Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29]Br>CN(C=O)C>[I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][N:7]([CH2:29][CH2:28][O:27][CH3:26])[C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
To a solution of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (100 mg, 0.27 mmol) in DMF (3 mL) was added potassium carbonate (55 mg, 0.40 mmol), followed by 2-bromoethyl methyl ether (28 μL, 0.37 mmol). The reaction mixture was stirred at RT for 24 hours. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 60% ethyl acetate in cyclohexane) to give the title compound as a white solid (67 mg, 59%). LCMS (Method B): RT=3.94 min, [M+H]+=424.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:17])=[C:6]([O:15][CH3:16])[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)[CH3:23]>C(C(C)=O)C>[C:1]([C:4]1[C:5]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH3:23])=[C:6]([O:15][CH3:16])[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Solvent: CCC(C)=O
Product: COc1ccc(CCN(C)CCCOc2c(C(C)=O)c(OC)c3ccoc3c2OC)cc1OC

Procedure:
39 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran are refluxed with 40 g of 3-chloropropyl-(2-(3,4-dimethoxyphenyl)-ethyl)-methylamine in 250 ml of methyl ethyl ketone for 14 hours. The mixture is filtered, the solvent is stripped off and the oily residue is dissolved in dilute HCl. The aqueous phase is washed with ether, rendered alkaline with dilute sodium hydroxide solution and extracted with ether. Stripping off the solvent gives 45 g of crude oily product which is further reacted without purification.
Reaction SMILES: C(N1CC[C:12](=[O:15])[CH2:11][CH2:10]1)CC1C=CC=CC=1.NC1C=C(O)C=CC=1.[CH2:24]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(=O)CC)(=O)CC.CN(C1C=CC=CN=1)C>C(N(CC)CC)C>[OH:45][C:41]1[CH:40]=[C:39]([N:38]([CH:35]2[CH2:34][CH2:33][N:32]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:37][CH2:36]2)[C:12](=[O:15])[CH2:11][CH3:10])[CH:44]=[CH:43][CH:42]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: Oc1cccc(NC2CCN(CCc3ccccc3)CC2)c1
Agent: CCC(=O)OC(=O)CC
Agent: CN(C)c1ccccn1
Agent: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1cccc(O)c1)C1CCN(CCc2ccccc2)CC1

Procedure:
As indicated in Scheme 11-D above, the desired mPEGn-O-fentanyl conjugates were prepared by first reacting 1-phenethylpiperidin-4-one with 3-aminophenol under reducing conditions to thereby convert the keto functionality into an amine, i.e., by reaction with the amino group of 3-aminophenol. The product, 3-(1-phenethylpiperidin-4-ylamino)phenol, was then reacted with propionic anhydride in the presence of base (e.g., triethyl amine) and dimethylaminopyridine (DMAP) under conditions effective to form N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide. Finally, introduction of the oligomeric PEG functionality was carried out by reacting the precursor, N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide, with a molar excess of mPEGoligotosylate under coupling conditions effective to form the desired conjugates. Ratios of reactants and reaction conditions generally employed are provided in the reaction schemes above.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[NH:12][N:13]=[C:14]([S:16][CH3:17])[N:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])[CH3:3].C1C=C([O:29]O)C(C(O)=O)=C(C(O)=O)C=1>C(O)C.O>[CH3:19][C:18]([C:7]1[CH:8]=[C:9]([C:11]2[NH:12][N:13]=[C:14]([S:16]([CH3:17])=[O:29])[N:15]=2)[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:22])([CH3:21])[CH3:20]
Reactant: CSc1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CCO
Solvent: O
Product: CS(=O)c1n[nH]c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A 50° C. solution of 1.0 g (3.13 mmol) of the methylthiotriazole (Example 43) in 50 ml of 95% ethanol is treated dropwise with a solution of 0.92 g (2.98 mmol) of 80% monoperoxyphthalic acid, magnesium salt (MMPP) in 4.5 ml of water over 20 minutes. The resulting reaction mixture is stirred at 40° to 50° C. for two hours and concentrated in vacuo. The residue is dissolved in ethyl acetate, extracted with saturated aqueous NaHCO3 (three times), water and brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, 5% methanol-chloroform, 26×6.5 cm) followed by recrystallization from acetone-water gives 0.30 g (1.05 g theor., 29%) of the sulfoxide as a white solid, mp 135°-145° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1>>[F:28][C:29]1[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cc(F)cnc2F)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cnc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a solid. UPLC-MS (Condition 3), tR=1.05 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.78 (br. s, 1H) 1.87 (br. s, 1H) 2.97 (br. s, 1H) 3.17-3.29 (m, 2H) 3.42 (dd, J=16.03, 7.04 Hz, 1H) 4.23 (br. s, 1H) 4.91 (br. s, 1H) 7.35 (m, J=8.60 Hz, 2H) 7.50 (br. s, 1H) 7.85 (m, J=8.99 Hz, 2H) 8.05-8.13 (m, 1H) 8.28-8.39 (m, 1H) 8.74-8.86 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=O.[Br-].[CH2:8]([O:15][C:16]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1C(CC)C1>[OH:5][CH:2]([CH2:1][OH:6])[CH:3]=[CH:18][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: O=CC(O)CO
Agent: CCC1CO1
Agent: [Br-]
Product: O=C(C=CC(O)CO)OCc1ccccc1

Procedure:
A mixture of DL-glycerinaldehyde (4,5 g, 50 mmole) and (benzyloxycarbonylmethyl)-triphenyl-phosphoniumbromide (24.57 g, 50 mmole) in 100 ml 1,2-epoxybutane was refluxed overnight. The mixture was evaporated under vacuum and the product was isolated by silica gel column chromatography.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.[OH-].[Na+]>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH:25][CH2:35][CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCc1ccccc1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)c1cccc(C(=NOCc2cccc(NCCCc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred solution of 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (125.0 mg, 0.35 mmol) in dry 1,2-dichloroethane (10 mL), under argon atmosphere, were added 3-phenylpropionaldehyde (66.6 mg, 0.49 mmol) and sodium triacetoxyborohydride (135 mg, 0.63 mmol) at room temperature. After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane (50 mL) and aq. NaOH (1 M, 30 mL) was added. After phase separation, the organic layer was washed with water (40 mL), dried over MgSO4 and concentrated in vacuo. Purification on silica gel afforded 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}-N-(3-phenylpropyl)pyridin-2-amine as an oil [82 mg, yield 47%; HPLC/MS: m/z=471 (M+H); logP(HCOOH)=2.57].
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[NH:18]1[C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=2[N:20]=[C:19]1[CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29]>C1COCC1>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]([C:27]1[CH:3]=[CH:2][C:1](=[O:5])[N:20]2[C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[NH:18][C:19]=12)=[O:29]
Reactant: C#CC(=O)O
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1cccs1)c1ccc(=O)n2c3c([nH]c12)CCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
126.2 mg (1.73 mmol) of propiolic acid and 336.6 mg (2.08 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole are dissolved in 10 ml THF. The mixture is stirred for 3 h at room temperature. To this solution 300 mg (1.15 mmol) of 2-(4,5,6,7-Tetrahydro-1H-benzimidazol-2-yl)-1-(2-thienyl)ethanone (example XII are added and the mixture is refluxed for 24 h. The solvent is evaporated under vacuum and sodium hydrogen carbonate—solution (saturated in water) is added to the crude. The solution is extracted ethyl acetate. The collected organic phases are reextracted with brine—solution an dried over sodium sulfate. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, Eluent: acetonitrile-Water Gradient) to yield 150 mg (43.6% of th.) 4-(2-Thienylcarbonyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-1(5H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a round bottom flask containing 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanamine (0.710 mmol) at 0° C. was added a solution of isobutyryl chloride (0.852 mmol, 1.2 eq.) and triethylamine (0.852 mmol, 1.2 eq.) in tetrahydrofuran (5 mL) that was pre-mixed and stirred 5 min prior to addition. After warming to room temperature, the resulting solution was stirred 2 h and quenched with saturated aqueous sodium bicarbonate solution (1 mL) and stirred 5 min. The reaction was diluted with 0.1N NaOH (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a yellow syrup that was purified by column chromatography to afford the final product as a white solid (0.344 mmol, 47% for 2 steps). HRMS: calcd for C29H32ClN3O3+H+, 506.22049; found (ESI, [M+H]+ Obs'd), 506.2208.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][CH:7]=[CH:6]2.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][CH:7]=[C:6]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: COc1cc2cc[nH]c2cc1Cl
Agent: Cl
Solvent: O
Product: COc1cc2c(C3=CCNCC3)c[nH]c2cc1Cl
Yield: 83 %

Procedure:
Beginning with 2.0 gm (11.0 mMol) 5-methoxy-6-chloro-1H-indole and 3.4 gm (22.0 mMol) 4-piperidone hydrochloride monohydrate, 2.4 gm (83%) of the title compound were recovered as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:18]=1)[C:10](=[O:17])[C:11]1[CH2:16][CH2:15][CH2:14][C:12]=1[N:13]=2)=[O:4].C[O-].[Na+].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:22](=[C:14]1[C:12]2[N:13]=[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:18][N:9]3[C:10](=[O:17])[C:11]=2[CH2:16][CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1

Procedure:
1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 153°-154° C. (5 g) in methanol (300 ml) containing 6.45 g of sodium methoxide was reacted with 10.9 g of benzaldehyde under stirring at reflux temperature for 96 hours. After cooling and concentration in vacuo to a small volume the precipitate was filtered and treated with acetic acid and then with water; the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2 /methanol and then from dioxane to give 3.25 g of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 309°-310° C., NMR (CF3COOD) δ ppm: 3.44 (m) (4H, cyclopentane protons), 7.68 (m) (6H, =CH-- and phenyl protons), 8.44 (d) (1H, C-5 proton), 9.15 (d.d) (1H, C-6 proton), 10.23 (d) (1H, C-8 proton).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:19](OC(=O)C)(=O)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:18])[O:17][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)c1cc(Cl)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1

Procedure:
This compounds was synthesised in the same manner as described above. 1-(5-Chloro-2,4-dihydroxy-phenyl)-2-phenyl-ethanone (1.5 g, 5.7 mmol), acetic anhydride (2.0 ml), Potassium carbonate (2.1 g 15.2 mmol). 6-Chloro-7-hydroxy-2-methyl-3-phenyl-chromen-4-one was obtained as white solid (1.4 g, 85.8%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.ClCCl.N1C=CN=C1.[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: NC(=O)Cc1coc2cc(O)ccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc2c(CC(N)=O)coc2c1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 77.6 %

Procedure:
To a solution of 2-(6-hydroxy-benzofuran-3-yl)-acetamide (0.23 g, 1.20 mmol) in a mixture of dry dichloromethane (20 mL) and DMF (6 mL) was added imidazole (0.34 g, 5.05 mmol), followed by tert-butyldiphenylchlorosilane (1.31 mL, 5.05 mmol) at room temperature and the mixture was stirred for two days. The solution was quenched with methanol and stirred for 10 min. The solvent was evaporated in vacuo and the residue was purified by column chromatography (methanol:dichloromethane; 5:95) to give the 2-[6-(tert-butyl-diphenyl-silanyloxy)-benzofuran-3-yl]-acetamide as a white solid (0.40 g, 78%). 1H NMR (DMSO-d6, 400 MHz) 1.06 (s, 9H), 3.38 (s, 2H), 6.74 (dd, J=1.8, 8.4 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.42-7.54 (m, 7H), 7.64 (s, 1H), 7.70 (m, 4H), 7.80 (s, 1H).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[Br:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([OH:14])=[O:13]>CO>[Br:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([O:14][CH3:1])=[O:13]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)C=Cc1cccc(Br)c1
Solvent: CO
Product: COC(=O)C=Cc1cccc(Br)c1
Reaction time: 4 h

Procedure:
Trimethylsilyl chloride (5.6 ml) was added dropwise to a stirred solution of m-bromocinnamic acid (5.0 g, 22 mmol) in methanol (110 ml). After 4 h, the mixture was evaporated to give product as a white solid, M+ 242; 360 MHz 1H n.m.r (CDCl3) 7.67 (1H, s), 7.60 (1H, d, J 16 Hz), 7.50 (1H, d, J 7.9 Hz), 7.43 (1H, d, J 7.9 Hz), 7.26 (1H, d, J 15.6 Hz), 6.43 (1H, d, J 16.1 Hz), 3.81 (3H, s).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.ClCCl>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 0.66 mg of [Ru(η5-2,4-DMP)((R)—(S)—PPF—PtBu2)(NCMe)]BF4 (0.0008 mmol, S/C 3,000) and 5 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (99.9% conversion) and an enantiomeric purity of 89%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:14]([C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=1)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (3.00 g, 10.14 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of oxalyl dichloride (4.50 g, 35.43 mmol, 3.00 equiv) dropwise with stirring at 0° C. To this was added N,N-dimethylformamide (one drop). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3.18 g (99%) of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([N:29](C)[C:30](=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH3:30])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CN(C(=O)OC(C)(C)C)C1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)cyclopropyl(methyl)carbamate (0.03 g, 0.058 mmol) in chloroform (0.5 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and the resulting crude product was purified via reverse phase preparative HPLC to afford ′1-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-N-methylcyclopropanamine as a white amorphous solid. MS (ESI) m/z: Calculated: 415.5; Observed: 416.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31][Mg]Br>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([OH:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:31][CH2:30][C:29]([F:35])([F:34])[F:28])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: FC(F)(F)CC[Mg]Br
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(CCC(F)(F)F)c2ccccn2)c2[nH]c(=O)[nH]c2c1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. (3,3,3-trifluoropropyl)magnesium bromide (0.5 M, 0.55 mL, 0.28 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water and concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL), heated to 65° C. for two hours, concentrated, then purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl[CH2:21][CH2:22][C:23]#[N:24]>>[C:23]([CH2:22][CH2:21][N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)#[N:24]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: N#CCCCl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CCC#N)c1=O
Yield: 78.9 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 3-chloropropionitrile as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 78.9%.