Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([C:6]([F:9])([F:8])[F:7])=[CH:3][CH:4]=[O:5].[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]([C:6]([F:9])([F:8])[F:7])=[CH:3][CH2:4][OH:5]
Reactant: O=CC=C(Cl)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC=C(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 3-chloro-4,4,4-trifluorobut-2-enal (10 g, 0.063 mol) and THF (30 mL) is introduced to a 100 mL round-bottomed reaction flask equipped with an addition funnel and a condenser under nitrogen purge. The flask, including the reaction mixture contained therein, is immersed in a water bath, and sodium borohydride (1.2 g, 0.032 mol) is added slowly, under purge of nitrogen, via a solid addition funnel such that the reaction mixture does hot rise above 45° C. After complete addition of the sodium borohydride, the reaction mixture is stirred at ambient temperature for one hour. The reaction mixture is then poured into cold water (30 mL) with mixing and extracted with diethyl ether (2×40 mL). The ether extract is dried using magnesium sulfate, filtered and concentrated to afford 10.1 g(quantitative yield) of 3-chloro-4,4,4-trifluorobut-2-en-l-ol as a clear liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[C:9]=2[C:12]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1oc2ccc(Cl)c(OC)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Cl)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To 105 mg of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was triturated with dichloromethane and dried under vacuum to give 82 mg (87% yield) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=[N:3]1.COCCN(S(F)(F)[F:31])CCOC.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C1COCC1.O>[F:31][C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:18]([O-:20])=[O:19])[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1(O)CCC2(CC1)OCCO2
Reactant: COCCN(CCOC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.68 g, 13.0 mmol) in dry DCM (80 mL) under nitrogen was added dropwise a solution of deoxo-Fluor® (50% in THF, 14.1 mL, 39.0 mmol). The reaction mixture was stirred at room temperature for 1 hr. After cooling to 0° C., saturated aqueous NaHCO3 (100 mL) was added, dropwise initially, and the mixture was extracted with DCM (2×75 mL). The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (30-50% EtOAc/isohexane) gave a pale yellow oil. A portion of this oil (780 mg, 2.74 mmol) was dissolved in THF (20 mL) and treated with 2 M aqueous HCl (3 mL). The reaction mixture was stirred at room temperature for 4 hr, heated at 60° C. for 7 hr and stirred at room temperature for 18 hr. Water (10 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (25-40% EtOAc/isohexane) gave 4-fluoro-4-(2-methyl-4-nitro-pyrazol-3-yl)cyclohexanone as a white solid (490 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.10 and 8.09 (2s, 1H), 4.17 and 4.15 (2s, 3H), 3.16-2.94 (m, 2H), 2.84-2.72 (m, 2H), 2.51 (dd, J=15.4, 5.6 Hz, 2H), 2.43-2.33 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N+:22]([O-:24])=[O:23])(=[O:32])=[O:33])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 2-nitrobenzenesulphonic acid chloride analogously to Example 2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([NH2:24])=[O:23])[S:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(#N)C.C(OCC)(=O)C.CC#N.CC#N.Cl[Pd]Cl>[NH2:24][C:22]([N:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[C:13]1[C:11]1[S:10][CH:9]=[C:8]([NH:7][C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1csc(C#Cc2ccccc2NC(N)=O)c1
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1csc(-c2cc3ccccc3n2C(N)=O)c1
Temperature: 90 °C

Procedure:
To a degassed solution of tert-butyl[5-({2-[(aminocarbonyl)amino]phenyl}ethynyl)-3-thienyl]carbamate (112 mg, 0.314 mmol, 1 eq) in anhydrous acetonitrile (2 mL) was added bis(acetonitrile)dichloropalladium(II) (16.3 mg, 0.2 eq). After the reaction mixture was heated at 90° C. for 50 minutes, it was cooled to room temp, and diluted with ethyl acetate. The mixture was washed with aqueous ammonium chloride, water, and brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the dark brown mixture was subject to a gradient column chromatography (EtOAc-hex from 1; 100 to 1:5) to yield tert-butyl {5-[1-(aminocarbonyl)-1H-indol-2-yl]-3-thienyl}carbamate as white powder in amount of 23 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:15])[CH2:7]1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14]([NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[O:15])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCNCC1
Yield: 175.1 %

Procedure:
Intermediate 15 (0.157 g) was stirred in dioxane (4 ml) containing 4.0M hydrogen chloride in dioxane (0.78 ml) for 16 h, at 23° C. under nitrogen. The solvent was removed in vacuo, azeotroped with dichloromethane (20 ml), triturated in ether and dried under vacuum to give the title compound as a pale yellow solid (0.12 g).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[I:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:12]3[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([I:9])[CH:11]=3)=[O:31])=[CH:20][N:21]=2)[CH2:26][CH2:27]1)=[O:5]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)nc2)cc1I
Temperature: 25 °C

Procedure:
6-[4-(3,3-Dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the addition 3,3-dimethyl-butyryl chloride (0.055 mmol) to N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide (0.05 mmol) partially dissolved in DCM followed by the addition of TEA and stirred at room temperature over night. The reaction was diluted with ethyl acetate washed with water and brine, dried over sodium sulfate, concentrated and the residue was trirturated with ether and hexanes to afford the product, 6-[4-(3,3-dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide. LCMS calcd for C23H29IN4O2 (m/e) 520, obsd 521 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[K].[NH2:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17]>[Cl-].C[N+](C)(C)C.S1(CCCC1)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:14][CH:15]([CH:16]([CH3:18])[CH3:17])[C:19]([OH:21])=[O:20]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 125 °C

Procedure:
A mixture of 3.04 parts of 3-chloro-4-fluorobenzotrifluoride, 4.5 parts of anhydrous potassium salt of valine, 0.98 parts of tetramethyl-ammonium chloride and 24.0 parts of sulfolane solvent was charged to a reaction vessel, the mixture was heated to 125° C. and maintained thereat for about 16 hours then cooled, diluted with water and acidified to a pH of 1. The aqueous layer was extracted several times with diethyl ether. The ether layer was then washed with copious amounts of water, then dried and concentrated to yield 3.4 parts of 2-(2-chloro-4-trifluoromethylphenyl-amino)-3methylbutanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 1,2-di(t-butoxycarbonylamino)-3-hydroxypropane (3 g.) and triethylamine (2 ml.) in CH2Cl2 (30 ml.) at 0° was added methanesulphonyl chloride (1.0 ml.) with stirring. Stirring at this temperature was continued for 1 hour and the mixture was then washed with water. The organic layer was separated, dried and the solvent evaporated to give 1,2-di(t-butoxycarbonylamino)-3-methanesulphonyloxypropane (2.9 g.), m.p. 94°-96°.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C:9]([C:17]1[CH:18]=[C:19]([O:23][Si](C(C)(C)C)(C)C)[CH:20]=[CH:21][CH:22]=1)([C:12]1SC=CN=1)[CH2:10]C>>[OH:8][C:9]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)([CH3:12])[CH3:10]
Reactant: CCC(O)(c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nccs1
Solvent: Oc1ccccc1
Product: CC(C)(O)c1cccc(O)c1

Procedure:
Following the procedure described for Phenol 7, Step 3 but substituting 3-(2-hydroxyprop-2-yl)(O-tert-butyldiphenylsilyl)phenol from Step 2 for 3-[1-hydroxy-1-(thiazol-2-yl)propyl)(O-tert-butyldimethylsilyl)phenol, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[N:36]([CH2:37][CH2:38][CH3:39])[CH:35]=[N:34][N:33]=2)[CH2:11][S:12][CH2:13][CH:14]([C:24]2[N:28]([CH2:29][CH2:30][CH3:31])[CH:27]=[N:26][N:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:32]2[N:36]([CH2:37][CH2:38][CH3:39])[CH:35]=[N:34][N:33]=2)[CH2:11][S:12][CH2:13][CH:14]([C:24]2[N:28]([CH2:29][CH2:30][CH3:31])[CH:27]=[N:26][N:25]=2)[C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[CH:8][CH:9]=1
Reactant: CCCn1cnnc1C(CSCC(c1ccc([N+](=O)[O-])cc1)c1nncn1CCC)c1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cnnc1C(CSCC(c1ccc(N)cc1)c1nncn1CCC)c1ccc(N)cc1
Yield: 105.2 %

Procedure:
4-nitrophenyl 2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfide (3.2 g), reduced iron (3.1 g) and calcium chloride (0.6 g) were added to 85% aqueous solution of ethanol (100 ml), and the mixture was refluxed for 3 hours. The reaction solution was filtered with Celite, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 4-aminophenyl 2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfide (3.0 g) as yellow amorphous.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:17]=[C:18]2[C:41](=[CH:42][CH:43]=1)[C:22]1=[N:23][O:24][C:25]([C:26]3[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:28][N:27]=3)=[C:21]1[CH2:20][CH2:19]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:5]1.C(#N)C.[ClH:47]>O>[OH:1][CH:2]([C:16]1[CH:17]=[C:18]2[C:41](=[CH:42][CH:43]=1)[C:22]1=[N:23][O:24][C:25]([C:26]3[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[O:28][N:27]=3)=[C:21]1[CH2:20][CH2:19]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1.[ClH:47]
Reactant: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=C(O)C[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 60 °C

Procedure:
To ethyl 2-((3R)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidin-3-yl)acetate (Preparation 19A, 125 mg, 0.210 mmol were added acetonitrile (3 mL) and 6N hydrochloric acid (3 mL). The reaction mixture was heated at 60° C. for 4 h. The reaction mixture was concentrated under reduced pressure to yield a solid. To the solid was added acetonitrile (0.5 mL) and water (10 mL). The contents were sonicated and lyophilized to yield 2-((3R)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidin-3-yl)acetic acid, hydrochloric acid (150 mg, 0.248 mmol, 70.3% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]([OH:36])[CH2:33][NH:34][CH3:35])[CH:29]=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]([OH:36])[CH2:33][N:34]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[CH:17]=2)[CH3:35])[CH:29]=[CH:30][CH:31]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.21 mmol), 1-(3-aminophenyl)-2-(methylamino)ethanol (Zhur. Obshchei Khim. (J. Gen. Chem.) 1952, 22, 496-502)(53 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 3 mL of water, left overnight) gave the title compound (62 mg) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[N:4][C:3]=1[CH3:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:18][C:3]1[N:4]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]=1[C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccs1
Reactant: Cc1nc(N2CCN(C)CC2)c2nnnn2c1Br
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)c2nnnn2c1-c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-6-methyl-8-(4-methylpiperazin-1-yl)tetrazolo[1,5-a]pyrazine (0.72 g, 2.3 mmol), thiophene-2-boronic acid (0.46 g, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol), Cs2CO3 (1.2 g, 3.7 mmol), 1,4-dioxane (12 mL) and water (6 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 100° C. under N2 atmosphere overnight. Work-up: the reaction mixture was poured into 0.1 M HCl (40 mL) and washed with EtOAc (50 mL×2). The aqueous layer was then basified with solid NaHCO3 and extracted with CH2Cl2 (50 mL×3). The combined CH2Cl2 layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% MeOH in CH2Cl2, to afford 165 mg (23%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 7.59 (dd, J=5.1, 1.2 Hz, 1H), 7.38 (dd, J=3.6, 1.2 Hz, 1H), 7.21 (dd, J=5.1, 3.6 Hz, 1H), 4.40 (br, 4H), 2.60 (t, J=5.1 Hz, 4H), 2.47 (s, 3H), 2.38 (s, 3H). MS m/z: 316 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[CH:6]=[C:7]1[C:12](=[CH:13]2)[CH:11]=[C:10]([OH:18])[CH:9]=[CH:8]1)=[O:3].C(N(CC)CC)C.O1CCCC1.[P:31](=[O:51])(Cl)([S:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:31](=[O:51])([S:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)([O:18][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:14]3[C:5]([CH:6]=2)=[C:4]([S:2]([CH3:1])=[O:3])[CH:17]=[CH:16][CH:15]=3)[CH:11]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(SP(=O)(Cl)Oc2ccc(F)cc2)cc1
Reactant: CS(=O)c1cccc2cc3cc(O)ccc3cc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)c1cccc2cc3cc(OP(=O)(Oc4ccc(F)cc4)Sc4ccc([N+](=O)[O-])cc4)ccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Methylsulfinyl-2-anthrol (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-fluorophenyl) S-(4-nitrophenyl) phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-fluorophenyl) O-(5-methylfulfinyl-2-anthryl) S-(4-nitrophenyl) phosphorothioate.
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:16]=[N:17][C:18]([C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[N:34][C:35]([N:38]5[C:42]([CH3:43])=[CH:41][CH:40]=[C:39]5[CH3:44])=[N:36][CH:37]=4)=[CH:28][CH:27]=3)([CH3:25])[CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)=[CH2:8])CCC.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CCO>[CH3:44][C:39]1[N:38]([C:35]2[N:34]=[CH:33][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:21]([C:18]4[N:17]=[CH:16][C:15]([C:12]5[N:11]=[N:10][C:9]([C:7](=[O:6])[CH3:8])=[CH:14][CH:13]=5)=[CH:20][CH:19]=4)([CH3:25])[CH:22]([CH3:23])[CH3:24])=[CH:31][CH:30]=3)=[CH:37][N:36]=2)[C:42]([CH3:43])=[CH:41][CH:40]=1
Reactant: C=C(OCCCC)c1ccc(-c2ccc(C(C)(c3ccc(-c4cnc(-n5c(C)ccc5C)nc4)cc3)C(C)C)nc2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(C(C)(c3ccc(-c4cnc(-n5c(C)ccc5C)nc4)cc3)C(C)C)nc2)nn1
Reaction time: 0.25 h

Procedure:
Hydrochloric acid (100 mL of a 1.0 M solution in EtOH) was added to a stirred solution of 4y (7.03 g, 12.3 mmol) in EtOH (50.0 mL) at 0° C. After approximately 15 min, a second portion of hydrochloric acid (100 mL of a 2.0 M aqueous solution) was added, and after another 15 min, a third portion of hydrochloric acid (100 mL of a 1.0 M solution in EtOH). After an additional 15 min, a final portion of hydrochloric acid (50 mL of a 6.0 M aqueous solution) was added, and the resulting reaction was aged for 30 min. The reaction was carefully neutralized by the addition of solid sodium bicarbonate. The resulting mixture was saturated with solid sodium chloride and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 4z m/z (ES) 517 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.32 (d, 1H, J=2.3 Hz), 8.95 (s, 2H), 8.47 (dd, 1H, J=2.3, 8.5 Hz), 8.22 (d, 1H, J=8.9 Hz), 8.04 (d, 1H, J=8.9 Hz), 7.58 (m, 4H), 7.50 (d, 1H, J=8.4 Hz), 5.91 (s, 2H), 3.24 (m, 1H), 2.94 (s, 3H), 2.37 (s, 6H), 1.82 (s, 3H), 0.94 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:7]=1[CH2:8]O.O=S(Cl)[Cl:20].C(N1C=CN=C1SC1C=NC=C(Cl)C=1CCl)CCC>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:7]=1[CH2:8][Cl:20]
Reactant: OCc1c(Cl)cncc1OCC1CCCCO1
Reactant: O=S(Cl)Cl
Agent: CCCCn1ccnc1Sc1cncc(Cl)c1CCl
Product: ClCc1c(Cl)cncc1OCC1CCCCO1

Procedure:
[3-Chloro-5-(tetrahydro-pyran-2-ylmethoxy)-pyridin-4-yl]-methanol (10 mg, 0.039 mmol) was chlorinated with SOCl2 according to the synthesis of 3-(1-butyl-1H-imidazol-2-ylsulfanyl)-5-chloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 276.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[CH2:15][C:14](=[O:16])[CH2:13]1)=O.[CH3:17]C(O)=O>CC#N>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)[N:1]([CH3:17])[C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Reactant: CC(=O)O
Solvent: CC#N
Product: Cn1c(C2CC(=O)C2)nc2ccc(Br)cc21

Procedure:
To a stirred solution of N-(2-amino-4-bromophenyl)-3-oxocyclobutanecarboxamide (2.7 g) in CH3CN (20 ml) was added AcOH (2 ml), and the mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo, and poured into saturated NaHCO3 solution. The mixture was extracted with EtOAc, washed with water and brine successively, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.0 g) as an off-white solid.