Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg+].[Br-].[OH:4][C:5]1[C:6]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:19][CH:18]=3)=[CH:15][S:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[C:11]#[N:12]>C1COCC1>[C:11]([C:10]1[C:9](=[O:13])[NH:8][C:7]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:21][CH:22]=3)[C:6]=2[C:5]=1[OH:4])(=[NH:12])[CH3:1]
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=N)c1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Temperature: 25 °C

Procedure:
MeMgBr (1.4 M in ether, 15 mL, 21 mmol) was slowly added to a solution of 4-hydroxy-3-(2′-hydroxy-1,1′-biphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (1.5 g, 4.18 mmol) in anhydrous THF (90 mL) at 0° C. The reaction mixture was slowly warmed to room temperature over 4 hours and quenched with 1N HCl. It was then filtered, concentrated, and purified on a RP-HPLC system to give the title compound. MS (ESI) m/e 375.0 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 12.37 (br s, 1H), 11.33 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 7.49 (d, J=8.59, 2H), 7.42 (d, J=8.59, 2H), 7.29 (dd, J=7.68, 1.85, 1H), 7.18–7.14 (m, 1H), 6.96 (dd, J=8.29, 1.23, 1H), 6.91–6.84 (m, 1H), 6.75 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)c(Cl)cc2Cl)[nH]1
Reaction time: 2 h

Procedure:
54.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid were dissolved in 400 ml of ethanol. A solution of 77.6 g of 2,4,5-trichlorobenzylhydrazine in 200 ml of ethanol was added dropwise thereto, under nitrogen. After stirring for a further two hours, the mixture was left to stand overnight and the precipitate which had separated out was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was repeatedly extracted with ether and subsequently slightly acidified with dilute acetic acid, whereupon the compound identified above precipitated. After recrystallisation from ethanol, this product melted at 195°-196°. 38 g (38%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@H:14]2[CH2:17][CH2:16][O:15]2)(=O)=O)=CC=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CS(C)=O>[N:18]([CH2:12][CH2:13][C@H:14]1[CH2:17][CH2:16][O:15]1)=[N+:19]=[N-:20]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H]2CCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC[C@H]1CCO1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
The mixture of (R)-2-(oxetan-2-yl)ethyl 4-methylbenzenesulfonate (80 mg, 0.31 mmol), NaN3 (30 m2, 0.465 mmol) and KI (5 mg) in DMSO (1 mL) was heated to 55° C. and stirred for 18 h. Then the mixture was cooled to RT, then it was poured into 20 mL of water, then extracted with MTBE (20 mL×3), the organic layers was washed with 1-120 (10 mL), brine (10 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. to give the titled compound which was used to the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)([CH3:6])([CH3:5])[CH3:4].[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21].Cl>CN(C)C=O>[C:20]([O:24][C:25](=[O:28])[CH2:26][N:13]1[C:14]2[C:10](=[C:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:19])[CH3:18])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 68 %

Procedure:
A dispersion of sodium hydride in mineral oil (55%, 61 mg, 1.4 mmol) was added to a solution of 4-(tert-butyl-dimethyl-silanyloxy)-1H-indole [251 mg, 1 mmol; Eur. Pat. Appl. (1986), EP 206225 A2] and bromo-acetic acid tert-butyl ester (160 μl. 1, 1.1 mmol) in N,N-dimethylformamide (10 ml) at 0° C. under an argon atmosphere. The reaction mixture was naturally warmed to ambient temperature, stirred for 14 h and cooled to 0° C. Ice water (10 ml) and concentrated HCl (2 ml) were added and the mixture was extracted three times with dichloromethane. The combined extracts were washed with brine and water and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow liquid which was purified by column chromatography (silica gel, heptane/AcOEt) to give 246 mg (0.68 mmol, 67%) of the title compound as light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:32])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCCC1>[OH:32][C:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCNCC1
Yield: 23.5 %

Procedure:
A solution of 4.5 gm (10.4 mMol) 1-tert-butoxycarbonyl-4-hydroxy-4-(6-benzyloxynaphth-2-yl)piperidine, 5 mL 5N hydrochloric acid in 20 mL ethyl acetate and 20 mL tetrahydrofuran was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 10% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.814 gm (24%) of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[OH-].[K+]>>[ClH:1].[CH3:23][N:3]([CH3:2])[CH2:4][CH2:5][CH:6]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7]1
Reactant: CN(C)CCC(Cc1ccccc1C(=O)O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)CCC1Cc2ccccc2C(=O)c2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 14.75 g (0.05 mole) of 2-(β-[2-dimethylaminoethyl] phenethyl)benzoic acid hydrochloride and 150 g polyphosphoric acid is heated at 110° C for 6 hrs. allowed to cool and poured onto crushed ice with stirring. The resulting solution is cooled on ice and made basic by the addition of solid potassium hydroxide, and extracted with methylene chloride. The methylene chloride is washed with water, dried over anhydride magnesium sulfate and evaporated in vacuo. The residue is dissolved in isopropanol, and treated with gaseous hydrogen chloride. The resulting precipitate is filtered and recrystallized from isopropanol to give the intermediate 10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one hydrochloride, m.p. 188° -190° C.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][C:11]([OH:13])=[O:12])[C:5](=[O:14])[C:4]=1[N+:15]([O-:17])=[O:16].[CH3:18]O>>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][C:11]([O:13][CH3:18])=[O:12])[C:5](=[O:14])[C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)Cn1c(C)cc(O)c([N+](=O)[O-])c1=O
Yield: 85 %

Procedure:
250 ml of methanol are saturated with a gaseous hydrochloric acid stream and 25 g (0.11 mol) of 4-hydroxy-6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-1-acetic acid are introduced in portions. The mixture is heated at reflux temperature for 4 hours and then the precipitate is filtered and it is dried in an oven. 23 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][C:18](=[O:20])[O:17][C:16](=[O:21])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:18](=[O:20])[CH2:19][N:14]([CH2:15][C:16]([OH:17])=[O:21])[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C1CN(c2cccc(Oc3ccccc3)c2)CC(=O)O1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Reaction time: 72 h

Procedure:
To a solution of 4-(3-phenoxyphenyl)morpholine-2,6-dione 26 (4.7 g, 0.0166 mol) in THF (50 mL) was added (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (4.11 g, 0.0221 mol). The reaction mixture was stirred for 3 days after which time a precipitate had formed. This material was collected by filtration, then washed with ethyl acetate to give the first crop of the title compound. A further crop was obtained by evaporating the filtrate in vacuo. The resultant residue was dissolved in ethyl acetate, washed with 10% hydrochloric acid and brine, dried (Na2SO4) and concentrated in vacuo. The second crop of title compound which precipitated was collected by filtration to give a total yield of 4.36 g (50%), as a cream solid. 1HNMR (300 MHz) (d6-DMSO, 100° C.)) δ 1.43 (9H, s), 1.75-2-20 (2H, 2×m), 2.75-3.1 (1H, br), 3.20-3.75 (4H, m), 4.09 (2H, s), 4.21 (2H, s), 6.22 (1H, br s), 6.37 2H, br t), 6.70 (1H, br), 6.99 (2H, d), 7.14 (2H, m) and 7.37 (2H, br t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[CH:19][N:18]=[C:17]1[CH2:23][N:24]([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.N(C(OCC)=O)=NC(OCC)=O>>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([CH2:21][N:51]3[C:47](=[O:57])[C:48]4=[CH:56][CH:55]=[CH:54][CH:53]=[C:49]4[C:50]3=[O:52])=[CH:19][N:18]=[C:17]2[CH2:23][N:24]([CH3:25])[CH3:26])=[C:9]([C:8](=[O:27])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)Cc1ncc(CO)n1-c1ccc(F)cc1C(=O)c1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 3, 2',5-difluoro-2-[2-[(dimethylamino)methyl]-5-hydroxymethylimidazol-1-yl]-benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-fluoro-2-(o-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]imidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [OH:1][C:2](CC1C=CC=CC=1)([C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][CH2:9]1.[H][H].C([O-])=O>CO.[Pd]>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C1NCN(CCCNCC(O)(Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: O=C1NCN(CCCNCC(O)c2ccc(O)cc2)c2ccccc21
Yield: 78.9 %

Procedure:
15.5 gm of 1-{-[2-hydroxy-2-(4-benzyloxy-phenyl)benzylethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone (m.p. 119°-121° C.) were dissolved in 250 ml of methanol and debenzylated by hydrogenation at 60° C. and 6 bars pressure in the presence of palladium as the catalyst. After 2 mols of hydrogen had been taken up, the hydrogenation was complete, yielding of 8 gm of 1-{3-[2-hydroxy-2-(4-hydroxyphenyl)ethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone, whose formate of the formula ##STR75## had a melting point of 174°-176° C. The yield was 61.5% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1>C(O)C.C(O)(=O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCCC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CCCCC(=O)O)cc1
Yield: 99.3 %

Procedure:
5-(4-methoxyphenyl)-5-oxopentanoic acid (8) (11.5 g) from the previous step was dissolved in ethyl alcohol (150 mL) and acetic acid (50 mL), 10% palladium-activated carbon (1.2 g) was added, then stirred overnight in hydrogen atmosphere at room temperature. After filtration and vacuum concentration, the above-identified compound was obtained as a colorless solid (10.7 g, yield 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([C@H:24]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([C@H:24]2[CH2:25][CH2:26][C@H:27]([O:30][C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)[CH2:28][CH2:29]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1ccncc1
Reactant: CCOC(=O)/C(=C/c1cn([C@H]2CC[C@@H](O)CC2)cn1)CCCNC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/c1cn([C@H]2CC[C@H](Oc3ccncc3)CC2)cn1)CCCNC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 5.5 h

Procedure:
The compound (170 mg) obtained in Step 2 of Example 37 was dissolved in tetrahydrofuran (6 mL). To the solution, triphenylphosphine (137 mg), 4-hydroxypyridine (50 mg), and a 40% solution of diisopropyl azodicarboxylate in toluene (276 μL) were added, and the mixture was stirred at 55° C. for 5.5 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=7/3-ethyl acetate) to obtain the title compound (51 mg).
Reaction SMILES: Br[C:2](=[CH2:12])[CH2:3][O:4]CC1C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1)[C:18]([O:20]CC1C=CC=CC=1)=[O:19]>CN(C=O)C.Cl[Pd](Cl)([P+](C1CCCCC1)(C1CCCCC1)C1C=CC=CC=1)[P+](C(C)(C)C)(C(C)(C)C)C(C)(C)C.[Pd]>[OH:4][CH2:3][CH:2]([C:30]1[CH:29]=[CH:28][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[O:14][CH3:13])[CH3:12]
Reactant: C=C(Br)COCc1ccccc1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P+](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[P+](c1ccccc1)(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1C(C)CO
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Dichloro-[dicyclohexyl(phenyl)phosphaniumyl]-tritert-butylphosphaniumyl-palladium (981 mg, 0.150 mmol) and 2-bromoallyloxymethylbenzene (341 mg, 1.50 mmol) were dissolved in DMF (1 mL). A solution of benzyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.11 g, 3.00 mmol) in DMF (3 mL) was added the mixture was heated at 90° C. for 3 h. The mixture was then filtered through Celite using ethyl acetate. The filtrate was then washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue from step 1 was taken up in isopropanol (2 mL) and was added to 10% Pd/C (160 mg, 0.150 mmol). The vessel was purged with nitrogen and a balloon of hydrogen was added and the reaction mixture was allowed to stir overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was partitioned between aqueous 2M Na2CO3 and ethyl acetate. The layers were separated and the organic phase was discarded. To the aqueous phase was added 1M HCl until the solution was pH 3. The solution was then extracted with EtOAc (3×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide 4-(1-hydroxypropan-2-yl)-3-methoxybenzoic acid. ESI-MS m/z calc 210.1. found 211.1 (M+1)+. Retention time: 1.19 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:50][C:51]1[CH:63]=[CH:62][C:54]2[N:55]([CH:59]([CH3:61])[CH3:60])[C:56]([SH:58])=[N:57][C:53]=2[CH:52]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:26][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:27])[C:2]([S:58][C:56]3[N:55]([CH:59]([CH3:61])[CH3:60])[C:54]4[CH:62]=[CH:63][C:51]([Cl:50])=[CH:52][C:53]=4[N:57]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C(C)C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (from Step 1 below) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 1.13 (d, J=6.1 Hz, 6H), 1.41 (d, J=7.1 Hz, 6H), 1.42-1.8 (m, 10H), 2.08-2.13 (m, 1H), 2.43-2.54 (m 3H), 2.79 (d, J=17.0, 1H), 4.44-4.48 (m, 1H), 4.63-4.69 (m, 1H), 6.89-6.91 (m, 2H), 6.95-7.00 (m, 2H), 7.14 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 12.0 (brs, 1H); Anal. Calcd. For C31H36Cl2N2O4S.1.0AcOH: C, 59.72; H, 6.07; N, 4.22; Found: C, 59.50; H, 6.16; N, 4.33. ESIMS (MH+): 604.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[CH:11]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc(CCO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1cc(CCOS(C)(=O)=O)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-(2-hydroxyethyl)thiophen-2-yl)ethyl acetate [Aromatic Intermediate 21, step b] (0.6 g) and triethylamine (0.47 mL) in DCM (30 mL) at 0° C. was treated dropwise over 20 minutes with a solution of methanesulphonyl chloride (0.24 mL) in DCM (3 mL). The mixture was stirred at 20° C. for 1 hour and then washed with water. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to afford the titled compound. Yield 0.80 g.
Reaction SMILES: [C:1]([NH:11][CH:12]([CH2:16][O:17][CH3:18])[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([NH:41][C:13](=[O:15])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][O:17][CH3:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCC(NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 11 (0.52 g, 2.04 mmol) in dry tetrahydrofuran (10 mL) was cooled to −78° C. in a dry ice-acetone bath under a N2 atmosphere. To this was added via a dry syringe 4-methylmorpholine (0.34 mL, 3.06 mmol). After stirring for 5 minutes, isobutyl chloroformate (0.4 mL, 3.06 mmol) was added via dry syringe and then the mixture stirred for 5 minutes. This was followed by the addition of benzylamine (0.32 mL, 3.06 mmol). After stirring at −78° C. for 5 minutes, the reaction was allowed to warm to room temperature, and stirring was continued at room temperature (30 min). The hydrochloride salt of 4-methyl morpholine was removed from the reaction by filtration. The clear filtrate was evaporated in vacuo and the residue was triturated with ethyl ether (5.0 mL). The white crystalline product obtained was isolated by filtration after washing with small amounts of ether and air-dried (0.55 g, 78%): mp 112°-114° C., Rf 0.6 (10% MeOH/CHCl3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](=O)[CH2:14]Br)[CH3:10]>C1(C)C=CC=CC=1.O>[CH2:9]([O:11][C:12]([C:13]1[N:8]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]2[CH:14]=1)=[O:17])[CH3:10]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Br)ccn1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2ccc(Br)cc2n1
Temperature: 115 °C
Yield: 104.5 %

Procedure:
To a stirred solution of 4-Bromo-pyridin-2-ylamine (4 g, 23.12 mmol) in toluene (40 mL) is added 3-Bromo-2-oxo-propionic acid ethyl ester (4.5 g, 23.12 mmol). The reaction mixture is heated at 115° C. for 16 hours. Reaction mixture is cooled to 0° C. then diluted with water and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo to afford the title compound (6.5 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.31 (t, J=7.2 Hz, 3H), 4.26-4.33 (q, J=7.2 Hz, 2H), 7.18-7.20 (dd, J1=1.92 Hz, J2=7.16 Hz, 1H), 7.98 (s, 1H), 8.53 (d, J=7.32 Hz, 1H), 8.57 (s, 1H). LC-MS (m/z): [M+H]=271.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26]([NH2:28])[N:25]=[C:24]1[CH3:29])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26]([NH:28][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[O:11])[N:25]=[C:24]1[CH3:29])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1nc(N)cn1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1nc(NC(=O)Nc2cccc(C(F)(F)F)c2)cn1CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
3-Trifluoromethylphenyl isocyanate (0.23 g, 1.2 mmol) was added to a solution of compound 40.2 (0.30 g, 1.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, concentrated and purified by flash column chromatography on silica gel using EtOAc to provide (2-{2-methyl-4-[3-(3-trifluoromethyl-phenyl)-ureido]-imidazol-1-yl}-ethyl)-carbamic acid tert-butyl ester (compound 40.3; 0.11 g, 21%). ES (+) MS m/e=428(M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:6][CH:5]=[CH:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=3[F:1])[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Fc1ccccc1C=CCCl
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1F)CC2
Yield: 36 %

Procedure:
Prepared from 2-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo-[5,4-d]azepine in chloroform. Yield: 36% of theory, Melting point: 96°-102° C. (ether).