Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20](Br)[C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Si:28]([O:35][C:36]1[CH:41]=[C:40]([CH3:42])[C:39](B(O)O)=[C:38]([CH3:46])[CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:39]4[C:40]([CH3:42])=[CH:41][C:36]([O:35][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:30])[CH3:29])=[CH:37][C:38]=4[CH3:46])[C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1B(O)O
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C#N)c3Br)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C#N)c3-c2c(C)cc(O[Si](C)(C)C(C)(C)C)cc2C)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
Under nitrogen atmosphere, (1S,2S)-2-[4-((R)-4-Bromo-5-cyano-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 13, 590 mg, 1.38 mmol), (4-{[tert-butyl(dimethyl)silyl]oxy}-2,6-dimethylphenyl)boronic acid (0.78 g, 2.77 mmol, WO2005/63729A1), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (54 mg, 0.138 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.37 mg, 0.07 mmol) and sodium carbonate (500 mg, 4.71 mmol) are suspended in 10 mL of toluene and 5 mL of water. The reaction mixture is stirred at 110° C. for 12 h then it is concentrated under vacuum. The crude product obtained is purified by flash chromatography (cyclohexane/ethyl acetate 100/01 4 80/20) to give the title compound (Yield: 500 mg).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)=[O:24]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=2)=[O:24])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCC(=O)Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCC(=O)Oc2ccc(OC(F)(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(trifluoromethoxy)phenyl β-alaninate in a similar manner as described for Example 164. Mass Spectrum: [M+H]+ 513.12, [M−H]− 511.16.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCCBr
Solvent: ClCCl
Solvent: CO
Product: O=C(CCBr)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, Mass.) is washed with deionized water to remove color. A mixture of 225 gm D-mannose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50Wx4 is treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction is monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction is complete after about four hours, and then allowed to cool to room temperature. The solution is filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate is stripped to an amber oil in a rotory evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CC1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-((2-methoxy-3-pyridinyl)methyl)piperazine (350 mg, 1.69 mmol), triethylamine (0.353 mL, 2.54 mmol), and 2-thiophenesulfonyl chloride (0.34 mL, 1.86 mmol, Aldrich, St. Louis, Mo.) in DCM (5 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow glass. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((2-methoxy-3-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (202 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:18]1(O[Si](C)(C)C)[CH2:20][CH2:19]1)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH:18]1[CH2:20][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C1CC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptan-5-ylcarboxylic acid tert-butyl ester (3.00 g, 15.13 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (3.96 g, 22.70 mmol) were dissolved in methanol (30 mL), and while stirring the solution at room temperature, acetic acid (0.87 mL, 5.13 mmol) and then sodium cyanoborohydride (1.06 g, 15.13 mmol) were added thereto. Then, the mixture was heated to reflux for 21 hours. The reaction liquor was left to cool naturally, then a saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added thereto, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel [chloroform-methanol (10:1)], to obtain the title compound (3.61 g, 100%) as an oily matter.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34](C(OCC)=O)=[N:35][N:36]=2)[CH:33]=1.O.[OH-].[Li+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.C1COCC1.O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=4[C:22]([F:24])([F:25])[F:23])[CH2:14][CH2:13]3)=[O:16])=[N:35][N:36]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Reaction time: 6 h
Yield: 34.8 %

Procedure:
To a solution of tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.246 g, 0.675 mmol) in dichloromethane (5 mL) was added HCl (2 M in ether, 10 mL). The mixture was stirred for 6 h and evaporated to afford a solid that was dissolved in DMF (4 mL). In a separate flask, to a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.182 g, 0.675 mmol) in THF (5 mL) was added a solution of lithium hydroxide hydrate (0.028 g, 0.675 mmol) in water (2 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to pH 6 and evaporated to dryness. To this residue were added benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (0.448 g, 1.01 mmol), N,N-diisopropylethylamine (0.349 g, 2.70 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine for three times, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an off-white solid (0.115 g, 34%): 1H NMR (300 MHz, CDCl3) δ9.37 (m, 1H), 7.79 (dd, J=9.6, 0.9 Hz, 1H), 7.50 (dd, J=9.6, 1.7 Hz, 1H), 6.96 (d, J=9.7 Hz, 1H), 6.84-6.77 (m, 1H), 5.77-5.72 (m, 1H), 5.00-4.95 (m, 1H), 3.44-3.29 (m, 2H), 3.01-2.92 (m, 1H), 2.01-1.69 (m, 4H); MS (ESI+) m/z 489 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=O)[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([C:27](OC)=O)=[N:3]1.[NH3:31]>>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([CH2:27][NH2:31])=[N:3]1
Reactant: N
Reactant: COC(=O)c1nc(NC(=O)CCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Product: Cn1nc(CN)nc1NCCCCOc1cccc(CN2CCCCC2)c1

Procedure:
A solution of methyl 1-methyl-5-[[1-oxo-4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino]-1H-1,2,4-triazole-3-carboxylate (1.94 g) in 0.88 ammonia was stirred at room temperature for 18 h. The mixture was evaporated to yield a yellow foam, which was triturated with ether to give a yellow solid (1.56 g) which was used without further purification. A portion of this solid (1.20 g) was suspended in tetrahydrofuran (50 ml) and treated at room temperature with lithium aluminium hydride (1.0 g). The mixture was heated under reflux for 24 h, cooled and quenched with water. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were evaporated to yield an oil (0.90 g) which was chromatographed to give the title compound as an oil (210 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH:7]=1.[OH-].[Na+].[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C1COCC1>[C:24]([O:23][C:21]([N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:17])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Clc1ccc(Br)cc1-c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc(Br)ccc2Cl)nc2ccccc21
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Method 2—Step b—Into a three necked round bottomed flask equipped with a magnetic stirrer, 2-(5-bromo-2-chlorophenyl)-1H-benzimidazole (30.7 g, 99.8 mmol) was suspended in THF(1 L). 50% NaOH (72.0 g, 598 mmol) was then added. The suspension was left at r.t. for 1 h under stirring. (BOC)2O (37.0 g, 169.7 mmol) was dissolved in THF (200 mL) and added to the reaction mixture. The reaction was left under stirring overnight. The solvent was evaporated under reduced pressure. The obtained residue was diluted with water (500 mL) filtered and dried under vacuum (60° C.), to give 39.8 g of a brown solid. (98%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1([CH2:17][N:18]([CH3:19])[CH3:20])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CN(C)C)CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(CN(C)C)CCNC1
Yield: 96.5 %

Procedure:
A mixture of 1-benzyl-3-dimethylaminomethyl-pyrrolidine-3-carboxylic acid methyl ester (400 mg), 10% Pd/C (40 mg) and methanol (30 ml) was shaken in a hydrogen parr shaker at 45 psi for overnight. The mixture was filtered through celite, washed with ethyl acetate. The combined filtrate was concentrated to give the title compound as oil (260 mg, 96%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 59% overall yield. FDMS m/e=426 (M+ of free base). α[D]589 =-11.39 (c=0.56, methanol).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([O:24]C)=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:6]=1
Reactant: COc1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCC(c2nc3cc(O)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
To a stirred solution of biphenyl-4-yl[4-(5-methoxy-1H-benzimidazol-2-yl)piperidin-1-yl]methanone (40 mg, 0.097 mmol) in DCM (1 mL) at −60° C. is added BBr (14 μL). After 30 mins the reaction mixture is warmed to room temperature, diluted with DCM and washed with water. The organic layer is concentrated under reduced pressure. Purification by preparative HPLC gives 6 mg of biphenyl-4-yl[4-(5-hydroxy-1H-benzimidazol-2-yl)piperidin-1-yl]methanone.
Reaction SMILES: [OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCn2ccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 55 °C
Reaction time: 42 h

Procedure:
A mixture of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(2-bromoethoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (45 mg, 0.073 mmol) (Example 19A), imidazole (25 mg, 0.36 mmol) and potassium carbonate (50 mg, 0.36 mmol) in acetone (2 mL) was heated with stirring at 55° C. under nitrogen for 42 h. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried, and evaporated to a residue. Purification by preparative TLC (CH2Cl2 -MeOH; 9:1, v/v) gave the title compound: Rf 0.5; MS, m/z 604 M+. ; NMR (CDCl3) δ 7.06 (bd, NCH=CHN), 7.76 (bs, NCH=N).
Reaction SMILES: [CH:1](=[C:8]([C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:21][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1(C)C=CC(C=O)=CC=1>C1CCCCC1>[CH3:21][C@:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])([OH:11])[C:8](=[CH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:9]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cc1ccc(C=O)cc1
Solvent: C1CCCCC1
Product: C[C@](O)(C(O)=Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The methyl benzylidene sorbitol was prepared in like manner as the benzylidene sorbitol in the foregoing Example 1. in which 32.0 g of 70% sorbitol, 44.3 g of para-tolualdehyde and 580 ml of cyclohexane were used. The acetal value of the reaction product in white powder from was about 345 which corresponds to the combination ratio of 3.0 moles of paratolualdehyde per 1 mole of sorbitol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>CO.[Pd]>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([O:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(F)c2)CC1
Yield: 90 %

Procedure:
tert-Butyl 4-(3-fluoro-4-nitro phenoxy)piperidine-1-carboxylate (9.22 g, 0.027 moles) was hydrogenated over 10% Pd/C (9.22 g) in methanol (92.2 mL) by bubbling hydrogen gas for 5 hours at ambient temperature. The mixture was filtered through a pad of celite, and the filtrate was concentrated under vacuum to obtain the title compound 7.54 g (Yield: 90%). The product was used as such in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of ethyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.70 g, 1.4 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N sodium hydroxide (3 mL). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.56 g, 84.8%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](=[O:11])[CH2:9]Br)=[C:5]([CH3:7])[N:6]=1.[C:12]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH2:27])[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:27][CH2:9][CH:8]([OH:11])[C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]
Reactant: Cc1nc(C)c(C(=O)CBr)s1
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2sc(C)nc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2,4-dimethyl-5-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed by reduction and purification of the base on a silica gel column using ethyl acetate/methanol=17:3.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>C1(C)C=CC=CC=1>[OH:28][CH2:27][CH:26]([NH:25][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])[CH3:29]
Reactant: CC(N)CO
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NC(C)CO)s1
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a stirred solution of 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (30 mg, 0.09 mmol) in toluene (0.5 mL) was added rac-2-amino-1-propanol (9 mg, 0.12 mmol) and TBD (4 mg, 0.03 mmol). After 15 h, the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (26 mg, 80%) as a white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:26](=[CH:27][CH:28]=5)[CH2:25][NH:24][CH2:23][CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([OH:33])(=[O:32])[CH:30]=[CH2:31].CCN(C(C)C)C(C)C>CO>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:26](=[CH:27][CH:28]=5)[CH2:25][N:24]([CH2:31][CH2:30][C:29]([OH:33])=[O:32])[CH2:23][CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CCNC6)sc4n3)CC2)cc1
Reactant: C=CC(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCN1CCc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc2C1
Temperature: 63 °C
Reaction time: 24 h

Procedure:
A mixture of 5-(1-phenylcyclopropyl)-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazolo[5,4-b]pyridine (28.1 mg, 0.073 mmol), acrylic acid (7.54 μl, 0.110 mmol), and DIPEA (1.276 μl, 7.33 μmol) in methanol (0.80 mL) was stirred at 63° C. for 1 d. The resulting suspension was then concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL)+TFA (50 μL) and purified by rpHPLC (10-100% CH3CN/H2O+0.1% TFA) to provide 3-(6-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid as a yellow solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.1 (M++1).