Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 24 h
Yield: 18.8 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (2.29 g, 0.0114 mol, 1.15 eq) and 4-hydroxypiperidine (1 g, 0.0099 mol, 1 eq) were stirred at room temperature in THF (10 ml) and acetic acid (0.6 ml) for 20 hours. To the solution was added 0.17 g of 5% palladium on carbon type 87L Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 24 hours. The catalyst was filtered off through CELITE™ and washed with THF (20 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (18.8% purity by HPLC area %) was not isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:15][CH2:16][CH2:17][Cl:18])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 100 g (0.549 mole) of methylvanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 L of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of title compound as a white powder, mp 104°-105° C. (2-propanol).
Reaction SMILES: [N+]([C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[N+:14]([O-:17])(O)=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:9]1[CH:8]=[CH:7][C:6]([CH3:10])=[CH:5][CH:4]=1)([O-:17])=[O:15]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
U.S. Pat. No. 2,362,743 describes the preparation of dinitrotoluene by the nitration of toluene with nitric acid of about a 70% concentration to produce mononitrotoluene, followed by further nitration with nitric acid of about 98% concentration to produce a crude dinitrotoluene. This patent states that the use of the concentrated nitric acid is an improvement over the use of sulfuric acid alone and mixtures of sulfuric and nitric acids as nitrating agents. The crude dinitrotoluene produced by the process of the patent is stated to be subjected to several steps of washing, neutralizing, alcohol treatment, and centrifuging to obtain the 2,4-dinitrotoluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16]>ClCCl.O=[Mn]=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[O:16]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c2ccccc12
Yield: 79.1 %

Procedure:
The title compound was prepared by treating (1,4-dimethoxy-naphthalen-2-yl)-methanol (6.5 g, 29.8 mmol, 1.0 equiv, [CAS RN 150556-57-3], prepared as described in C. Flader, J. Liu, R. F. Borch J. Med. Chem. 2000, 43, 3157-3167) with activated MnO2 (25.9 g, 297.8 mmol, 10.0 equiv) in dichloromethane for 4 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated by evaporation of the solvent under reduced pressure affording 5.1 g (81%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.02 (s, 3H), 4.10 (s, 3H), 7.14 (s, 1H), 7.61-7.65 (m, 2H), 8.18-8.30 (m, 2H), 10.58 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCBr)cc1
Yield: 43.9 %

Procedure:
A mixture of 1,2-dibromoethane (3.9 mL, 45 mmol), 4-hydroxybenzaldehyde (1.8 g, 15 mmol) and K2CO3 (10.4 g, 75 mmol) in acetone (40 mLO was heated to reflux for 18 hr. The mixture was cooled, diluted with ethyl acetate (200 mL) and washed with brine (200 mL). Then organic layer was dried (MgSO4), filtered and then concentrated. The resulting residue was subjected to flash chromatography (25% ethyl acetate/hexane) to provide 1.51 g (44%) of 4-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[ClH:20].[Cl:20][C:15]([C:13]1[C:14]2[C:5]([N:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:17]
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12
Yield: 96 %

Procedure:
Acridine-9-carboxylic acid (0.42 g, 1.87 mmol) was suspended in thionyl chloride (10 ml) and the suspension was refluxed under heating for 2 h. Excess thionyl chloride was distilled off the reaction mixture under reduced pressure to give 9-chlorocarbonylacridine hydrochloride (0.5 g, 96%). Then, the resulting 9-chlorocarbonylacridine hydrochloride (0.5 g) and 2-methylphenol (0.2 g, 1.9 mmol) were suspended in dichloromethane (15 ml) and triethylamine (1.0 ml) and a catalytic amount of dimethylaminopyridine were added to the suspension with stirring. The reaction mixture was stirred at room temperature for 15 h and thereafter washed with 1N HCl; water, a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in the order written. The organic layer was separated and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel column chromatography using a dichloromethane-hexane mixture as eluant, giving the desired compound, 2'-methylphenyl acridine-9-carboxylate, in an amount of 0.33 g.
Reaction SMILES: C(OCC)(=O)C[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=O)([C:5]([O:7][CH2:8][CH3:9])=O)O.O1CCCC1.[H][H]>C(O)C>[OH:7][CH2:5][CH2:3][CH:10]1[CH2:15][CH2:14][O:13][CH2:11]1.[OH:13][CH2:11][CH:10]1[CH2:9][CH2:8][O:7][CH2:5][CH2:3]1
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCO
Product: OCC1CCOCC1
Product: OCCC1CCOC1
Yield: 3.6 %
Yield: 49 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 225° C. and 200 bar together with 1100 ml of tetrahydrofuran and 60 g of catalyst H (3-mm tablets) until the take-up of hydrogen had ceased. The reaction product was freed from tetrahydrofuran and ethanol and distilled under reduced pressure, giving 93.6 g (49%) of 3-(2'-hydroxyethyl)tetrahydrofuran and 6.8 g (3.6%) of 4-hydroxymethyltetrahydropyran.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=O.B.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[F:1][C:2]([F:12])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH2:5]
Reactant: NC(=O)C(F)(F)c1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NCC(F)(F)c1ccccc1
Temperature: 0 °C
Yield: 40.9 %

Procedure:
2,2-Difluoro-2-phenylacetamide (2.4 g, 14 mmol), as prepared in the preceding step, was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this stirred solution was added 1.0 M borane in tetrahydrofuran (35 mL, 35 mmol) dropwise in 30 minutes, and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, a solution of potassium carbonate (5 g) in water (20 mL) was added to the reaction mixture. The mixture was concentrated in vacuo to about 50 mL and extracted with dichloromethane (3×50 mL). The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (900 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 5H), 3.18 (t, 2H, J=14.5 Hz), 1.60 (s(br), 2H).
Reaction SMILES: Cl[S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:4])=[O:3].[CH2:18]([OH:20])[CH3:19].C(N(CC)CC)C.O>C(OCC)(=O)C>[CH2:18]([O:20][S:2]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([OH:8])=[O:7])(=[O:3])=[O:4])[CH3:19]
Reactant: O=C(O)C(c1ccc2c(c1)CCO2)S(=O)(=O)Cl
Reactant: CCO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
α-Chlorosulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid (5 mmole) is added to 30 ml of ethyl acetate. To this mixture is added 5 mmole of ethanol in 10 ml of ethyl acetate which contains 10 mmole of triethylamine. The mixture is stirred at room temperature for about 1 hour and 50 ml of water is added. The pH is adjusted to about 6.5 and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give ethoxysulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Li]CCCC.[CH3:18][C:19]1[C:20](=O)[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].Cl.N>C1COCC1>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:20]3[CH:19]([CH3:18])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]=3[CH3:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: CC1=C(C)C(C)C(C)C1=O
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 4.4 g of 8-bromo-2-methylquinoline (20 mmol) in 50 ml of THF was cooled to −78° C., and 8.8 ml of n-BuLi (2.5 M in hexane, 22 mmol) were added dropwise with stirring. After the mixture had been stirred for 10 minutes, 3.5 g of 2,3,4,5-tetramethylcyclopentenone (25 mmol) were added dropwise, and the solution was warmed to room temperature, refluxed for one hour and cooled. Ice and hydrochloric acid were added to about pH 1, the mixture was neutralized using ammonia solution, the phases were separated, and the aqueous phase was extracted with pentane. After the combined organic extracts had been dried, the pentane was removed under reduced pressure, and the brown oil which remained was distilled under a high vacuum (b.p.: 115° C./0.01 mbar). 1-(2-Methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene was obtained as a yellow, viscous oil in a yield of 60% (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[C:13]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].Cl>ClCCl>[C:13]([C:15]1[CH:16]=[C:17]([S:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: Nc1nccs1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Yield: 66.6 %

Procedure:
To 2-aminothiazole (12.55 g, 125.3 mmol) was added pyridine (46 ml) and dichloromethane (75 mL) and the mixture stirred to give a solution. A solution of 3-cyano-4-fluorobenzenesulfonyl chloride (25 g, 114 mmol) in dichloromethane (50 ml) was added over approx 20 minutes at room temperature. The reaction was stirred at this temperature for 2 days before decanting the supernatant and concentrating in vacuo to furnish a dark oil. 2M HCl (200 ml) was added and the mixture triturated until solidification occurred. A brick red solid was filtered off, washed with water and dried to furnish 21.5 g of the title product. 1HNMR (d6-DMSO): δ 6.9 (d, 1H), 7.3 (m, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.3 (d, 1H), 12.9 (br s 1H). LCMS Rt=2.34 min MS m/z 284 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1O)[CH:5]=O.[ClH:14].[NH2:15]O.C1(C)C=CC(CS(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:14][C:9]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]([C:5]#[N:15])=[CH:3][C:2]=1[OH:1]
Reactant: Cl
Reactant: NO
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(CS(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (5 g, 27.3 mmol), hydroxylamine hydrochloride (2.467 g, 35.5 mmol), p-toluenemethanesulfonic acid (0.779 g, 4.10 mmol) and magnesium sulfate (26.3 g, 218 mmol) in toluene (25 ml) was heated at reflux for 6 hours. The reaction mixture was cooled to room temperature; the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and aqueous layer was extracted with ethyl acetate two more times. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to a small volume and a brown precipitate formed. The precipitate was collected by filtration and after drying under vacuum to give 4.1 g of 4-chloro-3-hydroxy-5-nitrobenzonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH2:11](O)[CH2:12][OH:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][CH:6]1[C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C2OCCO2)c1
Yield: 100 %

Procedure:
A mixture of 3-cyanobenzaldehyde (9.81 g), ethylene glycol (9.31 g), p-toluenesulfonic acid monohydrate (0.07 g) and toluene (200 ml) was heated under reflux for 15 hrs., while removing generated water with a Dean-Stark trap. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-(1,3-dioxolan-2-yl)benzonitrile (13.1 g, yield 100%) as a colorless oil. NMR (CDCl3) δ: 4.01–4.17 (4H, m), 5.83 (1H, s), 4.50 (1H, t, J=7.6 Hz), 7.63–7.74 (2H, m), 7.80 (1H, t, J=1.6 Hz).
Reaction SMILES: [CH:1]([CH:4]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([CH:16]([CH3:18])[CH3:17])[N:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[Rh]>[NH2:5][CH:4]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([NH2:6])[CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Agent: [Rh]
Solvent: CC(C)(C)O
Product: CC(C)C(N)CCCCCCCCC(N)C(C)C
Yield: 92.8 %

Procedure:
250 g (1 mole) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) are dissolved in 1000 ml of tert -butanol in an agitator autoclave. After addition of 25 g of a rhodium/alumina catalyst (5% by weight of rhodium), hydrogen is introduced up to a pressure of 130 to 150 bar, whereupon hydrogenation is effected at 150° to 180° C. until the hydrogen uptake is complete. After cooling, excess hydrogen is blown off, the suspension is removed from the autoclave by suction and the catalyst is filtered off with suction over a small amount of hyflo (filter aid). The filtrate is concentrated by rotary evaporation and the product is purified by distillation, affording as main fraction 238 g (92% of theory) of 3,12-diamino-2,13-dimethyltetradecane as a colourless oil [b.p. 106°-109° C./0.01 torr; nD20 =1.4600; IR spectrum (in liquid) includes bands at 3355, 3278, 1613 cm-1 ].
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([Cl:29])[N:3]=1.O.N(OC(C)(C)C)=[O:32]>C(O)(C)(C)C>[Cl:29][C:4]1[N:3]=[C:2]([OH:32])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(O)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (42.7 g, 100 mmoles) is dissolved in 2 liters of a tert-butyl alcohol:water mixture (1:1, v/v) with heating. After cooling the solution with an ice bath, tert-butyl nitrite (50 mL, 422 mmoles) is added in one portion. The ice bath is removed and the mixture is stirred at room temperature until gas evolution ceases (approximately 3 hours). The mixture is then frozen (dry ice/2-propanol) and lyophilized to afford the desired intermediate as a yellow solid that is used immediately or stored frozen at −20° C. without purification.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8](C(O)=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([NH2:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (12.5 g, 38.3 mmol) in tert-butanol (250 mL) were added triethylamine (5.5 mL, 40 mmol) and diphenylphosphoryl-azide (8.6 mL, 40 mmol). The reaction mixture was stirred at 95° C. for 16 hours, then allowed to cool down to RT, and concentrated in vacuo. The resultant residue was dissolved in EtOAc, washed successively with water, aqueous saturated sodium bicarbonate solution followed by brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (150 mL) and treated with TFA (50 mL). The reaction mixture was stirred at RT for 3 hours then concentrated in vacuo. The resulting residue was triturated with 20% EtOAc/cyclohexane and filtered to afford 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine as an off-white solid (7.94 g, 70%). LCMS: RT=3.13 min, [M+H]+=297/299
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(=O)(O)(O)O>[Cl-].[Zn+2].[Cl-].O>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccccc1
Reactant: Cc1ccccc1CCl
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 5 h
Yield: 86.6 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 200 parts of benzene is added to a mixture of 170 parts of 85 per cent strength by weight phosphoric acid, 22 parts of water and 75 parts of zinc chloride at 75° to 80° C, whilst stirring thoroughly. After a further 5 hours, the organic phase is separated off and 78 parts (86.6% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by fractional distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1(=O)[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.CCOC(C)=O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of zinc chloride (8.39 g, 1.14 mmol, 1 eq) in toluene at ambient temperature, ethyl 3-(4-fluorophenyl)-3-oxopropanoate (13 g, 2.74 mmol, 1 eq) was added and stirred at 70° C. for 15 min. Benzoquinone (6.66 g, 0.72 mmol, 1 eq) was added portion wise into the reaction mixture and stirred at the same temperature for 15-20 min. Dean-stark apparatus was assembled and the reaction mixture was heated at 140° C. for 12 h and cooled to ambient temperature. Reaction completion was judged by TLC. EtOAc was added to the reaction mass and filtered through the filter paper, to remove the inorganic material. Brine was added to the reaction mixture (filtrate) and extracted, dried over sodium sulphate and concentrated to get the crude material. Further it was purified by column chromatography using 10% EtOAc/Hexane system. Yield: 8.0 g (43%). 1H NMR (400 MHz, CDCl3): δ 1.38-1.42 (t, 3H, J=7.14 Hz), 4.37-4.42 (q, 2H, J=7.13 Hz), 5.2 (br s, 1H), 6.87-6.9 (q, 1H, J=3.81 Hz), 7.14-7.18 (q, 2H, J=5.82 Hz), 7.36-7.39 (d, 1H, J=8.80 Hz), 7.50-7.51 (d, 1H, J=2.56 Hz), 8.00-8.03 (m, 2H). LCMS: (ES+) m/z=301 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O:13]1[CH:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>>[ClH:1].[OH:13][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: NCCOc1ccc(O)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: Cl
Product: Oc1ccc(OCCNCC(O)COc2ccccc2)cc1
Yield: 15.6 %

Procedure:
A mixture of p-(2-aminoethoxy)phenol hydrochloride (1.89 g) triethylamine (1.01 g) and 1,2-epoxy-3-phenoxypropane (1.5 g) was heated under reflux for 24 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between dichloromethane (100 ml) and 10% w/v potassium carbonate solution. The organic layer was separated, dried (HgSO4), and the solvent was evaporated. The residual oil was dissolved in ethyl acetate and dry hydrogen chloride was passed through the solution until no further solid precipitated. The precipitate was collected and recrystallised from methanol and ethyl acetate to give p-(2-[2-hydroxy-3-phenoxypropylamino]ethoxy)phenol hydrochloride (0.53 g), mp, 171°-172° C.; microanalysis: found C, 60.3; H, 6.7; N, 4.0; Cl, 10.6%; required for C17H22NClO4 : C, 60.1; H, 6.5; N, 4.1; Cl, 10.5%.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C1(C)C=CC=CC=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[O:21]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:22])[N:2]1[NH:1][C:3](=[O:4])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 104.1 %

Procedure:
250 g of tert-butyl hydrazinecarboxylate was added to toluene (3 L) solution of 280 g of phthalic anhydride. Using a Dean-Stark water separator, the reaction mixture was heated under reflux for 3 hours. This was cooled to room temperature, the formed solid was taken out through filtration to obtain 516 g of crude tert-butyl (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:17]C(=O)OC(C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:4]=[CH:5][N:6]=1.N1(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)CCOCC1>>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[C:9]([NH2:17])[CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Product: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 90c but employing [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 91c) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a yellow crystalline solid, m.p. 130–133° C.