Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=2)[S:9]1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg, 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg, 0.38 nmuol) in 5.0 mL Et3N was purged with argon for 10 minutes. To this solution were added bis(triphenylphosphine)-palladium(II) chloride (88.0 mg, 0.12 mmol) and copper(I) iodide (22.9 mg, 0.12 mmol). After sparging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography of the residual solid, afforded 100 mg (72%) of ethyl 4-[(2,2-dimethyl-4-oxo-thiochroman-6-yl)ethynyl]-benzoate as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.53 (1H, dd, J=1.8, 8.2 Hz), 7.21 (1H, d, J=8.2 Hz), 4.37 (2H, q, J=7.1 Hz), 2.88 (2H, s), 1.47 (6H, s), 1.39 (3H, t, J=7.1 Hz).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].[OH-].[Na+]>C1COCC1>[CH3:12][NH:11][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the tide compound. MS (m/e): 312.0 ([M−H]−, 100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17]>C(OCC)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16](=[O:18])[CH3:17])[N:3]=1
Reactant: CC(=O)N(C)C
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1

Procedure:
29.7 g of 2,6-dibromopyridine were reacted with 86.1 ml of n-butyllithium (1.6-molar solution in n-hexane) and 12 g of N,N-dimethylacetamide in 300 ml of diethyl ether as described in the literature [J. Organomet. Chem. 56 (1973), 53-66; Chem. Ber. 125 (1992), 1169-1190] to give 2-bromo-6-acetylpyridine.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:15])[C:3]=1[F:16]>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:15])[C:3]=1[F:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(N)c(N)c(F)c1F

Procedure:
Prepared analogously to example 1b by hydrogenation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate using palladium/charcoal 10% in methanol and dichloromethane.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:8]([C:3]1=[CH:2][C:1]([O:6][C:4]1=[O:5])=[O:7])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
A styrene-maleic anhydride interpolymer is prepared by the following procedure. 176 parts of maleic anhydride are dissolved in 2641 parts of xylene. To this mixture at 105° C. is added first 188 parts of styrene. Then 1.83 parts benzoyl peroxide dissolved in 32 parts xylene are added over a 1.5 hour period. The mixture is maintained at 104°-106° C. for 4 hours, then is stripped to 150° C. at 200 torr. The resulting interpolymer has RSV of 0.25.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:3]=1
Reactant: C#CCCCCO
Reactant: Brc1cccnc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCC#Cc1cccnc1
Yield: 76.5 %

Procedure:
A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed for 15 minutes with argon, and 3 g (4,3 mmol) of bis(triphenylphosphine)palladium(II)chloride and 450 mg of cuprous iodide is added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2CO3), concentrated and bulb-to-bulb distilled (b.p. 120°-130° C./0.05 mbar), to give 63 g of 6-(3-pyridyl)hex-5-ynol as a yellow oil, which is dissolved in 500 ml of ethyl acetate and af ter addition of 15 ml of quinoline is hydrogenated f or 5 h over 6 g Lindlar catalyst (Pb-poisoned Pd catalyst) in a Parrhydrogenator. The crude product is evaporatively distilled (b.p. 120°-130° C./0.05 mbar), yielding 61 g (73%) of (Z)-6-(3-pyridyl)hex-5-enol as a colourless viscous liquid. (C11H15NO; F.W. 177.3).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][Si:8](Cl)([CH3:10])[CH3:9]>C[Si](N[Si](C)(C)C)(C)C>[Si:8]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][Si:8]([CH3:10])([CH3:9])[CH3:7])([CH3:10])([CH3:9])[CH3:7]
Reactant: OCCCCO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCCCCO[Si](C)(C)C
Temperature: 50 °C

Procedure:
1,4-Butanediol (54 g, 0.60 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.3 mL trimethylsilyl chloride. A portion of HMDS (ca. 20 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (120 mL, 0.66 tool total) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50° C. Heating was continued at 100° C. (3 h), and 150° C. (1.5 h) GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 127.8 g of colorless oil, bp 97°-99° C./15 mm. 1H NMR (CDCl3): 3.75-3.50 (m, 4H), 1.75-1.50 (m, 4H), 0.16 (s, 18H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(C#N)C=CC=3OCC2=O)CC1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1[CH:60]1[CH2:62][CH:61]1[CH:63]=O.C([BH3-])#N.[Na+]>>[F:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=1[CH:60]1[CH2:62][CH:61]1[CH2:63][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: O=CC1CC1c1cc(F)ccc1F
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NCC3CC3c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 42 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1 mmol), 2-(2,5-difluorophenyl)cyclopropanecarbaldehyde (Intermediate 68) (200 mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol) were reacted as described under Example 21 to give 196 mg (42%) product as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][O:14][C:15]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][O:14][C:15]([C:21]([F:22])([F:23])[F:24])([C:25]([F:26])([F:27])[F:28])[C:16]([OH:18])=[O:17])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 22 h
Yield: 43.3 %

Procedure:
A mixture of ethyl 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (502 mg.) potassium hydroxide (88 mg.), methanol (4 ml.) and water (1 ml.) is stirred at 20° C. for 22 hours, then evaporated in vacuo. The residue is dissolved in water, and the solution is acidified with 3 N-hydrochloric acid. The solid which separates is filtered off. Crystallisation from a mixture of cyclohexane and light petroleum (b.p. 40°-60° C.) gives prisms (204 mg.) of 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 134°-135° C.
Reaction SMILES: [C:1]([CH2:5][OH:6])([F:4])([F:3])[F:2].N1C=CC=CC=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl.N1C=CC=CC=1>>[C:1]([CH2:5][O:6][S:14]([CH3:13])(=[O:16])=[O:15])([F:4])([F:3])[F:2]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(F)(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added CF3CH2OH (337.1 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, methanesulfonyl chloride (364.15 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:16]N1C(=O)CCC1=O.[Na+].[Cl-]>C(Cl)(Cl)Cl>[Cl:16][C:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccccc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To benzaldehyde oxime (12.2 g, 0.1 mol) in chloroform was added catalytic amount of pyridine, followed by N-chlorosuccinimide (13.35 g, 0.1 mol) at room temperature. The reaction mixture was stirred for 1.5 h, then saturated aqueous NaCl was added. The organic phase was washed with saturated aqueous NaCl (twice) and dried with MgSO4. The solvent was removed under reduced pressure. 13.85 g α-chlorobenzaldehyde oxime was obtained. The yield was 87%.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:18]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of butane-1,4-diol (180.0 g, 2.0 mol), triethylamine (242.4 g, 2.4 mol) in DCM (1500 mL) was dropwised tert-butylchlorodimethylsilane (306 g, 2.03 mol) in 500 mL DCM, the mixture was stirred for about 1 hr at 0° C., then was warmed at RT for overnight. the reaction was washed with water (500 mL×3) and brine (500×3 mL), dried over Na2SO4 and concentrated to give the desired compound of 4-(tert-butyl dimethylsilyl oxy) butan-1-ol
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:15]1[C:21](=[O:22])[CH:20]2[N:23](C)[CH:17]([CH2:18][CH2:19]2)[C:16]1=[O:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([N:15]1[C:16](=[O:25])[CH:17]2[NH:23][CH:20]([CH2:19][CH2:18]2)[C:21]1=[O:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1C2CCC1C(=O)N(Cc1ccccc1)C2=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1
Yield: 5 %

Procedure:
In a dry flask were mixed 15 g of dry pyridine hydrochloride and 3.15 g (130 mmol) of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo [3.2.1] octane prepared according to U.S. Pat. No 3,328,398 in June 27, 1967. The mixture was heated in an oil bath preheated at 220° C. for 20 mn, cooled in an ice-bath, dissolved in 90 ml water, extracted four times with 100 ml ethyl ether. The organic layers were collected and dried over magnesium sulfate. After removing the solvent, the residue was chromatographed over silica-gel using dichloromethane/ethylacetate (80:20) to afford 1.5 g of the title compound (50%). M.P. 72° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of piperidine-2-ethanol (20 g, 155 mmol) in ethanol (240 mL) was added K2CO3 (106 g, 775.1 mmol) followed by addition of benzyl bromide (18.4 mL, 155.04 mmol) at 0° C. The reaction mixture was stirred at rt overnight, filtered through a sintered funnel and concentrated. The crude material was dissolved in ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to get liquid compound 49.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>C1COCC1>[CH:20]1([NH:19][C:18](=[O:10])[NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13 (52 mg, 0.058 mmol), HOBT (10 mg, 0.065 mmol) and DCC (16 mg, 0.079 mmol) in THF (2 ml) was stirred for 1 hour at room temperature and filtered to remove resulting dicyclohexyl urea. The filtrate was concentrated and the residue was dissolved in 1 ml of 50% aqueous dioxane. To the mixture was added a solution of D-3,4-dihydroxyphenylalanine (D-DOPA) (24 mg, 0.12 mmol) and triethylamine (20 μl, 0.14 mmol) in 1 ml of 50% aqueous dioxane. The mixture was stirred for 1 day at room temperature and then dioxane was removed under reduced pressure. To the residue was added 50 ml of H2O and the mixture was acidified with 1N HCl to pH 2. The precipitate formed was collected by filtration and chromatographed on a column of C-18 silica gel (Bondpak C18, 20 i.d.×200 mm). The column was eluted with 30-40% acetonitrile-1/1000N HCl and the desired fraction was concentrated and lyophilized to give 4'N-CBZ protected title compound (23 mg, yield 37%).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.Cl.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 3.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (270 mg) described in Preparation Example 25 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 170, the title compound (17 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:14](=[O:15])[CH2:13][Cl:12])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Yield: 95.6 %

Procedure:
3.0 g (17.5 mmol) of 2-amino-5-chlorobenzoic acid and 3.95 g (35.0 mmol) of chloroacetyl chloride were heated under reflux in 60 mL of toluene for 1 hour. Thereafter, the solvent was distilled off under reduced pressure, and H2O was added to the resulting residue. Solids were collected by filtration to give 4.15 g of 5-chloro-2-[(chloroacetyl)amino]benzoic acid (yield: 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([I:13])=[CH:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6]([I:13])=[CH:5]2
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc2ccc(Br)cc2cc1I
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-2-chloro-3-iodoquinoline (0.918 g, 2.492 mmol) and 4-methoxybenzylamine (2.279 mL, 17.44 mmol) in N-methyl-2-pyrrolidinone (3.56 mL). The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 20 min. The solution was poured into water and extracted with diethyl ether. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give the crude material 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine as a tan solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:12]2[CH:13]=[CH:14][C:10]([Cl:9])=[N:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccn(-c2ncccc2Cl)n1
Temperature: 100 °C

Procedure:
To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in N,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g, 1.06 mol), and the reaction mixture was then heated to 100° C. for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. The precipitated solids were filtered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford the title product as a white solid (39.75 g).
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]>CCCCCC.C(OCC)C>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: CCCCC1=CC=CC1
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1(CCCC)C=CC=C1

Procedure:
Being cooled in an ice-water bath, a solution of 49.8 ml of butyl lithium(0.125 mol) in 2.5M hexane was slowly dripped to a solution of 15.2 g(0.125 mol) of butyl-cyclopentadiene in 200 ml diethylether with stirring. After the dripping was finished, the resultant mixture was continuously stirred for 1 hour, a white muddy solution of butyl-cyclopentadienyl lithium was then obtained.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1ccccc1
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (3.23 mL, 1 equiv) and phenol (g, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (4.84 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow oil (g, %). (oil solidified in the freezer).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:30])[F:29])=[CH:13][CH:12]=1)=[O:10]>[Pd].CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:29])[F:30])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Reaction time: 12 h

Procedure:
A mixture of N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (step 8) (100 mg), methanol (10 ml) and 10% Pd/C (10 mg) was hydrogenated at 60 psi for 12 h. Filteration of the reaction mixture over celite bed and removal of solvent methanol under reduced pressure afforded N-(3,5-dichloropyrid-4-yl) -4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide as white solid. mp: >270° C.