Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+].C(CC(=O)C)(=O)C.O=O.C(OCC)(=O)C=CC1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[C:14]([O:17][CH:9]=[CH:8][C:7]([O:11][CH2:12][CH3:13])=[O:10])(=[O:16])[CH3:15]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: CCOC(=O)C=Cc1ccccc1
Agent: O=O
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C=COC(C)=O

Procedure:
In a flask, 15 mmol of benzene, 1.5 mmol of ethyl acrylate, 0.1 mmol of palladium(II) acetate, 0.02 mmol of H7PMo8V4O40, 0.08 mmol of sodium acetate, 0.1 mmol of acetylacetone, and 5 ml of acetic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 6 hours. The resulting reaction mixture was analyzed by gas chromatography to find that ethyl cinnamate, ethyl 3,3-diphernylacrylate, and ethyl 3-acetoxyacrylate were produced in yields of 63%, 5%, and 12%, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])[N:4]=[C:5]=[O:6].[Si:14]([O-:18])([O-:17])([O-:16])[O-:15].[Na+].[Na+].[Na+].[Na+]>>[Si:14]([OH:18])([OH:17])([OH:16])[OH:15].[CH3:1][C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])[N:4]=[C:5]=[O:6]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: Cc1ccc(N=C=O)cc1N=C=O
Agent: [Na+]
Product: O[Si](O)(O)O
Reaction time: 0.33 h

Procedure:
About 200 parts by weight of toluene diisocyanate. "TDI", 50 parts by weight of fine granular hydrated silica and 10 parts by weight of sodium silicate are mixed then heated to 30° C. to 35° C. while agitating for about 20 minutes thereby producing a toluene diisocyanate silicate prepolymer. The prepolymer is mixed with 70 parts by weight of trichlorotrifluoroethane.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C>C1(C)C=CC=CC=1>[OH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(=O)OC=Cc1ccccc1
Agent: C=C(C)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: OC=Cc1ccccc1

Procedure:
Tert-butyl methacrylate (5.7 g; 40 mmol) and 9.7 g (60 mmol) of acetoxystyrene were dissolved in toluene (80 mL). The reaction product was separated by the same method as that described in example 2, except that 0.67 g of AIBN was added.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O
Temperature: 115 °C
Reaction time: 4 h

Procedure:
18.0 g (46.4 mmol) of 3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile was dissolved in 200 ml of dimethylformamide (DMF). 13.3 g (92.8 mmol) of methyl 2-acetamidoacrylate, 2.82 g (9.28 mmol) of tris(2-methylphenyl)phosphine, 1.04 g (4.64 mmol) of palladium (II) acetate and 12.9 ml (92.8 mmol) of triethylamine were added to the obtained solution, and they were stirred at 115° C. for 4 hours. The solvent was evaporated to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.P([O-])(OCC)OCC>ClCCCl.CCOC(C)=O.C(OCC)C>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CCOP([O-])OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
Reaction time: 5 h
Yield: 43.9 %

Procedure:
To a suspension of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (Preparation 165, 118 g, 0.45 mol) in 1,2-dichloroethane (1.25 L) was added N-bromosuccinimide (91 g, 0.51 mol) and benzoyl peroxide (5 g, 20 mmol) and the mixture heated to reflux for 18 hours. N-bromosuccinimide (30 g, 0.17 mol) was then added and the solution heated 24 hours more. A further portion of N-bromosuccinimide (20 g, 0.11 mol) was added and the solution heated for 3 hours, then cooled and washed with water (1 L) containing aqueous sodium thiosulphate solution (200 mL, 0.5 M). The organic layer was washed with water (500 mL), dried over sodium sulphate and concentrated in vacuo to yield a crude solid. To a solution of this crude solid in EtOAc (1 L) was added diisopropylethylamine (130 mL, 0.75 mol) and diethyl phosphite (27.6 g, 0.2 mol) and the mixture stirred for 5 hours under nitrogen, then washed with aqueous hydrochloric acid (1 L, 2 M), dried over magnesium sulphate and evaporated to yield a dark solid. Trituration with diethyl ether (200 mL) gave the first crop of title compound as a tan solid (68 g). The filtrate was purified by silica gel chromatography eluting with 10% EtOAc in DCM containing acetic acid (1%), followed by crystallization from acetonitrile (130 mL) to yield the second crop of the title compound (30 g):
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 90.6 %

Procedure:
To a solution of 2-chloro-5-nitrobenzoic acid (3.0 g, 0.14 mol) in methanol (500 mL) was added sodium methoxide (28.1 g, 0.520 mol). The reaction mass was refluxed for 15 h. Excess of solvent was removed under vacuum and the reaction mass was diluted with water and acidified with dilute HCl to obtain solid which was filtered off to afford 25.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 7.36 (d, J=9.3 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.45 (s, 1H), 13.32 (br s, 1H)); MS (m/z): 198.25 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(CCCC(=O)O)C4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of ethyl 4-[9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]butanoate (Preparation 68) (61.7 g, 123 mmol) in ethanol (600 ml) was treated with 2M sodium hydroxide (123 ml, 247 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in water (1 liter). The aqueous solution was cooled in ice/water and treated slowly with glacial acetic acid (28.3 ml, 494 mmol). The resulting gum was stirred vigorously until a filterable solid was obtained which was then collected by filtration and washed with more water (2×500 ml). After sucking the pad dry the material was dissolved in a 95:5 mixture of dichloromethane/methanol and dried (sodium sulphate). The solvent was removed by evaporation and the resulting solid was triturated under diethyl ether (200 ml), collected by filtration, washed with diethyl ether and dried to give the title compound as a colourless solid (54 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][CH2:12][O:13][C:14]([CH:16]([C:20]([CH3:22])=O)[C:17]([CH3:19])=O)=[O:15]>>[CH2:12]([O:13][C:14]([C:16]1[C:17]([CH3:19])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[C:20]=1[CH3:22])=[O:15])[CH3:11]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2cccc(Cl)c2)c1C
Yield: 58 %

Procedure:
In analogy to the procedure described in Example 38A], 3-chlorophenylhydrazine hydrochloride and ethyl diacetoacetate gave the title compound after purification by flash column chromatography (n-heptane:EtOAc 9:1-1:1) in 58% yield as light yellow solid. MS: 279.0 (MH+, 1 Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.C(Cl)Cl.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.C1C2C(=CC3C(C=2)=CC=CC=3)C=CC=1>[OH-].[NH4+].O.[Zn]>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccc2cc3ccccc3cc2c1
Solvent: O
Product: Clc1ccc2cc3ccccc3cc2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 14.4 %

Procedure:
A stirred suspension of 2-chloroanthraquinone (1260 g, 5.19 moles) in concentrated ammonium hydroxide (7.5 L) and water (2.5 L) was warmed to 40° C. Zinc dust (845 g, 12.93 moles) was added in one portion, changing the color to deep red. The mixture was stirred for 45 min at 50° C., then cautiously treated with a second portion of zinc dust (845 g). After the addition, the stirred mixture was heated gradually over 3 h to 90° C., then maintained at 90°-95° C. for 2 h (red color dissipated). TLC analysis [silica gel/hexane:methylene chloride (3:1)] showed complete conversion of the anthraquinone (Rf =0.35) to the desired anthracene (Rf =0.80). The reaction mixture was stirred overnight as it cooled to room temperature. The cooled mixture was treated with methylene chloride (4 L), stirred for 2 h, then filtered through Celite to remove the excess zinc. The filter cake was washed with methylene chloride (6×1 L). The methylene chloride layer was separated from the aqueous, then treated with 6N hydrochloric acid (3 L) and stirred for 2 h. A first crop of 2-chloroanthracene was collected by filtration and washed with water (4×1 L). Vacuum drying afforded a light yellow crystalline product weighing 804.6 g (mp 220°-221° C.). The methylene chloride portion of the filtrate was concentrated in vacuo to 10% of its original volume. This produced an additional 158.5 g of the desired compound for a total yield of 963.1 g (87.2%). 1H NMR (CDCl3): δ8.39 (s, 1H), 8.30 (s,1H), 7.96 (s, 4H), 7.49 (s, 2H), 7.36 (d, J=8.7 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH2:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of 2-nitrophenol (10.0 g, 72.0 mmol) and K2CO3 (9.96 g, 72.0 mmol) in DMF (150 mL) was added dropwise benzyl bromide (9.40 mL, 79.2 mmol) at 0° C. After being stirred at room temperature for 3 hr, the reaction mixture was diluted with water, which was extracted with Et2O. The extracts were washed with brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with hexane-EtOAc (2:1, v/v) as eluent gave 2-benzyloxy nitrobenzene (14.7 g, 89%) as a yellow oil. 1H-NMR (CDCl3) δ5.24 (s, 2H), 7.04 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.31-7.50 (m, 5H), 7.51 (d, J=1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.5 Hz, 1H).
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc(Cl)c1
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1

Procedure:
4-(4-Aminophenoxy)-2-chloropyridine was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-aminophenol and 2,4-dichloropyridine MS ES: 221 (M+H)+, calcd 221, RT=0.32 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-])=O.C([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[NH2:12]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc(CC(=O)O)ccc1O
Reaction time: 4 h

Procedure:
92.4 g of 4-hydroxy-3-nitrophenylacetic acid are suspended in a solution constituted by 785 ml of H2O and 21.2 g of NaHCO3. 5 g of a catalyst constituted by 5% Pd-on-carbon are suspended in the solution, which is then hydrogenated at ambient temperature for 4 hours, to obtain 4-hydroxy-3-aminophenylacetic acid. The catalyst is separated by filtration in a nitrogen environment, and the aqueous solution is used for the reaction with 4-fluorobenzoyl chloride, which is carried out in the following manner: the aqueous solution is cooled to 5° C. in a nitrogen environment, 460 ml of t-butylmethylether are added, and then 74 ml of 4-fluorobenzoyl chloride dissolved in 170 ml of t-butylmethylether are fed slowly.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][S:15]([CH2:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=O.[I-].[Na+]>CC(C)=O>[CH3:14][S:15][CH2:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)CS(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)CSC
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
A solution of trifluoroacetic anhydride (1.68 g) in acetone (5 ml) was added to a stirred mixture of 1-methylsulphinylheptadecan-2-one (1.58 g) and sodium iodide (1.8 g) in acetone (10 ml) cooled in an ice bath. The mixture was stirred for a further 10 minutes and then evaporated. Water (50 ml) was added to the residue and the mixture was extracted with diethyl ether (2×40 ml). The ether extract was washed with a solution of sodium thiosulphate (3 g) in water (50 ml), dried over magnesium sulphate and evaporated to give 1-methylthioheptadecan-2-one (1.3 g), m.p. 40° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(F)s1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Ca+2]
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cc21
Yield: 23.1 %

Procedure:
A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg), (5-fluorothiophen-2-yl)methanol (376 mg), tributylphosphine (1.07 ml), 1,1′-(azodicarbonyl)dipiperidine (1.08 g) and THF (40 ml) was stirred at 60° C. under a dry atmosphere (CaCl2 tube) for 3 h. After solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (130 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].[C:10](Cl)(Cl)=[S:11].CN(C=O)C>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[S:11]
Reactant: Nc1c(F)cccc1Cl
Reactant: S=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: Fc1cccc(Cl)c1N=C=S
Yield: 96.4 %

Procedure:
To a solution of 2-chloro-6-fluorobenzenamine (5.0 g, 34 mmol) in chlorobenzene (52 mL) was added carbonothioic dichloride (thiophosgene) (5.1 g, 45 mmol) and DMF (0.27 mL). The reaction mixture was refluxed for 2 h and then concentrated to leave the title compound as a brown oil (6.15 g), which was used in Step C without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Br.[Br:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2](=[O:3])[NH:16][CH2:15][CH2:14][Br:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Benzyl chloroformate (26 mL, 0.176 mole) was added in one portion to a stirring mixture of bromoethylamine hydrobromide (44 g, 0.21 mole), triethylamine (64 mL, 0.46 mole), and methylene chloride (1 L) at below −40° C. After the addition, the cooling bath was removed, and the reaction was allowed to stir for 3 h. The mixture was transferred to a 2 L separatory funnel, and sequentially washed with water (2×500 mL), 2N HCl (250 mL), and water (500 mL). The resulting solution was suction filtered through a 100 g pad of silica gel and washed with methylene chloride. Evaporation of the solvents afforded the product 14 (40 g, 89%) as an oil. 1H NMR (300 MHz, CDCl3) δ 3.46 (t, 2H), 3.60 (q, 2H), 5.11 (s, 2H), 5.20 (br s, 1H), 7.35 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.[Br:16][CH2:17][CH2:18][NH2:19]>[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:19][CH2:18][CH2:17][Br:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NCCBr)OCc1ccccc1

Procedure:
A solution of 0.46 mol (78.5 g) of benzyloxycarbonyl chloride in 1 volume of acetone is added slowly to a solution of 0.45 mol (92.2 g) of 2-bromoethylamine in 1 liter of nomal sodium hydroxide solution. When the reaction has ended (about 48 hours), the acetone is evaporated off under reduced pressure and the residue is then acidified to between pH 1 and 2 and extracted with ether. Benzyloxycarbonylamino-2-bromoethane is obtained after evaporation. This product is reacted with N-hydroxyphthalimide following the procedure of Example 1-a to give N-2-benzyloxycarbonylaminoethoxyphthalimide in the form of white crystals melting at 95° C. with a yield of 73%. After treatment with hydrazine under the conditions of Example 1-a, 2-benzyloxycarbonylaminoethoxyamine hydrochloride melting at 178° C. is obtained (yield=95% relative to the phthalimide).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0 mg, 0.34 mmol) in ethanol (3 mL) and tetrahydrofuiran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 85.0 mg (86%) of the title compound as an orange solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1.[N:19]1[CH:20]=[C:21]2[N:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=13)[S:24][C:23]([C:31](O)=[O:32])=[CH:22]2.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[C:13]1([CH2:12][CH2:11][CH2:10][N:7]2[CH2:8][CH2:9][CH:4]([NH:3][C:31]([C:23]3[S:24][C:25]4[N:30]5[C:21](=[CH:20][N:19]=[C:29]5[CH:28]=[CH:27][CH:26]=4)[CH:22]=3)=[O:32])[CH2:5][CH2:6]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(CCCc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
Triethylamine (1.34 ml) was added dropwise to a suspension of 4-amino-1-(3-phenylpropyl)piperidine dihydrochloride (1.40 g) and dimethylformamide (10 ml). Into the mixture which was stirred for 10 minutes, 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.00 g) and diethyl cyanophosphonate (0.81 ml) were added. The mixture was stirred for 1 hour at room temperature, and 2 hours at 55° C. Ethyl acetate:tetrahydrofuran=4:1 (1.75 ml) and 1N-sodium hydroxide (30 ml) were added into the reaction mixture. The organic layer which was washed with sodium hydroxide (30 ml×3) and water (30 ml×2) was concentrated. The residual crystal which was added acetate (4 ml) was stirred for 1 hour at room temperature. This was dried under reduced pressure to obtain N-[1-(3-phenylpropan-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.07 g, 63.6%).