Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1>Cl.C(=O)([O-])[O-].[Na+].[Na+]>[ClH:1].[CH3:2][N:3]1[CH2:4][CH:5]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CN1CCC(c2c[nH]c3ccc(CCNS(C)(=O)=O)cc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1CC=C(c2c[nH]c3ccc(CCNS(C)(=O)=O)cc23)CC1

Procedure:
The product of Stage (ii) (0.93 g) was dissolved in hydrochloric acid (2N, 15 ml) and the resulting solution was basified in sodium carbonate solution (2N) and extracted with ethyl acetate. The insoluble solid (title compound free base, 0.28 g) was filtered off and the combined organic extract was dried (MgSO4) and evaporated to dryness to give more title compound base as a solid (0.42 g) m.p. 198°-200°. A sample of this material (0.21 g) was dissolved in methanol (6 ml) and treated with ethereal hydrogen chloride. On diluting with ether (30 ml), the title salt was precipitated. This was triturated with ether (200 ml) and then dried at 50° in vacuo to give the title compound as a solid (0.19 g), m.p. 126°-9°. (dec).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([Cl:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>C(Cl)Cl>[ClH:45].[F:25][C:10]1([C:6]2[CH:5]=[C:4]([NH:3][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=3)(=[O:44])=[O:43])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:15]1
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3(F)CCN(CCOc4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a suspension of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride (100 mg, 0.26 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (118 mg, 0.91 mmol) and the mixture stirred at room temperature until a clear solution resulted. This solution was then cooled to 0° C. and 4-methyl-benzenesulfonyl chloride (58 mg, 0.28 mmol) was then added and the reaction stirred at 0° C. for 1 hour then room temperature for 3 hours. After this time the mixture was quenched by the addition of 25% ammonium chloride solution (10 mL). The organic layer was separated and the aqueous extracted with ethyl acetate (2×10 mL). The combined extracts were dried over magnesium sulfate and filtered and concentrated. The residue was re-dissolved in ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated to a viscous yellow oil which was treated with 10% methanolic hydrogen chloride (10 mL) and re-concentrated. The residue was triturated with ethyl acetate (5 mL) and then dried under high vacuum to afford a 49% yield of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:25])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:4]1([CH2:1][C:2](=[O:25])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH3:18]
Reactant: C=CCC1(CC)CCc2cc(OC)ccc2C1=O
Reactant: O=C1C=CC(=O)C=C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: CCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-allyl-2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (931 mg, 3.82 mmol) in acetonitrile (11 mL) was treated with benzoquinone (619 mg, 5.73 mmol), palladium(II) acetate (172 mg, 0.76 mmol), water (0.56 mL, 31 mmol), and perchloric acid (70%, 0.15 mL, 1.74 mmol). The resulting mixture was stirred overnight at room temperature, then filtered through a small plug of silica gel. The filtrate was diluted with CH2Cl2, washed with water, and the aqueous phase was back-extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to afford crude 2-ethyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone as an orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].Br[C:21]1[CH:22]=[C:23]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccc(B(O)O)cc1OCCOC
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1ccc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)cc1OCCOC
Yield: 63.5 %

Procedure:
A vial is charged with 81.0 mg (0.300 mmol) of 3,4-bis (2-methoxyethoxy)phenylboronic acid, 60.6 mg (0.200 mmol) of 5-bromo-3-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine and 8.3 mg (5 mol %) of bis(triphenylphosphino)palladium(II)-dichloride. 1.5 ml of acetonitrile and 1.5 ml of a 2 M aqueous solution of sodium carbonate were added and the mixture irradiated in a Personal Chemistry® microwave reactor to 150° C. for 15 minutes. The mixture was extracted with three times with 15 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The dark brown residue (187 mg) was purified by flash chromatography on silicon using a gradient of ethyl acetate in hexane to give 57 mg of 5-[3,4-bis-(2-methoxy-ethoxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a colorless powder. 1H-NMR (d4-methanol) δ: 8.41 [1H] d (2.0 Hz), 8.17 [1H] d (2.0 Hz), 7.63 [1H] s, 7.56 [1H] dd (1.5 Hz, 7.5 Hz), 7.30 [1H] m, 7.26 [1H] d (2.5 Hz), 7.20 [1H] dd (2.3 Hz, 8.3 Hz), 7.11 [1H] d (8 Hz), 7.08 [1H] d (8.5 Hz), 7.05 [1H] dt (1 Hz, 7.5 Hz) 4.24 [2H] m, 4.19 [2H] m, 3.77 [4H] m, 3.44 [3H] s, 3.43 [3H] s. MS m/z: 449.2 [MH+], 471.1.1 [MNa+].
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([NH:19][C:20]([O:22]C3C=CC=CC=3)=O)[S:18][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CN(C=O)C.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([NH:19][C:20]([NH:2][CH3:1])=[O:22])[S:18][C:12]=2[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
25 mg methylamine was added to 200 mg 2-phenoxycarbonylamino-6,7-dihydro-4H-thiazolo-[5,4-c]pyridine-5-carboxylic acid tert-butyl ester in 25 mL DMF. The reaction was stirred for 12 h at RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated. The residue was purified by column chromatographie (silica gel, eluent: 40% ethylacetate in hexane) to give 151 mg of desired product. (M+H)+: 313
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17](=[O:29])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.O>[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]4[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17](=[O:29])[CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=5)=[CH:30][CH:31]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CNC(=O)Cc5cccc(C(F)(F)F)c5)cc4)cnc3c2)cc1
Temperature: 45 °C

Procedure:
In a 12 mL septum capped vial purged with N2 add N-[4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzyl]-2-(m-trifluoromethyl-phenyl)-acetamide (144 mg, 0.32 mmol), 4-(methylsulfonyl)phenyl boronic acid (89 mg, 0.44 mmols), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (23.6 mg) [X-Phos is alternatively used as the ligand in this reaction], Pd(OAc)2 (6 mg), K3PO4 (218 mg, 1.02 mmol), 1,4-dioxane: H2O 2:1 (5 mL). Deoxygenate the vial again with N2 then heat to 45° C. for 24 hours. Cool the reaction and transfer to a separatory funnel and discard the bottom aqueous layer. Evaporate the solvents under vacuum and take up the residue into CH2Cl2 with a trace of MeOH. Chromatograph the crude reaction on SiO2 eluting with a gradient of 0% to 8% of 2 M NH3 in MeOH with the balance CH2Cl2 Dry the product in a vacuum oven at 40° C. for 24 hours to give 38.6 mg (21%) MS (ES), m/z 564.3 (M+1).
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.Cl[CH2:23][C:24](=[O:26])[CH3:25]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:24](=[O:26])[CH3:25])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.05 h
Yield: 50.3 %

Procedure:
In an atmosphere of argon, a mixture of 26 mg (3.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 800 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 3 minutes. The mixture was further stirred for 30 minutes. To the mixture was then added a mixture of 332 mg of chloroacetone and 2 ml of DMF. The mixture was then stirred for 8 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 487 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-(2-oxopropyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 267 mg of 2-[N-(4-chlorophenyl)-N-(2-oxopropyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance. 1) 2-[(4-Chlorophenyl)imino]-2,3-dihydro-3-(2-oxopropyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5](F)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[C:17]1([C:13]2[CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:12]=4)[CH:5]=[CH:4][N:3]=3)[CH:16]=[CH:15][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Product: c1ccc(-c2cccc(Nc3ccnc(Nc4cccc(-c5ccccc5)c4)n3)c2)cc1

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobiphenyl were reacted to provide N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine. LCMS: purity: 98%; MS (m/e): 415 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (137 mg, 47%). LCMS (m/e) 540 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.08 (s, 1H), 7.38-7.25 (m, 3H), 7.15 (s, 1H), 7.10 (d, 1H, J=7.8 Hz), 6.90 (d, 1H, J=7.8 Hz), 6.82 (s, 1H), 6.14-6.07 (m, 1H), 3.44-3.35 (m, 2H), 3.28 (s, 2H), 3.15 (s, 3H), 3.00 (s, 3H), 2.89-2.83 (m, 2H), 2.80-2.73 (m, 2H), 2.70-2.61 (m, 4H), 1.14 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:24])=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][C:16]=3[C:22]=2[NH2:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O1CCOCC1>[Cl:25][CH2:26][C:27]([NH:23][C:22]1[C:16]2[NH:17][C:18](=[O:21])[CH2:19][O:20][C:15]=2[CH:14]=[C:13]([F:24])[C:12]=1[C:3]1[C:2]([Cl:1])=[C:6]([C:7]([F:9])([F:8])[F:10])[N:5]([CH3:11])[N:4]=1)=[O:28]
Reactant: Cn1nc(-c2c(F)cc3c(c2N)NC(=O)CO3)c(Cl)c1C(F)(F)F
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: Cn1nc(-c2c(F)cc3c(c2NC(=O)CCl)NC(=O)CO3)c(Cl)c1C(F)(F)F
Yield: 84.5 %

Procedure:
4-Chloro-3-[7-fluoro-5-amino-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-5-trifluoromethyl-1H-pyrazole (400 mg, 1.10 mmol) was dissolved in anhydrous dioxane and chloroacetyl chloride (139.5 mg, 1.20 mmol) was added. Solution was heated to reflux for 2 hr and solvent removed in vacuo. The residue was washed with ether to afford the title compound (410 mg, 0.93 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Product: CN(C(=O)Oc1ccc(-c2ccc(Br)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-bromo-4′-hydroxybiphenyl and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol) (72%, white crystals). HPLC-MS m/z=382.0) (M+1), Rt: 5.41 min.
Reaction SMILES: S(=O)(=O)=O.N1C=CC=CC=1.[OH:11][C@H:12]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)/[CH:13]=[CH:14]/[C@@H:15]1[C@@H:22]2[C@@H:18]([O:19][C:20](=[O:23])[CH2:21]2)[CH2:17][C@H:16]1[O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[O:11]=[C:12]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)/[CH:13]=[CH:14]/[C@@H:15]1[C@@H:22]2[C@@H:18]([O:19][C:20](=[O:23])[CH2:21]2)[CH2:17][C@H:16]1[O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](O)CCc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)CCc1ccccc1
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of pyridine sulfur trioxide (0.32 g) in DMSO (3.5 mL) was added dropwise to a stirred solution of compound [6a] (0.30 g) and triethylamine (0.40 g) in dichloromethane (4 mL) at −5-0° C. The mixture was stirred at the same temperature for 1 hour (TLC monitoring) and poured into cold water (15 mL). The mixture was stirred for 10 min at 0-5° C. The organic layer was separated, the water layer was extracted with dichloromethane (3×5 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. A solution of the residue in methanol (1 mL) was cold to −10° C. and kept at the same temperature for 3 hours. The precipitated crystals were filtered, washed on filter with cold methanol (2×1 mL) and dried under reduced pressure to a constant weight to give 0.26 g (87% yield) of crystalline compound [4a] with 94% purity by HPLC.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(O)=[O:2].C(Cl)(=O)C([Cl:19])=O>O1CCCC1>[C:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:1]([Cl:19])=[O:2])=[CH:6][CH:7]=1)([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)Cc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC(=O)Cl)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A 3.04 g portion of methyl 4-carboxymethylphenylacetate, prepared above, was dissolved in 50 mL of anhydrous tetrahydrofuran. After the addition of 2.5 mL oxalyl chloride, the mixture was stirred for 4 hours. The solvents were evaporated under a stream of dry nitrogen as the flask was warmed to 45° C. Any remaining solvent or oxalyl chloride was then removed under high vacuum; the product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(Br)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc(Br)cn2)CC1
Temperature: 190 °C
Yield: 99 %

Procedure:
5-Bromo-2-fluoropyridine A-5 (0.31 mL, 3.0 mmol) and ethyl piperidine-4-carboxylate (1.39 mL, 9.0 mmol) were dissolved in anhydrous pyridine (2.0 mL) at room temperature under an argon atmosphere, in a 10 mL microwave reactor vial. The reaction mixture was sealed and heated at 190° C. for 60 mins under microwave irradiation, then successively cooled to room temperature, diluted with methylene chloride (60 mL), quenched with a 1 N aqueous solution of hydrogen chloride (40 mL) and decanted. The aqueous layer was extracted with methylene chloride (2×100 mL); the combined extracts were sequentially washed with water (70 mL), brine (70 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give ethyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate A-14 (935.0 mg, Yield=99%). MS (ESI), [M+1]+ 313, 315.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:26]([CH2:29][NH:30][C:31](=[O:44])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)(=[O:28])[NH2:27]>ClCCl.C(N(CC)CC)C>[C:26]([CH2:29][NH:30][C:31](=[O:44])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:41])=[O:42])=[CH:36][CH:35]=1)(=[O:28])[NH2:27]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: NC(=O)CNC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) was dissolved in 20 ml of dichloromethane and 0.5 ml of triethylamine, and N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]acetamide (158 mg) was added. The reaction mixture was stirred at room temperature for 24 hr. Dichloromethane (100 ml) was added to the reaction mixture. The reaction mixture was washed with saturated NaCl solution, and 0.1N sodium bicarbonate solution. Dichloromethane layer was separated and dried over anhydrous magnesium sulfate. Dichloromethane was evaporated under reduced pressure to give syrupy material, which was lyophilized in vacuo. 237 mg of the titled product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])O1>>[Br:1][C:2]1[CH:7]=[C:6]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(Br)cc(I)cc1C(C)(C)C
Reactant: CC1(C)OB(c2ccc(F)cc2F)OC1(C)C
Product: COc1c(Br)cc(-c2ccc(F)cc2F)cc1C(C)(C)C

Procedure:
The product from Example 1 Part A (0.185 g, 0.501 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-difluorobenzene (0.120 g, 0.501 mmol) were reacted in the same manner as Example 1 Part B for 16 hours. The crude product was purified on an Isco 12 g silica cartridge eluting with 5% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[O:36][C:37](=O)[C:38]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:46]Cl>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:46][C:39]4[C:38](=[C:43]([O:44][CH3:45])[CH:42]=[CH:41][CH:40]=4)[C:37]3=[O:36])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1c(CCl)cccc1OC
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc2c1C(=O)N(C[C@@H]1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1[C@@H](C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
2-Amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.55 g, 1.42 mmol) and triethylamine (396 I, 2.84 mmol) was heated in acetonitrile (15 ml) under an atmosphere of nitrogen to 60° C. whereupon a solution of 2-chloromethyl-6-methoxy-benzoic acid methyl ester (0.32 g, 1.49 mmol) in acetonitrile (5 ml) was added dropwise over the course of 3 hours, keeping the reaction mixture at 60° C. The reaction was allowed to cool to room temperature and was left for 16 hours before the solvent was evaporated in vacuo. The product was purified by column chromatography (SiO2, Flash 40, ethyl acetate-petrol ether) to give 400 mg (53%) of 2-amino-5-(S)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-((S)-1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.