Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:5])([NH2:4])[CH2:2][CH3:3].Br.Br[CH:8]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O>CN(C=O)C>[CH2:2]([C:1]1[S:5][C:8]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:4]=1)[CH3:3]
Reactant: O=C(c1ccc(F)cc1)C(Br)c1ccncc1
Reactant: CCC(N)=S
Agent: Br
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccncc2)s1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At room temperature, 1.31 g (14.7 mmol) propanethioamide are added to a solution of 5.00 g (13.3 mmol) of 2-bromo-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone hydrobromide (described, for example, in Chem. Pharm. Bull. 2005, 53, 410-418) in 30 ml of DMF, and the mixture is stirred for 16 h. Subsequently, the reaction mixture is stirred into 100 ml of ice-water, 50 ml of a saturated aqueous Na—HCO3 are added and the mixture is extracted with ethyl acetate (3×100 ml). The combined organic phases are washed with water (2×100 ml), dried over MgSO4 and freed from the solvent under reduced pressure. The crude product is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 2.85 g (75%) of the desired product; 1H-NMR (DMSO-d6) δ: 8.53 (d, 2H), 7.47 (m, 2H), 7.26 (d, 2H), 7.17 (m, 2H), 3.05 (q, 2H), 1.37 (t, 3H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9].CO>C1COCC1>[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@@H:7]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Yield: 62.7 %

Procedure:
Aqueous potassium hydroxide (1 N, 2.40 mL, 2.40 mmol) was added to a stirred solution of (S)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (0.88 g, 1.21 mmol) in THF (12 mL)/methanol (8 mL). After 2 h the solution was concentrated, diluted with water (50 mL) and acidified with 10% aqueous HCl. The reaction mixture was then partitioned between water and ether. The ether phase was concentrated and triturated with ether and pet. ether. It was then recrystalized from methanol to provide the title compound as a white solid (0.54 g, 63%): [a]D25 =-24.81° (10.08 mg/mL CHCl3); NMR (CDCl3); δ8.36 (d, J=8 Hz, 1 H), 7.81 (d, J=8 Hz, 1 H), 7.68 (ddd, J=8, 5, 3 Hz, 1 H), 7.58 (dd, J=10, 2 Hz, 2 H), 7.54-7.48 (m, 2 H), 7.44-7.27 (m, 6 H), 7.16 (ddd, J=8, 7, 1), 6.72 (d, J=8 Hz, 1 H), 5.45 (t, J=7 Hz, 1 H), 3.59 (d, J=7 Hz, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 708 (24%), 710 (80%) 712 (100%) 714 (40%); Anal. Calc. for C31H19Br3O3S: C, 52.35, H, 2.69, N, 0.00. Found: C, 52.05, H, 2.59, N, 0.10. Chiral analytical HPLC determined that this compound had approx. 100% EE [column:Chirobiotic V, 5 micron (4.6 ×250 mm); isocratic, 1:1 ethanol:hexane; flow rate =0.80 mL/min; injection volume =0.3 pL; sample conc. =0.25 mg/mL; retention time, R-enantiomer =21 min; retention time, S-enantiomer =16 min.]
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH3:23])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH3:23]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Temperature: 180 °C
Yield: 17.3 %

Procedure:
A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.0 g (0.040 mol) of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 180° C. for two hours. The mixture is cooled and then suspended in hot chloroform and filtered to give 1.8 g of 2-ethyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 278°-280° C. after recrystallization from pyridine.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1COCC1.C(OCC)(=O)C>[F:19][C:17]1[CH:18]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:16]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trifluoroethanol in 4 mL dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0° C. The resulting mixture was added dropwise to the solution of 2,4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 mL dry THF at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[CH:73][CH:72]=1)([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:72]=[CH:73][C:74]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:75][CH:76]=1)([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA (110 uL, 0.62 mmol) and 4-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 55 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH3:17])[CH2:13][CH2:12]2)[CH3:10])=[C:6]([NH2:18])[CH:5]=[C:4]([Cl:19])[N:3]=1.[CH2:20](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:7]2[N:8]([CH:9]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH3:17])[CH2:13][CH2:12]3)[CH3:10])[CH:20]=[N:18][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1
Reactant: CC(Nc1c(N)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1
Reactant: CCOC(OCC)OCC
Product: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(Cl)nc(Cl)c21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of 2,6-dichloro-N3-(1-(trans-4-methylcyclohexyl)ethyl)pyridine-3,4-diamine (35 g, 0.116 mol) in triethylorthoformate (200 mL, 1.16 mol) was stirred at 100° C. for 3 h. TLC (petroleum ether/ethyl acetate=3/1) showed the reaction was complete. The solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give the crude product, which was washed with a mixture of petroleum ether/ethyl acetate=10:1 to afford 4,6-dichloro-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine. 1H NMR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 7.86 (s, 1H), 4.98 (bs, 1H), 1.76-1.67 (m, 3H), 1.58-1.56 (m, 4H), 1.23-1.20 (m, 2H), 1.07-0.99 (m, 2H), 0.84-0.79 (m, 5H). MS ESI calc'd. for C15H19Cl2N3 [M+H]+ 312. found 312.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][CH2:5][C:6]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C1(CCC(OC)OC)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COC(CCC1(CO)CCCC1)OC
Reaction time: 4 h

Procedure:
A solution of 0.25 mol of the compound prepared in Stage A of Example 10 in 200 ml of ether is added dropwise to a suspension, stirred at 0° C., of 0.25 mol of lithium aluminum hydride in 200 ml of ether. When the addition is complete, the reaction medium is allowed to return to room temperature, and is then stirred for 4 hours at this temperature before being hydrolyzed by adding 20 ml of water. The salts are filtered off and washed twice with ether, and the filtrate is dried and concentrated.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)([OH:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:11][CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:24]=1)[OH:18])(=[O:33])[CH3:32]
Reactant: CN(C)CCOc1ccc(C(O)(c2ccccc2)C(CCO)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN(C)C)cc1
Temperature: 90 °C

Procedure:
The reaction is performed under dry conditions. 40.5 g of either (RR,SS)- or (RS,SR)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol and 150 ml of acetic acid anhydride are placed in a flask. The temperature is raised to 90° C., where it is kept until the primaryOH-group is completely acetylated. [4-acetoxy-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]butan-1-ol is obtained as intermediate: m.p. of the (RR,SS)-isomer pair is 97°-9° C⟧ While stirring the reaction mixture, 30 ml of acetyl chloride in 50 ml of aceticacid anhydride are added at 90° C. The stirring is continued at thistemperature for 2 h. The solvent is evaporated. Then 1M sodium carbonate solution is added in excess, after which the product is extracted in toluene. The solution is dried over sodium sulfate, and the solvent is evaporated. The yield of the pure isomer mixture (Z:E 2:1) is quantitative. The m.p. of the (Z)-isomer is 88° -90° C. prepared from the corresponding (Z)-alcohol by refluxing in acetic acid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([C:33](OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:40][C:41]([F:46])([F:45])[C:42](O)=O>ClCCl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:15]5[CH:20]=[CH:19][C:42]([C:41]([F:46])([F:45])[F:40])=[CH:17][CH:16]=5)[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(OC[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(COc2ccc(-c3ccc(N4CCN(Cc5ccc(C(F)(F)F)cc5)CC4)cc3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
790 mg of (R)-2-methyl-2-(4′-(4-tert-butoxycarbonylpiperazin-1-yl)biphenyl-4-yloxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole was dissolved in 10 ml of trifluoroacetic acid and 5 ml of dichloromethane, followed by stirring at room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure, and then, 6 ml of dichloromethane and 6 ml of triethylamine were added thereto. The mixture was stirred at room temperature for 5 minutes, and it was then concentrated under a reduced pressure. The residue was dissolved in 15 ml of DMF, and then, 0.4 ml of 4-trifluoromethylbenzaldehyde and 625 mg of triacetoxy sodium borohydride were added thereto while cooled by ice, followed by stirring at room temperature overnight. Thereafter, water was added to the reaction solution, the mixture was stirred, and the insoluble precipitate was removed by filtration. The filtrate was washed with water and then dissolved in dichloromethane. The obtained solution was washed with a saturated aqueous solution of sodium chloride, and then dried over sodium sulfate. The sodium sulfate was filtered, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resultant product was then recrystallized from a mixed solvent consisting of dichloromethane and ethyl acetate to obtain 585 mg (yield: 60.5%) of light yellow powders, (R)-2-methyl-6-nitro-2-(4′-(4-(4-trifluoromethylbenzyl)piperazin-1-yl)biphenyl-4-yloxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:28]=[CH:27][C:16]2[NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[NH:20][C:21](=[O:22])[C:15]=2[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1.O>[O:22]=[C:21]1[NH:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:16]2[CH:27]=[CH:28][C:13]([NH:12][C:10]([NH2:9])=[S:11])=[CH:14][C:15]1=2
Reactant: O=C(NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Yield: 90.7 %

Procedure:
To a stirred solution of 1-benzoyl-3-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 8, 0.6 g, 1.54 mmol) in 10 mL of tetrahydrofuran was added 1.8 mL of 2.0 N aqueous sodium hydroxide. The mixture was heated to reflux for 3 hrs, diluted with water (10 mL) and extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried with magnesium sulfate and concentrated under reduced pressure. The solid was washed with 1:1 ethyl acetate/hexanes (50 mL) to give a solid (yield 397 mg, 90.3%). H1 NMR (methanol d4) δ: 9.83 (s, 1H), 9.50 (s, 1H), 7.81 (s, 1H), 7.55-7.54 (d, 1H, J=1.9), 7.32-7.30 (m, 2H), 6.96-6.86 (m, 5H), 5.72 (s, 1H), MS (ES): MH+ 285.1.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[OH:13][C:14]1[C:15]([CH3:30])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH3:29])([C:26](O)=[O:27])[CH2:18][CH2:17]2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:26]([C:19]2([CH3:29])[CH2:18][CH2:17][C:16]3[C:21](=[C:22]([CH3:25])[C:23]([CH3:24])=[C:14]([OH:13])[C:15]=3[CH3:30])[O:20]2)=[O:27])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(=O)N1CCN(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(NC(=O)C2(C)CCc3c(C)c(O)c(C)c(C)c3O2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (300 mg), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (382 mg), 1-hydroxybenzotriazole (244 mg) in N,N-dimethylformamide (6 ml) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodimide hydrochloride (350 mg) and triethylamine (0.78 ml) at 5° C. The mixture was stirred at 5° C. for 2 hours and then poured into ethyl acetate and brine. The organic layer was combined, dried over magnesium sulfate, and concentrated. The residue was crystallized from ethyl acetate to give N-(4-acetyl-1-piperazinyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (0.17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][OH:12])=[N:7][C:6]=2[CH:13]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[N:7][C:6]=2[CH:13]=1
Reactant: OCCc1nc2cc(Br)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1nc2cc(Br)ccc2s1

Procedure:
To a mixture of 2-(5-bromo-benzothiazol-2-yl)-ethanol (0.94 g, 3.6 mmol) in 10 mL CH2Cl2, Et3N (0.99 g, 9.8 mmol), was added methanesulfonyl chloride (0.46 g, 4.0 mmol) dropwise at room temperature. The reaction was worked up by concentrating under vacuum and then used in the next step, Example 1C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][NH2:13])=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.[C:28]([N:35]([CH3:41])[C@H:36]([C:38](O)=[O:39])[CH3:37])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:14])[CH2:12][NH:13][C:38](=[O:39])[C@@H:36]([N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:41])[CH3:37])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)CN)cc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)CNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 73.8 %

Procedure:
4-(2-Amino-acetyl)-benzoic acid methyl ester hydrochloride (2.22 mmol), WSC.HCl (2.44 mmol), Boc-N-methyl-(L)-alanine (2.44 mmol) and HOBt (2.77 mmol) were suspended in dichloromethane (10 ml). NMM (2.44 mmol) was added and the reaction stirred for 2 h. The reaction was diluted with ethyl acetate (50 ml) and washed with 10% citric acid (2×25 ml) and saturated sodium hydrogen carbonate (2×25 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a brown oil residue. Purification by silica chromatography eluting with 10-50% ethyl acetate/iso-hexane gave the title compound (620 mg) as a pale yellow oil m/z=379 in MS ES+.
Reaction SMILES: NC1C([O:12][C:13]([F:16])([F:15])[F:14])=CC=CC=1C(OC)=O.[CH:17]([O:20][C:21]([N:23]1[CH2:29][CH2:28][CH2:27][CH:26]([N:30]([C:46](=[O:48])[CH3:47])[CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:25]2[CH:49]=[CH:50][CH:51]=[CH:52][C:24]1=2)=[O:22])([CH3:19])[CH3:18]>>[C:46]([N:30]([CH2:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=1)[CH:26]1[CH2:27][CH2:28][CH2:29][N:23]([C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[O:22])[C:24]2[C:52]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:51][CH:50]=[CH:49][C:25]1=2)(=[O:48])[CH3:47]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Reactant: COC(=O)c1cccc(OC(F)(F)F)c1N
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(OC(F)(F)F)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-trifluoromethoxybenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 601 (M+H).
Reaction SMILES: C(N)C.Br[C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8].Cl.NO.[C:14]([S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH3:29])[C:25]([CH3:31])([CH3:30])[CH2:24][CH2:23][C:22]2([CH3:33])[CH3:32])(=[O:18])=[O:17])#[CH:15].[Cl-].[NH4+]>O.CO.[Cu]Cl.C(OCC)(=O)C>[CH3:29][C:28]1[C:19]([S:16]([C:14]#[C:15][C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])(=[O:18])=[O:17])=[CH:20][C:21]2[C:22]([CH3:33])([CH3:32])[CH2:23][CH2:24][C:25]([CH3:30])([CH3:31])[C:26]=2[CH:27]=1
Reactant: C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: COC(=O)C#CBr
Agent: Cl[Cu]
Agent: CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C#CC#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 70% solution of ethylamine in water (563 μl) is added dropwise to a mixture of methyl 3-bromopropynoate (632 mg, 2.88 mmol), hydroxylamine hydrochloride (162 mg, 2.33 mmol) and copper (I) chloride (10 mg) in methanol. A solution of 6-ethynylsulphonyl-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (Example 7(b)) (500 mg, 1.94 mmol) in methanol (5 ml) is then added dropwise. The reaction medium is stirred for 15 h at room temperature and treated with saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and concentrated. The product is obtained in the form of an oil after purification by flash chromatography on silica (80/20 heptane/CH2Cl2). 1H NMR/CDCl3: 1.26 to 1.28 (s, 12H); 1.67 (s, 4H); 2.35 (s, 3H); 3.78 (s, 3H); 7.14 (s, 1H); 7.48 (s, 1H); 13C NMR/CDCl3: 19.7; CH3/31.8; 4*CH3/34.1; Cq/34.3; Cq/34.9; 2*CH2/52.9; CH3/71.7; CH/72.1; CH/80.2; Cq/124.5; Cq/127.6; Cq/12.8.3; CH/129.3; CH/134.8; Cq/144.6; Cq/146.2; Cq/153.4; Cq.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 110 °C
Yield: 78 %

Procedure:
441 mg (corresponding to 2.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 449 mg (corresponding to 2.0 mmol) of 2-amino-5-iodopyridine were dissolved in 15 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 526 mg (corresponding to 1.56 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 1-7, Step 2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=2[C:29](O)=[O:30])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=2[CH2:29][OH:30])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(CO)c1
Yield: 77.4 %

Procedure:
To a stirred suspension of 10 g of lithium aluminum hydride in 1 in liter dry ether under nitrogen was added over a period of one hour a solution of 35 g of 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid in 300 ml of tetrahydrofuran. The mixture was heated at reflux for three hours, then cooled, and water (20 ml) was slowly added. The solid material was removed by filtration and the filtrate concentrated in vacuo. The residue was crystallized and recrystallized from a benzene-cyclohexane-hexane mixture to yield 26 g of 2-(4-benzyloxyphenylamino)-5-methoxybenzenemethanol, light tan crystals, m.p. 100°-101° C.