Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:20][C:12]3=[CH:13][C:14]([OH:19])=[C:15]([OH:18])[C:16]([OH:17])=[C:11]3[C:9](=[O:10])[CH:8]=2)=[CH:5][CH:6]=1.[CH2:21]=O.[OH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>CO>[OH:17][C:16]1[C:15]([OH:18])=[C:14]([OH:19])[C:13]([CH2:21][N:26]2[CH2:27][CH2:28][CH:24]([OH:23])[CH2:25]2)=[C:12]2[C:11]=1[C:9](=[O:10])[CH:8]=[C:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[O:20]2
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)c(O)c(O)c12
Reactant: OC1CCNC1
Reactant: C=O
Solvent: CO
Product: O=c1cc(-c2ccccc2)oc2c(CN3CCC(O)C3)c(O)c(O)c(O)c12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The mixture of Baicalein (27 g), methanol (350 ml), 37% formaldehyde solution (8.04 ml), 3-hydroxyl-pyrrolidine (8.8 g) was stirred under for 4 hours at 50° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 36.0 g of purity 99.0%. MS: (API-ES) m/z 370.1[M+H]+, 739.2 [2M+H]+, 761.2[2M+Na]+; 1H NMR (DMSO-d6, 400 MHz): δ 8.05˜8.07 (m, 2H, Ar-2′,6′-H), 7.58˜7.59 (m, 3H, Ar-3′,4′,5′-H), 6.87 (s, 1H, 3-H), 4.17 (s, 2H, CH2), 3.32 (m, 1H, CH), 2.28, 2.53 (m, 2H, CH2), 2.20, 2.30 (m, 2H, CH2), 1.81, 1.62 (m, 2H, CH2).
Reaction SMILES: P(Br)(Br)Br.[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21](O)[CH3:22])[C:16]=1[CH3:24].O1CCCCC1[O:32][NH2:33]>N1C=CC=CC=1.CN(C)C=O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:33][OH:32])[CH3:22])[C:16]=1[CH3:24]
Reactant: NOC1CCCCO1
Reactant: COC(=O)c1ccccc1Nc1cccc(C(C)O)c1C
Agent: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1Nc1cccc(C(C)NO)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus tribromide (4.2 mL, 1 M solution in dichloromethane) is added dropwise to a solution of 2-[[3-(1-hydroxyethyl)-2-methylphenyl]amino]benzoic acid methyl ester (2.0 g, 7.0 mmol) and pyridine (2 drops) in dicholoromethane (50 mL) at 0° C. After the reaction mixture is stirred at room temperature for 1 hour, it is poured into a solution of O-tetrahydropyranylhydroxylamine (8.2 g, 70 mmol) in dimethylformamide (50 mL). The dichloromethane is evaporated under reduced pressure, and the reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with 200 mL water and extracted with 300 mL ether. The organic layer is washed with water and brine, and then evaporated to an oil. The crude intermediate THP-protected hydroxylamine is taken up in methanol and acidified with concentrated HCl to pH=1. The reaction mixture is heated at reflux for 30 minutes, cooled, and quenched by the careful addition of saturated aqueous sodium bicarbonate. The methanol is evaporated under reduced pressure and the product is extracted into ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and evaporated to give the crude hydroxylamine as an oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=O)[CH:10]=[N:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.P(Cl)(Cl)([Cl:20])=O>>[Cl-:20].[C:1]1([N+:7]2[S:8][N:9]=[CH:10][C:11]=2[Cl:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnsn1-c1ccccc1
Solvent: CCOCC
Product: Clc1cns[n+]1-c1ccccc1
Product: [Cl-]

Procedure:
2-Phenyl-1,2,5-thiadiazole-3-one (3.1 g., 0.02 mole) was refluxed for 4 minutes in phosphorus oxychloride (20 ml.) and then cooled slowly. Ether (60-100 ml.) was added and the precipitate was filtered in a stream of nitrogen and washed well with anhydrous ether. The precipitate was then triturated with acetonitrile, refiltered and rewashed with acetonitrile and dried in a stream of nitrogen, m.p. (dec.) 110° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[N:16]1[CH:17]=[CH:18][C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:14][CH:15]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Clc1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccncc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A suspension of 274.5 g (2.0 moles) of anthranilic acid, 300 g (2.0 moles) of 4-chloropyridine hydrochloride and 180 g (2.19 moles) of anhydrous sodium acetate in 855 ml of glacial acetic acid was stirred at reflux for three hours. The mixture was cooled to room temperature and the precipitated solid was filtered. The product was washed with a small amount of cold acetic acid followed by cold ether. It was dried at 75° C., in vacuo to give 428 g (85.6%) of 2-(4-pyridinylamino)benzoic acid as the hydrochloride salt, m.p. 275°-280° C.(decompn.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:32]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([OH:72])=[O:71])=[C:68]([CH3:75])[CH:67]=1>C(Cl)Cl>[CH3:32][O:71][C:70](=[O:72])[C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:67][C:68]=1[CH3:75]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(N)ccc1C(=O)O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.30 mL, 1.72 mmol) and 4-amino-2-methyl-benzoic acid (Aldrich, 114 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 102 mg.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=O)[CH2:29]1)(=[O:27])[CH3:26].CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([NH:64][C:57]2[CH:56]=[C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]4[C:49]=3[CH:48]=[CH:47][NH:46]4)[CH:63]=[C:62]3[C:58]=2[CH:59]=[N:60][NH:61]3)=[O:36])[CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCOC(C(=O)O)C1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of HATU (0.107 g, 0.28 mmol) in dry DMF (3 ml) was added 4-acetyl-2-morpholinecarboxylic acid (0.05 g, 0.282 mmol). DIPEA (0.098 ml, 0.56 mmol) was added and the mixture was left to stand for 10 min. 6-(1H-indol-4-yl)-1H-indazol-4-amine (0.04 g, 0.14 mmol), dissolved in dry DMF (3 ml) was added and the solution was left to stand at room temperature for 20 hr. DMF was removed by blow down under a stream of nitrogen, then the residue was dissolved and purified by Mass Directed AutoPrep Method B. The solvent was removed in vacuo and product dried in a vacuum oven at 50° C. overnight to give the title compound as a brown oil (17 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11]Br.[OH-].[C:15]([OH:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([OH:25])=[O:24])([C:19]([OH:21])=[O:20])[OH:18]>C(#N)C>[C:15]([O-:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([O-:25])=[O:24])([C:19]([O-:21])=[O:20])[OH:18].[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11][N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11][N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11][N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1ccncc1
Reactant: CC(C)=CCBr
Agent: [OH-]
Solvent: CC#N
Product: CC(C)=CC[n+]1ccc(C)cc1
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
4-Picoline is reacted with 3-methyl-2-butenyl bromide in acetonitrile; the halide intermediate is converted to the hydroxide with Rexyn 201, and then reacted with citric acid.
Reaction SMILES: [CH2:1]([C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[C:12](=[O:16])[NH:13]2)=[CH:9][C:8]=1[N+:23]([O-])=O)=O)[CH2:2][CH3:3].[H][H]>[Pd].C(O)C>[CH2:1]([C:4]1[NH:6][C:7]2[CH:15]=[C:14]3[NH:13][C:12](=[O:16])[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[C:10]3=[CH:9][C:8]=2[N:23]=1)[CH2:2][CH3:3]
Reactant: CCCC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(C)(C(=O)OCC)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Analogously to Example 5, 1.40 g. (4.0 mmole) 6-propylcarbonylamino-5-nitro-3-ethoxycarbonyl-3-methylindolin-2-one is suspended in 140 ml. ethanol and hydrogenated in the presence of 0.1 g. 10% palladium on charcoal at normal pressure and ambient temperature. After 270 ml. of hydrogen have been taken up, the catalyst is filtered off with suction and the filtrate is evaporated to dryness. The residue is stirred for 1 hour at 60° C. in 10 ml. glacial acetic acid, the glacial acetic acid is distilled off and the residue is taken up in water and neutralised with 2N aqueous sodium hydroxide solution. The mixture is shaken out three times with dichloromethane and the combined dichloromethane phases are dried over anhydrous sodium sulphate, filtered and the filtrate evaporated to dryness. After crystallisation of the residue from isopropanol, there is obtained 0.4 g. (33% of theory) of the title compound; m.p. 258°-261° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([NH2:23])[CH:19]=[CH:20][C:21]=1[F:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.FC(F)(F)C(O)=O>[F:15][C:16]1[CH:17]=[C:18]([NH:23][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(NC2CCNCC2)cc1F

Procedure:
Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol), 3,4-difluoro-phenylamine (1.16 g, 9.0 mmol) and sodium triacetoxyborohydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.26 g, 66%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(O)(O[CH2:19][CH2:20][NH2:21])(=O)=O>O.CO.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:11][CH2:19][CH2:20][NH:21][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(COC[C@H]2CNCCO2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition the reaction mixture was stirred at 40° C. for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol) then toluene (70 mL) and stirred at 65° C. overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (˜14 g), which was used without purification. MS m/z 208 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:24]=[C:25]([NH2:27])[S:26][CH:2]=3)=[C:6]([CH3:23])[CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: NC(N)=S
Reactant: COc1ccc(S(=O)(=O)c2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)c2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 64.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylsulfonyl)-2,6 dimethylphenyl)ethanone (1.33 g, 3.4 mmol, 1.0 equiv) and thiourea (254.8 mg, 3.4 mmol, 1.0 equiv) in EtOH (5.0 mL) was heated at reflux for 1.0 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO 3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The resultant solids were washed with hexanes to give 4-(4-(4-methoxyphenylsulfonyl)-2,6-dimethylphenyl)thiazol-2-amine (839.2 mg, 2.2 mmol) as yellow solids in 65% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.89 (d, J=8.9 Hz, 2 H), 7.61 (s, 2 H), 7.13 (d, J=8.9 Hz, 2 H), 6.95 (brs, 2 H), 6.43 (s, 1 H), 3.83 (s, 3 H), 2.16 (s, 6 H); ESI-MS: m/z 375.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=[O:13].[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].C(O)C>CC(C)=O>[Cl:1][C:2]1[CH:9]([C:8]([Cl:11])([O:13][CH3:12])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)[O:10][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COC1C(Cl)=CC(C=O)=CC1(Cl)OC
Yield: 53.4 %

Procedure:
The compound was prepared according to general procedure E with 3,5-dichloro-4-hydroxybenzaldehyde (1.6 mmol) in dry acetone (15 ml), anhydrous K2CO3 (2.1 mmol), and ethylbromoacetate (2.4 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 354 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 264 mg of purified compound were obtained (60% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.32 (t, J=7.2 Hz, 3H), 4.30 (q, J=7.2 Hz, 2H), 4.74 (s, 2H), 7.82 (s, 2H), 9.67 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.0, 62.3, 70.8, 131.2, 131.4, 135.4, 156.4, 168.4, 190.5
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2.[N+:22]([O-])([O:24]C(C)C)=[O:23]>>[Br:6][CH2:7][C:8]1[CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2
Reactant: CC(C)O[N+](=O)[O-]
Reactant: COc1nc2cccc(CBr)c2nc1OC
Agent: O=S(=O)(O)O
Product: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
25 ml of sulfuric acid are cooled to 0° C. and 9.5 g (33.55 mmol) of 5-bromomethyl-2,3-dimethoxyquinoxaline are then added. After a further 10 minutes, 3.39 ml (1 eq.) of isopropyl nitrate are added and the mixture is stirred at 0° C. for 1 hour. The mixture is poured onto ice, and the solid is filtered off and washed with water. The title compound is obtained as a beige solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:33].Cl.[S:35]1[CH:39]=[C:38]([CH2:40][C@@H:41]([C:43]([N:45]2[CH2:52][CH2:51][CH2:50][C@H:46]2[C:47]([NH2:49])=[O:48])=[O:44])[NH2:42])[N:37]=[CH:36]1.C(N(CC)CC)C>CN(C)C=O>[ClH:33].[ClH:33].[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:42][C@H:41]([C:43]([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([NH2:49])=[O:48])=[O:44])[CH2:40][C:38]1[N:37]=[CH:36][S:35][CH:39]=1)=[O:9]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 2 h

Procedure:
L-Pyroglutamic acid (1.76 g, 13.64 mmol) and N-hydroxysuccinimide (1.73 g, 15 mmol) were dissolved in N,N-dimethylformamide (50 ml). To this solution was added the solution of DCC (3.09 g, 15 mmol) in N,N-dimethylformamide (10 ml) under ice-cooling and the resulting mixture was stirred for 2 h at, the same temperature. 3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (4) (6.67 g, 15 mmol) and triethylamine (4.6 ml. 33 mmol) were added successively to the solution and the reaction mixture was stirred overnight. After the precipitation which appeared was filtered off, to the filtrate was added sodium hydrogencarbonate aq. to adjust pH 8. The reaction mixture was subjected to gel filtration column chromatography (MCI gel CHP-20P, 200 ml, aq. MeOH) to give the compound (I-1) (2.54 g, 49%).
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2].C([Li])CCC.[CH2:29]=[O:30]>CCOCC.CCCCCC>[CH:21]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[C:5]1([CH2:29][OH:30])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:23])[CH3:22]
Reactant: CC(C)[Si](C(C)C)(C(C)C)C1c2ccccc2-c2ccccc21
Reactant: C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)C1(CO)c2ccccc2-c2ccccc21
Yield: 57.7 %

Procedure:
To a solution of 1.0 g of 9-triisopropylsilylfluorene in 10 mL of dry ether and 30 mL of dry hexane was added dropwise 2.5 mL of 1.5M n-butyllithium. The mixture was refluxed for 15 hours and cooled in an ice bath. Gaseous formaldehyde, generated by heating dried paraformaldehyde at 170° C., was passed through a 8-mm tube into the reaction mixture with the aid of a slow stream of nitrogen until the deep red color had faded to pale yellow (ca. 5 min). The mixture was quenched immediately with 40 mL of half sat'd NH4Cl and washed with brine (10 mL) and water (20 mL). The pooled aqueous layer was extracted with ether (2×20 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to give an oil which was chromatographed on silica gel (230-400 mesh, 2×40-cm packed column) with an eluant consisting of Skelly B--ether (3:1), to afford 0.63 g (57.7%) of the alcohol as a white solid. Recrystallization from Skelly F gave 0.38 g (34.8%) of the pure 9-triisopropylsilyl-9-fluorenemethanol as colorless crystals m.p. 106°-107.5° C.; IR (KBr): 3505, 3405 cm-1 (OH); 1H NMR (CDCl3): δ 0.83 (d, 18H, Si-C-Me2), 1.20-1.42 (hept, 3H, C--S--CH), 4.71 (s, 2H, CH2), 7.20-7.95 (m, 8H, aryl).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:2].[O:13]([C:15]#[N:16])[Na]>CC(O)=O>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)[C:15]([NH2:16])=[O:13])[CH3:2]
Reactant: N#CO[Na]
Reactant: CCNc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: CCN(C(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of N-ethyl-3,4-(methylenedioxy)aniline (8.1 g) in AcOH (100 mL) was added NaOCN (3.0 g) at 10° C. The cold bath was removed and the mixture was stirred at rt for 24 h. The solvent was removed in vacuo and the resulting residue was neutralized with 2 N NaOH. The mixture was extracted with chloroform (3×50 mL). The combined organic phase was washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was recrystallized from chloroform/hexane to yield the title compound (5.7 g, 56%). 1NMR (CDCl3): 6.78-6.72 (m, 3H), 6.02 (s, 2H), 4.38 (br s, 2H), 3.66 (q, J=7.0, 2H), 1.11 (t, J=7.0, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH3:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>CCOCC>[Cl-:1].[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH2:4][CH2:3][CH2:2][C:25]2[CH:24]=[NH+:23][CH:22]=[CH:21][C:20]=2[C:17]2[S:18][CH:19]=[C:15]([CH3:14])[N:16]=2)=[O:6])=[CH:8][CH:9]=1
Reactant: Cc1csc(-c2ccncc2)n1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Solvent: CCOCC
Product: Cc1csc(-c2cc[nH+]cc2CCCC(=O)c2ccc(F)cc2)n1
Product: [Cl-]

Procedure:
A 1.0 g. portion of γ-chloro-p-fluorobutyrophenone and 0.9 g. of 4-(4-methyl-2-thiazolyl)pyridine are heated in an oil bath at 95°-100° C. overnight. Ether is added and the mixture is filtered. The solid is recrystallized from acetonitrile. This solid is recrystallized from a mixture of alcohol and ether, m.p. 226°-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18]>CC(C)=O>[CH3:15][O:16][C:17]([NH:19][C:20](=[S:21])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: COCSc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1

Procedure:
1 G. of 1-amino-2-nitro-4-methoxymethylthiobenzene, prepared according to Example VIII, in 50 ml. acetone is treated with 3 g. methoxy carbonyl isothiocyanate at room temperature for several days. The solution is concentrated and the residue triturated with methanol and recrystallized from acetone to afford 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-methoxymethylthiobenzene. This latter compound is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform, washed with water, then the solvent is evaporated to afford 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-methoxymethylthiobenzene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4](Cl)[CH:3]=1.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.O>CN(C)C=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH3:16])[CH:3]=1
Reactant: Cc1ncc[nH]1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 30 h
Yield: 61.9 %

Procedure:
To a solution of 20.0 g (~83 mmol) 4-amino-2-chloro-5-nitrobenzotrifluoride in 50 ml dry N,N-dimethylformamide was added 30 g (~370 mmol) 2-methylimidazole, and stirring was continued at 180° C. for 30 h. The reaction mixture was poured into 400 ml water to give the title compound (14.7 g; 62%). M.p. 222°-225° C.