Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>O>[Br:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: C1COCCN1
Solvent: O
Product: Brc1csc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of 2,4-dibromothiazole (500 mg, 2.06 mmol) in morpholine (4.0 mL, 22.3 mmol) was warmed at 50° C. in a sealed tube. After 16 hours, the mixture was cooled to room temperature, diluted with 20 mL of water and extracted with three 30 mL portions of diethyl ether. The combined organic layers was washed with five 30 mL portions of water, 30 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed over SiO2 using ethyl acetate in hexanes (0-30% gradient) to afford 458 mg (89%) of 4-(4-bromothiazol-2-yl)morpholine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7](=O)[C:6]=2[CH:20]=1.C1(C)C(S([CH2:30][N+:31]#[C-])(=O)=O)=CC=CC=1.[O-]CC.[Na+].[Na]>O1CCCC1.C(O)C>[C:30]([CH:7]1[C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)#[N:31]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=C1CC(CCc2ccccc2)Oc2ccc(F)cc21
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC1CC(CCc2ccccc2)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (8.9 gm) was dissolved in anhydrous tetrahydrofuran, and toluenesulfonylmethylisocyanide (12.9 gm) added, followed by freshly prepared sodium ethoxide in ethanol (prepared from sodium (1.5 gm) in ethanol (60 mL) and the mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo, and the residue partitioned between ethyl acetate and H2O, and the organic layer washed with H2O, brine, dried, filtered and evaporated. The residue was purified by column chromatography (2:1 hexanes/diethyl ether) to yield 4-cyano-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran (2.7 gm, ir: 2250 cm-1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[NH:8][CH2:7]1)=[O:5])[CH3:2].[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([CH2:28]O)=[CH:23][N:22]=1>>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([CH2:28][C:12]2[C:13]([O:16][CH3:17])=[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=2)[NH:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:15]3)=[CH:23][N:22]=1
Reactant: CCOC(=O)C1CNc2c(OC)ccc(OC)c2C1
Reactant: Nc1ncc(CO)c(N)n1
Product: CCOC(=O)C1CNc2c(OC)cc(Cc3cnc(N)nc3N)c(OC)c2C1
Yield: 49 %

Procedure:
Ethyl-1,2,3,4-tetrahydro-5,8-dimethoxy-3-quinolinecarboxylate (0.38 g, 1.43 mmol) was reacted with 2,4-diamino-5-hydroxymethylpyrimidine as in Example 17, and the product worked up as before. The product was purified on a silica gel column eluted with methylene chloride:methanol/19:1 to give 0.27 g (49%) of the title compound, mp 186°-188° (absolute ethanol). Anal. Calcd. for C19H25N5O4 : C, 58.90; H, 6.50; N, 18.08. Found: C, 58.95; H, 6.52; N, 18.08.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCCl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: Nc1cccc(C=O)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-neck round-bottom flask, 6-Amino-pyridine-2-carbaldehyde (2.85 g, 23.3 mmol), 1-Methylpiperazine (5.00 mL, 45.1 mmol), 1,2-Dichloroethane (100 mL, 1000 mmol) and Acetic acid (2.50 mL, 44.0 mmol) were added and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (14.8 g, 70.0 mmol) was added portion wise over 20 minutes. The reaction mixture was stirred at room temperature over night. The reaction was partitioned with Sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and stripped to give a yellow solid. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 20% methano). The collected fractions afforded 6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine as a yellow solid (1.20, 25%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C1C(=O)N([I:18])C(=O)C1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:18])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc2c(I)n[nH]c2cn1
Temperature: 25 °C

Procedure:
A solution containing 5-bromo-1H-pyrazolo[3,4-c]pyridine (168.0 g, 848.4 mmol) and NIS (286.3 g, 1.27 mol) in DMF (1.2 L) was stirred on at room temperature. The reaction mixture was poured into water then filtered. The solid was washed with water and 5% Na2S2O5. The crude product was dried under high vacuum overnight to give 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].[CH3:37][CH:38]([CH:41]([CH3:43])[OH:42])CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:15][CH2:16][C:17]3([O:42][CH:41]([CH3:43])[CH:38]([CH3:37])[O:20]3)[CH2:18][CH2:19]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(O)C(C)CO
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)C(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
A mixture of 4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), 2,3-dimethylpropane-1,3-diol (0.56 g), p-toluenesulfonic acid monohydrate (0.036 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 100%).
Reaction SMILES: [CH:1]1([CH:6]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1>>[CH:1]1([CH:6]([OH:7])[C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=CC1CCCC1
Product: CCOC(=O)c1ccc(C(O)C2CCCC2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopentanecarbaldehyde and ethyl 4-iodobenzoate. 1H NMR (400 MHz, CDCl3, δ): 8.01 (d, J=8.4 Hz, 2H), 7.40-7.44 (m, 2H), 4.49 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.19-2.21 (m, 1H), 1.82-1.87 (m, 2H), 1.41-1.67 (m, 6H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:23][NH:24][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1cccc(C(=O)c2ccc(OC)cc2C(=O)O)c1
Solvent: O
Product: COc1cccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(3-methoxybenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([OH:40])[C:31]=1[O:41][CH3:42]>C(Cl)Cl>[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([O:40][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]=1[O:41][CH3:42]
Reactant: C1=COCCC1
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1OC1CCCCO1
Reaction time: 8 h

Procedure:
3,4-Dihydro-2H-pyran (51.9 mg, 56 μL, 0.617 mmol) was added to a stirred solution of p-toluenesulfonic acid (2.3 mg, 0.0123 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (52.0 mg, 0.123 mmol) in dry CH2Cl2 (6.1 mL) at room temperature under N2 and the reaction was stirred overnight. The reaction mixture was diluted with CH2Cl2 (45 mL) and washed with saturated NaHCO3 (5 mL) and 30% saturated Na2SO3 (5 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 2-{[2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran. Rf=0.59 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 5.77 (s, 1H), 4.97 (dd, J=4.9, 2.9 Hz, 1H), 4.49 (d, J=9.8 Hz, 1H), 4.37 (d, J=9.8 Hz, 1H), 3.89-3.87 (m, 1H), 3.61-3.49 (m, 1H), 3.46 (s, 3H), 3.27-3.21 (m, 1H), 1.89-1.83 (m, 1H), 1.78-1.70 (m, 1H) 1.64-1.48 (m, 3H), 1.26 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])N)C>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[S:20][CH2:19][CH:17]([C:16]([OH:21])=[O:15])[N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#CCc1cc(F)cc(F)c1
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Product: O=C(O)C1CSC(Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure G and using 3,5-difluorophenylacetonitrile and L-cysteine ethyl ester hydrochloride (Aldrich), the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][SH:24].C([Li])CCC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)CCS
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A 25 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-9H-β-carboline (98 mg, 0.37 mmol) in 2 ml of anhydrous DMF. A second 10 ml round-bottom flask with magnetic stirrer was charged with 2-dimethylamino-ethanethiol hydrochloride (100 mg, 0.70 mmol) in 2 ml anhydrous DMF. To the resulting suspension was added n-butyllithium (0.43 ml of 1.6 M solution in hexanes, 0.69 mmol) via syringe and the mixture was stirred for 5 min at RT. Next, the thioanion solution was added via syringe to 6-chloro-7-fluoro-8-nitro-9H-β-carboline, and the resulting red solution was stirred at RT for 30 min. The reaction mixture was slowly added to a 5:1 mixture of H2O/saturated aqueous sodium bicarbonate (30 ml) and allowed to sit at RT for several hours. The resulting precipitated solid was collected via suction filtration and air-dried to afford 109 mg of [2-(6-chloro-8-nitro-9H-β-carbolin-7-ylsulfanyl)-ethyl]-dimethyl-amine as an orange solid (83%). LCMS (ammonium acetate standard method) retention time=1.35 min. (M+=351; M−=349). 1H-NMR (300 MHz, CD3OD, ppm) δ 8.92 (1H, d, J=1.0 Hz) 8.66 (1H, s) 8.43 (1H, d) 8.19 (1H, dd) 3.18-3.13 (2H, m) 2.57-2.52 (2H, m) 2.21 (6H, s).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH:18][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[N:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: Cc1ccccc1C
Product: O=C(O)C=CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 145 °C
Yield: 63.1 %

Procedure:
585 mg of preground maleic anhydride are added to 1 g of 6-chloro-1H-indazole-3-amine in 30 cm3 of ortho-xylene. The reaction medium is refluxed at 145° C. for ten minutes and then cooled in a water bath. The insoluble material is filtered off and washed successively with 2×25 cm3 of ethyl acetate and then with 2×25 cm3 of diisopropyl ether. The solid is then dried under reduced pressure (90 Pa; 50° C.) to give 1 g of 4-[(6-chloro-1H-indazol-3-yl)amino]-4-oxo-2-butenoic acid (Z form) in the form of yellow crystals melting at 230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][NH:28][CH2:27][CH2:26]4)[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][N:28]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:27][CH2:26]4)[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNC4)nc12
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CC(=O)N(C)C)C4)nc12

Procedure:
2-{6-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-3,4-dihydro-1H-isoquinolin-2-yl}-N,N-dimethyl-acetamide was prepared from [8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine (0.150 g, 0.341 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.053 mL, 0.512 mmol) in a manner analogous to Example 313 to give product (0.060 g, 34%). MP=99-102° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.38 (m, 3H), 7.05 (t, 1H), 6.90 (d, 1H), 3.85 (s, 3H), 3.52 (s, 2H), 3.28 (s, 2H), 3.05 (s, 3H), 2.82 (s, 3H), 2.70 (br m, 4H): MS=525 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1nccc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1ccc(OCC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A mixture of 4-(1-methyl-1H-pyrazol-5-yl)phenol (500 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (999 mg), potassium carbonate (793 g) and acetonitrile (5.0 mL) was stirred at 90° C. for 2 hours. Thereafter, the reaction solution was diluted with chloroform, and insoluble matters were then removed by filtration. The filtrate was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel 60N, chloroform:methanol=100:0 to 98:2), so as to obtain the title compound (485 mg) in the form of a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:29][CH:28]=1)#[N:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 22.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-cyanophenylboronic acid (available from Combi-Blocks Inc.; 59 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (20 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (br s, 1H), 8.49 (s, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 2.1 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.56-7.64 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[C:50]#[CH:51]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1([N:13]([CH:51]=[CH:50][C:49]([O:53][CH2:54][CH3:55])=[O:52])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reactant: C#CC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=CN(C1(C(=O)OC(C)(C)C)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a mixture of 1-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-cyclopentanecarboxylic acid tert-butyl ester (1.0 g, 2.3 mmole) in 10 mL THF and 2.3 mL (2.3 mmole) 1M tetrabutylammonium fluoride in THF was added 0.23 mL (2.3 mmole) ethyl propiolate at ambient temperature. After stirring 1 hour the reaction was complete by HPLC and was stripped to dryness in vacuo. The residue was dissolved in 20 mL ethyl acetate and washed with 2×10 mL water and the organic solution stripped to an oil. This oil was chromatographed over silica gel, eluting with 10% ethyl acetate/hexane to yield 0.95 g (77% yield) 1-{(2-ethoxycarbonyl-vinyl)-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-amino}-cyclopentanecarboxylic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]#[N:23])[CH:18]=[CH:19][CH:20]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>O1CCCC1.Cl>[CH3:36][O:35][C:33](=[O:34])[CH2:32][C:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22]#[N:23])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1cccc(C(C#N)Cc2ccccc2)c1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of diisopropylamine (0.7 ml, 5.1 mmol) in 20 ml dry tetrahydrofuran at −78° C. was added n-butyl lithium (1.6 M in hexan, 3.2 ml, 5.1 mmol) and stirred for 1 h. A solution of 2-(3-methoxy-phenyl)-3-phenyl-propionitrile (1.0 g, 4.2 mmol) in 5 ml dry tetrahydrofuran was added to the mixture, stirred for 30 min, followed by addition of methyl 2-bromoacetate (0.6 ml, 6.3 mmol). The mixture was stirred over night at room temperature, diluted with 50 ml 1M HCl and the resulting mixture extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium bicarbonate, filtered and the solvent evaporated to obtain a yellow oil (1.3 g). Purification on 12 g SiO2 using dichloromethane afforded a clear colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.C1C[O:17][CH2:16]C1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:16]=[O:17])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=Cc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 23.7 g (100 mmol) of 2,6-dibromopyridine in 150 mL of anhydrous, degassed THF cooled to −78° C. was added dropwise under N2 a solution of 11.0 mL (110 mmol) of 10.0 M n-BuLi in 150 mL anhydrous, degassed Et2O. After 2 hours at −78° C., 24.2 mL (300 mmol) of anhydrous degassed DMF was added dropwise with rapid stirring. This solution was stirred at −78° C. for 2 hours, and was then allowed to warm to room temperature (RT) overnight. The solution was cooled to −78° C. and 100 mL of 1.0 M aq. HCl was added slowly. The organic phase was separated and the aqueous phase was washed with 3×50 mL Et2O. The organic washes were combined and washed with 3×50 mL H2O and 3×50 mL brine, then dried over Na2SO4. The volatiles were removed in vacuo to provide an orange oil. The oil was triturated with hexanes to give 2-bromo-6-formylpyridine as a pale orange solid that was washed with cold pentanes and dried under vacuum overnight.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([CH2:68][C:69](O)=[O:70])[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([C:69](=[O:70])[CH2:68][CH:65]5[CH2:66][CH2:67][N:62]([C:60]([O:59][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:61])[CH2:63][CH2:64]5)[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-((2-(Piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (225 mg, 0.688 mmol) (Intermediate 15) dissolved in DMF (10 mL) was added triethylamine (4 eq.) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (2 eq.). The solution was stirred for 5 minutes and 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1.5 eq.) was added and was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to afford the desired product. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.40 (1H, d), 8.00 (1H, d), 7.93 (1H, s), 7.86 (1H, dd), 5.34 (2H, s), 4.78 (1H, m), 4.35 (1H, m), 3.85-3.94 (3H, m), 3.21 (1H, m), 2.64-2.82 (3H, m), 2.27 (2H, d), 2.10 (2H, m), 1.86 (3H, m), 1.60 (2H, d), 1.35 (9H, s), 1.99 (2H, m).