Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([C:35]2[CH:36]=[C:31]([NH2:30])[CH:32]=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 60 °C
Yield: 92.6 %

Procedure:
Twenty-five grams of 2,4-dichloro-6,7-dimethoxyquinazoline was suspended in 2.25 L of a mixed solution consisting of toluene:tetrahydrofuran:a 2 N sodium carbonate solution=1:1:1. To the reaction mixture was added 21.5 g of 3-aminophenyl boronic acid ½ sulfate, and the mixture was degassed, the atmosphere in the reaction vessel was replaced with nitrogen. To the reaction mixture was added 2.23 g of tetrakis(triphenylphosphine)palladium(0), followed by stirring at 60° C. under a nitrogen atmosphere. Eighteen hours after initiation of the reaction, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture, and the stirring was continued. Thirty hours later, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was further added to the reaction mixture, and stirring was further continued. Forty-eight hours after initiation of the reaction, the reaction mixture was cooled, and it was then transferred into a separatory funnel, so as to separate an organic layer. The obtained organic layer was washed with 300 mL of brine, and was then dried over anhydrous magnesium sulfate. The desiccant was removed by passing it through 250 g of silica gel. The silica gel was washed with 1.5 L of ethyl acetate, and the obtained organic layers were combined and concentrated to dryness. The residue was triturated with 200 mL of ethyl acetate, and the obtained solid was then filtrated. The solid was washed with 100 mL of diethyl ether and 200 mL of a mixed solution consisting of n-heptane:ethyl acetate=1:1, and dried under aeration to yield 28.2 g of a target product. Yield: 92.5%
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1.[N:13]#[C:14][Br:15]>CCO.O>[BrH:15].[F:12][C:2]([F:1])([F:11])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:14]([NH2:13])=[N:10][N:9]=2)[CH:8]=1
Reactant: N#CBr
Reactant: NNc1ccc(C(F)(F)F)cn1
Solvent: CCO
Solvent: O
Product: Br
Product: Nc1nnc2ccc(C(F)(F)F)cn12
Yield: 41.2 %

Procedure:
5-(Trifluoromethyl)pyrid-2-ylhydrazine (500 mg) was dissolved at RT in a mixture of EtOH/water (7.5/1.5 ml) while stirring. Thereafter, cyanogen bromide solution (314 mg dissolved in EtOH/water 0.75/0.15 ml) was slowly and cautiously added dropwise within 30 min. After stirring at RT for 3 h, the precipitate was filtered off with suction and dried under high vacuum (oil pump). 329 mg of 6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylamine hydrobromide were obtained.
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:8])[CH2:2]2.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[C:10]1([CH:9]=[C:2]2[C:3](=[O:8])[CH:4]3[CH2:7][N:1]2[CH2:6][CH2:5]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN2CCC1C2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)N2CCC1C2

Procedure:
A mixture of 1-azabicyclo [2.2.1] heptan-3-one (2.65 g), benzaldehyde (3.64 ml) and sodium hydroxide (1.15 g) in ethanol (25 ml) was heated at reflux for 40 min. After cooling the solvent was removed in vacuo and the residue partitioned between dichloromethane (300 ml) and water (300 ml). The aqueous layer was further extracted with dichloromethane (2×300 ml). The organic extracts were combined, backwashed with brine (100 ml), dried and concentrated in vacuo to give an orange oil (5.84 g). The oil was purified by FCC, using gradient elution with petrol/ethyl acetate 6:1 to 3:1 to give the title compound as a yellow solid (3.80 g). m.p. 61-63°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol), SEMCl (0.898 mL, 5.08 mmol) and DIPEA (1.768 mL, 10.15 mmol) in DCM (20.0 mL) was stirred at RT. After 3 nights the mixture was evaporated to dryness. The residues were purified on silica eluting with isohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing the title compound (1.65 g). LCMS (A): m/z (M+H)+ 327/329, C13H19BrN2OSi requires 326/328 (basic).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1

Procedure:
A stirred mixture of 2-nitrophenol (13.9 g, 0.10 mol), benzyl bromide (12.0 ml, 0.10 mol) and anhydrous potassium carbonate (30 g, 0.22 mol) in acetone (200 ml) is heated under reflux for 16 hours, cooled, poured onto ice-dilute hydrochloric acid, and extracted with dichloromethane. The extract is dried and evaporated and the residue is crystallized from ether-hexane as pale crystals, m.p. <50° C.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([O:15][C:16]([CH3:18])=[O:17])(OCC)[CH2:8][CH:7]=1)(=O)=O.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[OH-].[K+].[C:30](#N)[CH3:31]>>[C:16]([O:15][C:9]1[CH:8]=[CH:7][C:6]([CH2:30][CH2:31][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)(=[O:17])[CH3:18]
Reactant: CC#N
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC1(OC(C)=O)C=CC(OS(C)(=O)=O)=CC1
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 95 %

Procedure:
10.3 g (39.9 mmole) 4-(methylcarbonyloxy)phenetyl methanesulfonate, 5.37 g (44 mmole) p-hydroxybenzaldehyde and 10 g (72.5 mmole) potassium hydroxide were refluxed in 100 ml acetonitrile for 2 hours. The salts were filtered off and the solvents was evaporated. The residue was dissolved in ethyl acetate and washed with water 3 times, dried and evaporated in vacuo to give 10.8 g (yield 95%) of 4-[2-(4-formylphenoxy)ethyl]phenyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24]C)=[O:23])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[C:1]([O:5][C:6]([N:8]([CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:32][C:33]=1[CH3:34])[C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([OH:24])=[O:23])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1OCc1ccc(N(Cc2nc(-c3ccccc3)oc2C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CN(C(=O)OC(C)(C)C)c1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetate (0.30 g), tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was added a 1N aqueous sodium hydroxide solution (1.0 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (1.0 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetic acid as a colorless amorphous compound (0.19 g, 66%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:4].[Li+].[OH-].[ClH:35]>O1CCOCC1.O>[Cl-:35].[C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[CH:11]1[CH2:16][CH2:15][NH+:14]([CH3:17])[CH2:13][CH2:12]1)([OH:4])=[O:2]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[NH+]1CCC(N(c2cc(-c3ccccc3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Product: [Cl-]
Temperature: 25 °C

Procedure:
A mixture of 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (176 mg, 0.387 mmol) and LiOH.monohydrate (48.8 mg, 1.16 mmol, 4.0 eq) in dioxane:water (3:1, 3.9 mL, 0.1 M) was heated at 50° C. for 5 h, cooled to room temp, acidified with aq. 1N HCl, concentrated, diluted with small amount of water and filtered off the product, and then dried (136 mg), which was triturated with hexanes several times to remove 4-methylcyclohexylacid furnished 4-[(2-carboxy-5-phenyl-thiophen-3-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-1-methyl-piperidinium chloride (Compound 11), 101 mg, 60% yield).
Reaction SMILES: O[CH:2]1[CH:9]2[CH:5]3[CH:6]([CH2:12][CH:3]1[CH2:4]3)[S:7](=[O:11])(=[O:10])[O:8]2.[CH2:13](Cl)Cl>>[CH:5]12[CH2:4][CH:3]([CH:2]=[CH:9]1)[CH2:12][CH:6]2[S:7]([O:8][CH3:13])(=[O:10])=[O:11]
Reactant: O=S1(=O)OC2C(O)C3CC2C1C3
Reactant: ClCCl
Product: COS(=O)(=O)C1CC2C=CC1C2

Procedure:
According to Example 1 described in JP-A-2007-31355, 2-hydroxy-4-oxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide was synthesized. Specifically, firstly, into a four-necked flask having an inner volume of 5 L equipped with a stirrer, a thermometer and a dropping funnel, methyl 5-norbornene-2-sulfonate (128.8 g, purity: 92.1%) which was obtained in the above-described Comparative Example 1 and methylene chloride (2650 g) were charged. m-Chlorobenzoic acid (200.0 g) was charged slowly under stirring in a state cooled with an ice bath so that the inner temperature of the reaction system did not rise to 5° C. or higher. After confirming disappearance of methyl 5-norbornene-2-sulfonate, 20% by mass sodium sulfite aqueous solution (687.1 g) was added dropwise so that the inner temperature of the reaction system was maintained in a range of 5 to 10° C. After that, the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution (500 g) three times. By concentrating the resultant organic layer under the reduced pressure, methyl 5,6-epoxynorbornane-2-sulfonate (125.9 g, purity was 87.2% as a peak area percentage in gas chromatography analysis) was obtained.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: COCCCCCCOc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(OCCCCCCOC)cc3)CC2)cc1
Temperature: 150 °C
Yield: 70.8 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (1.90 g) and 1-[4-(6-methoxyhexyloxy)phenyl]piperazine (3.00 g) in dimethylsulfoxide (45 ml) was treated with potassium carbonate (4.25 g), and the mixture was heated at 150° C. for 22 hours. After cooling, water (200 ml) was added to the reaction mixture, and the resulting precipitate was collected by filtration, washed with water and dried under reduced pressure at 50° C. for 7 hours to give ethyl 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoate (3.20 g) as an ocher solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)ccn1
Temperature: 80 °C
Yield: 35.3 %

Procedure:
N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (55 mg, 0.36 mmol), 0.3 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (31 mg, 35%). ESI-MS m/z calc. 439.1. found 440.3 (M+1)+. Retention time 2.12 minutes.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:18](O)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.N1C=CC=CC=1>[C:19]1([C:18]2[O:1][N:2]=[C:3]([N:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]3)[N:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (7 g, 28.6 mmol) in anhydrous DCM (150 mL) was added benzoic acid (3.49 g, 28.6 mmol) followed by diisopropyl carbodiimide (DIC, 3.6 g, 28.6 mmol). The reaction mixture was stirred at RT for 8 hours and filtered. The filtrate was evaporated and the residue obtained was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried and the solvent was evaporated. The residue was purified by chromatography using petrol ether/EtOAc (9/1) as eluent to afford 5 g (53%) of the title compound as a solid. TLC—Pet ether/EtOAc (9/1): Rf=0.7). HPLC purity: 96%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([N:17]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:32]([Si:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([N:17]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si:36]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCCO)c1ccc(C=O)c(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.63 g (4.59 mmol) of 2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]benzaldehyde and 1.2 g (17.63 mmol) of imidazole. To this mixture, 1.27 g (4.62 mmol) of tert-butylchlorodiphenylsilane was added dropwise with stirring at room temperature. The mixture was stirred for 2 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, and drying over anhydrous sodium sulfate were performed. The residue was purified by silica gel column chromatography to give 2.08 g of a colorless oily matter (yield: 76.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.N.OO.Cl.Cl.[C:16]1([NH2:23])[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CC(C)=O.O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:23])=[CH:17][CH:18]=2)[C:4](=[O:10])[CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: COc1ccc(O)cc1N
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Solvent: CC(C)=O
Product: NC1=CC(=O)C(Nc2ccc(N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.75 mole (10.5 g) of 3-amino-4-methoxy phenol is dissolved in 50 cc of acetone to which have been added 50 cc of ammonia (22° Be') and 250 cc of H2O2 (20 volumes). To this solution there is immediately added 0.05 mole (9.0 g) of paraphenylene diamine dihydrochloride in solution in 100 cc of water. The resulting reaction mixture is agitated for two hours at ambient temperature at which time the reaction mixture is filtered to recover the precipitate which has formed. After recrystallizing the precipitate in ethylacetate and washing the recrystallized product initially with a little methyl cellosolve and then with a little ether, 2-amino-5-[4'-(amino)anilino]-1,4-benzoquinone is obtained which is chromatographically pure and which melts with decomposition above 260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[CH3:35])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1CO
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccc4C)cc3)c2cc1OC
Yield: 95.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methylphenyl)methanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (143 mg, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].B(Br)(Br)Br.S(Cl)(Cl)=O.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15 g, 25 mmol) in anhydrous methylene chloride (15 ml) was cooled to 40° under nitrogen atmosphere. Boron tribromide in CH2Cl2 (27 ml of 1.0 M) was added over 1 h using a syringe pump. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled in an ice bath and quenched with MeOH (15 ml). The reaction mixture was poured into brine (100 ml) and extracted with EtOAc. The organic extracts were dried over anhydrous MgSO4, and the solvent was removed on rotary evaporator. The residue was triturated with hexane and the yellow solid was filtered and dissolved in anhydrous MeOH (30 ml). The solution was cooled in an ice bath and thionyl chloride (1.9 ml, 26 mmol) was added dropwise. After 72 h, water (100 ml) was added and solid was collected. Purification of the crude product on a 300 cm3 silica gel in a 5×15 cm plug using EtOAc provided 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (4.53 g).
Reaction SMILES: [ClH:1].[C:2]([O:5][CH2:6][CH2:7][SH:8])(=[O:4])[CH3:3].[CH2:9]=O.[Cl-].[Ca+2].[Cl-]>C(Cl)Cl>[Cl:1][CH2:9][S:8][CH2:7][CH2:6][O:5][C:2](=[O:4])[CH3:3]
Reactant: C=O
Reactant: Cl
Reactant: CC(=O)OCCS
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OCCSCCl
Reaction time: 4 h

Procedure:
Hydrogen chloride gas was introduced into a mixture of 2-acetoxyethanethiol (24.0 g) and paraformaldehyde (6.0 g) at a moderate rate with external cooling for 3 hours. Calcium chloride (25 g) was added and the reaction mixture allowed to stand in a salt-ice bath for 4 hours. Methylene chloride (200 ml) was added, the reaction mixture filtered and the solvent evaporated with rigorous exclusion of moisture. The residual oil was distilled to give 2-acetyloxyethyl chloromethyl sulfide (18.5 g, bp 82°-87° C. at 3 mm Hg).