Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=CC=CC=3)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O>[CH:13]1[C:14]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:12]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
534 gms of anthracene and 326 ml of concentrated sulfuric acid were added to a 2 liter round bottom flask fitted with a stirrer. The contents of the flask were heated to 140° C. for 90 minutes with continuous stirring. 1 ml of the mass was placed in a beaker and 3 ml water was added with shaking. It was observed to form a clear solution without a free naphthalene smell, confirming the completion of sulfonation. The sulfonated mass was transferred to a reactor fitted with a thermometer, stirrer and a dropping funnel. The mass was stirred continuously for a period of 10 min. while maintaining the temperature at 80° C. A mixture of 5.4 gms oxalic acid, 4.14 gms salicylic acid and 10 gms phthalic acid dissolved in 50 ml water was added to the above sulfonated mass and stirring was continued at 80° C. 1.5 gms of polymethacrylic acid was added to the sulphonic acid mixture and the mixture was heated to 80° C. for 1 hour. A small portion of the reaction mixture was transferred to a beaker and 2 ml water was added to the mass. The pH of the solution in the beaker was adjusted to 3 and a clear solution was obtained, indicating the completion of the reaction. About 540 ml of water was added to the mass and transferred to a bucket after cooling the reaction mass to room temperature. The pH of the mass was raised to 3 by adding a solution of 220 gms of sodium hydroxide in 500 ml water, followed by the addition of an aqueous solution of 200 gms of sodium carbonate in 400 ml water. The slurry was aerated for 45 minutes conventionally and filtered using a cloth of pore size 5–10μ. The filtrate was spray dried at 260° C. and the white powder obtained was stored in a plastic container. The prepared syntan was added to delimed sheepskins at 1.0% w/w (weight of syntan to weight of pelt) along with 5% basic chrominum sulfate (BCS) w/w (weight of BCS to weight of pelt) at a float of 20% v/w (volume of water to weight of pelt) in a small tanning drum. The drum was run for 1 hr and 80% water v/w (volume of water to weight of pelt) was added. The drum was run for another 1 hr and penetration of the tanning chemicals into the skins was assessed by checking uniform blue color along a cut section. The pH of the solution and the cut section was found to be 4.4. The bath was drained and the wet blue leathers were piled. On the next day, the leathers were post-tanned using a conventional garment leather processing recipe. The chromium exhaustion of the spent tan liquor was found to be 95%. The fullness of the crust leathers was found to be superior to that of conventional chrome tanned leathers.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[C:4]([I:25])[C:3]=1[OH:26].[CH3:27]I>>[CH3:27][O:26][C:3]1[C:2]([I:1])=[CH:7][C:6]([C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][C:4]=1[I:25]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1
Reactant: CI
Product: COc1c(I)cc(C(=O)NCCCCCCCCc2ccccc2)cc1I

Procedure:
The title compound was prepared as a solid (0.691 g, 94%) from 2,6-diiodo-4-(8-phenyl-octylcarbamoyl)phenol using methyl iodide and a procedure similar to step 4 of Example 93; 1H NMR (DMSO-d6) δ1.19-1.34 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.59 (m, 2H), 3.21 (dd, J=6.4, 14.1 Hz, 2H), 3.78 (s, 3H), 7.10-7.21 (m, 3H), 7.21-7.31 (m 2H), 8.28 (s, 2H), 8.53 (t, J=5.6 Hz, 1H); mass spectrum [(+) ESI], m/z 592 (M+H)+, 614 (M+Na)+.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])C(Cl)=O.[Cl:7][C:8]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].CN(C)C=O>O1CCCC1>[C:1]([Cl:6])([Cl:7])=[O:5].[Cl:7][C:8]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Agent: Cn1cc(-c2ccc(C(=O)O)c(Cl)c2)cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)Cl
Temperature: 35 °C

Procedure:
Oxalyl chloride (0.49 ml) was added to a solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid (0.41 g) from Example 114 and dimethylformamide (0.012 ml) in anhydrous tetrahydrofuran (20 ml). The reaction was heated at 35° C. for ten minutes. The resulting solution was evaporated in vacuo to dryness to yield the crude 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid carbonyl chloride. Following co-evaporation with anhydrous methylene chloride, the acid chloride was dissolved in dichloromethane (20 ml) followed by the addition of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.888 g) and diisopropylethylamine (1.06 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by 1N hydrochloric acid. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The dichloromethane was filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography on silica pressure eluting with hexane/ethyl acetate (2/1) to afford 1.4 g of the title compound as a colorless solid m.p. 105-109° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([Br:13])[CH:9]=[CH:10][C:11]=1[F:12]>OS(O)(=O)=O>[Br:13][C:8]1[CH:7]=[C:6]([F:5])[C:11]([F:12])=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: Fc1ccc(Br)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)cc1Br
Temperature: 0 °C

Procedure:
Dissolve fuming nitric acid (24 mL) in concentrated H2SO4 in a round bottom flask. Add 3,4-difluorobromobenzene (20 g, 104 mmol) dropwise via pipette with vigorous stirring. After addition, stir the reaction at room temperature for 2 hours, pour the reaction into ice water and extract with Et2O (2×250 mL). Collect and combine the organic layers, dry over MgSO4, filter, and remove the solvent to give 1-bromo-4,5-difluoro-2-nitrobenzene as a light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[C:8]([C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:18]([C:16]1[CH:15]=[C:14]([CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:17]=1)[O:22][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: N#CCCCCBr
Product: CC(C)(C)c1cc(OCCCCC#N)cc(C(C)(C)C)c1
Yield: 61.9 %

Procedure:
Using the method of Example 1, 17.8 g (0.11 mole) of 5-bromo-pentanenitrile was reacted with 20.6 g (0.10 mole) of 3,5-di-t-butylphenol to give 17.8 g of white crystalline 5-(3,5-di-t-butylphenoxy)pentanenitrile, m.p. 61°-64° C. Analysis: Calculated for: C19H29NO: %C, 79.4; , %H, 10.2; %N, 4.9; Found: %C, 79.0; %H, 10.3; %N, 5.1.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][C@H:5]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]12[CH3:4])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH3:8][C@@H:7]1[CH2:6][C@H:5]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]2([CH3:4])[C:2]1=[O:1])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)C1=O
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
A solution of 4.58 g of 17β-hydroxy-16α-methyl-4,9(10)-estradien-3-one (prepared according to 1[e]) in 200 ml of acetone is combined under ice water cooling dropwise with 8.5 ml of Jones reagent (J. Chem. Soc. [London] 1946, 39). The mixture is stirred, after this addition, at room temperature for 20 minutes, thereafter poured into water, and extracted with methylene chloride. The methylene chloride extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. Crystallization from ethyl acetate/diisopropyl ether yields 4.3 g of 16α-methyl-4,9(10)-estradiene-3,17-dione, m.p. 140°-143° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[N:40]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[C:31]1[CH:30]=[C:29]([C:28]2[CH2:27][C:26](=[O:42])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (80 mg).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:18])[C:15]([CH3:17])=[CH2:16])=[CH:10][CH:9]=1.[CH2:19](Cl)[CH:20]=[CH:21][CH3:22]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:19]([O:18][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)[C:15]([CH3:17])=[CH2:16])[CH:20]=[CH:21][CH3:22]
Reactant: CC=CCCl
Reactant: C=C(C)C(O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: C=C(C)C(OCC=CC)c1ccc(C)cc1
Temperature: 5 °C
Yield: 93 %

Procedure:
Solid potassium tert-butylate (47 g, 0.411 mol) was added portion-wise (ca 15 min) to a solution of 1-(4-methylphenyl)-2-methyl-2-propen-1-ol (96% pure, 46.27 g, 0.274 mol) in dry THF (500 ml) at room temperature under nitrogen (exothermic to 30° C.). After 1 more hour at room temperature, the reaction was cooled to 5° C. and tetra butyl ammonium iodide (5.2 g, 0.014 mol) was added followed by crotyl chloride (74.4 g, 0.822 mol) drop-wise. The reaction was warmed up to room temperature overnight and poured onto water (800 ml). The reaction was extracted twice with ethyl acetate. Each organic phase was washed with water and brine. Combined extracts were dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by distillation under vacuum through a 20-cm Widmer column A 3:1 mixture of E/Z isomers was obtained (96% pure, 57.58 g, yield=93%). B.P.=74° C./0.005 mbar
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH:38]3[C:42]([O:44]C)=[O:43])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H: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])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH:38]3[C:42]([OH:44])=[O:43])=[CH:35][CH:36]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCN1c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCCC3C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylate (61.2 mg, 0.091.4 mmol, example 11) in THF (4.00 ml) was added a solution of LITHIUM HYDROXIDE monohydrate (22.6 mg, 0.539 mmol) in Water (2.00 ml) dropwise. The reaction mixture was stirred at rt for 2 hrs before it was neutralized with 1N HCl. it was then diluted with EtOAc, washed with water (2×10 mL), brine (2×10 mL), dried and evaporated to give 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylic acid as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 655. found: 655.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:4]=[CH:5][C:6]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11]O.C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[F:26][CH2:11][CH2:10][CH2:9][C:8]#[C:7][C:6]1[CH:5]=[CH:4][N:3]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:2]2[N:1]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCC#Cc1ccn2c(n1)nc1ccccc12
Solvent: ClCCl
Product: FCCCC#Cc1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To 5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pent-4-yn-1-ol (20 mg, 0.08 mmol) in 1 mL dry DCM at 0° C. was added (Diethylamino)sulfur trifluoride (64 mg, 0.4 mmol) dropwise. The reaction was warmed to rt and stirred for 1 h and quenched onto a mixture of ice (10 g) in saturated Na2CO3 (10 mL). The mixture was extracted with EtOAc (2×10 mL) and the organic phase was dried over MgSO4 and concentrated. The residue was purified by silica chromatography (EtOAc in DCM, 5% to 50%) to afford 2-(5-fluoropent-1-yn-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine as a yellow oil (3 mg, 15%). 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J=6.8 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.58 (m, 1H), 7.43 (m, 1H), 6.93 (d, J=7.2 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.57 (t, J=5.6 Hz, 1H), 2.70 (t, J=5.6 Hz, 2H), 2.14-2.00 (m, 2H); MS (ESI) m/z [M+H]+254.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: COCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOCCOS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
A solution of 8.16 g (0.040M) of tetraethylene glycol monomethyl ether and 5.0 g (0.044M) of methanesulfonyl chloride in 100 ml of methylene chloride was stirred at 0° C. while 5.7 g (0.044M) of diisopropylethylamine was added dropwise so the temperature remained below 5° C. Stirring was continued at 0° C. for 20 minutes and the temperature was allowed to rise to room temperature over 2 hours. The solution was washed twice with an equal volume of water. It was then dried and concentrated to an oil, yielding 11 g (96%).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Br[C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Br)ccc1F
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1F
Yield: 14.4 %

Procedure:
The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (165 mg, 0.55 mmol), methyl 5-bromo-2-fluorobenzoate (128 mg, 0.55 mmol), palladium acetate (12.3 mg, 0.05 mmol), BINAP (68.3 mg, 0.11 mmol) and cesium carbonate (536 mg, 1.65 mmol), to obtain 33 mg of the title compound as a yellow oily substance (14%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([Br:23])=[CH:18][N:17]=2)(O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]=[C:11]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([Br:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1C1(O)CCCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1cc(Br)cnc1C1=CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (1.90 g) in pyridine (20 ml) was added thionyl chloride (1.47 g) under ice-cooling, and stirred at the same temperature for 1 hour. After completion of the reaction, saturated sodium bicarbonate water was added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give a mixture (1.02 g) of 4-(5-bromo-3-methylpyridin-2-yl)-2,3,6,7-tetrahydroazepine-1-carboxylic acid tert-butyl ester and 4-(5-bromo-3-methylpyridin-2-yl)-2,3,4,7-tetrahydroazepine-1-carboxylic acid tert-butyl ester as a colorless clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[C:20]([OH:25])[CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[C:20]([O:25][CH2:32][CH3:33])[CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2c(O)cccc2N1C1CCN(Cc2ccccc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc2c1CCC(=O)N2C1CCN(Cc2ccccc2)CC1
Reaction time: 6.5 h

Procedure:
1-(1-Benzyl-4-piperidinyl)-5-hydroxy-3,4-dihydrocarbostyril (500 mg) is dissolved in acetone (20 ml) and thereto are added potassium carbonate (246 mg) and ethyl iodide (0.18 ml). The mixture is refluxed with stirring for 6.5 hours. After the reaction, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. Dichloromethane is added to the resulting residue and the mixture is washed with 5% aqueous sodium hydroxide solution and then dried with magnesium sulfate. The solvent is evaporated and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1) to give 1-(1-benzyl-4-piperidinyl)-5-ethoxy-3,4-dihydrocarbostyril (0.27 g).
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.[ClH:21]>>[ClH:21].[OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OCC(O)CNC(C)C)cc1
Agent: Cl
Product: CC(C)NCC(O)COc1ccc(CC(=O)O)cc1

Procedure:
A solution of methyl 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenylacetate (563 mg, 2.00 mmol) in 6M hydrochloric acid (15 ml) was heated at 100° C. for 4 hours. The reaction mixture was concentrated (rotavapor) and the residue was taken up in water and lyophilised. 1H and 13C NMR spectra were in accordance with the strucure and MALDI mass spectrometry gave a M+H at 268 as expected.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)O)[N:8]([CH:25]([CH3:27])[CH3:26])[C:7]=1[Br:28])=[O:5])[CH3:2].[NH2:29][C:30]1[CH:31]=[C:32]([Cl:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([CH:16]([NH:29][C:30]2[CH:31]=[C:32]([Cl:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:8]([CH:25]([CH3:27])[CH3:26])[C:7]=1[Br:28])=[O:5])[CH3:2]
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1c(C(=O)OCC)c(C(O)c2ccc(Cl)cc2)n(C(C)C)c1Br
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: CCOC(=O)c1c(C(=O)OCC)c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)n(C(C)C)c1Br

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3,4-dicarboxylic acid diethyl ester (Step BM2) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a blue foam. tR: 1.28 min (HPLC 3); ESI-MS: tR=1.25 min, [M+H]+ 612/614/616 (LC-MS 1); TLC: Rf=0.17 (2:1 EtOAc/heptanes).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[N:12][C:9]=3[C:10]=2[N:11]=1.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]3[CH:15]=[CH:14][CH:13]=[N:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Oc1nc2ccc3cccnc3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 500 mg (2,35 mmol) 2,3-dihydroxy-pyrido(2,3-f)quinoxaline in 25 ml sulfuric acid (95-97%) was ice-cooled, and 238 mg (2,35 mmol) potassium nitrate was added. Stirring was continued at 0° C. for 1/2 h and then at 25° C. for 4 h. The reaction mixture was poured into 100 ml ice-water. The precipitate was filtered off and washed with water. The crude product was recrystallized (dimethyl formamide - water) to give 425 mg (70%) of pure 2,3-dihydroxy-6-nitropyrido-(2,3-f)quinoxaline, m.p. >300° C.1H NMR (DMSO-d6): 13,7 (2H,broad s), 9,0 (1H,d), 8,8 (1H,d), 7,86 (1H,s), 7,6 (1H, double d).
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10][S:31]([CH3:30])(=[O:33])=[O:32])[N:6]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-hydroxypropyl)-1-triphenylmethylimidazole in pyridine was treated with methanesulphonyl chloride. Work-up as for the starting material of Example 9 gave 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.03 (m, 2H); 2.52 (t, 2H); 2.94 (s, 3H); 4.21 (t, 2H); 6.27 (s, 1H); 7.0-7.5 (m, 15H).