Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:47])[CH:5]([C:10]1[CH:11]=[C:12]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[N:17]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[N:17]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)[CH:15]=1)[C:4]([OH:47])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccc(C(F)(F)F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccc(C(F)(F)F)cc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-methyl-2-{4′-trifluoromethyl-5-[6-trifluoromethyl-1-(4-trifluoromethyl-benzyl)-piperidin-2-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester, compound 8a (25 mg, 0.037 mmol), in EtOH (2 mL) was added 2M KOH (74 μl, 0.148 mmol). The reaction was heated to 78° C. for 5 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, followed by salt exchange with aqueous 1N HCl gave the product as a white solid. (2.1 mg, 9%) 1H NMR (300 MHz, MeOD) δ ppm 0.86-0.96 (m, 6 H) 1.43-1.50 (m, 1 H) 1.54-1.64 (m, J=13.52, 6.97, 6.83, 3.58 Hz, 2 H) 1.83-1.98 (m, 5 H) 2.10-2.30 (m, 1 H) 3.58-3.73 (m, 2 H) 3.98 (d, J=17.71 Hz, 3 H) 7.18-7.26 (m, 2 H) 7.35 (d, J=8.67 Hz, 3 H) 7.44-7.49 (m, 2 H) 7.60-7.65 (m, 2 H) 7.68-7.74 (m, 2 H) Calcd for C33H32F9NO2 (M+H) 645.60, Found 646.3.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(=[O:6])[O:3][CH2:4][CH3:5].[NH2:24][CH:25]1[CH2:30][S:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:26]1=[O:43]>>[CH2:4]([O:3][P:2]([NH:24][CH:25]1[CH2:30][S:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:26]1=[O:43])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[O:6])[CH3:5]
Reactant: CCOP(=O)(Cl)CCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCCCN2C(=O)c3ccccc3C2=O)OCC)CS[C@@H]1c1ccccc1

Procedure:
Chloro(6-phthalimidohexyl)phosphinic acid, ethyl ester and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester are reacted according to the procedure of Example 1(f) to give (R)-dihydro-5-[[ethoxy(6-phthalimidohexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
Reaction SMILES: [O-:1]Cl=O.[Na+].[Cl:5][C:6]1[N:7]=[C:8]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[CH:11]=[O:12].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[Cl:5][C:6]1[N:7]=[C:8]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C:10]=1[C:11]([OH:1])=[O:12]
Reactant: [O-][Cl+][O-]
Reactant: CN(C)S(=O)(=O)c1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaClO2 (0.21 g, 2.31 mmol) and NaH2PO4.H2O (0.19 g, 1.39 mmol) in H2O (0.5 mL) was added to a solution of 4-chloro-5-formyl-N,N-dimethyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide (0.085 g, 0.23 mmol) and 2-methyl-2-butene (1.39 mL of a 2M solution in THF, 2.77 mmol) in THF (0.70 mL) and t-BuOH (0.16 mL). The reaction mixture was stirred at RT for 1 h and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and dried to provide 4-chloro-2-[(dimethylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid as a clear oil that was assumed to be quantitative and used without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][CH2:26][O:27][CH3:28])=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][O:27][CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COCCN1CCCC1c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nccs3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN1CCCC1c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-1-(1-(2-methoxyethyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.046 g, 0.080 mmol) was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was washed twice with methanol, then the product was liberated by flushing the column several times with a 2.0M ammonia/methanol solution. The product-containing solution was concentrated to afford 1-(1-(2-methoxyethyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm=8.79 (br. s., 1H), 8.53 (d, J=5.7 Hz, 1H), 8.46 (s, 1H), 8.00 (d, J=5.9 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.17 (d, J=4.2 Hz, 1H), 6.74 (d, J=4.3 Hz, 1H), 4.60 (br. s., 1H), 3.55 (br. s., 2H), 2.96 (s, 3H), 2.82 (br. s., 1H), 2.71 (br. s., 2H), 2.42 (br. s., 1H), 2.00 (d, J=11.6 Hz, 2H), 1.95 (d, J=12.8 Hz, 1H). m/z (ESI) 419.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12](O)=O.C=O>CO>[CH2:1]([N:8]([CH:9]([OH:11])[CH3:10])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)NCc1ccccc1
Reactant: O=CO
Agent: C=O
Solvent: CO
Product: CC(O)N(C)Cc1ccccc1
Yield: 84 %

Procedure:
A mixture consisting of 151 g (1 mol) of N-benzylaminoethanol, 120 ml of 90% formic acid, 120 ml of a 35% aqueous formaldehyde solution and 1 liter of methanol is heated under reflux for 20 hours. The solvent is evaporated off in vacuo and the residue is treated with an aqueous sodium hydroxide solution and then extracted with methylene chloride. After customary treatment, the product is purified by distillation. 138 g of the desired product are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C@:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Reactant: CC(C)(C)Cc1ccc(OCCCI)c(Cl)c1
Product: CC[C@@]1(C(=O)O)Cc2cc(OCCCOc3ccc(CC(C)(C)C)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4 employing the chiral phenol prepared in Example 10, Step 2 and the iodide prepared in Step 1.
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39].C(O)CCC>COC(C)(C)C>[CH3:17][C@@H:10]([C@@H:9]1[C@@:18]2([CH3:29])[CH2:19][CH2:20][C@@H:21]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C@:2]4([OH:1])[C@H:3]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH2:30])[CH:4]=[C:5]3[C@@H:6]2[CH2:7][CH2:8]1)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: NCCCCNCCCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCNCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 58 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and spermidine (6.4 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give Dendrogenin B (5α-Hydroxy-6β-[4-(3-aminopropylamino)-butylamino]-cholest-7-en-3β-ol) as a white solid (7.0 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1.Cl>CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1([C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]1
Reactant: OC(Cc1ccccc1)(c1ccccc1)C1(OCCCCCl)C=CC=CC1
Agent: Cl
Solvent: CO
Product: ClCCCCOC1(C(=Cc2ccccc2)c2ccccc2)C=CC=CC1
Reaction time: 2 h

Procedure:
Combine 1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethanol (17.0 kg, 20.2 mol) and methanol (30 L). Add aqueous 3M hydrochloric acid solution (40 L). Heat to reflux. After 2 hours, remove most of the methanol by distillation and cool the aqueous reaction mixture. Extract with chloroform. Extract the organic layer with aqueous saturated sodium carbonate solution. Separate the organic layer and evaporate in vacuo to give (E and Z)-1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethylene.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 158 μmol) in dichloromethane (4 mL) was added TFA (1.48 g, 1 mL, 13.0 mmol, Eq: 82.4), the reaction mixture turned orange and was stirred at 25° C. for 2 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane (with a couple of drops of MeOH) and purified by chromatography (40 g column, 20-40 μm spherical silica, HP Gold from Teledyne/Isco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 128 μmol, 81.1%). MS (M+H)+=486 (100% purity); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.78-7.95 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.19 (s, 1H), 4.55 (t, J=6.2 Hz, 2H), 2.17-2.30 (m, 2H), 2.12 (s, 7H), 1.99-2.07 (m, 2H), 1.49 (s, 10H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C([BH3-])#N.[Na+]>C(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:18]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNC1Cc2ccccc2C1
Reaction time: 8 h
Yield: 50.4 %

Procedure:
2-Indanone (25.1 g. 0.19 mol) and glycine ethyl ester hydrochloride (34.5 g, 0.247 mol) were dissolved in absolute ethanol (700 mL) and sodium cyanoborohydride (25.8 g, 0.41 mol) was added in portions to the solution. After addition the mixture was allowed to sit at room temperature overnight. The ethanol was removed under reduced pressure and the residue treated with water and extracted into ethyl acetate. The organic extract was repeatedly washed with saturated aqueous solutions of sodium bicarbonate and sodium chloride before being dried over magnesium sulfate and filtered. After the solvent was concentrated under vacuum an oil remained which was taken up in ether/ethanol (250/50 mL) and cooled by mean of an ice-water bath. Ether which had previously been saturated with anhydrous hydrogen chloride was slowly added to the solution. The precipitated product was filtered and washed with cold ether/ethanol to yield a white solid (21 g) melting at 166°-168° C.
Reaction SMILES: N[C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].FC(F)(F)C(SCC)=O>CO>[C@@H:3]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[CH2:2]1
Reactant: N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: CCSC(=O)C(F)(F)F
Solvent: CO
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2'-amino,2'-deoxyuridine (2.0 g, 8.22 mmoles) in methanol (150 ml) was added S-ethyl trifluorothioacetate (1.6 ml, 12.48 mmoles, 1.5 eq.). This mixture was stirred at room temperature overnight. Nitrogen was bubbled through the reaction mixture for 2 h to remove volatile thio-byproducts. The mixture was evaporated to dryness and the solid was recrystallized from methanol/chloroform to yield 2.3 g (82%) of 2'-trifluoroacetylamino, 2'-deoxyuridine. The analytical data agreed with the literature (Imazawa and Eckstein (1979) supra).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.Cl.[NH2:13][C@@H:14]([C:18]([NH2:20])=[O:19])[CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]([CH:15]([CH3:17])[CH3:16])[C:18]([NH2:20])=[O:19])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](Nc1nc(Cl)nc2c1SCC2)C(N)=O
Temperature: 120 °C
Yield: 74 %

Procedure:
800 mg 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 800 mg D-valinamide hydrochloride are placed in 8 ml dioxane, then 2.7 ml diisopropylethylamine are added. The reaction mixture is heated to 120° C. in the microwave for 2 hours. The residue is mixed with water. The precipitate formed is suction filtered and dried. 820 mg of the product are obtained as a powder. Analytical HPLC (method B): RT=2.64 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][C:11]=1[CH3:19]>>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][C:11]=1[CH3:19]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: Nc1ccccc1O
Product: Cc1cc(-c2nc3ccccc3o2)ccc1Br
Temperature: 200 °C
Reaction time: 8 h

Procedure:
Polyphosphoric acid (100 mL) was added to a beaker containing 2-aminophenol (17.7 g, 162 mmol) and 4-bromo-3-methylbenzoic acid (13.6 g, 64 mmol). The mixture was heated at 200° C. for 1 h, then poured into ice water (1 L) and allowed to stand overnight. The mixture was filtered and dried to afford 2-(4-bromo-3-methyl(phenyl))-benzoxazole as a colorless solid. A solution of 2-(4-bromo-3-methyl(phenyl))-benzoxazole (670 mg, 2.3 mmol), 2-(tributylstannyl)pyridine (850 mg, 2.3 mmol), Pd(Ph3P)4 (270 mg, 0.23 mmol) and DMF (23 mL) was degassed with bubbling argon for 15 min. The reaction mixture was heated at 100° C. for 8 h. The reaction was cooled to rt, and KF (500 mg) and H2O (250 mL) were added. The mixture was extracted with MTBE (3×50 mL), and the combined organic extracts were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), and concentrated to afford an oil. Purification of the oil by flash chromatography on silica gel (EtOAc:hexanes 1:2) afforded the desired 2-(3-methyl-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.91 (d, 1H), 8.52 (t, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 7.97 (br t, 1H), 7.89 (d, 1H), 7.70–7.72 (m, 1H), 7.61 (d, 1H), 7.51–7.54 (m, 1H), 7.30–7.33 (m, 2H), 2.45 (s, 3H), MS (ESI) 287 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[Br:24]Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Br:24])=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: ClCCl
Product: CCCc1cc(Br)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reaction time: 0.25 h

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran (1 gm; 3.22mmoles) in methylene chloride (30 mL) was cooled at 0° C. and bromine (0.52 gm; 3.22mmoles) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 15 minutes. The reaction mixture was washed with a saturated sodium bicarbonate solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC, eluting with 15% ethylacetate in hexane to yield 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-bromobenzofuran, mp. 110°-112° C.
Reaction SMILES: O[CH:2]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[OH2:18]>P(=O)(O)(O)O.P([O-])([O-])(O)=O.[K+].[K+]>[OH:14][CH:15]1[CH:16]=[CH:17][C:13](=[O:18])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCCCCCC(O)c1ccco1
Reactant: O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: COC(=O)CCCCCCC1C(=O)C=CC1O
Yield: 80.7 %

Procedure:
Into a four necked-flask equipped with a stirrer and a thermometer, 2-(1-hydroxy-7-methoxycarbonylheptyl)-furan 114 g), water (4560 g) and potassium monohydrogen phosphate-phosphoric acid buffer (3.8 g) were charged, and the resulting mixture (pH 4.2) was stirred at 100° C. under nitrogen stream until the starting compound was consumed perfectly. The reaction mixture was cooled and extracted with methylisobutylketone (600 ml) two times. The extracts were combined together and concentrated under reduced pressure to give a mixture (92 g) of 3-hydroxy-2-(6-methoxycarbonylhexyl)-4-cyclopentenone and 4-hydroxy-2-(6-methoxycarbonylhexyl)-2-cyclopentenone. Yield, 80.7%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([OH:12])=O)=[O:4].[NH2:16][CH2:17][C@@H:18]([OH:36])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[CH3:35])[CH2:22][CH2:21]1>>[Cl:34][C:29]1[C:28]([CH3:35])=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[O:26][CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C@H:18]([OH:36])[CH2:17][NH:16][C:10](=[O:12])[CH2:9][O:8][C:7]2[CH:6]=[C:5]([CH:15]=[CH:14][CH:13]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:25][CH2:24]1
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Product: COC(=O)c1cccc(OCC(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3C)CC2)c1

Procedure:
Prepared as for Example 15, Step 2 using [3-(methoxycarbonyl)phenoxy]acetic acid [Asian Journal of Chemistry 1992, 4(4), 920-3] and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a pale yellow oil (0.11 g).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][C:17]=3[Cl:26])=[CH:12][CH:11]=2)[C:7]([CH3:27])=[N:6][C:5]=1[CH3:28])(=[O:3])[NH2:2].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.[NH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64]>CN(C=O)C>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:24])=[CH:18][C:17]=3[Cl:26])=[CH:12][CH:11]=2)[C:7]([CH3:27])=[N:6][C:5]=1[CH3:28])(=[O:3])[NH2:2]
Reactant: COC(=O)CN
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 250 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0.79 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (85 mg, 0.63 mmol) and N-ethyl-N-isopropylpropan-2-amine (242 μL, 1.39 mmol) in DMF (2499 μL) was treated with a solution of methyl 2-aminoacetate hydrochloride (87 mg, 0.69 mmol) in DMF (417 μL) at 23° C. The resulting solution was stirred at RT for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (25 mL), and washed sequentially with saturated brine (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)acetate (266 mg, 90%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 90.3 %

Procedure:
To a suspension of amide 1 (9.6 g, 26 mmol) in anhydrous 1,4-dioxane (100 mL) was added phosphorus oxychloride (POCl3) (9.2 mL, 100 mmol) slowly. The whole was then heated at 100° C. overnight. After cooling to RT, the mixture was poured into ice (200 g) with stirring. Filtration, followed by recrystallization in DCM/hexanes gave a pale grey solid 2 (8.2 g, in 90% yield).