Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:13][C:14]1[C:23]([O:24]S(=O)(=O)O)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[OH:24][C:23]1[C:14]([CH2:13][CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2
Reactant: O=C(COc1ccccc1)NC(Cc1ccc2cccnc2c1OS(=O)(=O)O)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(COc1ccccc1)NC(Cc1ccc2cccnc2c1O)c1ccccc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a stirring solution of the 2-[8-(benzyloxy)quinolin-7-yl]-1-phenylethanol (0.302 mmol) in phenoxyacetonitrile (9.05 mmol, 30 eq.) at −10° C. was dropwise added conc. sulfuric acid (1.51 mmol, 5.0 eq.). On completion of addition, the reaction mixture was allowed to warm to room temperature and was stirred 16 h. The reaction was then diluted with ice that was allowed to melt and was then stirred 2 h. The mixture was next brought to pH=7 by the addition of saturated aqueous sodium bicarbonate solution and then diluted with water (5 mL) and extracted with ethyl acetate (2×5 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to give sulfuric acid mono-{7-[2-(2-phenoxy-acetylamino)-2-phenyl-ethyl]-quinolin-8-yl}ester as a yellow oil that was purified by column chromatography using 20% methanol/dichloromethane. To a stirring suspension of the sulfuric acid mono-{7-[2-(2-phenoxy-acetylamino)-2-phenyl-ethyl]-quinolin-8-yl}ester (0.089 mmol, 1.0 eq.) from the initial step in methanol (9 mL) was added 3N HCl (18 mL) and the resulting suspension was heated to 55° C. and stirred 2 h. The reaction mixture was then cooled to room temperature and organic solvents were removed by rotary evaporation resulting in a precipitate that was filtered yielding the pure product as a yellow solid (0.059 mmol, 12% for 2 steps). HRMS: calcd for C25H22N2O3+H+, 399.17032; found (ESI-FTMS, [M+H]1+), 399.17059.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C@H:36]([C:41](O)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C@H:36]([C:41]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:12]([OH:14])=[O:13])=[O:42])[CH2:37][C:38]([NH2:39])=[O:40])(=[O:33])=[O:34])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-(4-methylbenzenesulfonyl)-L-asparagine (90 mg, 0.3 mmol) which was prepared in step A of example 47. The final product was triturated with ether to yield 95 mg (15%) of the desired material.
Reaction SMILES: Cl.[C:2]12([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[C:2]12([C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[CH:16][CH:17]=3)[CH2:9][CH:8]3[CH2:10][CH:4]([CH2:5][CH:6]([CH2:7]3)[CH2:11]1)[CH2:3]2
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
5.28 g (20 mmol) of 4-adamantan-1-yl-phenylamine hydrochloride were placed in 100 ml of methylene chloride and treated with 3.22 g (42.0 mmol) of pyridine. A solution of 2.39 g (22.0 mmol) of ethyl chloroformate in 15 ml of methylene chloride was added dropwise to this suspension at room temperature while stirring during 15 minutes. The reaction mixture was stirred at room temperature for 2 hours. Subsequently, the mixture was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylene chloride/n-hexane. 5.6 g of ethyl 4-adamantan-1-yl-phenyl-carbamate were obtained as a white crystallizate. M.p.: 132°-134°.
Reaction SMILES: C(O)(=O)[C:2](O)=[O:3].[CH2:7]([O:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=[O:11])[CH3:8]>O>[CH2:7]([O:9][C:10]([C:12]1([CH:2]=[O:3])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)C1CC1
Solvent: O
Product: CCOC(=O)C1(C=O)CC1
Yield: 51.1 %

Procedure:
Oxalic acid (11.2 g, 0.124 mol) was dissolved in water (40 mL) and 144,4,6-trimethyl-[1,3]oxazinan-2-yl)-cyclopropanecarboxylic acid ethyl ester (15 g, 0.062 mol) was added. Steam distillation of this mixture was carried out until 500 mL of distillate had been collected. The distillate was saturated with NaCl and extracted with EtOAc (2×100 mL). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-formyl-cyclopropanecarboxylic acid ethyl ester (4.5 g, 51%). 1H NMR (CDCl3 400 MHz): δ10.39 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 1.67-1.64 (m, 2H), 1.61-1.58 (m, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1([CH3:18])[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:9]2[S:10][CH:11]=[CH:12][C:8]1=2.[C:19]([O-])([O-])=[O:20].[K+].[K+].C(Cl)Cl>C(Cl)Cl.CN(C=O)C>[CH3:6][C:7]1([CH3:18])[C:8]2[CH:12]=[C:11]([CH:19]=[O:20])[S:10][C:9]=2[C:13]2[S:14][CH:15]=[CH:16][C:17]1=2
Reactant: CC1(C)c2ccsc2-c2sccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)c2ccsc2-c2sc(C=O)cc21
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
1 mL POCl3 was added to a vigorously stirred solution of 4,4-dimethyl-4H-cyclopenta[2,1-b:3,4-b′]dithiophene (381.2 mg, 1.85 mmol) in 6 mL 5:1 CH2Cl2/DMF solvent mixture. The mixture was sealed in a pressure vessel and stirred at 100° C. for 10 min. The solution turned yellow then red upon cooling down. The reaction mixture was then basified with K2CO3 solution, stirred for 30 min more at room temperature to allow complete hydrolysis. The organic product was then extracted with CH2Cl2, concentrated, and purified by column chromatography (SiO2, CH2Cl2) to furnish a yellow oil that solidifies on standing (204 mg, 47%). Rf (silica gel, CH2Cl2)=0.41; 1H NMR (400 MHz, CDCl3): δ 1.50 (s, 6 H, 2 CH3), 7.05 (d, J=4.8 Hz, 1 H, ArH), 7.40 (d, J=4.8 Hz, 1 H, ArH), 7.63 (s, 1 H, ArH), 9.83 (s, 1 H, CHO); MS (EI): m/z=234 [M]+.
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].C(N(CC)CC)C.[CH3:16][N:17]=[C:18]=[O:19].P(=O)(O)(O)O>O>[CH3:16][NH:17][C:18]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:19]
Reactant: CN=C=O
Reactant: CSC(C)(C)C=NO
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)ON=CC(C)(C)SC
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
Into a one liter glass resin kettle equipped with a metal pitched-blade agitator, a pressure-equalizing dropping funnel with Teflon® tube for subsurface addition, a thermometer and a dry ice/acetone cooled condenser was added 66.5 grams (0.50 mole) of 2-methyl-2-(methylthio) propionaldehyde oxime and 112 milliliters of water. After cooling the mixture to a temperature of 2° C.-3° C. with a water/salt/ice bath, 0.52 grams (0.005 mole) of triethylamine was added to the kettle under a nitrogen atmosphere. A stoichiometric amount of methyl isocyanate (29.5 milliliters, 0.50 mole) was then added over a period of 30 minutes at a temperature of 4° C.-14° C. with vigorous stirring. The water/salt/ice bath was removed and the mixture was stirred for an additional 75 minutes at a temperature of 10° C.-18° C. after which an additional 2.0 milliliters (0.03 mole) of methyl isocyanate was added and the mixture stirred for an additional period of 30 minutes. The water/salt/ice bath was then put back in place and 2.9 grams of phosphoric acid in 10 milliliters of water was added in a slow stream subsurface. The resulting solid product was filtered off on a sintered glass funnel and rinsed with hexane to give 104.4 grams (wet weight) of a fluffy white powder. High pressure liquid chromatographic analysis (internal standard) indicated the following: 84.00 percent 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (89.1 percent yield based on aldicarb oxime) and 2.38 percent 2-methyl-2-(methylthio) propionaldehyde oxime; 13.62 percent water content was determined by Karl Fischer titration.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH3:27])=[O:8])=[CH:5][C:4]=1[N+:30]([O-])=O)#[N:2].[Sn](Cl)(Cl)(Cl)Cl.Cl.[OH-].[Na+]>COCCOCCOC>[NH2:30][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:3]=1[C:1]#[N:2])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:23])([F:24])[F:25])[C:18]([F:19])([F:20])[F:21])=[CH:12][C:11]=1[CH3:27])=[O:8]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
4-Cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (1.0 g, 2.16 mmol) (Example I1) was dissolved in diethylene glycol dimethyl ether (“diglyme”) (25 ml) and tin chloride (1.229 g, 6.48 mmol) was added. The mixture was cooled to 0° C. and aqueous hydrochloric acid (concentrated) (4 ml) was added slowly. The reaction mixture was stirred at 80° C. for 0.5 hours. Aqueous sodium hydroxide (30% w/v) (80 ml) was added to adjust the pH to 7-8. The aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1 to 0:1) to give 3-amino-4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.48 g, 51% yield). 1H-NMR (400 MHz, CDCl3): 7.54 (s, 1H), 7.49 (d, 2H), 7.36 (m, 3H), 7.15 (q, 1H), 2.3 (s, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2([CH2:12][CH2:13][C:14]=1OS(C(F)(F)F)(=O)=O)[OH+:11][CH2:10][CH2:9][O:8]2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1B(O)O>CN(C)C=O>[F:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[C:14]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC2(C1)OCC[OH+]2
Reactant: OB(O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(c2cc(F)c(F)cc2F)CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-(methoxycarbonyl)-8-{[(trifluoromethyl)sulfonyl]oxy}-4-oxa-1-oxoniaspiro[4.5]dec-7-ene (5.65 g, 16.0 mmol) dissolved in N,N-dimethylformamide (190 mL) were added aqueous sodium carbonate solution (2.0M, 20 mL, 39.0 mmol) and 2,4,5-trifluorophenylboronic acid (4.11 g, 23.4 mmol). The resulting mixture was degassed and treated with PdCl2(dppf) ([1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1), 1274 mg). The resulting mixture was stirred under a nitrogen atmosphere at room temperature overnight, filtered over Celite, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate, evaporated and the crude product was purified by chromatography on a Biotage® system (silica gel, ethyl acetate in hexanes gradient 30-50%) to yield the title compound.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.CO[C:16]1[C:25](=[O:26])[C:20]2[N:21]=[C:22]([CH3:24])[S:23][C:19]=2[C:18](=[O:27])[CH:17]=1>CO>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:16]1[C:25](=[O:26])[C:20]2[N:21]=[C:22]([CH3:24])[S:23][C:19]=2[C:18](=[O:27])[CH:17]=1
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nc2c(s1)C(=O)C=C(NCCCBr)C2=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.57 g (7.17 mmol; 1.5 equivalent) of 3-bromopropylamine hydrobromide and 1.02 ml (7.17 mmol; 1.5 equivalent) of triethylamine are added to 1 g (4.78 mmol) of 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione in solution in 100 ml of methanol. The reaction mixture is maintained under stirring for 2 hours at 60° C., then the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 97/3). The 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione is obtained in the form of a red oil.
Reaction SMILES: C(N(CC)CC)C.C([O:10][C:11]([C:13]1[N:14]([CH2:27][C:28]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29]2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=2)=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:10]=[C:11]1[C:13]2=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[N:14]2[CH2:27][C:28]2([CH2:29][CH2:30][CH2:31]2)[CH2:32][NH:33]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCC1)CNC3=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
Triethylamine (23.3 mL, 167.5 mmol) is added to a mixture of crude 1-(1-aminomethyl-cyclobutylmethyl)-1H-indole-2,6-dicarboxylic acid diethyl ester from the preceding step and K2CO3 (23.16 g, 167.5 mmol) in ethanol (1.2 L). The reaction mixture is heated at 80° C. for 2 h then is cooled down to room temperature and stirred for another 16 h. The solid K2CO3 is removed by filtration and the filtrate is concentrated to afford the crude compound which is purified by flash column chromatography using 3% methanol in CH2Cl2 to afford the title compound (7 g, 40% for 3 steps) as a white solid.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+]>C1C=CC=CC=1>[CH2:23]([O:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: O=C1C=CCS1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cccs1
Reaction time: 24 h

Procedure:
A mixture of 20 g (0.2 mole) of 3-thiolen-2-one [R. T. Hawkins, Journal Heterocyclic Chemistry, 11, (3), 291-4 (1974)], 61.1 g (0.2 mole) of 1-bromohexadecane, and 4.8 g (0.2 mole) of sodium hydride in dry benzene is refluxed with stirring for 24 hours after which the solvent is removed and the product distilled to give 2-hexadecyloxythiophene.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OC)=[O:30])=[CH:23][CH:22]=3)[O:16][C:15]2=[O:33])=[CH:10][CH:9]=1.Cl>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:23][CH:22]=3)[O:16][C:15]2=[O:33])=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1ccc(OCC2CN(c3ccc(Cl)cc3)C(=O)O2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1OC(COc2ccc(CCCO)cc2)CN1c1ccc(Cl)cc1
Yield: 71.5 %

Procedure:
Lithium aluminum hydride (59 mg) was added to a tetrahydrofuran (15 ml) solution of 750 mg of methyl 3-{4-[3-(4-chlorophenyl)-2-oxooxazolidin-5-yl]methoxy-phenyl}propionate (compound 191) obtained in Example 32. The mixture was stirred with ice-cooling for 40 minutes in a stream of nitrogen. To the reaction mixture was added 5% hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 498 mg of the title compound (compound 194) in a yield of 71%.
Reaction SMILES: C([N:4]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6])C=C>C1(C)C=CC=CC=1>[NH:4]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[C:5]1=[O:6]
Reactant: C=CCN1C(=O)C(=O)c2cnccc21
Solvent: Cc1ccccc1
Product: O=C1Nc2ccncc2C1=O
Reaction time: 0.25 h

Procedure:
A solution of N-allyl-5-azaisatin (5.3 mmol), (Ph3P)3RhCl (0.5 mmol) in aqueous toluene is stirred under a nitrogen atmosphere at room temperature overnight. The organic layer is dried (MgSO4) and the solvent is evaporated. The residue is stirred in 1N HCl/MeOH for 15 min after which time the methanol is evaporated and the pH of the water is adjusted to 7. A precipitate is formed and purified by silica gel chromatography (1% MeOH:CHCl3) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[N:33]=[C:32]([CH2:34][CH2:35][CH2:36]O)[O:31][N:30]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:57]1[CH:62]=[CH:61][C:60]([CH2:63][O:64][C:65](/[N:67]=[N:68]/[C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])=[O:66])=[CH:59][CH:58]=1>C1COCC1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:36][CH2:35][CH2:34][C:32]3[O:31][N:30]=[C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=4)[N:33]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH:76]1[CH:75]=[CH:74][C:73]([CH2:72][O:71][C:69](/[N:68]=[N:67]/[C:65]([O:64][CH2:63][C:60]2[CH:61]=[CH:62][CH:57]=[CH:58][CH:59]=2)=[O:66])=[O:70])=[CH:78][CH:77]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: OCCCc1nc(Cc2ccc(Cl)cc2)no1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.10 g, 0.34 mmol), 3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-1-propanol (0.086 g, 0.34 mmol) and triphenylphosphine (0.186 g, 0.69 mmol) in THF (5 ml) was added dibenzylazodicarboxylate (0.204 g, 0.68 mmol) and the solution stirred for 18 h. The solution was then concentrated and the residues chromatographed over silica (20 g, SPE) eluting with DCM initially then DCM/Et2O mixtures to yield the title compound contaminated with dibenzylazodicarboxylate by-products (0.18 g). Material used crude in deprotection step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:39]1([N:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:46](=[O:47])[N:45]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:10]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(CO)cccc1OCC(=O)OC(C)(C)C
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(COC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
A solution of (3-hydroxymethyl-2-methylphenoxy)acetic acid te/t-butyl ester (80.1 g, 318 mmol) dissolved in tetrahydrofuran (400 mL) was cooled to −50° C. and treated with lithium diisopropylamide (325 mmol) freshly prepared from diisopropylamine (49 mL) and 2.5M n-butyllithium (130 mL) in tetrahydrofuran (100 mL). After about 10 minutes at −50° C., a solution of diphenylcarbamyl chloride (80.8 g, 350 mmol) dissolved in tetrahydrofuran (100 mL) was added. The entire reaction mixture was stirred for an additional 30 minutes and then allowed to warm to room temperature over a period of 3 hours. The solution was evaporated in vacuo, poured into dilute hydrochloric acid, and extracted with diethyl ether. The organic layer was dried over brine, evaporated, and purified by silica gel chromatography, eluting with acetone/hexane (1:5→1:3), to give {3-[(diphenylcarbamoyloxy)-methyl]-2-methylphenoxy}acetic acid tert-butyl ester as a white solid (104.1 g, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A solution of 4-hydroxy-3-nitro-benzaldehyde (6.9 g) and ethyl bromoacetate (5.0 mL) in dimethylformamide (250 mL) was treated with anhydrous potassium carbonate (10 g) and the mixture was heated at 60° C. for 18 hours and evaporated to dryness. The residue was partitioned between water and diethyl ether, and the diethyl ether layer was washed with 0.5M sodium hydroxide. It was then dried over anhydrous sodium sulfate and evaporated to give an oil that was chromatographed on silica gel (ethyl acetate/dichloromethane) to afford an oil (1.9 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6].[N:11]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:11])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: NNc1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 69 %

Procedure:
In a 500 ml round bottom flask provided with efficient stirring and external cooling arrangement, 51 ml (, 0.5 mole) of conc. HCl was cooled to below 5 deg C and 25 gms (0.13 mole) 3-chloro-4-fluoroaniline was added. The hydrochloride thus precipitated was then diazotised below 0 deg C with 12 gms (0.17 mole)sodium nitrite and the resulting diazonium salt was decomposed with 100 gms (0.79 mole)sodium sulphite and 12 ml caustic lye. The reaction mixture was filtered to remove impurities.225 ml conc. HCl was added and stirred well and allowed to stand overnight. The 3-chloro-4-fluorophenylhydrazine hydrochloride thus precipitated was filtered and recrystallized from water. The dried product was 18 gms (yield 69%) M.pt: decomposed at 193 deg C. IR (KBr) cm−1 2939 and 2690(NH), 1506 (C═C), 1114 (C—F), 744(C—Cl)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([F:14])[C:9]([CH2:10][OH:11])=[C:8]([Cl:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:5][C:6]1[CH:13]=[C:12]([F:14])[C:9]([CH2:10][O:11][C:29]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]2[CH2:32][CH3:33])=[O:30])=[C:8]([Cl:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CCCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 90 %

Procedure:
This compound was prepared from 4-butoxy-2-chloro-6-fluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (505 mg; 90%); MS (ISP): 490.4 (M+NH4)+.