Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]1([C:8]2[N:13]=[C:12]([C:14]([NH:16][C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])=[O:15])[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>>[CH:1]1([NH:4][C:19]([C:18]2[CH:22]=[CH:23][N:24]=[CH:25][C:17]=2[NH:16][C:14]([C:12]2[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=[C:8]([CH:5]3[CH2:7][CH2:6]3)[N:13]=2)=[O:15])=[O:20])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 28 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclopropylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (28%) as yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6])#[CH:2].[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(N(CC)CC)C>[CH3:11][Si:12]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:1]#[CH:2])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: C#Cc1ccccc1CO
Solvent: CCN(CC)CC
Product: C#Cc1ccccc1CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
970 mg of 2-ethynyl-benzyl alcohol were dissolved in 50 ml of diethyl ester. 1.9 ml of triethylamine was added, followed by dropwise addition of 0.9 ml of trimethylsilyl chloride. The reaction mixture was stirred at room temperature for 4 hours, poured onto ice/5% aqueous sodium bicarbonate and extracted with ether. The oily residue obtained after drying and evaporation of the solvent was distilled to give 1.3 g of 2-ethynylbenzyl trimethylsilyl ether as a colourless oil, b.p. 85-89° C./0.8 mm.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][NH:6][C:5](=[O:12])[C:4]=2[CH:3]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:3]1[C:4]2[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH2:9][C:10]=2[S:11][C:2]=1[CH3:1])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1cc2c(s1)CCCNC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1sc2c(c1C(=O)CCCCl)C(=O)NCCC2
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one and 5 g of 4-chlorobutyryl chloride in 50 ml of dichloroethane was added 8.6 g of aluminum chloride under ice-cooling and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 1.2 g of 3-(4-chlorobutyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one as white crystals, m.p. 113°-115° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8](C(=O)CCl)[C:7]=2[CH:6]=1)=[O:4].[ClH:23]>C(O)(=O)C>[Cl:23][CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc2c(c1)N(C(=O)CCl)c1ccccc1S2
Reactant: Cl
Solvent: CC(=O)O
Product: O=C(CCl)c1ccc2c(c1)Nc1ccccc1S2
Yield: 82 %

Procedure:
2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone (2.2 g; 5.55 mmol; prepared according to a protocol described in J. Heterocyclic. Chem. (1978), 15, 175, followed by a Friedel-Crafts reaction) is dissolved hot in a mixture of acetic acid (20 ml) and 20% HCl (5.5 ml) and the mixture obtained is heated under reflux for 30 minutes. The reaction mixture is allowed to cool down, the precipitate is filtered, the mixture rinsed with acetic acid (5 ml) and dried under Vacuum, the solid obtained is purified by crystallization from toluene in order to produce a brown product with a yield of 82%. Melting point: 190-191° C. (value in the literature: 197-198° C.).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C)CCN(C)C.CCCCCCCCCCCCC>C1COCC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: CN(C)CCN(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 67 h
Yield: 70 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.901 g; 4.00 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then THF (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), N,N,N′,N′ tetramethylethylenediamine (0.151 ml; 0.116 g; 1.00 mmol), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in THF (2 ml). The reaction mixture was then heated to 65° C. and stirred for 67 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.40 mmol (70% yield) of diphenylacetylene and 0.49 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: CC([O-])(C)C.[Na+].[CH2:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].Cl[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:7]([N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccc(Cl)cc1
Reactant: CCCCNCCCC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol, 0.05 mol % Pd), 2 [Example 1] (2.9 mg, 0.0075 mmol, 0.075 mol %), and NaOt-Bu (1.34 g, 13.9 mmol). Toluene (10 mL), di-n-butylamine (2.00 mL, 11.9 mmol), and 4-chlorotoluene (1.18 mL, 10.0 mmol) were added and the mixture was degassed using three freeze-pump-thaw cycles. The reaction vessel was placed under argon, sealed with a teflon screw cap, and stirred in a 100° C. oil bath for 20 h after which time GC analysis showed the aryl halide had been completely consumed. The reaction mixture was cooled to room temperature, diluted with ether (100 mL) and extracted with 1 M HCl (3×100 mL). The combined aqueous acid phase was basified with 3N NaOH, then extracted with ether (3×150 mL). The ethereal extracts were dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.01 g (95%) of a pale yellow oil.
Reaction SMILES: N[C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].C(ON=O)CC(C)C.[ClH:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C.C(OCC)(=O)C>[CH2:6]([C@H:5]1[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3](=[O:17])[CH:2]1[Cl:26])[CH:7]=[CH2:8]
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: Cl
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CC[C@@H]1C(Cl)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of methyl 2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.0 g) in methylene chloride (10 ml) was cooled to -65° C., and isopentylnitrite (1.01 ml) and a solution of hydrogen chloride (524 mg) in ethyl ether (8 ml) were added. The mixture was allowed to warm to 0° C. during a period of 45 minutes and stirred for one hour and half at 0° C. The reaction mixture was poured into a mixture of ethyl acetate (40 ml) and dilute aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried ove magnesium sulfate and evaporated to leave an oil, which was chromatographed on silica gel (15 g) eluting with a mixture of methylene chloride and acetone (100:2-100:5) to give methyl 2-[(4R)-4-allyl-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (658 mg) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:14]2[C:13](=[O:15])[O:12][C:11](=[O:16])[NH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[O:17][CH3:18].I[CH2:20][CH3:21]>CN(C)C=O>[CH2:20]([N:10]1[C:9]2[CH:8]=[CH:7][C:6]([O:17][CH3:18])=[C:5]([O:4][CH3:3])[C:14]=2[C:13](=[O:15])[O:12][C:11]1=[O:16])[CH3:21]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)oc(=O)c2c(OC)c(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a stirred suspension of sodium Hydride (4.64 g, 116 mmol) in N,N-Dimethyl formamide (DMF) (50 mL) in an ice bath under N2 was added 5,6-dimethoxy-1H-benzo[d][1,3]oxazine-2,4-dione (22 g, 97 mmol) in N,N-Dimethylformamide (DMF) (350 mL). After stirring for 15 min at r.t., iodoethane (15.61 mL, 193 mmol) in N,N-Dimethylformamide (DMF) (50 mL) was added dropwise, and the resulting mixture was allowed to stir at r.t. overnight. The mixture was concentrated in vacuo to one-third of the original volume and then poured into ice-water (600 mL). The precipitate was collected by filtration and recrystallized from THF to afford 1-ethyl-5,6-dimethoxy-1H-benzo[d][1,3]oxazine-2,4-dione (15 g, 54.3 mmol, 56.2% yield) as a light brown pellet.
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].Cl>CC(C)=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)C1CCCC1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
The general method of procedure A was followed with cyclopentanesulfonamide (3 g), acetone (200 ml), 1N sodium hydroxide (20 ml), and 3,4-dichlorophenyl isocyanate (3.6 g) dissolved in acetone (50 ml). After two hours, 1N HCl (20 ml) was added and the resulting solid diluted with water and collected. After drying at 65° C., 5.5 g of solid product were obtained.
Reaction SMILES: [CH3:1][N:2]([C:14]1[N:23]=[C:22]([NH2:24])[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=2)[N:15]=1)[CH2:3][CH2:4][CH2:5][NH:6]C(C1OCCC1)=O.NC1C2C(=CC(OC)=C(OC)C=2)N=C(Cl)N=1.CNCCC#N>C(O)CC(C)C>[NH2:24][C:22]1[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=2)[N:15]=[C:14]([N:2]([CH2:3][CH2:4][C:5]#[N:6])[CH3:1])[N:23]=1
Reactant: COc1cc2nc(N(C)CCCNC(=O)C3CCCO3)nc(N)c2cc1OC
Agent: CNCCC#N
Agent: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC

Procedure:
The patent 007' teaches the preparation of alfuzosin or a salt thereof by reacting 4-amino-2-chloro-6,7-dimethoxy quinazoline of formula (II) with 3-methylaminopropionitrile of formula (III) in the presence of isoamyl alcohol to obtain N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine of formula (IV) which is further hydrogenated in the presence of Raney-Nickel using 15% ammoniacal ethanol by applying 80 Kg pressure at 70° C. for 96 hours to obtain N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine of formula (V) which is then converted to the hydrochloride salt. The obtained N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methylpropylenediamine hydrochloride is then treated with carbonyldiimidazole-activated tetrahydrofuroic acid by adding a diamine compound in the presence of carbonyldiimidazole to obtain alfuzosin base which is then converted into alfuzosin hydrochloride salt.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:29])[CH:14]([NH:18]C(OCC2C=CC=CC=2)=O)[CH:15]([F:17])[CH3:16])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]>C(O)C.[Pd]>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:29])[CH:14]([NH2:18])[CH:15]([F:17])[CH3:16])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)N1CCN(C(=O)C(NC(=O)OCc2ccccc2)C(C)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCOC(=O)N1CCN(C(=O)C(N)C(C)F)CC1
Reaction time: 1 h

Procedure:
To a solution of 591 mg 4-(2-Benzyloxycarbonylamino-3-fluoro-butyryl)-piperazine-1-carboxylic acid propyl ester in 20 ml ethanol were added 0.1 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 1 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was used in the subsequent reaction. Yield: 347 mg.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([CH2:20][CH3:21])[C:12]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[NH2:17][C:15]1[CH:16]=[C:11]([CH2:9][CH3:10])[C:12]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[C:13]([CH2:20][CH3:21])[CH:14]=1
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(N)cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 24.8 %

Procedure:
A solution of sodium dithionite (772 mg) in water (6 mL) was added to a solution of N-(2,6-diethyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide (309 mg) in tetrahydrofuran (6 mL) and the resulting mixture was stirred at 50° C. for 20 hours. After cooling, the water was saturated with potassium carbonate and extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 70 mg (25%) of the title compound as a off-white solid. The product was used directly in the following reaction without spectral characterization.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(Cl)(C(Cl)=O)=O.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([NH2:33])[C:27]=2[CH:26]=[CH:25]1.C(NC(C)C)(C)C>C(Cl)Cl.O.CN(C=O)C>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:27]=3[CH:26]=[CH:25][NH:24]4)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc3[nH]ccc23)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 0.23 g; 0.98 mmol) in DCM (5 ml) was treated with DMF (1 drop of a 10% solution in DCM) followed by (COCl)2 (0.1 ml; 1.15 mmol). After stirring at 0° C. for 30 minutes, the mixture was treated with 1H-indol-4-amine (Aldrich, 146 mg; 1.1 mmol) and diisopropylamine (0.5 ml; 2.9 mmol). After stirring overnight, water was added and the layers separated. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of Et2O to give the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([OH:29])[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:30])[CH:10]2[NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:7])[CH2:3][CH2:2]1.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(N(CC)CC)C>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([O:29][S:59]([CH3:58])(=[O:61])=[O:60])[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C:11](=[O:30])[CH:10]2[NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (904 mg) in a mixture (9.5 ml) of tetrahydrofuran and hexamethylphosphorotriamide (20:1) are added methanesulfonyl chloride (0.26 ml) and triethylamine (0.37 ml). After 2 hours, the reaction mixture is poured into ice water, and extracted with chloroform. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.12 g). Yellow foam. IR: νmaxCHCl3 3426, 1785, 1722-1704br, 1640, 1601, 1160, 1175, 986 cm-1. NMR: δCDCl3 0.32-1.25m5H, 2.57s3H, 2.72s3H, 3.99d(7 Hz)2H, 4.55s2H, 5.33-5.99m4H, 6.82-7.62m7H 8.21d(8.5 Hz)2H.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([OH:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([OH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C(OCC)(=O)C>[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: OC1c2ccccc2C(O)c2ccccc21
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 24 %

Procedure:
A mixture of 5 mmol of 9,10-dihydroanthracene-9,10-diol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of ethyl acetate was stirred at 75° C. in an oxygen atmosphere (1 atm) for 18 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 36%. Separately, as a result of a gas chromatographic analysis of the reaction mixture, the conversion rate from 9,10-dihydroanthracene-9,10-diol was 27%, and anthraquinone was formed in yield of 24%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[CH:25]=[C:26]([N:30]([CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Br:20][CH2:23][C:24]1[CH:25]=[C:26]([N:30]([CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: BrBr
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CBr)c1
Reaction time: 0.25 h

Procedure:
Resin-supported triphenylphosphine (1.6 g, 3 mmol per gram resin) was dispersed on dichloromethane. At 0° C., bromine (0.850 g, 5.3 mmol) solution was added dropwise to the resin. And the mixture was stirred for 15 min, followed by dropping a solution of N-(3-hydroxymethylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.930 g, 3 mmol). After 1 h, the resin was filtered and washed with CHCl3. Evaporation afforded the title compound. 1H NMR:, 8.81 (s,1H), 8.68 (d,1H, J=5.4 Hz), 8.47 (d,1H,J=8.3 Hz), 7.91 (m,1H), 7.26-7.39 (m,1H), 5.16 (s,2H), 4.40 (s,2H), 3.12 (q,2H,J=7.3 Hz), 1.40 (t,3H,J=7.3 Hz). MS calcd. 370.0; MS (M+1) 371.1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([O:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([O:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:41]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: COCCCOc1cc(CBr)ccc1C(=O)OC
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)OC

Procedure:
Analogously to Method D, 3.25 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 4.05 g of methyl 4-bromomethyl-2-(3-methoxypropoxy)benzoate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 toluene-EtOAc); Rt=6.00.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([OH:24])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:27][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[N:15]=[C:16]([OH:24])[C:17]=2[CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCNC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCN(C)C3)cc1
Reaction time: 0.17 h
Yield: 345.7 %

Procedure:
A suspension of 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (1.4 g, 4.34 mmol, Example 9c), formaldehyde (0.423 g, 5.21 mmol) and acetic acid (0.025 mL, 0.43 mmol) in MeOH (25 mL) was stirred for 10 min. Sodium cyanoborohydride (0.273 g, 4.34 mmol) was added and the reaction was stirred for an additional 10 min after which water (2 mL) was added. Solvent was evaporated and EtOAc (2 mL) was added followed by the addition of potassium carbonate solution (sat. aq., 1 mL). The solution was stirred and the formed precipitate was filtered off to give 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (0.500 g, 34.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[NH:17][C:18]2=[O:27])=[N:13]1.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:16](=[O:28])[N:17]([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:18]2=[O:27])=[N:13]1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Cn1c(=O)n(CCN2CCOCC2)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(2-chloroethyl)morpholine using potassium carbonate as a base. Mass: 565.17 (M+H).