Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=2[OH:18])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([S:5]([C:8]2[C:9]([OH:18])=[C:10]([CH:11]=[CH:12][C:13]=2[Cl:14])[NH2:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 99.8 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 1-(azetidin-1-yl)sulfonyl-6-chloro-2-hydroxy-3-nitrobenzene (240 mg, 0.82 mmol) was reduced with hydrogen and 10% Pd/C (110 mg) to form the desired product (215 mg, 100%). 1H NMR (MeOD-d4): δ 6.91 (m, 2H), 4.01 (t, 4H), 2.23 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[F:1])\[CH3:16])[CH3:11]
Reactant: Cc1cccc(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1F
Yield: 22.3 %

Procedure:
To a stirred mixture of 2-fluoro-3-methyl-phenol (20.0 g, 0.158 mol) and ethyl-2-butynoate (33.6 g, 0.300 mol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.4 g, 0.167 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 330 g, 0% to 15% ethyl acetate/hexanes) which afforded (E)-3-(2-fluoro-3-methyl-phenoxy)-but-2-enoic acid ethyl ester (8.40 g, 23%) as a clear oil.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6]Cl)([CH3:3])[CH3:2].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].CN(C)C=O>O>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
A mixture of 0.92 g (4.4 mmol) of 2, 6-diisopropylbenzyl chloride, 0.97 g (5.24 mmol) of potassium phthalimide and 8 ml of N, N-dimethylformamide was stirred at 70° C. for 1.5 hours. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was mixed with 15 ml of hexane and 2 ml of ethyl acetate, stirred at room temperature, and the precipitated crystals were filtered to give 1.01 g of N-(2, 6-diisopropylbenzyl)-phthalimide.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:20]=[N+]=[N-].[Na+].CS(C)=O>O>[NH2:20][C:2]1[CH:19]=[CH:18][C:5]([CH:6]([C:8]2[C:13]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: CCCOc1cccnc1C(=O)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cccnc1C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-propoxypyridine (4.46 g) and sodium azide (3.34 g) in. DMSO (50 ml) was stirred for 22 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (4.8 g) in THF (50 ml) was added dropwise to a suspension of aluminum lithium hydride (1.3 g) in. THF (40 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, water (1.3 ml), 15% aqueous solution of sodium hydroxide (1.3 ml) and water (3.9 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred at room temperature for 2 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give (4-aminophenyl)(3-propoxypyridin-2-yl)methanol (2.82 g) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:16][O:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:16][O:15][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: NC1COC(c2ccccc2)C1
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ncnc(NC2COC(c3ccccc3)C2)c1Cl

Procedure:
1.50 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 1.39 g (8.5 mmol) of 4-amino-2-phenyltetrahydrofuran and 2 ml (14 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After the mixture had been dried and concentrated, the residue was purified by column chromatography using petroleum etherlethyl acetate (9:1, 8:2). This gave 1.63 g (63% of theory) of a colorless oil (diastereomers 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH:5]=[CH:6][C:7]1[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=1.[H][H]>[C].[Pd].C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]2[S:8][C:9]([CH3:14])=[C:10]([CH2:12][CH3:13])[N:11]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CCc1nc(C=Cc2cccc(N)c2)sc1C
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(CCc2cccc(N)c2)sc1C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
An amount of 1.0 g of 2-(3-aminostyryl)-4-ethyl-5-methylthiazole and 200 mg of 5% palladium-carbon were added to 20 ml of ethanol and catalytic reduction was carried out in a hydrogen gas atmosphere at room temperature and normal pressure for 12 hours. After the reaction mixture was filtered, the solvent was evaporated under reduced pressure to give 0.90 g (yield 90%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[NH2:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:15](=[O:16])[O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(N)CN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(N)CNC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a 65 g sample of 1,2-diamino-2-methylpropane dissolved in 650 mL of toluene cooled to -5° C. was added dropwise over 45 minutes a toluene solution (200 mL) of benzylchloroformate (52 g, 1.18 mmol). The reaction was warmed to room temperature and stirred for 2 hours before it was filtered and the filtrate was stripped of all solvent under reduced pressure. The residue, dissolved in CH2Cl2 (100 mL), was filtered and the filtrate again was stripped of all solvent to produce the title compound (54 g) as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.C(P(C(C)C)C(C)C)(C)C.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:26][CH2:27]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)P(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A 100 mL round bottom flask was mixed with 4-triflouromethylbromobenzene (3.2 g, 15.0 mmol), triisopropylphosphine (10.0 mg, 0.062 mmol), Pd(OAc)2 (3.0 mg, 0.013 mmol) and xylenes (50 mL). The reaction mixture was allowed to heat at 110° C. for a period of 30 min at which it was mixed with tert-butyl piperidin-4-ylcarbamate (1.0 g 5.0 mmol). The reaction mixture stirred at 120° C. for 4.0 hours and then cooled to RT. The reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organics were dried over MgSO4 and concentrated to a crude oil. The oil was purified using silica gel chromatography (90% hexanes/10% EtOAc) to yield a total of 472 mg of mostly pure solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[C:11]#[N:12].[I-:13].[Na+].Cl.O>C(#N)C>[I:13][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc2sccc2nc1Cl
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc2sccc2nc1I

Procedure:
A solution of 5 g of 5-chlorothieno[3,2-b]pyridine-6-carbonitrile, 10 g of sodium iodide and 1 ml of concentrated hydrochloric acid in 70 ml of acetonitrile was heated at reflux for 65 hours. The mixture was then poured into water and the resulting solid was separated by filtration. The solid was recrystallized from acetone to give 5-iodothieno[3,2-b]pyridine-6-carbonitrile as white needles melting at about 190°-191° C.
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]([CH3:10])([CH3:9])[C:5]([NH:7][CH3:8])=[O:6].[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23]([CH:26]=O)[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]>>[F:11][C:12]1[C:13]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[C:14]([CH:22]=[C:23]([CH:26]=[N:1][O:2][CH2:3][C:4]([CH3:10])([C:5](=[O:6])[NH:7][CH3:8])[CH3:9])[C:24]=1[F:25])[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CNC(=O)C(C)(C)CON
Product: CNC(=O)C(C)(C)CON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
The title compound was synthesized as a mixture of E/Z geometric isomers, using the procedure described in Step C of Example 19, from 3-aminooxy-2,2,N-trimethyl-propionamide obtained in Step B and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy-benzamide obtained in Step F of Example 1.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>C(O)(=O)C>[C:13]([O:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1ccc(F)cc1F
Yield: 75.9 %

Procedure:
A solution of 2-chloro-2',4'-difluoroacetophenone (19.0 g) and anhydrous sodium acetate (16.4 g) in acetic acid (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave an oil which was triturated with hexane. The resulting solid was filtered off, washed with hexane and dried to give the title compound, (16.2 g), m.p. 54°-56°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18](O)[C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nccc(-c2c(-c3cccc(C(F)(F)F)c3)nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2O)n1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CO
Product: CSc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a stirring solution of 4-[1-hydroxy-5-(2-methylthiopyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]piperidine-1-carboxylic acid benzyl ester (9.5 g. crude, 0.0146 mole) in methanol (130 mL) at 20° C. was added titanium (III) chloride (25 mL, 0.029 mole, 15% wt in 20-30% HCl) dropwise over 10 minutes. The reaction was allowed to stir for 3 hours then quenched by pouring slowly into a mixture of 10% aqueous sodium bicarbonate (1.5 L) and ethyl acetate (600 mL). After stirring for 30 minutes the organic layer was removed and aqueous extract washed with ethyl acetate (2×200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated to an oil. The oil was chromatographed on silica using 60% ethyl acetate/hexane to give 6.35 g of a yellow foam upon concentration of product containing fractions.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)Cl.[Si:10]([O:27][C@H:28]([CH3:44])[C@H:29]([NH:39][CH2:40][C@@H:41]([OH:43])[CH3:42])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Si:10]([O:27][C@H:28]([CH3:44])[C@H:29]([N:39]1[CH2:40][C@H:41]([CH3:42])[O:43][C:2](=[O:3])[C:1]1=[O:5])[C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=1)([C:23]([CH3:25])([CH3:26])[CH3:24])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN([C@H](c2cc(F)c(F)c(F)c2)[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)C(=O)O1
Reaction time: 2 h

Procedure:
In nitrogen atmosphere, oxalyl chloride (45 μL) was dropwise added under ice-cooling to a methylene chloride solution (2 mL) of (S)-1-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]propan-2-ol (171 mg), TEA (0.17 mL), and 4-(N,N-dimethylamino)pyridine (8 mg). The resulting reaction solution was stirred at the same temperature for 2 hr, and then iced-water and ethyl acetate were added thereto. The organic layer was separated and washed with water, 1 N hydrochloric acid, water, a saturated sodium hydrogencarbonate aqueous solution, and saturated saline in this order. Then, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=9:1 to 3: 1) to give 96 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:14][C:15](=[O:21])[CH:16]=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([C:16](=[CH:17][N:18]([CH3:20])[CH3:19])[C:15]([O:14][CH2:12][CH3:13])=[O:21])=[O:5]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)ccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)ccc1F
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 11.3 %

Procedure:
A solution of 2,5-difluorobenzoyl chloride (5.26 g, 29.8 mmol) in toluene (100 mL) was treated with ethyl-3-(dimethylamino)-2-propenoate (5.27 g, 36.8 mmol), followed by triethylamine (5.9 mL, 42.5 mmol). The mixture was stirred at 90° C. for 6.5 h then allowed to cool, and the precipitate removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography (silica gel, 50-100% diethyl ether in petroleum ether [b.p. 40-60° C.]) to give the title compound as a yellow oil (0.95 g); ESMS m/z 284.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:26])=[CH:12][C:13]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.[ClH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:26][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:12][C:13]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CC(CCCc1ccccc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccccc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
1.25 g. (3.5 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-phenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta[c] [1] benzopyran, 0.76 g. (3.63 mmoles) of γ-morpholinobutyric acid hydrochloride and 0.76 g. (3.70 mmoles) of dicyclohexylcarbodiimide are combined in 75 ml. of methylene chloride and stirred at room temperature for 24 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the methylene chloride solution is concentrated to 20 ml. Cyclohexane is added until the desired compound is obtained as a colorless solid. Recrystallization from methylene chloride/cyclohexane gives the desired crystalline product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.CC(C[AlH]CC(C)C)C.CO.O>C(Cl)Cl.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][C:21]2[O:22][C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH:9]4[CH2:8][CH2:7][CH:6]([CH2:5][CH:4]=[O:3])[CH2:11][CH2:10]4)=[CH:13][CH:14]=3)=[CH:19][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=CCC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a solution of (4-{4-[2-(3-Chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-acetic acid ethyl ester (500 mg, 1.14 mmol) in DCM (20 mL) at −78° C. is added DIBAL-H (1 M in toluene, 2.14 mL, 2.14 mmol) and the mixture is allowed to stir at −78° C. for 2 h. Methanol (3 mL) is added to quench the reaction. The reaction mixture is then poured in ice and Rochelle's salt (4 g). Water (20 mL) is added and the mixture is extracted with EtOAc (3×30 mL). The organic phase is washed with brine (3×30 mL), dried with Na2SO4 and concentrated to give the title compound (253 mg) as a white solid: (M+H)+ 395.2.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][CH2:14][CH2:15][CH3:16])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCNCc1ccc(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.178 g (0.1 mmol) of the product of Step A and 0.206 g (3.5 mmol) of n-propylamine dissolved in 10 mL of CH2Cl2 was added 0.5 g of finely powdered 4 Å molecular sieves. The reaction mixture was stirred under a nitrogen atmosphere at room temperature overnight, then 0.53 g (2.5 mmol) of sodium triacetoxyborohydride was added. The reaction was then stirred an addition 8 h at room temperature, then diluted with CH2Cl2 and MeOH. The mixture was filtered through a pad of Celite filter aid eluted with CH2Cl2, and the filtrate was washed with saturated aqueous NaHCO3. The organic layer was the separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a flash chromatography column eluted with CH2Cl2-MeOH—NH4OH (95:4:1) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21](Cl)[Cl:22]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O>[Cl:22][CH2:21][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (S)-2-(t-butoxycarbonylamino)-3-methylbutanoic acid (28.6 g, 130 mmol) and NaHCO3 (44 g, 520 mmol) and Bu4NHSO4 (4.4 g, 13 mmol) in DCM (200 mL) and water (200 mL) was added chloromethyl sulfochloridate (26 g, 158 mmol) at 0° C. The mixture was stirred at room temperature for 24 hours, and then was extracted with DCM (3×150 mL). The combined organic layers were washed with water (2×300 mL), and the DCM layer was purified by flash column (petroleum ether:EA=15:1) to yield the title compound as a yellow solid (35 g). LC-MS: 266 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:11][CH3:12])[C:6]=1[C:7]([O:9]C)=O.C(O)(=O)C.[CH:17](N)=[NH:18].CCN(C(C)C)C(C)C>C(O)CCC>[CH2:11]([N:5]1[C:6]2[C:7]([OH:9])=[N:18][CH:17]=[N:1][C:2]=2[CH:3]=[N:4]1)[CH3:12]
Reactant: CCn1ncc(N)c1C(=O)OC
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2ncnc(O)c21
Temperature: 120 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
A mixture of methyl 4-amino-1-ethyl-1H-pyrazole-5-carboxylate (1.75 g), formamidine acetate (1.615 g), n-butanol (20 mL) and DIPEA (20 mL) was stirred at 120° C. for 3 h. The mixture was concentrated under reduced pressure, and the residual crystals were washed with AcOEt/hexane to give the title compound (1.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:32][C:30]3[CH:29]=[CH:28][C:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:26]([F:25])[CH:31]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (0.43 mmol, 1.0 eq.) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 152 mg (0.65 mmol, 1.5 eq.) of tert-butyl 2-fluoro-4-aminophenylcarboxylate were reacted according to General Method 5C. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 20%-50% mixtures). Yield: 250 mg (purity 93%, 99% of theory)