Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)NC(C)C
Solvent: CCO
Product: CCOC(=O)CCCN(C(C)C)C(C)C
Yield: 21.4 %

Procedure:
Ethyl 4-diisopropylaminobutyrate may be obtained in the following manner: diisopropylamine (40.4 g) is added dropwise to a solution of ethyl 4-bromobutyrate (39 g) in ethanol (80 cc). The solution obtained is heated to reflux for 6 hours. After the insoluble material formed has been filtered off, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with distilled water (15 cc) and 4 N aqueous hydrochloric acid solution (100 cc). The aqueous phase is washed with ethyl ether (3×75 cc) and then alkalinized with 10 N aqueous sodium hydroxide solution. The oil formed is extracted with ethyl ether (3×75 cc). The organic phase obtained is concentrated to dryness under reduced pressure (2.7 kPa). Ethyl 4-diisopropylaminobutyrate (9.2 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C(Cl)Cl>[C:33]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (300 mg, 0.82 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Propionyl chloride (0.358 mL, 4.1 mmol) was then added dropwise and the mixture was stirred at room temperature for 48 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.382 g, 98%). 1H NMR (Acetone d6, 400 MHz) δ 8.01 (d, J=8 Hz, 2H), 7.64-7.53 (m, 4H), 7.02 (d, J=9 Hz, 1H), 5.73 (d, J=9 Hz, 1H), 5.69-5.62 (m, 1H), 5.44 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3H), 2.35 (q, J=7 Hz, 1H), 2.34 (q, J=7 Hz, 1H), 1.46 (d, J=6 Hz, 3H) and 1.03 (t, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:6])[CH2:3][CH2:4][CH3:5].ClCCl.F[C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH2:26])[N:12]=1>C(O)CO>[CH3:1][C@@H:2]([NH:6][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH2:26])[N:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CCC[C@@H](C)N
Solvent: ClCCl
Solvent: OCCO
Product: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
A crude sample of (2R)-2-pentanamine containing dichloromethane (11.12 g containing ca 3.1 g, 35.6 mmol of amine) was added to a suspension of 2-fluoro -9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.00 g, 21.08 mmol) in ethylene glycol (50 ml). The mixture was heated at 110° C. for 20 hours and then cooled to room temperature and partitioned between water (200 ml) and ethyl acetate (200 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo and the residue triturated with diethyl ether and some insoluble starting material removed by filtration. Evaporation of the ether filtrate afforded the title compound as an off-white foam (2.34 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.Cl.[CH3:39][O:40][C:41]([C:43]1[N:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:45]2[C:50]([C:51](=[O:55])[C:52]=1[CH2:53][NH2:54])=[CH:49][CH:48]=[C:47]([Cl:56])[CH:46]=2)=[O:42]>C(Cl)Cl>[CH3:39][O:40][C:41]([C:43]1[N:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:45]2[C:50]([C:51](=[O:55])[C:52]=1[CH2:53][NH:54][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=1)=[CH:49][CH:48]=[C:47]([Cl:56])[CH:46]=2)=[O:42]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)c2ccc(S(C)(=O)=O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(methanesulfonyl)benzoic acid (50.2 mg, 0.251 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (140 mg, 0.301 mmol) N,N-diisopropylethylamine (162 mg, 1.25 mmol) and CH2Cl2 (10 mL) was stirred at room temperature for 5 min. After this time, 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (95 mg, 0.251 mmol) was added. The reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated and purified by preparative reverse-phase HPLC, providing 7-chloro-3-[(4-methanesulfonyl-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydroquin-oline-2-carboxylic acid methyl ester. MS calcd. for C26H22ClN2O6S [(M+H)+] 525.1, obsd. 525.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:32][NH:33][O:34][CH3:35].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]([O:34][CH3:35])[CH3:32])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNOC
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of 1 g of the 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide (2.04 mmol, 1 equiv.), 1.2 g of N,O-Dimethylhydroxylamine hydrochloride (12.25 mmol, 9 equiv.), and 1.5 g of sodium bicarbonate (18.38 mmol, 9 equiv.) in DMF (10 ml) was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the crude product was filtered. After flash chromatography (ethyl acetate:methanol:triethylamine 40:4:1), 0.486 g of the title compound was isolated (50.7% yield); mp 210-217° C.
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[NH3:13]>[Cu]Cl>[NH2:13][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: Cl[Cu]
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: 130 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
30 g (157 mmol) of 2,3-dichlorobenzoic acid and 0.78 g (7.85 mmol) of copper(I) chloride were weighed into an autoclave, and 95.6 g (1570 mmol) of 28% ammonia water was added. The autoclave was sealed, and heated in an oil bath at 130° C. and 8 atmospheres for 20 hours. After the completion of the reaction, the autoclave was cooled to room temperature, and the reaction mixture was transferred into a reaction flask, and heated at 90° C. to remove the ammonia. Then, the reaction solution was cooled to room temperature, and the pH value was adjusted to 3 using hydrochloric acid. The precipitated crystals were filtered and dried to obtain 19.1 g of 2-amino-3-chlorobenzoic acid as white crystals with a yield of 71%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:17][C:18]2[C:23]([O:24][CH3:25])=[CH:22][C:21]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH3:33])[CH:27]=3)=[C:20]([F:34])[CH:19]=2)=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+].C[O:41][CH2:42][C:43]([O:45][CH3:46])=O>C(Cl)Cl.CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:16]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:17]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH3:33])[CH:27]=3)=[C:20]([F:34])[CH:19]=1)[C:42](=[O:41])[C:43]([O:45][CH3:46])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(SCc2ccccc2)cc1C=O
Reactant: COCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1-n1c(=O)c(OC)cc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Yield: 45.7 %

Procedure:
A flask was charged with 5-(benzylthio)-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzaldehyde (0.809 g, 1.644 mmol) and a MeOH solution of sodium methoxide (16.44 ml, 8.22 mmol) was added. Then methyl methoxyacetate (0.489 ml, 4.93 mmol) followed by toluene (1.644 ml) were added. A reflux condenser was attached and the mixture was heated at 70° C. for 48 h. The resulting solution was concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal DCM and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep® Gold pre-packed silica gel column (40 g) using 95:5 Heptane: EtOAc to 100% EtOAc gradient (with 1% DCM for solubility) to afford 6-(benzylthio)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3-methoxyquinolin-2(1H)-one (0.410 g, 0.751 mmol, 45.7% yield) as a off-white amorphous solid. (ESI) 546.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([F:19])([F:18])[F:17])[CH2:11][C:12](OC)=[O:13])=[CH:6][CH:5]=1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:16]([F:17])([F:18])[F:19])[CH2:11][CH:12]=[O:13])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C(CC(=O)OC)C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C(CC=O)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(4-ethoxyphenyl)-4,4,4-trifluorobutanoate (2.0 g, 7.2×10-3 moles) in toluene (25 cm3) at -78° C. was added one molar diisobutylaluminium hydride (7.2 ml, 7.2×10-3 moles) in toluene. The resulting solution was stirred at -78° C. for two hours before quenching the reaction by the sequential addition of acetic acid (0.48 cm3, 8.4×10-3 moles), water (1 cm3) and sodium sulphate (10 g). The resulting slurry was allowed to warm to room temperature and after a further twenty minutes stirring the solids were filtered off through a silica plug. The solvent was removed to leave a colourless oil which was characterised as the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:10])[CH2:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:17]/[C:18](/[C:28]([CH2:33][F:34])([CH2:31][F:32])[CH2:29][F:30])=[CH:19]\[C@@H:20]1[C@H:22]([C:23](Cl)=[O:24])[C:21]1([CH3:27])[CH3:26]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:17]/[C:18](/[C:28]([CH2:33][F:34])([CH2:29][F:30])[CH2:31][F:32])=[CH:19]\[C@@H:20]1[C@H:22]([C:23]([O:10][CH:6]2[CH2:7][C:8]([CH3:9])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]2)=[O:24])[C:21]1([CH3:26])[CH3:27]
Reactant: C=CCC1=C(C)CC(O)C1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(CF)(CF)CF)[C@@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(CF)(CF)CF)C2(C)C)C1
Yield: 81 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-ol (190 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (140 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (353 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 382 mg of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 34). Yield 77% nD24 1.4721
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C@H:4]([O:11][C:12]1[C:17]([NH:18]C(=O)C)=[CH:16][C:15](C2C=CC=CC=2C([O-])=O)=[C:14]([N+:31]([O-:33])=[O:32])[CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O.Cl>C(O)C>[CH3:3][C@H:4]([O:11][C:12]1[C:17]([NH2:18])=[CH:16][C:15]([OH:1])=[C:14]([N+:31]([O-:33])=[O:32])[CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(-c2ccccc2C(=O)[O-])cc1NC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(O)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Sodium hydroxide (687 mg, 17.2 mmol) was carefully added to a stirred solution of 50a (294 mg, 0.69 mmol), water (8 ml), and ethanol (25 ml). The reaction mixture was stirred overnight at 25° C. and then was neutralized with concentrated HCl. The resulting solution was extracted twice with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was concentrated and purified via flash chromatography over silica gel with gradual elutions from 90/10 to 80/20 (v/v, Hex/EtOAc). Evaporation of the solvent yielded 164 mg (84%) of an orange oil which eventually solidified.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(O)ccc(F)c3F)c(N)n2)CC1
Temperature: 7 °C
Reaction time: 2.5 h
Yield: 39 %

Procedure:
A suspension of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (200 mg, 0.45 mmol, Example 105) in methylene chloride (40 mL) was treated at 0–5° C. with aluminum chloride (620 mg, 4.7 mmol). The solution was stirred at ˜7° C. for 2.5 hours and treated with ice water (20 mL). The mixture was treated with 10% NaHCO3 (15 mL) and extracted with a mixture of tetrahydrofuran and methylene chloride (2×), dried (Na2SO4), and filtered. Removal of solvent gave an oil that crystallized upon trituration with methylene chloride. This crude solid was purified by silica gel chromatography (5–10% methanol/methylene chloride to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-hydroxy-phenyl)-methanone as a white solid (75 mg, 39%) after solvent removal. HRMS, observed: 428.1203; Calcd for (M+H)+: 428.1199
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:20]1=[O:46].N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:20]1=[O:46])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCCCCN)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCCCCNC(C)=O)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A solution of 0.034 g of acetyl chloride in 0.5 ml of DCM is added at RT to a solution of 0.276 g of the compound obtained in EXAMPLE 199, in the form of the free base, and 2 ml of pyridine in 2 ml of DCM and the mixture is stirred for 1 hour. A further 0.034 g of acetyl chloride is added and the reaction mixture is stirred for 30 minutes at RT and concentrated under vacuum. The residue is taken up with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent to give 0.14 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=195°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=2)[CH2:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:30][O:31]C1C=C(C=CC=1CC1C2C(=CC=C(NC(=O)C(F)(F)F)C=2)C=C1)C(OC)=O.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3]1([O:31][CH3:30])[C:12]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH:21]=3)[CH2:16][CH:15]=2)=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4]1
Reactant: COC(=O)c1ccc(CC2=CCc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Reactant: COC(=O)c1ccc(CC2C=Cc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)C1=CC=C(CC2=CCc3ccc(NC(=O)C(F)(F)F)cc32)C(OC)(OC)C1
Yield: 27 %

Procedure:
A solution of n-butyllithium in hexane (1.4M, 38.82 ml) was added to a -78° C. solution of diisopropylamine (7.85 ml) in tetrahydrofuran (25 ml). After stirring for 15 min, a solution of 6-(trifluoroacetamido)-3H-indene (5.92 g) in tetrahydrofuran (25 ml) was added and stirred for 1 h. The reaction mixture was cooled to -100° C. and a solution of methyl 4-bromomethyl-3-methoxybenzoate (8.44 g) in tetrahydrofuran (35 ml) was added. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was added to saturated ammonium chloride (100 ml) and ethyl acetate (150 ml). The mixture was washed (water, brine), dried (MgSO4) and evaporated. The residue was recrystallized from 10:1 methylene chloride:hexane to give methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]benzoate (1.48 g, 14%). The residue derived from the filtrate was recrystallized from 3:1 methylene chloride:hexane to give a mixture of methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]benzoate and methyl 3-methoxy-4-[6-(trifluoroacetamido)-1H-inden-1-ylmethyl]benzoate (1.92 g). This mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.11 g) and tetrahydrofuran (20 ml) for 18 h. After partitioning between ethyl acetate (85 ml) and 1N hydrochloric acid, the organic layer was washed (brine) and dried (MgSO4). Evaporation and trituration with methylene chloride gave a colorless solid. This was combined with the above material to give methyl 3-methoxy-4-[6-(trifluoroacetamido)-3H-inden-1-ylmethyl]-3-methoxybenzoate (2.81 g, 27% total yield from 6-(trifluoroacetamido)-3H-indene); mp 198.5°-200.0° C.; MS(CI), m/e=406(M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].N.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:13]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Agent: N
Product: O=C(N[C@@H]1c2ccccc2C[C@H]1O)c1ccccc1

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride. The resulting benzamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4C=CC=C(C(F)(F)F)C=4)[CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])=[N:4][C:3]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC1SC(NC(C2CN(C3C=CC=CN=3)CCC2[C:59]2[N:63](C)[CH:62]=[N:61][N:60]=2)=O)=NC=1C1C=CC=CC=1.ClC1C=CC(C(NC2SC(C)=C(C3C=CC=CC=3)N=2)=O)=CN=1.CN1C=NN=C1C1CCNCC1>>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[N:63]([CH3:62])[CH:59]=[N:60][N:61]=4)[CH2:20][CH2:21]3)=[N:14][CH:15]=2)=[O:9])=[N:4][C:3]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1sc(NC(=O)C2CN(c3ccccn3)CCC2c2nncn2C)nc1-c1ccccc1
Reactant: Cc1sc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)nc1-c1ccccc1
Agent: Cc1sc(NC(=O)c2ccc(Cl)nc2)nc1-c1ccccc1
Agent: Cn1cnnc1C1CCNCC1
Product: Cc1sc(NC(=O)c2ccc(N3CCC(c4nncn4C)CC3)nc2)nc1-c1ccccc1

Procedure:
With a method similar to that used for the preparation of 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide, 4-(4-methyl-4H-[1,2,4]triazol-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide was prepared from 6-chloro-N-(5-methyl-4-phenyl-thiazol-2-yl)-nicotinamide and 4-(4-methyl-4H-[1,2,4]triazol-3-yl)-piperidine. LCMS calcd for C24H25N7OS (m/e) 459, obsd 460 (M+H).