Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 4 h
Yield: 18.6 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (200 mg), piperazine (250 mg) in anhydrous DMSO (2 ml) was stirred at 70° to 80° C. for 4 hours. After the reacting mixture was concentrated under reduced pressure, to the resulting residue was added methanol and the resulting precipitate was filtered off. After the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting chloroform-methanol (20:1) chloroform-methanol-concentrated aqueous ammonia (10:10:1) and further purified by preparative thin layer chromatography eluting chloroform-methanol (20:1)→chloroform methanol-concentrated aqueous ammonia (10:10:1→10:10:3) to give the title compound (46 mg) as redish powder, mp 300° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C(O)C.[C:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: Nc1cccc2ccccc12
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of (2S,4S)-2-formyl4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound(1)) ( 711 mg), ethanol(25 ml), 1-naphthylamine(333 mg) and 3A molecular sieves(4.5 g.) was stirred under an argon atmosphere at ambient temperature for 6 hours. Acetic acid (0.4 ml) was added followed by sodium cyanoborohydride(l 70 mg). The mixture was then stirred for a further 20 hours when the sieves were removed by filtration. The filtrate was concentrated under reduced pressure and the residue applied to a silica column and eluted with ethyl acetate/hexane(20:80) to give (2S,4S)-1-allyloxycarbonyl-2[(naphthalen-1-ylamino )-methyl]-4-BOCsulfanylpyrrolidine (compound(31)) as a clear oil (560 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].O>CO>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
In an atmosphere of argon, 25 g (145.3 mmols) of 4-bromoaniline was dissolved in 50 ml of methanol, and the solution obtained was cooled to 0° C., and thereafter 27.4 ml (2.0-fold equivalent weight) of acetic anhydride was dropwise added thereto. Thereafter, the solution obtained was restored to room temperature, and stirred for 20 minutes. To the reaction solution obtained, 250 ml of water was added, and a white solid deposited was collected by filtration, which was then washed with water, followed by natural drying to obtain 30.8 g of N-acetyl-4-bromoaniline (yield: 99.1%; a while solid).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][O:22]CC3C=CC=CC=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:31]
Reactant: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCO
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of 9-(2-benzyloxy-ethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (36) (600 mg, 1.4 mmol) in methanol (40 mL) was added a slurry of Pd/C (100 mg) in methanol (5 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo to afford 460 mg (80%) of 6-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (37) as a yellow oil which was used in the next step without purification. The structure was confirmed by 1H NMR (300 MHz, MeOD-d3) δH 1.18 (3H, t, J==9 Hz, N(CH2CH3)2), 1.35 (3H, t, J=9 Hz, N(CH2CH3)2), 1.80-2.20 (4H, m, 2- and 3-CH2), 2.69-3.88 (2H, m, 1-CH2), 3.40-3.86 (6H, m, N(CH2CH3)2 and NCH2CH2OH), 4.03-4.22 (3H, m, NCH2CH2OH and 4-CH), 6.75-6.95 (2H, m, NCCHCHCFCH), and 7.05-7.15 (1H, m, NCCHCHCFCH.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1

Procedure:
To a solution of 3-nitrobenzylbromide (3 g, 13.9 mmol) in anhydrous THF (30 ml) was added a solution of pyrrolidine (2.3 ml, 27.8 mmol) in anhydrous THF (10 ml) dropwise with stirring. Following the addition the mixture was stirred at ambient temperature overnight. The reaction mixture was filtered, The filter cake was washed with a small volume of anhydrous THF and the filtrate was concentrated to leave the intermediate 1-(3-nitrobenzyl)pyrrolidine as an oil. This oil was dissolved in methanol (50 ml) and three equivalents of both ammonium chloride and sodium sulfide nonahydrate were added. The mixture was heated to reflux for 2 hours. After cooling the mixture was filtered. The filtercake was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and dried over sodium sulfate. Filtration and evaporation of solvent left 2i quantitatively as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27]([N+:34]([O-:36])=[O:35])[C:5]=1[C:6]([NH:8][NH:9][C:10](=[O:26])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]=1[N+:23]([O-:25])=[O:24])=O)([O-:3])=[O:2].ClCCCl.P(Cl)(Cl)(Cl)(Cl)Cl>CO>[C:5]1([C:6]2[O:26][C:10]([C:11]3[C:12]([N+:23]([O-:25])=[O:24])=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[CH:15][C:16]=3[N+:17]([O-:19])=[O:18])=[N:9][N:8]=2)[C:27]([N+:34]([O-:36])=[O:35])=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(NNC(=O)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])o2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.6 %

Procedure:
To 7.4 g (0.0145 mol) of N,N'-bis(2,4,6-trinitrobenzoyl)hydrazine and 65 ml of 1,2-dichloroethane stirred in a 200 ml round bottom flask was added 7.4 g (0.0355 mol) of phosphorus pentachloride. The mixture was heated to reflux temperature in an oil bath and was held at this temperature for 2.5 hrs. The mixture was cooled to room temperature and the insoluble material (3.2 g of crude 2,5-dipicryl-1,3,4-oxadiazole, mp 318° C. (dec), was removed by filtration. The crude oxadiazole was dissolved in boiling acetone (300 ml), the solution was filtered and the filtrate was concentrated by distillation until much of the acetone had been removed and an appreciable amount of crystals had formed. Methanol was slowly added with continued distillation until the distillate temperature approached 65° C. The mixture was cooled to room temperature and filtered to give 2.9 g of pure 2,5-dipicryl1,3,4-oxadiazole, mp 335° C. (vigorous decomposition). NMR (DMSO-d6):9.52 (s).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27]([N+:34]([O-:36])=[O:35])[C:5]=1[C:6]([NH:8][NH:9][C:10](=[O:26])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]=1[N+:23]([O-:25])=[O:24])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl>>[C:5]1([C:6]2[O:26][C:10]([C:11]3[C:12]([N+:23]([O-:25])=[O:24])=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[CH:15][C:16]=3[N+:17]([O-:19])=[O:18])=[N:9][N:8]=2)[C:27]([N+:34]([O-:36])=[O:35])=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(NNC(=O)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])o2)c([N+](=O)[O-])c1

Procedure:
The present process uses the reaction of N,N'-bis(2,4,6-trinitrobenzoyl)hydrazine (I) with phosphorus pentachloride to produce 2,5-dipicryl-1,3,4-oxadiazole (II), ##STR1##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1Cl
Product: O=C(Cl)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 30.0 gm (0.176 mole) of o-chlorophenylacetic acid and 40.0 mL of thionyl chloride was stirred at ambient temperature for 18 hours. The volatiles were then removed in vacuo to give 32.76 gm (99.0 %) of o-chlorophenylacetyl chloride as a transparent, pale yellow, mobile liquid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8g, 0.013 mol) NaHCO3 (1.1 g), several crystal of KI, 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 5.7 g of a thick yellow oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid. The solid was recrystallized from ethyl alcohol to afford 2.7 g (50%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl[propoxy]-3-hydroxyphenyl]ethanone as a pale Yellow solid, m.p.=122°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-nitrophenol (5.2 g, 23.8 mmol) in 2-butanone (100 ml) was added potassium carbonate (9.0 g, 65.1 mmol) followed by benzyl bromide (2.6 ml, 21.8 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux overnight. The solids were then removed by filtration, washing with acetone, and the filtrate reduced in vacuo. The residue was dissolved in ethyl acetate and washed with 2M aqueous sodium hydroxide solution (×3) and then brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and reduced in vacuo to afford the title product. 1H-NMR (d6-DMSO) δ 8.14 (1H, d, J 3.5 Hz), 7.84 (1H, dd, J 11.0, 3.5 Hz), 7.45-7.39 (5H, m), 7.37-7.33 (2H, m), 5.32 (2H, s).
Reaction SMILES: O[Li].O.O.C([O:9][C:10]([C:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2([C:33]([O:35]CCCC)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])CCC>CCO>[C:33]([C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:40])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]2([C:10]([OH:11])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:29][CH2:30][CH2:31][CH2:32]1)([OH:35])=[O:34]
Reactant: CCCCOC(=O)C1(CCCCCC(=O)CCCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
LiOH.H2O (7.83 g, 187 mmol) and H2O (100 mL) were added to a solution of butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate (21.03 g, 90% pure by 1H NMR, 37.3 mmol) in EtOH (300 mL) and the resulting mixture was stirred at reflux temperature for 2 d, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (100 mL) was added and the resulting mixture was extracted with Et2O (100 mL), acidified with conc aqueous HCl (25 mL) and extracted with Et2O (3×150 mL). The latter organic layers were combined, dried (Na2SO4; To avoid loss of material, a minimal amount of Na2SO4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo. The remaining residue was purified by recrystallization from a mixture of iPr2O and heptane to give 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (12.15 g, 83%) as white granules. mp=78-85° C. 1H NMR (CDCl3): δ=2.37 (t, J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m, 8H). 13C NMR (CDCl3): δ=211.5, 184.8 (2×), 54.0 (2×), 42.4 (2×), 38.9 (2×), 35.9 (4×), 29.2 (2×), 25.5 (2×), 24.9 (4×), 23.5 (2×). Anal. calcd for C23H38O5: C, 70.02; H, 9.71. found: C, 70.37; H, 9.72.
Reaction SMILES: O=O.[CH3:3][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:5]>CO>[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C@H:9]([CH2:11][CH2:12][OH:13])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: CO
Product: CC(C)=CCC[C@@H](C)CCO
Yield: 97.6 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 pm) with 27.0 g (175.0 mmol) of geraniol, 36 ml of methanol and 100 ml of catalyst solution prepared according to Example 6. The hydrogenation was carried out at 20° C., a constant pressure of 60 bar of H2 and while stirring intensively. The conversion was 100% after 22 hours. The pale yellow hydrogenation solution was flushed from the autoclave and evaporated on a rotary evaporator at 60°/17 mbar. The residue was distilled at 65°/0.01 mbar. 26.7 g (99.0%) of (R)-citronellol were obtained as a colourless oil, with an enantiomeric purity of 74.3% e.e.. The determination of the e.e. value was effected by GC analysis of the diastereomeric ester prepared with Trolox™ methyl ether.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: C1CN2CCC(CC2)N1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g, 113 mmol) in absolute dioxane (130 ml), LiAlH4 (4.9 g, 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperatre. To this reaction mixture, water (5 ml in 10 ml of dioxane) was added, by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g, 78%) as colourless hygroscopic material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:30])C=C>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:30])=[CH:6][CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(CCCO)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COC(=O)c1ccc(CCCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(#N)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:18]1[CH2:17][CH2:16][C:15]2([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14]2)[CH2:20][CH2:19]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.000172 mol) was added to tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (18.5 mg, 0.0000668 mol) in acetonitrile (1.0 mL, 0.019 mol), followed by methanesulfonyl chloride (10.0 μL, 0.000129 mol). After stirring for 1 h the solvent was evaporated, and the residue was dried under high vacuum and was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5].[CH2:14]1[CH2:19][O:18][CH:17]=[CH:16][CH2:15]1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:19][O:18]2)[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: COCc1cc(O)cc(O)c1C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Yield: 86.8 %

Procedure:
A solution of 2,4-dihydroxy-6-methoxymethylbenzaldehyde (4.08 g, 22.4 mmol) in dichloromethane (100 mL) was treated with PPTS (100 mg) and DHP (4.06 mL, 44.8 mmol) at room temperature overnight. The reaction was concentrated to dryness. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=3:1) to afford the title compound (5.18 g, 87%). 1H NMR (300 MHz, CD3OD) δ 12.34 (s, 1H), 10.12 (s, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 5.58 (m, 1H), 4.63 (s, 2H), 3.84-3.81 (m, 1H), 3.66-3.62 (m, 1H), 3.40 (s, 3H), 1.95-1.86 (m, 2H), 1.75-1.62 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].CCOCC>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH3:19]
Reactant: CCI
Reactant: OCCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCO
Temperature: 42.5 °C
Reaction time: 12 h

Procedure:
To a suspension of 1.00 g (7.24 mmol) of 2-hydroxyphenethyl alcohol and 1.35 g (8.68 mmol) of potassium carbonate in 15 ml of N,N-dimethylformamide was added 2.00 g (14.48 mmol) of iodoethane at 0° C. The reaction mixture was stirred at 40-45° C. for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml ×3), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 9:1 hexane/ethyl acetate to afford the 2-ethoxyphenethyl alcohol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14])=[O:23]
Reactant: O=C=Nc1ccccc1Br
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 4 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 73%) as a pale brown powder. 1H-NMR (CDCl3) δ3.55 (s, 2H), 3.70 (s, 3H), 6.97 (dd, J=7.3, 1.5 Hz, 1H), 7.22 (dd, J=8.5, 2.2 Hz, 1H), 7.29-7.33 (m, 2H), 7.48 (d, J=1.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 8.01 (m, 2H); MS (ESI) m/z 443 (M++1), 445 (M++3), 447 (M++5).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=1>C(O)(C)C>[Cl:3][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(Nc2nccc(O)n2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Phosphorous oxychloride (104 gm) was added slowly to 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (12 gm) at 0° C. and then heated to reflux for 1 hour. The solution was then cooled to room temperature, stirred for 30 minutes and filtered. The precipitated solid thus obtained was dissolved in isopropyl alcohol at 0 to 5° C. and stirred for 1 hour at 0 to 5° C. The solid obtained was collected by filtration and then dried to obtain 9.75 gm of 4-(4-chloropyrimidin-2-ylamino)benzonitrile.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[N+]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-])=O>CC1C=CC=CC=1C>[CH:1]([NH:4][C:15]1[C:14]2[C:13](=[O:23])[C:12]3[C:21](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:20](=[O:22])[C:19]=2[CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(C)N
Solvent: Cc1ccccc1C
Product: CC(C)Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
384 g of isopropylamine and 1,390 g of o-xylene are initially introduced into a stainless steel autoclave, which has a capacity of 5 l and is fitted with a stirrer and steam jacket heating, and are heated to 165° C. A suspension of 543 g of 1-nitroanthraquinone with a purity of 98.4% by weight in 815 g of o-xylene is injected into the autoclave in the course of 20 minutes (molar ratio 3:1). During the addition the pressure rises from 10 to 40 bars and the temperature rises from 165 to 170° C. The reaction has ended after a further 30 minutes at 170° C. After cooling and letting-down, the residual solution is evaporated. 548 g of 1-isopropylaminoanthraquinone with a purity of more than 98% are obtained.