0.096 mmol) was heated with benzylamine (21 uL, 0.19 mmol, 2.0 Eq.) and DIPEA (50 uL, 0.29 mmol, 3.0 Eq.) in THF (2 mL) under microwave conditions at 100° C. for 10 minutes. The reaction was concentrated and the residue dissolved in THF (5 mL). LiOH.H2O (20 mg, 0.48 mmol, 5.0 Eq.) in water (1 mL) was added and the reaction stirred for 1 hour. The reaction mixture was concentrated and the residue treated with MeOH. The obtained white precipitate was isolated by filtration and dried under vacuum (13 mg, 36% over 2 steps).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7]2[CH:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH:31]=[CH:30][C:8]=2[C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:10])[CH2:2]1.C=O.O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:29])[CH:25]=1)[CH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:11][C:9](=[O:10])[C:8]1[CH:30]=[CH:31][C:32]([N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[CH:33][C:7]=1[NH:6][CH2:5][CH:3]1[CH2:2][N:1]([CH3:44])[CH2:4]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C)C3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a solution of 2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide (100 mg, 0.14 mmol) in dichloromethane (2 mL) were added formaldehyde 37 wt. % in water (0.014 mL, 0.168 mmol), TEA (0.4 mmol) and sodium triacetoxyborohydride (45 mg, 0.21 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with acqueous NaHCO3 sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 100:10:1 as the eluant, affording 5 mg of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[CH:11]1(OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][CH:14]=[CH:13][CH2:12]1.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:15]1
Reactant: Sc1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC2CC=CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccccc1SC1CC=CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
NaH (316 mg, 55% in mineral oil, 7.24 mmol) was suspended in DMF (6 ml) and the suspension was cooled to 0° C. A solution of 2-chloro-thiophenol (880 ml, 97% purity, 7.55 mmol) in DMF (2 ml) was added dropwise. After stirring for 45 min at 0° C. a solution of toluene-4-sulfonic acid cyclopent-3-enyl ester (1500 mg, 6.29 mmol) in DMF (3 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 days. Water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with water, saturated NaHCO3 solution and brine, dried over Na2OS4 and evaporated. The remaining brown oil was purified by silica gel chromatography (heptane/EtOAc 100:0-99:1) to obtain the title compound (1.047 g, 79%) as colorless liquid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1.Br[CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>CN(C)C=O>[C:13]12([CH2:12][N:8]3[CH:9]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]3=[O:10])[CH2:14][CH:15]3[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]3)[CH2:22]1)[CH2:20]2
Reactant: BrCC12CC3CC(CC(C3)C1)C2
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CC12CC3CC(CC(C3)C1)C2
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
To an ambient suspension of NaH (185 mg, 4.63 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (30 mL) was added 5-bromopyridin-2(1H)-one (700 mg, 4.02 mmol). The reaction mixture was stirred for 15 minutes, and 1-(bromomethyl)adamantane (968 mg 4.22 mmol) was added. The mixture was heated to 120° C. overnight, cooled to room temperature, and quenched by the addition of water and ether. The layers were separated, and the aqueous extracted with additional ether (twice). The combined organics were washed with brine, dried over Na2SO4, and filtered. Chromatography on silica gel, eluting with a gradient of 5 to 30% ethyl acetate in hexanes, provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24](=O)[O:25]N2C(=O)CCC2=O)=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24]([N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[O:25])=[CH:20][CH:19]=1
Reactant: COc1nccnc1NCC1CCNCC1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 127, STEP 3) (0.093 g, 0.00042 mol) and N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A) (118 mg) in DMF (2 mL) was stirred at rt for 18 h. The reaction was diluted with ethyl acetate (30 mL), washed with 10% aqueous sodium bicarbonate (20 mL) followed by brine (10 mL), concentrated in vacuo and chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane. Concentration in vacuo followed by crystallization from ether/hexane gave the title compound. M.S. (M+1): 371.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[C:31]1([S:37]([C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[C:20]1[CH3:29]
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
A mixture of triethylsilane (0.71 g), trifluoroacetic acid (0.53 g) and 1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.091 g), 2-benzenesulfonylbenzaldehyde (0.12 g) and 1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at −10° C. for 15 minutes and then at room temperature for 2 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 to 0:1 by volume) to afford the title compound as a colourless gum (0.17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: CCc1ccc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: CCc1ccc(C(=O)OC)cc1Br

Procedure:
3-Bromo-4-ethyl-benzoic acid (D43) (19.40 g) was dissolved in MeOH (200 mL) and then treated with conc. H2SO4 (1 mL). The mixture was heated at reflux overnight, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution, extracting again with EtOAc. The combined extracts were then washed with brine, dried (MgSO4). The solvent was evaporated in vacuo to afford the title compound (15.8 g). 1H NMR (CDCl3) δ 1.24 (3H, t), 2.79 (2H, q), 3.91 (3H, s), 7.29 (1H, d), 7.89 (1H, dd), 8.19 (1H, d).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:7](O)=[O:8]>>[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:7]([Cl:3])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCC(C)C(=O)O
Product: CCCCCCCCC(C)C(=O)Cl
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
To thionyl chloride (93 g, 782 mmol), cooled to 15° C. in a water bath was added during 1 hour 2-methyl decanoic acid (64 g, 344 mmol). The cold water bath was removed and the mixture was heated at 50° C. with stirring for 45 minutes. The excess thionyl chloride was removed by distillation and the crude acid chloride was then fractionally distilled (b.p. 143°-45° C./5.8 mm) to give 69 g of product (99% yield) that showed an assay of >98% by GC.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])[N:8]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc2cc([N+](=O)[O-])cc(CNc3cccc(C(=O)O)c3)c2nc1OC

Procedure:
350 mg (1.06 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 153 mg (1.05 equiv.) of 3-aminobenzoic acid and 0.165 ml (1.1 equiv.) of triethylamine are combined in 10 ml of acetonitrile, and heated at boiling at reflux for 24 hours. The reacton mixture is concentrated by evaporation, extracted with ethyl acetate and 1 N HCl and washed once with brine. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cc(C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde 1 (11.47 g, 62 mmol) in MeOH (230 mL) and water (85 mL) was added ammonium chloride (24.2 g, 452 mmol) and iron (18.4 g, 329 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered, partially concentrated under reduced pressure, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The crude aniline was dissolved in CH2Cl2 (˜150 mL), diluted with hexanes (˜300 mL), and cooled to 0° C. The solid was collected by filtration and washed with hexanes to give 3-amino-4-chlorobenzaldehyde 2 (5.36 g, 56% yield) as a yellow solid. Mass spectrum: calculated for C7H5ClNO 155.0. found 156.1 (M++1).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[Cl:8][C:9]1[C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]>O>[Cl:8][C:9]1[C:17]([S:18](=[O:19])(=[O:20])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred solution 7.3 gof n-butylamine, 8 g of sodium hydroxide in 200 ml of water, 30 g of 4-chloro-5-chlorosulfonyl-3-nitrobenzoic acid are added portionwise while keeping the temperature between 0° and 5°. After 1/2 hour the mixture is allowed to warm to room temperature for 2 hours. The supernatant solution is filtered, the filtrate combined with 25 ml of 2N of hydrochloric acid, the precipitate formed collected and recrystallized from aqueous ethanol, to yield the 4-chloro-3-nitro-5-n-butylsulfamoylbenzoic acid melting at 199°-201°.
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:20][C:21]1[C:26]([OH:27])=[C:25]([NH:28][C:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([C:35]#[N:36])=[C:23]([CH3:37])[C:22]=1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=1>O>[Br:20][C:21]1[C:22]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=2)=[C:23]([CH3:37])[C:24]([C:35]#[N:36])=[C:25]2[C:26]=1[O:27][C:29]([C:30]([CH3:32])([CH3:31])[CH3:33])=[N:28]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccc(O)c2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 94.5 %

Procedure:
Toluene (45 ml), p-toluenesulfonic acid monohydrate (21.0 mg, 111 μmol) were added to N-(2-bromo-5-cyano-3,3′-dihydroxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-16) (446 mg, 1.11 mmol), followed by refluxing with a Dean-Stark condenser for 3 hours. After cooling, water (50 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the entitled compound (404 mg, 95%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[CH:8]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].C(N(CC)CC)C>C1COCC1>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCC(C(=O)NCC(F)(F)F)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
2-(4-Nitro-1H-imidazol-1-yl)octanoic acid (7.8 mmoles,2.0 g) was treated with 25 ml oxalyl chloride, concentrated and added to a solution of trifluoroethylamine hydrochloride (7.8 mmoles, 1.06 g) and triethylamine (2 ml) in 50 ml THF. After stirring at room temperature for 16 hours, the mixture was added to ice, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel to yield 0.6 g of N-(2,2,2-trifluoro)ethyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [CH3:1][I:2].[NH2:3][C:4](=[S:31])[C:5]1[NH:6][C:7]([CH3:30])=[C:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CO>[IH:2].[NH:3]=[C:4]([S:31][CH3:1])[C:5]1[NH:6][C:7]([CH3:30])=[C:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1=C(C)NC(C(N)=S)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CI
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(C(=N)SC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Product: I
Reaction time: 24 h
Yield: 63.1 %

Procedure:
Methyl iodide (0.06 ml, 0.96 mmoles) was added to a solution of diethyl 2-(aminothioxomethyl)-1,4-dihydro- 6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (0.2 g, 0.48 mmoles) in methanol (10 ml). After stirring for 16 hours at room temperature methyl iodide (0.1 ml) was added and the stirring continued for 1 day. The solvent was evaporated and the residue crystallised on addition of ether. The hydroscopic solid was filtered and dried in vacuo to give the title compound (0.17 g). Nmr (CDCl3) δ 5.9 (s,H), 2.9 (s,SMe).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[OH:19])=[O:5])C.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:31]([C:30]3[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=3)[CH2:21][CH2:20]2)[CH:7]([OH:19])[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2O
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-3-hydroxy-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (618 mg, 1.92 mmol) and 4-(trifluoromethoxy)aniline (516 μL, 3.85 mmol) in toluene (5 ml) under an argon atmosphere at room temperature, was added dimethylaluminium chloride (0.9M solution in heptane, 4.27 ml, 3.85 mmol) and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and quenched with sat. Na2SO4 (aq) solution and the mixture was filtered through Celite® and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (1:1 AcOEt/heptane) to give (5SR,6RS)-8-benzyl-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (620 mg, 77%) as a white solid. MS (ESI): 405.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH2:15]
Reactant: NN
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CCO
Solvent: O
Product: NN=C1C(=O)Nc2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a stirred slurry of 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate, resulting in a red solution. The solution was heated under reflux for 3.5 hours, during which time a precipitate appeared. The reaction mixture was stirred overnight, and then the precipitate was recovered by filtration to give 5-chloro-3-hydrazono-2-oxindole as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4 g.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>CC(C)=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH2:27][CH3:28])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 20.0 g of 2-(p-prenylphenyl)propionic acid and 14.0 g of potassium carbonate in 150 ml of acetone was stirred at room temperature for one hour. To the solution was added dropwise a solution of 15.6 g of diethyl sulfate in 50 ml of acetone with stirring at 25° C. After stirring at room temperature for 3 hours, the mixture was refluxed for an additional one hour with stirring. The precipitate which formed was removed by filtration, and the acetone was evaporated. To the residue was added ice-water, and the mixture was extracted with n-hexane. The extract was washed with water, aqueous sodium bicarbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 18.7 g of ethyl 2-(p-prenylphenyl)propionate. b.p. 108° C./0.15 mmHg, IR νmaxneat ; 1730 cm-1.