Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH3:25])(C(OCC)=O)[C:5]([O:7][C:8](C)(C)[CH3:9])=[O:6])[CH:2]=[CH2:3].C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:1]([CH:4]([C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH3:25])=[O:26])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OCC)(C(=O)OC(C)(C)C)C(=O)c1ccccc1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=CCC(C(=O)OCC)C(=O)c1ccccc1CC
Temperature: 140 °C
Yield: 71.6 %

Procedure:
A mixture of t-butyl ethyl 2-allyl-2-(2-ethylbenzoyl)malonate (14.3 g.), acetic anhydride (4 ml.) and p-toluenesulphonic acid (100 mg.) in acetic acid (200 ml.) was heated at 140° C. under nitrogen for 75 minutes and then evaporated. The residue was shaken with a mixture of saturated sodium bicarbonate solution (100 ml.) and ethyl acetate (100 ml.). The organic phase was dried (MgSO4) and evaporated. The oil obtained (9.3 g.) was purified by flash column chromatography (280 g.) using toluene as eluant to give ethyl 2-allyl-3-(2-ethylphenyl)-3-oxopropionate (7.4 g.) as a pale yellow oil; NMR: 1.19 (6H,m), 2.74 (4H,m), 4.15 (3H,m), 5.05 (2H,m), 5.79 (1H,m), 7.30 (3H,m) and 7.61 (1H,m) ppm.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[NH:25][C:24]4[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH3:29])[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH3:33])[C:19]=4[N:18]=3)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)#[N:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Si]([N:58]=[N+:59]=[N-:60])(C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:30]=[C:21]1[N:20]([CH2:31][CH2:32][CH3:33])[C:19]2[N:18]=[C:17]([C:12]34[CH2:15][CH2:16][C:9]([CH2:8][CH2:7][C:6]5[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:60]=[N:59][N:58]=5)([CH2:14][CH2:13]3)[CH2:10][CH2:11]4)[NH:25][C:24]=2[C:23](=[O:26])[N:22]1[CH2:27][CH2:28][CH3:29]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)NCCC#N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCc5nnnn5CCC#N)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 24 h
Yield: 3.8 %

Procedure:
A solution of N-(2-cyano-ethyl)-3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionamide (500 ng, 1.06 mmol, 1.0 eq), Ph3P (2.0 eq, 2.13 mmol, 560 mg), TMSN3 (2.0 eq, 2.13 mmol, 245 mg), and DEAD (2.0 eq, 2.13 mmol, 371 mg) in THF (10 ml) was stirred at rt for 24 h. The reaction vessel was re-charged with the reagent cocktail (2.0 eq, 2.13 mmol) and stirring was continued for an additional 24 h. The reaction was quenched by the addition of a 50% aqueous solution of (NH4)2Ce(NO3)6 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to afford a viscous orange oil. A portion of the material was purified by preparative LC to afford 20 mg of pure material. MS: 494 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27]Cl)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:30]#[CH:31].[I-].[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:35]4[CH2:36][CH2:37][N:32]([CH2:29][C:30]#[CH:31])[CH2:33][CH2:34]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#CCN1CCNCC1
Reactant: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C#CCN1CCN(CCCOc2cc3ncnc(Nc4c(Cl)cnc5c4OCO5)c3cc2OC)CC1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-6-methoxyquinazoline (0.08 g), 1-prop-2-ynylpiperazine (0.047 g), potassium iodide (0.01 g) and DMA (2 ml) was stirred and heated to 80° C. for 3.5 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous ammonium chloride solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol and then a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The resulting gum was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.066 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.2-3.6 (br m, 10H), 3.75 (s, 1H), 3.95 (br s, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 511 and 513.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1.O>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cn1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(CCl)cn1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of (6-methyl-3-pyridyl)-methanol (50 g, 0.506 mol) in toluene (500 ml) and water (9 ml) at 35° C. under nitrogen was added thionyl chloride (66.9 ml, 1.06 mol) dropwise After stirring at 35° C. overnight 300 ml was distilled off under vacuum and rediluted with toluene (250 ml) and water (10 ml) to give a solution of 5-chloromethyl-2-methyl-pyridine (J. Med. Chem, 2004, 47(11), 4787). The mixture was then heated to 40° C. and morpholine (112.2 ml, 1.29 mol) added and the slurry heated to 80° C. for 3 hrs. After cooling to room temperature saturated sodium carbonate solution (150 ml) was added and the aqueous phase separated and extracted with toluene (200 ml). The combined organic layer was washed with brine and concentrated. The oil was dissolved in iso-octane (300 ml) at 40° C. then cooled to −5° C. overnight. Two crops were obtained which gave 53.65 g, 72% yield of 4-[(6-methylpyridin-3-yl)methyl]morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR: (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][C:16](=[O:20])[NH:17]2)=[C:13]([Cl:21])[N:12]=1.CO.[CH3:24]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[Cl:21][C:13]1[N:12]=[C:11]([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[CH:24]2)[N:19]=[C:18]2[C:14]=1[NH:15][C:16](=[O:20])[NH:17]2
Reactant: COC(OC)OC
Reactant: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: CO
Product: N#Cc1ccc2ncn(-c3nc(Cl)c4[nH]c(=O)[nH]c4n3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a solution of crude 4-amino-3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile (1.23 mmol) in anhydrous DMSO (10 mL) was added methanol (150 mL), followed by anhydrous trimethylorthoformate (5 mL) and p-toluene sulfonic acid (100 mg) and the reaction mixture was stirred under Ar at room temperature for 3 h (LC-MS monitoring). The solvent was removed in vacuo and the residue redissolved in 7 mL of DMSO, then 40 mL of water were added. The pink solid formed was filtered under vacuo using a fine porosity Buchner filter funnel, washed with water, then dried in the vacuum oven at 60° C. to give 0.26 g of the desired product (67% yield on 2 steps). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.24 (s, 1H), 9.00 (s, 1H), 7.91 (d, 1H), 7.69 (d, 1H); MS (EI) m/z 312.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC1N=C(C2C=CC([CH:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[N:21]=4)[CH2:15][CH2:14]3)=CC=2)ON=1.Cl.[O:35]1[C:39]([C:40]2[CH:45]=[CH:44][C:43](C3COCCNC3)=[CH:42][CH:41]=2)=[N:38][CH:37]=[N:36]1>>[CH3:26][N:25]1[C:24](=[O:27])[CH:23]=[C:22]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:21]=[C:20]1[N:16]1[CH2:15][CH:14]([C:43]2[CH:42]=[CH:41][C:40]([C:39]3[O:35][N:36]=[CH:37][N:38]=3)=[CH:45][CH:44]=2)[CH2:13][O:19][CH2:18][CH2:17]1
Reactant: Cc1noc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)n1
Reactant: c1noc(-c2ccc(C3CNCCOC3)cc2)n1
Agent: Cl
Product: Cn1c(N2CCOCC(c3ccc(-c4ncno4)cc3)C2)nc(-c2ccncn2)cc1=O

Procedure:
1-Methyl-2-[6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one was prepared by the same procedure as that of 2-{7-[4-(3-Methyl-[1,2,4]-oxadiazole-5-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one except for utilizing 6-(4-[1,2,4]Oxadiazol-5-yl-phenyl)-[1,4]oxazepane hydrochloride instead of 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride. 1-Methyl-2-[6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (A080) was obtained as white solid (0.02 g, 0.04 mmol, 50%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][C@@H:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:7]1
Reactant: BrCc1ccccn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of (S)-2-methyl-4-N—BOC-piperazine (400 mg, 1.997 mmol) and 2-(bromomethyl)pyridine hydrobromide (505 mg, 1.997 mmol) in anhydrous THF (5 ml) was added triethylamine (0.7 ml, 4.99 mmol) and the resulting mixture stirred at RT for 3 days. The mixture partitioned between water and EtOAc; organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by column chromatography (eluent: 5% MeOH in DCM) to give 320 mg (55%) to afford the title compound as a yellow oil. 1H NMR (CDCl3): 1.14 (d, J 6.2 Hz, 3H), 1.47 (s, 9H), 2.25 (t, J 9.5 Hz, 1H), 2.51 (m, 1H), 2.70 (d, J 11.6 Hz, 1H), 2.84 (brs, 1H), 3.15 (t, J 10.1, 1H), 3.47 (d, J 14.2 Hz, 1H), 3.69 (d, J 13.0 Hz, 1H), 3.75 (brs, 1H), 4.08 (d, J 14.0, 1H), 7.17 (dd, J 7.1 and 5.3, 1H), 7.45 (d, J 7.8, 1H), 7.66 (m, 1H), 8.56 (d, J=4.7 Hz, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5Cl)[CH:25]=4)[N:22]=3)[N:17]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:25]=4)[N:22]=3)[N:17]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: C1CCNC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(N5CCCC5)c4s3)cnc21
Yield: 85.6 %

Procedure:
A solution of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (40 mg, 0.064 mmol) in pyrrolidine (5.32 ml, 64.3 mmol) was heated in a microwave reactor at 100° C. for 2 h. The reaction mixture was evaporated to dryness under vacuum. The crude residue was suspended in MeOH (0.5 mL) and the resultant solid collected by filtration, washing with MeOH, to give 36 mg (85%) 2-(7-pyrrolidin-1-yl-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][O:18][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 116.3 %

Procedure:
To a solution of 3-[3-(benzyloxy)phenyl]-1-propanol (1.73 g) in DMF (20 mL) were added imidazole (1.07 g) and tert-butyldimethylchlorosilane (1.83 g) at ambient temperature and the mixture was stirred at the same temperature for 2 hours. Water (20 mL) was added to the mixture at ambient temperature and the mixture was extracted with EtOAc (20 mL) two times. The organic layer was washed successively with 12% NaCl aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford {3-[3-(benzyloxy)phenyl]propoxy}(tert-butyl)dimethylsilane (2.96 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(=O)n(C)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(-c2ccc(O)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one (10 g, 46.3 mmol) in 15 mL DCM cooled on an ice-water bath to ˜5° C. was added 93 mL of BBr3 (1M soln in DCM) over 5 min. The ice bath was removed and the solution stirred at rt for 4 h. The reaction was cooled on an ice-bath and saturated NH4Cl solution (100 mL) added slowly. After the addition was complete, the DCM was removed under reduced pressure, excess water added and the product collected, washed 1× with MeOH (˜20 mL) and dried to give 9.2 g (98%): Mp 242-245° C. 1H NMR (DMSO-d6) δ 3.8 (s, 3H), 6.85 (d, 2H), 7.0 (d, 1H), 7.7 (d, 2H), 7.95 (d, 1H), 9.8 (s, 1H); MS m/z=203 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[N+:20]([O-])=O)=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[C:10]([CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(N)c1

Procedure:
The material from step 1 dissolved in ethanol (5 mL) was combined with a solution of tin dichloride dihydrate (12 mmol) in ethanol (5 mL) and heated to 70 for 5 h. The solvent was removed under a stream of nitrogen and the residue was redissolved in a mix of dichloromethane and 1 N NaOH solution. The mixture was applied to an Extrelut QE solid phase extraction column that was prepped with 1 N NaOH solution. The organic was collected and the solvent was removed under a stream of nitrogen. The residue was redissolved in diethyl ether and treated with 4 N HCl in dioxane. The precipate was collected to give the product as the HCl salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH:32]1(O)[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([O:18][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: OC1CCCC1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A solution of N-benzyloxycarbonyl-L-isoleucine (10.0 g, 37.7 mmol) in DCM (150 mL) was treated with N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (7.94 g, 41.5 mmol), cyclopentanol (3.90 g, 45.2 mmol) and N,N-dimethylaminopyridine (20 mg). The reaction was allowed to stand at room temperature for 18 hours. The reaction mixture was washed with 1M hydrochloric acid, saturated sodium bicarbonate, and brine before drying over magnesium sulphate, filtration and removal of solvent under reduced pressure to leave N-benzyloxycarbonyl-L-isoleucine cyclopentyl ester as a colorless oil (10.99 g, 87%). 1H-NMR; δ (CDCl3) 7.44-7.30 (5H, m), 5.37-5.34 (1H, m), 5.22-5.18 (1H, m), 5.11 (2H, s), 4.33-4.27 (1H, m), 1.90-1.55 (10H, m), 1.51-135 (1H, m), 1.28-1.20 (2H, m), 0.93 (3H, d, J 6.9 Hz) and 0.91 (3H, d, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.CCOC(C)=O>[CH:15]1([CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:17][CH2:16]1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C1CCCc2c(OCC3CC3)cccc21
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To a solution of 5-hydroxy-1-tetralone (1.8 g, 11.0 mmol) in butanone was added (bromomethyl)cyclopropane (1.8 g, 13.2 mmol) and K2CO3 (3.0 g, 22.0 mmol) at rt. The mixture was heated at 80° C. overnight. After the reaction was cooled to rt, it was diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (20:1 PE/EtOAc) to give 1.9 g (78%) of the title compound as a tan oil. 1H NMR (300 MHz, CDCl3): δ 0.35-0.40 (2H, m), 0.62-0.68 (2H, m), 1.27-1.32 (1H, m), 2.05-2.17 (2H, m), 2.64 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.0 Hz), 3.86 (2H, d, J=6.9 Hz), 6.98 (1H, d, J=8.1 Hz), 7.24 (1H, t, J=8.7 Hz), 7.65 (1H, d, J=8.1 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](N(OC)C)=[O:38])[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:44][Mg]Br.Cl>O1CCCC1>[CH3:28][C:26]1[N:27]=[C:19]2[N:18]([C@H:29]3[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][C:37](=[O:38])[CH3:44])[CH2:33][CH2:34]3)[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2nc(C)nn12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.7 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:13])=[O:12])=[CH:5][N:4]=1.[CH2:14](N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5][N:4]=1
Reactant: CCN(CC)CC
Reactant: COc1ncc(C(=O)O)c(OC)n1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC)nc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a suspension of 2,4-Bis(methyloxy)-5-pyrimidinecarboxylic acid (Prep31, 1.000 g, 5.43 mmol) in N,N-Dimethylformamide (DMF) (35 mL) at 0° C. N,N′-Carbonyldiimidazole (1.321 g, 8.15 mmol) was added and the mixture was stirred for 1 hour at 0° C., then left stirring at rt. After 4 h Triethylamine (2.271 mL, 16.29 mmol) and N,N′-Carbonyldiimidazole (1.321 g, 8.15 mmol), were added to the white suspension. After other 4 h, N,N′-Carbonyldiimidazole (1.321 g, 8.15 mmol) of another batch was added to the suspension. The reaction was left overnight at rt. The solution was then concentrated in vacuo and methanol was added. The solution was stirred at reflux for 2 h. Then the mixture was evaporated in vacuo, the residue was dissolved in DCM and washed with NaHCO3 sat. sol. and then with H2O. Organic phase was dried with Na2SO4 anhydrous, filtered and evaporated in vacuo to obtain 550 mg of the title compound, which was used in the following step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.ON1C2C=CC=CC=2N=N1.[CH2:34]([NH2:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:34]([NH:42][C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCN
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reaction time: 72 h
Yield: 33.3 %

Procedure:
1 g (3.1 mmol) of 4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-carboxylic acid, 15 ml of dimethylformamide, 460 mg (3.4 mmol) of 1-hydroxybenzotriazole and 500 μl (3.1 mmol) of n-octylamine are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 0.59 g (3.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added portionwise. The mixture is stirred for three days while allowing the temperature to rise. The reaction medium is poured into water and extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. 450 mg (33%) of the desired product are obtained.
Reaction SMILES: CO.C(N[C:12]1[CH:20]=[C:19](/C=C/C2C=CC=C(OC)C=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=O)C1C=CC=CC=1>[C].[Pd].C(OCC)(=O)C>[C:14]([OH:16])(=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:12]=1
Reactant: COc1cccc(/C=C/c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 mL of methanol, 2.0 mL of ethyl acetate and 2.0 mg of 5% palladium-carbon were added to the obtained 2-(benzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 2 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 6.3 mg of 2-(benzamido)-4-(2-3-methoxyphenyl)ethyl)benzoic acid as white solid.