Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:28](=[O:32])[NH:27][CH:26]=[N:25][C:24]2=3)[O:12]1)(=O)C1C=CC=CC=1.CO>N>[F:22][C@:14]1([CH3:21])[C:15]([OH:17])([CH3:16])[C@@H:11]([CH2:10][OH:9])[O:12][CH:13]1[N:23]1[CH:31]=[N:30][C:29]2[C:28](=[O:32])[NH:27][CH:26]=[N:25][C:24]1=2
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(=O)[nH]cnc32)[C@]1(C)F
Agent: N
Solvent: CO
Product: CC1(O)[C@@H](CO)OC(n2cnc3c(=O)[nH]cnc32)[C@]1(C)F
Yield: 35 %

Procedure:
To a solution of ((2R,4R)-3-acetoxy-4-fluoro-3,4-dimethyl-5-(6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-2-yl)methyl benzoate (about 0.30 g, 0.67 mmol) in methanolic ammonia (25% w/w, 10 ml) was stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography, methanol was removed under reduced pressure, water added to the crude and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by silica gel column chromatography using 5% methanol in dichloromethane to elude title compound (0.07 g) as a colorless solid. Yield: 35%; 1H NMR (300 MHz, CD3OD): δ 8.14 (d, 1H, J=3.6 Hz), 8.06 (s, 1H), 6.41 (d, 1H, J=21.9 Hz), 4.43-4.40 (m, 1H), 3.88-3.83 (m, 2H), 1.38-1.28 (m, 6H); Mass: [M+1]+ 299 (100%), [M+Na]+321 (30%); HPLC: 95.2%.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][CH3:22])[S:10]2)[C@H:6]1[O:23]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:15][CH2:14][C@H:13]1[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][CH3:22])[S:10]2)[C@@H:6]([OH:23])[C@@H:5]1[OH:4]
Reactant: CCCNC1=N[C@@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]2S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(propylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (100 g, 257 mmol) in methanol (800 mL) was added potassium carbonate (18 g, 130 mmol). The resulting solution was stirred overnight at 40° C. and then cooled down to 0° C. to yield a solid This was collected by filtration, washed with cold methanol and dried. The product 15 was obtained as a white solid (50 g, 74%). (ES, m/z): [M+H]+ 262.9; 1H NMR (300 MHz, D2O) δ 6.17-6.19 (d, J=6.3 Hz, 1H), 4.07-4.10 (m, 1H), 3.93-3.96 (m, 1H), 3.71-3.76 (m, 1H), 3.45-3.69 (m, 3H), 3.04-3.13 (m, 2H), 1.39-1.51 (m, 2H), 0.82-0.91 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH:14]=[CH:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[N:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:7]2=[O:32].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>O=[Pt]=O.CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[N:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:7]2=[O:32]
Reactant: COc1ccc(CN2C(=O)c3cccc(Cl)c3C23C=CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=[Pt]=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: COc1ccc(CN2C(=O)c3cccc(Cl)c3C23CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 72 h

Procedure:
Tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate (1.69 g, 3.71 mmol, 1.0 equiv) and PtO2 (100 mg, 0.440 mmol, 12 mol %) were added to a solution of 1:1 4.0 M HCl:MeCN (200 mL). The mixture was transferred to a Parr hydrogenation vessel and hydrogenated at 55 psi for 3 d. After this time the vessel was vented and the pale yellow solution filtered through a bed of Celite. The mixture was evaporated and the residue was dissolved in 1:1 MeCN:10% aq K2CO3 (200 mL); Boc2O (1.21 g, 5.56 mmol, 1.5 equiv) was added and the mixture was stirred for 17 h. After this time the solution was evaporated and the residue was diluted with EtOAc. The organic layer was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The reduced product was purified by flash chromatography on silica gel, eluting with 20-80% EtOAc in hexanes. Tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate was isolated as a pale yellow foam (0.702 g, 1.54 mmol, 42%).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCc1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
[1,1′-biphenyl]-4-pentanol (3.34 g, 13.90 mmol) and carbon tetrabromide (5.99 g, 18.07 mmol) were dissolved in dry methylene chloride (20 mL) and cooled to 0° C. Triphenyl phosphine (4.98 g, 18.07 mmol) in methylene chloride (10 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The mixture was poured into hexanes (100 mL) and then filtered through a short silica gel column, washed with ethylacetate/hexanes (1/4). The combined organic solvents were evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (hexanes:ethylacetate 30:1) to afford 4.18 g of the title compound. Yield: 99%. 1H NMR (300 MHz, CDCl3) δ 1.52 (m, 2H), 1.67 (m, 2H), 1.91 (m, 2H), 2.67 (t, J=7.5 Hz, 2H), 3.41 (t, J=6.9 Hz, 2H), 7.21-7.60 (m, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 28.2, 30.9, 33.0, 34.1, 35.6, 127.1, 127.2, 128.8, 128.9, 138.8, 141.2, 141.5 ppm.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]([CH3:30])[C:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:16]=[C:17]2Cl)=[CH:12][C:11]=1[O:28][CH3:29])=[O:9]>>[CH3:30][N:7]([CH3:6])[C:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:16]=[C:17]2[O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:12][C:11]=1[O:28][CH3:29])=[O:9]
Reactant: OC1CCC1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C(=O)N(C)C
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCC3)c2cc1C(=O)N(C)C

Procedure:
Similar procedure as described in example 400 was used, starting from cyclobutanol and 1-Chloro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide to give 1-Cyclobutoxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide, LC-MS: m/e 396(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:10])[C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:26])[C:21]=2[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:27]([C:24]2[S:23][C:22]3[CH:31]=[CH:32][C:19]([Cl:18])=[CH:20][C:21]=3[C:25]=2[CH3:26])(=[O:29])=[O:28])=[C:5]([CH3:10])[C:4]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1ccc(N)c(C)c1N1CCN(C)CC1
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(C)c1N1CCN(C)CC1

Procedure:
The title compound (E125) was prepared from 4-methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenylamine (D33) (58 mg, 0.247 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (70 mg, 0.247 mmol) using the method of Example 1 (103 mg, 81%). MH+=480/482.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:21])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1
Reactant: Oc1ccc(-c2ccc(F)cc2)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
2-Chloro-4′-fluorobiphenyl-4-ol (Preparation 73, 503 mg, 2.26 mmol) was dissolved in dichloromethane (5 mL) and acetic acid (5 mL). Concentrated sulfuric acid (0.05 mL) was added followed by N-iodosuccinimide (508 mg, 2.26 mmol) and the reaction stirred at room temperature for 2 hours before partitioning it between water and dichloromethane. The organic layer was separated and washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (553 mg, 70%) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].C([Li])CCC.[CH:16]1([Sn:22](Cl)([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O.C(OCC)C.CCCCCC>[CH:29]1([Sn:22]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([OH:10])[CH3:9])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(O)c1ccccc1Br
Reactant: Cl[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
10.1 g of o-bromo-1-phenylethanol (50.2 mmol) and 50 ml of diethylether were mixed together in a 500 ml two-neck flask, which was equipped with a stirrer and isobaric dropping funnel. To this mixture, 64.5 ml of hexane solution of n-butyl lithium was gradually added dropwise at -78° C. Subsequently, the temperature was raised to -30° C., and the mixture was stirred for 1 hour while maintaining the same temperature. The reaction mixture was cooled back to -78° C., and a mixed solvent solution containing 20.2 g of tricyclohexyltin chloride (50.1 mmol), 100 ml of hexane, and 50 ml of diethylether was added dropwise thereto. The temperature was raised back to -30° C., and the mixture was stirred for 12 hours at the same temperature. Upon completion of the reaction, 100 ml of water was added, and the organic substance was extracted three times, with 200 ml of diethylether for each. After the solvent was removed under reduced pressure, the oily product was purified by column chromatography on silica gel (for which, 50 g of silica gel, and a mixed solvent of hexane and diethylether, as a developing solvent, were employed) to yield 17.9 g of the final product (yield=73.0%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[CH:33]=[N:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[CH:33]=[N:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3cnc(C(F)(F)F)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyrazine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=1.06 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[CH2:1]([N:4]([CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH:2]=[CH2:3]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccc(C(F)(F)F)cc2)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 1-fluoro-4-trifluoromethyl-benzene were converted to yield Allyl-methyl-{5-[1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pentyl}-amine as light brown oil, MS: 401 (MH+).
Reaction SMILES: [CH3:1][N:2]1C=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24]([F:32])[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.C[N:34]1N=C(NC(C2C=C(OC3C=CC(C#N)=C(F)C=3)C3CC(C)(C)OC=3C=2)=O)C=N1>>[CH3:1][N:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24]([F:32])[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:17])([CH3:18])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[N:34]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Reactant: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (184) (150 mg, 0.368 mmol) and used without further purification for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][C:24]1(C)[C:28](C)(C)OB(C(C)=C)O1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]=[C:24]([C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:28]
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)c1cc(-c2coc(CCC(=O)OC)n2)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 69.4 %

Procedure:
A suspension of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44, 0.605 g, 1.60 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.404 g, 2.40 mmol) and potassium acetate (2.36 g, 24.0 mmol) in toluene (50.0 mL) and water (1.00 mL) was evacuated and purged with nitrogen. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.277 g, 0.240 mmol) and the resulting reaction mixture was heated at 100° C. for 10 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.377 g, 68%) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][O:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[O:48][CH2:49][C@H:50]([OH:57])[CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56])=[CH:29][CH:30]=1
Reactant: COCCOC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Solvent: CO
Product: COCCOC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1) (l) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-1-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-2-ol as colorless oil; MS: 690.3 (M+H)+.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[CH3:45][O:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](O)=[O:50]>>[CH3:45][O:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49]([NH:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29])=[O:50]
Reactant: COc1ccccc1C(=O)O
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3OC)nn2)cc1
Yield: 93.2 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 2-methoxybenzoic acid (68 mg, 0.45 mmol) to give 2-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino-}-1,2,4-triazin-6-yl)ethyl]benzamide (145 mg) as a yellow solid. MS m/z 380 (M+1).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1CCN2C(=NCCC2)CC1>CC#N.CC(=O)OCC.O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ncsc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncsc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
To a solution of methyl 5-bromo-1,3-thiazole-4-carboxylate (10 g) in MeCN (120 mL) was added 1-Boc-piperazine (8.56 g) followed by DBU (10.1 mL). The resulting solution was stirred at 80° C. for 5 h. The reaction mixture was diluted with EA and water. The layers were separated and the org. phase was further washed with water. The combined aq. layers were extracted with EA. The combined org. layers were dried over Na2SO4, filtrated off and evaporated in vacuo. The crude was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 10 for 2CV, 10 to 50 over 12CV, 50 for 3CV) to afford 7.65 g of yellow oil. LC-MS (B): tR=0.79 min; [M+H]+: 328.37.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][C:4]1([C:9]([O:11]C)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>CO>[Cl:1][C:2](=[CH2:13])[CH2:3][C:4]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C=C(Cl)CC1(C(=O)OC)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(Cl)CC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(2-chloroallyl)cyclopentanecarboxylate (1.82 g, 8.98 mmol) in MeOH (30 mL) was added 1M NaOH (26.9 mL, 26.9 mmol) at room temperature. The mixture was stirred at room temperature for 2 hour then heated at 60° C. for 24 hours. The reaction mixture was quenched with excess of aq. 1 M HCl. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography using 30% EtOAc/heptane to 100% EtOAc to give 1-(2-chloroallyl)cyclopentanecarboxylic acid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.82 (m, 6H), 2.04-2.28 (m, 2H), 2.69 (s, 2H), 5.08 (s, 1H), 5.17 (d, J=1.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: O=C1CCO1
Reactant: Cc1ccccc1S
Solvent: CC#N
Product: Cc1ccccc1SCCC(=O)O
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A solution of acetonitrile (30 mL) and o-thiocresol (5.0 g, 40 mmol) was heated to reflux. Next β-propiolactone (2.8 mL, 40 mmol) was added dropwise over 5 min. Heating was continued at reflux for 20 h at which time additional β-propiolactone (2.8 mL, 40 mmol) was added in one portion. After heating for an additional 24 h, the reaction mixture was concentrated in vacuo. The resulting solid-oil mixture was treated at 23° C. with 2N aqueous NaOH (150 mL). This basic solution was washed with Et2O (2×200 mL). The separated aqueous layer was acidified with conc. aqueous HCl unit pH<1. This heterogeneous solution was concentrated in vacuo to half of its original volume. Then it was allowed to stand at 23° C. for 2 h. The solid product was collected by vacuum filtration, washed with H2O (20 mL), and dried under vacuum at 65° C. for 2 h to afford 3-[(2-methylphenyl)sulfanyl]propanoic acid (4.62 g, 59%) as a white powder. 1H NMR (CHCl3, 300 MHz) δ7.31 (d, 1H, J=7.0 Hz), 7.20-7.15 (m, 3H), 3.14 (t, 2H, J=7.3 Hz), 2.69 (t, 2H, J=7.4 Hz), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[N:35]=[C:34]1[CH3:42]>>[CH3:32][N:33]1[CH:37]=[C:36]([S:38]([N:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]2)(=[O:40])=[O:39])[N:35]=[C:34]1[CH3:42]
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2cn(C)c(C)n2)c1-c1ccccc1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and (1,2-dimethyl-1H-imidazol-4-yl)sulfonyl chloride (253 mg), the title compound was obtained as a colorless solid (yield 294 mg, 86%).