Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=O.[CH3:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18].[Na]>C(O)C>[CH3:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[CH:16]([C:17]#[N:18])[C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(CC#N)c(C)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCC(=O)C(C#N)c1ccc(C)cc1C
Yield: 78 %

Procedure:
This material was prepared using 130.65 g (0.750 mol) of diethyl succinate, 72.60 g (0.500 mol of 2,4-dimethylbenzyl cyanide, 14.95 g (0.65 mol) of sodium, and 168 ml of dry ethanol using the procedure described in Part A of Example I. The product was obtained as a dark red oil, 106.5 g (78% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:24]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(OC)cc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (21.75 g, 143 mmol) in 240 mL acetonitrile were successively added Cs2CO3 (55.9 g, 1.2 eq.) and ethyl bromoacetate (16.6 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 2 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents left 34.36 g of the title product, sufficiently pure to be used for the next step.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)C=O>C(Cl)(Cl)Cl>[OH:17][CH:3]([CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1
Reactant: O=C1CCc2ccc(OCC(O)CCl)cc2N1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1CCc2ccc(OCC(O)CN3CCN(c4ccccc4)CC3)cc2N1

Procedure:
5.1 Grams of 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril and 8 g of 4-phenylpiperazine are mixed with 50 ml of dimethylformamide and reacted at 50°-60° C. for 5 hours under stirring conditions. The reaction mixture is concentrated under a reduced pressure to dryness and the residue thus obtained is dissolved in 80 ml of chloroform, then the chloroform layer is washed 3 times with 5% of sodium hydrogencarbonate aqueous solution and washed 3 times with water and dried with anhydrous sodium sulfate. Chloroform is removed by distillation under a reduced pressure and the residue thus obtained is purified by a silica gel-chromatography [silica gel: Wako C-200, extracting solvent:chloroform:methanol=30:1 (v/v)]. Then the extracted product is converted into its hydrochloride by using ethanol containing hydrogen chloride and ethanol is removed by distillation under a reduced pressure. The thus obtained residue is recrystallized from water to obtain 5.6 g of 7-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.monohydrochloride.1/2 hydrate in the form of colorless crystals with a melting point of 122° C. (decomp.).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([CH:18]=1)[C@@H:10]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[CH2:11]1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N>C1COCC1>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][C:3]#[C:4][C:5]2[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([CH:18]=2)[C@@H:10]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[CH2:11]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCO
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
A solution of pre-dried 5-(3-hydroxy-1-propynyl)-2′-deoxyuridine (Robins, M. J. et al. (1983)) (565 mg, 2 mmol) in 40 mL of anhydrous THF under argon was treated with 4-nitrophenol (696 mg, 5 mmol), triphenylphosphine (787 mg, 3 mmol), and diisopropyl azodicarboxylate (590 liters, 3 mmol), and the reaction mixture heated at 60° C. until the solution was clear, and then 1 hour longer. The mixture was allowed to cool to 23° C. and then it was evaporated onto SiO2 and purified by chromatography using MeOH/CH2Cl2 as eluent to afford 107 mg (13%) of the desired ether product: melting point 112-118° C. H NMR ((CD3)2SO) δ11.65 (s, exchanges with D2O, 1, NH), 8.29 (s, 1, H6), 8.24 (d, J=9.3 Hz, 2, m-ArH), 7.23 (d, J=9.3 Hz, 2, o-ArH), 6.09 (pseudo-t, 1, H1′), 5.17 (s, 2, propargyl-CH2), 4.22 (m, 1, H3′), 3.80 (m, 1, H4′), 3.59 (m, 2, 5′-CH2), 2.13 (pseudo-t, 2, 2′-CH2). Low-resolution mass spectrum (DCI—NH3) onper-trimethylsilyated material, m/z 547 [M(TMS)2H+], 565 [M(TMS)2NH4+], 620 [M(TMS)3H+].
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[N:18][OH:19])[NH2:17])=[C:5]2[C@@H:4]2[CH2:20][CH2:21][N:3]12.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:22][CH2:23][C:24]1[O:19][N:18]=[C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:21][CH2:20][C@H:4]4[C:5]=23)[N:17]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 57.6 %

Procedure:
34.5 g (122 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were stirred with 23 g (140 mmol) of chloroacetic anhydride in 200 ml of N,N-dimethylformamide at room temperature overnight and at 110° for 2 hours. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel while eluting with methylene chloride/methanol 19/1. There were obtained 24 g (58%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one of m.p. 205°-207°.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].C(OCC)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[Mg]I>C1(C)C=CC=CC=1>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=2[Cl:36])[C:7]1=[O:8])[CH3:23]
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(Cl)cc2Cl)c2c1cc(I)cc2C(F)(F)F
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (150 mg, 0.341 mmol) in a mixed solvent of diethyl ether (2 mL) and toluene (1 mL) was added dropwise a freshly prepared 0.794 N 2,4-dichlorophenyl magnesium iodide in ether (0.45 mL, 0.387 mmol) at room temperature. The mixture was stirred for 1 h at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (111 mg, 55%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:16]=1)[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[CH2:27].N1C=CC=CC=1>CCOCC>[C:25]([O:13][CH2:12][C:11]1[CH:10]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:14]=1)(=[O:29])[C:26]([CH3:28])=[CH2:27]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(CO)cc(O[Si](C)(C)C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C(=O)OCc1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
3,5-Di-tert-butyldimethylsilyloxybenzyl alcohol (13.0 g, 35.2 mmole) and freshly distilled methacryloyl chloride (4.06 g, 38.8 mmole) were dissolved in 75 ml of ether and cooled to 0° C. Pyridine (3.21 g, 40.6 mmole) in ether (10 ml) was added dropwise and the reaction mixture was stirred overnight at room temperature. The pyridinium hydrochloride was filtered off and the filtrate was passed over a silica bed to remove the traces of methacrylic acid. Through the silica bed were passed another 75 ml of ether, and after combination of the fractions, the ether was removed under reduced pressure to obtain an oily product (14.2 g, 32.7 mmole, 93%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:8]=1)(=O)=O.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([Cl:35])[C:26]=1[NH2:36]>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[N:8]=1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#Cc1ccc(Nc2nccc(OS(=O)(=O)C(F)(F)F)n2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nccc(Nc3c(Cl)cc(C(F)(F)F)cc3Cl)n2)cc1
Temperature: 170 °C
Yield: 9.2 %

Procedure:
2-[(4-cyanophenyl)amino]-4-pyrimidinyl trifluoromethanesulfonate (0.0022 mol) and 2,6-dichloro-4-(trifluoromethyl)-benzenamine (0.0044 mol) were combined in 1,4-dioxane (2.5 ml) and heated in a sealed tube under Ar at 170° C. for 40 hours. The reaction mixture was allowed to cool to room temperature. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 97:2.7:0.3). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from CH3CN, filtered off and dried, yielding 0.086 g (9.2%) of 4-[[4-[[2,6-dichloro-4-(trifluoromethyl)-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile (compound 66).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6]P(=O)(OCC)OCC)#[N:4].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C=O.O>O1CCCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:6]=[CH:5][C:3]#[N:4]
Reactant: CCOP(=O)(CCC#N)OCC
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1ccccn1
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Sodium hydride (ca. 60%, 1.0 g, 28.1 mmol) was suspended in tetrahydrofuran (12 ml), and a solution of diethyl cyanoethylphosphonate (4.7 g, 26.8 mmol) in tetrahydrofuran (12 ml) was added thereto under ice cooling condition. The reaction mixture was stirred for 1 hr. A solution of 2-pyridinecarbaldehyde (2.7 g, 25.0 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at 0° C. to room temperature for 6 hrs. The reaction mixture was combined with water under ice cooling condition, concentrated to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give Z-form of the titled compound (0.50 g, 15%). And simultaneously, the fractions eluted with hexane-ethyl acetate (3:2, v/v) were collected and concentrated to give E-form of the titled compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH2:27][NH2:28]>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:33])([F:34])[F:35])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(C(F)(F)F)c(F)c2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3-fluoro-4-trifluoromethylbenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (44.7 mg, 98% yield). 1HNMR (500 MHz, CDCl3) δ: 12.13 (1H, s), 7.88 (1H, br s), 7.57–7.47 (4H, m), 7.06 (2H, dd, J=8.54, 7.32 Hz), 4.59 (2H, d, J=6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C20H12F6N3O3 (M−H): 456.0782; found: 456.0788.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 53 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (374 mg, 2.7 mmol) and 2-dimethylaminoethyl chloride hydrochloride. (46 mg, 0.32 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using a gradient of 1% methanol in dichloromethane to 5% methanol in dichloromethane afforded 24 mg (53%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-dimethylaminoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ −8.86 (d, 1H), 8.23 (d, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.43 (s, 1H), 4.20 (t, 2H), 2.80 (t, 2H), 2.37 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)C(C)C)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
15.0 g of 4'-hydroxy-3'-methoxy-2-methyl-propiophenone are dissolved in 300 ml of glacial acetic acid and 7.65 ml of 50.5 percent nitric acid (11.2N) in 40 ml of glacial acetic acid are added dropwise thereto while stiring within 15 minutes. After 15 minutes the reaction mixture is poured into ice-water and the separated crystals are filtered under suction, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up on methylene chloride and filtered over 100 g of silica gel. The thus-obtained crystals are recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 85°-87°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([NH2:22])[C:17]([NH2:21])=[CH:18][C:19]=1[F:20]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:21][C:17]3[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=3[N:22]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2[nH]1
Temperature: 180 °C
Yield: 77 %

Procedure:
To a suspension of 4-chloro-2-methoxy-benzoic acid (5 g, 0.026 mol; CAS Reg. No. 78955-90-5) in polyphosphoric acid (50 g) was added compound 4,5-difluoro-benzene-1,2-diamine (3.86 g, 0.026 mol; CAS Reg. No. 76179-40-3) and the resulting mixture was heated to 180° C. for 1 h. The reaction mixture was then cooled and neutralized with ice cold 10% aqueous sodium carbonate solution, and then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (25% ethyl acetate/n-hexane) to give the desired compound as a brown solid (77%). MS (Turbo Spray): m/z=295.1 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[S:8][C:9]3[CH2:14][CH:13]([CH2:15][C:16]([O-:18])=[O:17])[CH2:12][CH2:11][C:10]=3[C:3]1=2.[C:19]([C:21]1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:19]([O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[C:3]3[C:2](=[O:1])[NH:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH:14]=1)[CH3:21]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C([O-])CC1CCc2c(sc3nc[nH]c(=O)c23)C1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc2c(c1)sc1nc[nH]c(=O)c12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
(4-Oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)acetate (5 g, 17.10 mmol, from step 2) was added to DDQ (9.71 g, 42.76 mmol, 2.5 equiv) in 1,4-dioxane (50 mL) solution under argon. The reaction mixture was heated to 90° C. for 15 h. The mixture was then allowed to cool to rt and the brown solid precipitated from solution. The solid was filtered and washed with 1,4-dioxane (2×30 mL). The filtrate was concentrated in vacuo. Saturated aqueous NaHCO3 (150 mL) was then slowly poured into the concentrated filtrate at 0° C. The mixture was stirred at 0° C. for 10 min then extracted with DCM (3×300 mL). The combined organic layer was washed with saturated aqueous NaHCO3 (100 mL), brine (30 mL) and dried (Na2SO4), then concentrated in vacuo. Ethyl ether (2×15 mL) was used to triturated the product. After drying, 1.78 g (6.18 mmol, 35%) of the desired product was obtained as a brown solid and it was used without further purification. 1H-NMR (CD3OD) δ 8.46 (d, J=8.1 Hz, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 7.43 (d, J=8.2 Hz, 1H), 4.14 (q, 2H), 3.79 (s, 2H), 1.25 (t, 3H), LCMS RT=2.52 min, [M+H]+=289
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:17]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([NH2:17])=[O:9])=[CH:2]1
Reactant: O=C(O)Cc1ccsc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)Cc1ccsc1
Reaction time: 8 h

Procedure:
Commercially available 3-thiophene acetic acid (2.0 g, 14.07 mmol) was dissolved in DCM (45 mL) under nitrogen. Then oxalyl chloride (1.35 mL, 15.48 mmol) was added and the reaction was stirred overnight. Then ammonium hydroxide (30% as NH3 solution) (8.22 mL) was added dropwise with stirring. The reaction mixture was evaporated to provide 2-(3-thienyl)acetamide as a beige solid (3.2082 g). LCMS: (M+H)+=142.1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:31][S:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:37]([C:36]2[CH:39]=[CH:40][C:33]([S:32][CH3:31])=[CH:34][CH:35]=2)[OH:38])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)cnc21
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 45.1 %

Procedure:
To a solution of 1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (3 g, 10.87 mmol) in dry tetrahydrofuran (40 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (2.5 M, 6.8 mL 17 mmol). The mixture was stirred at −78° C. for 35 min and then treated with 4-methylsulfanyl-benzaldehyde (2.8 mL, 21.0 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanol as a white solid (2.1 g, 45.2%): LC/MS m/e calcd for C21H17FN2O3S2 [M+H]+ 429.51, observed 428.7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15](Br)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[S:42]([CH3:45])(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([C:38]3[CH:39]=[CH:40][C:41]([S:42]([CH3:45])(=[O:43])=[O:44])=[C:36]([F:35])[CH:37]=3)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Yield: 36.5 %

Procedure:
Dissolve 1-{2-[4-(6-benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (350 mg, 0.65 mmol) and 3-fluoro-4-methanesulfonyl-phenyl-boronic acid (213 mg, 0.98 mmol) in dioxane (10 mL) and add 10% aqueous sodium carbonate (9 mL) and Pd(PPh3)4 (75 mg, 0.065 mmol). Heat to reflux for 3 hours. Partition the reaction mixture between dichloromethane (20 mL) and saturated aqueous ammonium chloride (20 mL). Wash the organic layer with brine (30 mL), dry with sodium sulfate, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 5%) to give 150 mg of the title compound contaminated with a 2-H reduced byproduct. Take the mixture on to the next step without further purification.