Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][N:9]([CH3:30])[C:10]([CH:12]1[CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([F:29])[CH:18]=2)(O)[CH2:13]1)=[O:11].CN(C)C(C1CC(C2C=CC(N3CCCC3)=C(F)C=2C)(O)C1)=O>>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][N:9]([CH3:30])[C:10]([CH:12]1[CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([F:29])[CH:18]=2)=[CH:13]1)=[O:11]
Reactant: CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: Cc1c(C2(O)CC(C(=O)N(C)C)C2)ccc(N2CCCC2)c1F
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 75 °C

Procedure:
TFA (9.9 ml, 128 mmol) was added to a DCE solution (64 ml) of example 19, 3-(3-fluoro-4-pyrrolidin-1-yl-methyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid dimethylamide (2.05 g, 6.4 mmol) and the mixture was heated to 75° C. for 18 hrs and concentrated down to obtain TFA salt of intermediate 3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobut-2-enecarboxylic acid dimethylamide. This was redissolved in absolute EtOH (64 ml), Wilkinson's catalyst (296 mg) was then added and this mixture was subjected to hydrogenation at 60° C. using 45 psi H2. After 1 hr 45 min reaction time, it was concentrated down and the residue was redissolved into 1N HCl (50 m) and extracted twice with EtOAc (2×120 ml). The aqueous layer was then basified with 15% aq. NaOH (40 ml) and extracted with EtOAc (3×200 ml). The combined organic phases were dried over MgSO4, and concentrated down to obtain crude material. This was purified by flash chromatography using a 120 g ISCO™ column and 4% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were combined and concentrated under reduced pressure to give the title compound (1.0 g, 51% yield). Rf=0.40 (10% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C18H25FN2O, 304.4, found, 305.4 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.10 (t, J=7.8 Hz, 1H), 6.78 (dd, J=1.2, 6.6 Hz, 1H), 6.72 (dd, J=1.7, 11.2 Hz, 1H), 3.4 (s, 2H), 3.48-3.38 (m, 1H), 3.13-3.04 (m, 1H), 2.79 (s, 3H), 2.70 (s, 3H), 2.58-2.50 (m, 2H), 2.37-2.30 (m 4H), 2.22-2.12 (m, 2H), 1.60-1.52 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 174.3, 161.2 (d, JC-F=245.7 Hz), 147.0, 131.4, 123.4 (d, JC-F=15.0 Hz), 121.9, 113.0 (d, JC-F=22.5 Hz), 54.0, 52.5, 36.7, 35.8, 35.5, 33.3, 31.6, 23.5.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[OH-:19].[K+]>CO>[OH:15][C:16]1[C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:19])=[O:17]
Reactant: Cc1ccccc1Oc1cccc2c1OC(=O)C2
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1Oc1cccc(CC(=O)O)c1O
Yield: 46.5 %

Procedure:
7-(o-Tolyloxy)-2,3-dihydrobenzofuran-2-one (2.20 g) was dissolved in a solution of potassium hydroxide (2.0 g) in methanol (30 ml), and the solution was allowed to stand at room temperature for an hour. The reaction mixture was evaporated, and the residue was dissolved in water, washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The oily residue was allowed to stand at room temperature and the precipitating crystals were recrystallized from a mixture of benzene and n-hexane to give prisms of 2-[2-hydroxy-3-(o-tolyloxy)phenyl]acetic acid (1.10 g). mp 116°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH:27]=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(/C=C/C=C/C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(CCCCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadien-1-al was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-2,4-oxazolidinedione. The product was recrystallized from dichloromethane-ether to give colorless prisms, m.p.114-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:14])[C:3]=1[I:13]
Reactant: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (16 g, 47 mmol) and potassium carbonate (17 g, 120 mmol) in DMF (40 mL) was treated with methyl iodide (6.4 mL, 100 mmol) and stirred at 60° C. for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (twice). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated to give a crude solid. The crude material was purified by flash column chromatography using EtOAc in hexanes (5%-30%) to give the desired product (14 g, 84%) as an orange solid. LCMS for C9H8Cl2IO2 (M+H)+: m/z=344.9, 346.9. Found: 344.8, 346.9.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]([CH2:13][CH2:14][C:15]1[S:16][C:17]2[CH:18]=[CH:19][C:20]3[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=3[C:22](=[C:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:23]=2[CH:24]=1)=[O:12])[CH3:9]>O1CCOCC1>[NH:28]1[CH2:29][CH2:30][C:25](=[C:22]2[C:21]3[CH:38]=[CH:39][CH:40]=[CH:41][C:20]=3[CH:19]=[CH:18][C:17]3[S:16][C:15]([CH2:14][CH2:13][C:11]([O:10][CH2:8][CH3:9])=[O:12])=[CH:24][C:23]2=3)[CH2:26][CH2:27]1
Reactant: CCOC(=O)CCc1cc2c(s1)C=Cc1ccccc1C2=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CCc1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
Hydrogen chloride-dioxane (7.5 mL, equivalent to 30 mmol of hydrogen chloride) was added to a dioxane (30 mL) solution of the compound obtained in Example 35 (2.9 g, 6.0 mmol), and the mixture was stirred at room temperature for 5 hours. The solvents were distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform-methanol=19:1), to give 2.0 g (88%) of the captioned compound in the form of an oily product.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])(=O)C>ClCCl.C(Cl)(=O)OCOC(=O)C1C=CC=CC=1>[O:33]=[S:30]1(=[O:34])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[C:11]4[CH:12]=[CH:23][CH:22]=[CH:21][CH:26]=4)=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: O=C(Cl)OCOC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)OCOC(=O)c1ccccc1
Yield: 98 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (500.0 mg, 1.5 mmol) in dichloromethane (14 mL) and benzoyloxymethyl carbonochloridate (7k) gave the titled product in 98% yield (744.5 mg, 1.43 mmol). 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 2H), 7.60 (t, 1H), 7.46 (q, 3H), 7.20 (t, 1H), 7.13 (dd, 1H), 5.98 (q, 2H), 5.36 (t, 1H), 4.77-4.83 (m, 1H), 4.05 (t, 1H), 3.80 (dd, 1H), 3.68 (ddd, 1H), 3.57 (dt, 1H), 3.12-3.19 (m, 4H), 3.08 (dt, 1H), 2.31-2.45 (m, 2H), 2.13-2.21 (m, 2H).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:30][C:31]1[N:32](S(N(C)C)(=O)=O)[CH:33]=[CH:34][N:35]=1)[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:14])(=O)=O.Cl.O1CCOCC1>>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1)[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14]
Reactant: CN(C)S(=O)(=O)n1ccnc1CN(Cc1nccn1S(=O)(=O)N(C)C)C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CCNCC1)N(Cc1ncc[nH]1)Cc1ncc[nH]1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To the compound (3.00 g) obtained in Example 9, 4N hydrogen chloride/dioxane (15 mL) was added. The reaction solution was stirred at 60° C. for 15 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and a carbonate resin (trade name: MP-Carbonate, manufactured by Argonaut Co., product number: 800267, 10 g) was added, followed by stirring at room temperature for 3 hours. After the resin was removed by filtration, the filtrate was concentrated under reduced pressure. The title compound was obtained without purifying the residue.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)=[N:8][OH:9].[OH-].[K+].C(OCCO)C>[Cu](Cl)Cl.CCCCCC>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:7]2[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[O:9][N:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=NO)c2sccc2Br)c1
Agent: Cl[Cu]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCCO
Product: COc1cccc(-c2noc3ccsc23)c1
Yield: 67.6 %

Procedure:
Reflux a mixture of (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone oxime (10 g, 0.032 mol), KOH (3.6 g, 0.064 mol dissolved in 10 mL water) and 2-ethoxyethanol (100 mL) under nitrogen for one hour at 105–110° C. Add copper chloride (0.16 g, 0.0016 mol) whereupon the reaction mixture becomes dark brown in color. Heat the reaction for an additional one hour. Add water and extract the organics into ether. Wash the ether phase with water, dry (MgSO4), filter and concentrate to yield an oil. Purify the oil by column (alumina) chromatography, and elute with 15% ether in hexane to obtain white crystals. Recrystallize the crystals from ether:hexane to yield the title compound (5 g, 68% Yield), m.p. 51–52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+:26].[OH-]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O-:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1.[Li+:26]
Reactant: CCOC(=O)C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Yield: 125.1 %

Procedure:
Part A: A mixture of ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (3.97 g, 0.01 mol) in methanol/water is reacted with LiOH (1.3 gram, 0.054 mol) at room temperature for 16 hours. The resulting mixture is concentrated in vacuo to give crude lithium 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate (4.7 gram).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.O=[Pt]=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:23])[CH2:10]2)=[N:15][CH:16]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1Cc1ccccc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N2CCN(Cc3ccccc3)C(=O)C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
The 1-benzyl-4-(5-nitropyridin-2-yl)piperazin-2-one (B-14) (195 mg, 0.63 mmol) was stirred in EtOAc (30 mL) and MeOH (15 mL). The mixture was treated with PtO2 (72 mg) and stirred at RT under 1 atm of H2 for 1 h 10 min. Then, the reaction mixture was filtered over a pad of celite and concentrated to yield 4-(5-aminopyridin-2-yl)-1-benzyl-piperazin-2-one (B-15) (176 mg, 100% yield). MS (M+1): 283.2
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[CH:14]=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>ClCCl>[CH:1]1([C:6]2[C:7]3[C:14]([I:15])=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1I
Reactant: c1nc(C2CCCC2)c2cc[nH]c2n1
Solvent: ClCCl
Product: Ic1c[nH]c2ncnc(C3CCCC3)c12
Reaction time: 8 h
Yield: 371.2 %

Procedure:
4-Cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (48, 0.099 g, 0.53 mmol) was dissolved in 3.4 mL of dichloromethane under an atmosphere of nitrogen and N-iodosuccinimide (0.131 g, 0.582 mmol) was added. The mixture was stirred overnight, then quenched with aqueous sodium thiosulfate. The aqueous layer was separated and washed with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to provide the desired compound (49, 0.616 g), used in the next step without further purification. MS (ESI) [M+H+]+=313.9.
Reaction SMILES: [F:1][C:2]1[C:12]2[CH:11]=[CH:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c2c1NCCC=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c2c1NCCCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 101 %

Procedure:
To a solution of 6-fluoro-9-nitro-2,3-dihydro-1H-benzo[b]azepine (225.4 mg, 1.0826 mmol) in EtOAc (15 mL) was added a slurry of 10% Pd/C (50 mg) in IMS (4 mL) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 20 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo affording the title compound as a purple oil (197 mg, quantitative). LCMS (Method J): RT 1.69 min [M+H]+ 181\
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)[C@H](C)O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[O:29][C:30]=2[CH3:36])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Reactant: COc1ccc(-c2nc(CCO)c(C)o2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy]-benzo[b]thiophen-7-yl)-propionic acid as colorless amorphous solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Br-]>C(OCC)(=O)C.CO.CCOC(C)=O.C(#N)C>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][S:8][CH2:7]2)[CH2:24][CH2:23]1
Reactant: O=C1CSCN1CCCCBr
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CSCN1CCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 80 °C
Reaction time: 19 h
Yield: 91.1 %

Procedure:
A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.00 g), 1-(2-quinolinyl)piperazine (3.94 g), K2CO3 (6.97 g), NaI (230 mg) and acetonitrile (150 mL) was heated at 80° C. (bath temperature) under nitrogen. After 19 hours, TLC analysis (silica gel, 13% MeOH/EtOAc) showed the absence of starting bromide and the presence of one major product, Rf =0.19. The reaction mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was filtered. The filtrate was concentrated in vacuo to a solid and triturated with EtOAc. The mixture was filtered again to remove insoluble materials and the filtrate concentrated in vacuo to 6.32 g of beige solid. Chromatography of the crude product by HPLC (Waters Prep 500, one silica gel column 8% MeOH/CH2Cl2) yielded 5.67 g of a solid, mp 105°-107° C. It was recrystallized from ethyl acetate/cyclohexane to give 3.62 g of off-white crystals, mp 106°-107.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([C:16]2[N:17]=[N:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=2)=[O:15])=[CH:4][CH:3]=1.[Br:40]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:40][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([C:16]2[N:17]=[N:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1ccccc1-c1ccc(CBr)cc1
Yield: 100.6 %

Procedure:
400 mg of 4'-methyl-2-(2-trityltetrazol-5-ylcarbonyl)biphenyl (prepared as described in Preparation 12), 150 mg of N-bromosuccinimide and 20 mg of benzoyl peroxide were treated in the same manner as described in Preparation 8, to give 465 mg of the title compound as a crystalline powder, melting at 161°-163° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[N:30]=[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)=[N:20][C:19](Br)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH:45]=2)O1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:30]1[C:22]([C:21]2[N:20]=[C:19]([C:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=3)[CH:18]=[N:17][C:16]=2[N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:23][N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nc2ccccn2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccn4n3)n2)CC1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-3-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-5-bromopyrazin-2-ylcarbamate (92 mg, 0.1872 mmol) was dissolved in DMF (1.5 mL) and treated with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (86.83 mg, 0.2808 mmol), PdCl2(PPh3)2 (13.14 mg, 0.01872 mmol) and K2CO3 (280.8 μL of 2 M, 0.5616 mmol). The mixture was allowed to heat at 100° C. for 1 hour and then allowed to cool to ambient temperature. The reaction was treated with EtOAc/water, the organics separated, washed with water (2×) followed by brine (2×), dried (MgSO4), filtered and concentrated to a brown oil. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petrol) to afford the title compound as a white solid (77 mg, 69% Yield). MS (ES+) 594.0
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:20][C:21]1([CH3:28])[CH2:24][CH:23]([C:25](Cl)=[O:26])[CH2:22]1>O1CCCC1.[Cu]I>[CH3:20][C:21]1([CH3:28])[CH2:24][CH:23]([C:25]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:26])[CH2:22]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC1(C)CC(C(=O)Cl)C1
Agent: [Cu]I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a −40° C. solution of ethyl 4-iodobenzoate (2.30 g, 8.30 mmol) in tetrahydrofuran (20 mL) was added isopropylmagnesium chloride lithium chloride (7.1 mL, 1.3 M in THF, 9.2 mmol) dropwise. The mixture was stirred for 1 hour at −40° C. Copper (I) iodide (476 mg, 2.50 mmol) was then added and the reaction was allowed to warm to −10° C. and stir for 20 minutes. The solution was cooled again to −40° C. and a solution of the previously prepared 3,3-dimethylcyclobutanecarbonylchloride (1.54 g, 10.5 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was allowed to warm to 0° C. and stir for 2 hours. The reaction was quenched with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3×15 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (1.80 g, 83%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.15 (d, J=8.4 Hz, 2 H), 7.98 (d, J=8.4 Hz, 2H), 4.20-4.47 (m, 2H), 3.89-3.98 (m, 1H), 2.22-2.27 (m, 2H), 2.09-2.15 (m, 2H), 1.45 (t, J=7.2 Hz, 3H), 1.32 (s, 3H), 1.13 (s, 3H).