Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N)=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:30][OH:31]>>[ClH:1].[OH:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:31][CH3:30])=[O:17])=[CH:11][CH:10]=1
Reactant: NC(=O)Cc1ccc(OCCNCC(O)c2ccccc2)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OCCNCC(O)c2ccccc2)cc1

Procedure:
4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (2.5 g) was heated under reflux in methanol (50 ml) containing concentrated sulphuric acid (1.5 ml) for 24 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was partitioned between dichloromethane (150 ml) and 5% NaHCO3 solution (150 ml). The organic layer was separated and washed successively with 5% NaHCO3 solution (20 ml) and water (20 ml), dried over MgSO4 and then the solvent was removed under reduced pressure. The residue was dissolved in methyl acetate (40 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from a mixture of methanol and methyl acetate to give methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate hydrochloride (1.8 g), m.p. 169°-171° C.; microanalysis: found C, 62.5; H, 6.6; N, 3.8; Cl, 9.7%; required for C19H24ClNO 4 : C, 62.4; H, 6.6; N, 3.8; Cl, 9.7%.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:10][C:4]=2[O:3]1>[Pd].C(O)C>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:18]([Cl:32])=[CH:19][C:20]([OH:24])=[CH:21][C:22]=3[Cl:23])=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(O)cc3Cl)cc2O1

Procedure:
A mixture of 0.29 gram (0.59 millimole) of, 2-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-5-oxy)butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene and 0.05 gram (catalyst) of 10% palladium on carbon in 50 mL of ethanol was subjected to hydrogenation conditions using a Parr Hydrogenator, yielding 0.24 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([C@H:7]([CH3:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>ClCCl>[C:1]1([C@H:7]([CH3:10])[CH2:8][O:9][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
To a solution of 20 g of (S)-(−)-2-phenyl-1-propanol in 240 ml of dichloromethane was added in portions 28 g of p-toluenesulfonyl chloride (146.8 mmol). After stirring for 18 h at room temperature, the organic phase was washed with 100 ml of water, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 43 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].CO.[OH-].[Na+]>CC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Br:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)c(F)c(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: Nc1c(F)c(-c2cc(F)c(Br)cc2F)nc(C(=O)O)c1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of methyl 4-amino-6-(4-bromo-2,5-difluorophenyl)-3-chloro-5-fluoropicolinate (0.160 g, 0.404 mmol) in a 1:1 mixture of MeOH (0.674 mL) and acetone (0.674 mL) was added a 2 N aqueous solution of sodium hydroxide (0.607 mL, 1.213 mmol). The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated, poured into a 2 N aqueous solution of HCl, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, concentrated and dried in vacuo to afford the title compound as a light brown solid (126 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br-:12].[Br-:13].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.O>[Br:12][C:6]1([Br:13])[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1Nc2cc(Cl)ccc2C1(Br)Br
Reaction time: 3.5 h
Yield: 101.2 %

Procedure:
At room temperature, to a solution of 6-chlorooxindole (10.0 g, 59.7 mmol ) in t-BuOH (500 mL) and water (2.6 mL) was added pyridinium tribromide (57.25 g, 79 mmol, 3 eq) and the reaction was stirred for 3.5 hr. The reaction was diluted with water (500 mL) and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaHCO3 (3×), dried over MgSO4, filtered and concentrated to give the title compound as a tan solid (19.66 g, 100% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 325 [M+H].
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH2:13][CH3:14])=[CH:6][C:5]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[OH-:21].[K+].O>CO>[C:15]([C:5]1[CH:6]=[C:7]([CH2:13][CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCc1cc(C(C)(C)C)c(COC(=O)[O-])cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of (2-tert-butyl-4-ethyl-5-nitro-phenyl)methyl carbonate (3.9 g, 13.86 mmol) in methanol (100 mL) was added KOH (1.8 g, 32.08 mmol) at room temperature. The mixture was stirred overnight. Water was added and the reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-tert-butyl-4-ethyl-5-nitrophenol (2.8 g, 91%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11])=[O:5])[CH3:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C1CCCC1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
A solution of 2-hydroxy-cyclopentanecarboxylic acid ethyl ester (3.5 g, 22.12 mmol) in methylene chloride (147.5 mL) was treated with 3,4-dihydro-2H-pyran (3.03 mL, 33.1 mmol) and pyridinium p-toluenesulfonate (556 mg, 2.21 mmol). This solution was stirred at 25° C. for 5 h. The reaction was then washed with a half-saturated aqueous sodium chloride solution (2×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(tetrahydro-pyran-2-yloxy)-cyclopentanecarboxylic acid ethyl ester (4.7 g, 87.7%) as a clear liquid: EI-HRMS m/e calcd for C13H22O4 (M+) 242.1518 found 242.1521.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([Br:1])=[CH:3][N:4]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Temperature: 85 °C

Procedure:
A mixture of 5,8-dibromoimidazo[1,2-a]pyrazine (2 g, 7.3 mmol), 4-amino benzoic acid methyl ester (0.93 g, 6.2 mmol), NaOtBu (0.98 g, 10.2 mmol), Pd2(dba)3 (133 mg, 0.14 mmol), Xantphos (168 mg, 0.29 mmol) and toluene is degassed with nitrogen, then heated at 85° C. for 18 hours. The toluene is removed in vacuo, then MeOH is added to the crude residue. The solid is collected by filtration and dried in the vacuum oven. The solid is identified as the desired title ester. The filtrate is chromatographed with petrol:EtOAc (70:30 followed by 50:50) and the fractions containing the desired product, combined, evaporated and triturated with MeOH. The resultant solid is collected by filtration and is also identified as the desired ester.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:4][OH:5].[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1)[CH2:4][O:5][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@H](COc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
(2R)-3-Methyl-2-{[4-(trifluoromethyl)phenyl]amino}butan-1-ol (50 mg, 0.201 mmol), which is the compound obtained in Step 1 of Example 2, phenol (19 mg) and triphenylphosphine (63 mg) were dissolved in tetrahydrofuran (1 mL), and after cooling to 0° C., diisopropyl azodicarboxylate (0.13 mL) was added dropwise. The mixture was stirred overnight at 50° C. and purified by purification step A to give the title compound (2.18 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13]C2)[CH:3]=1.O1C2(CCC(C3C=C(O)N4N=CC=C4N=3)C2)OCC1.O1C2(CCC(C3C=C(O)N4N=CC=C4N=3)CC2)OCC1>>[Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:13]2)[CH:3]=1
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Oc1cc(C2CCC3(C2)OCCO3)nc2ccnn12
Agent: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Clc1cc(C2CCC3(C2)OCCO3)nc2ccnn12

Procedure:
7-Chloro-5-(1,4-dioxaspiro[4.4]nonan-7-yl)pyrazolo[1,5-a]pyrimidine is synthesized in a manner similar to the synthesis of 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine, but with 5-(1,4-dioxaspiro[4.4]nonan-7-yl)pyrazolo[1,5-a]pyrimidin-7-ol substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:23][C@@H:24]3[C@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:27][N:26]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:25]3)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:44])([CH3:43])[C:8]1=[O:45].[H-].[Na+].[CH2:48](I)[CH3:49].[Cl-].[NH4+]>CN(C=O)C>[CH2:48]([N:23]([C:21]([C:14]1[C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]2[O:10][C:9]([CH3:44])([CH3:43])[C:8](=[O:45])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C@@H:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:27][N:26]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:25]1)[CH3:49]
Reactant: CCI
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3c3ccccc3)cc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCCCOC)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({[4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)-4-phenylpiperidine-1-carboxylate (386 mg) in DMF (1 ml) was added sodium hydride (48.7 mg) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added ethyl iodide (126 μl), and the mixture was stirred at room temperature for 5 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×2) and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=3/1) to give the title compound (128 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1C(OCC)=O.S(=O)(=O)(O)O>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2c(F)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=S(=O)(O)O
Product: Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Yield: 82.1 %

Procedure:
250 g (0.71 mol) of 5-amino-4-ethoxycarbonyl-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole are heated in 650 ml of 50% strength aqueous sulphuric acid at 120° C. for 2 hours, during which the volatile constituents distil off. The mixture is heated at 115° C. to 120° C. for a further 5 hours and then cooled, 3 l of ice-water are added, the pH is adjusted to 8 to 9 using aqueous sodium hydroxide solution, and the precipitate formed is filtered off, washed with water and dried in vacuo at 50° C. 163 g (82% of theory) of 5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 87°-90° C. are obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[N+:24]([O-:26])=[O:25])=[N:14][NH:15][CH:16]=1>N1C=CC=CC=1>[O:4]([C:2]([C:16]1[NH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[N+:24]([O-:26])=[O:25])[C:12]=1[Cl:11])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1[nH]nc(-c2cccc(Cl)c2[N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
1.0 ml of phenyl chloroformate is added, in small portions, to a solution, cooled to 0° C., of 1.3 g of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole in 20 ml of pyridine. Stirring is continued for 8 hours at room temperature. The reaction mixture is concentrated dryness under reduced pressure and taken up in 100 ml of an H2O/ethyl acetate (1/1) mixture. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residual solid is purified by recrystallisation from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]2([CH2:23][CH:22]([NH2:24])[CH2:21]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:24][CH:22]2[CH2:21][C:19]3([CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:20]3)[CH2:23]2)[C:2]=1[Cl:1]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CC(N)C2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC2(CC(Nc3ncnc(N)c3Cl)C2)C1
Temperature: 155 °C
Reaction time: 4 h

Procedure:
In a round bottom flask containing 5,6-dichloro-pyrimidin-4-ylamine (300.00 mg; 1.83 mmol; 1.00 eq.) and 6-amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (466.02 mg; 2.20 mmol; 1.20 eq.) in NMP (1.00 ml) was added DIPEA (0.91 ml; 5.49 mmol; 3.00 eq.). The reaction mixture was stirred at 155° C. for 4 h before it was concentrated.
Reaction SMILES: Cl.[CH3:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1>C(O)C>[CH3:2][NH:3][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 76.3 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 905 mg (13.4 mmol) of methylamine hydrochloride, 1.85 g (13.4 mmol) of potassium carbonate and 800 mg (1.34 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 511 mg of ethyl 4′-(3-methylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=141° C., yield=76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[C:31]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[OH:40])[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O.O>[C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:40][C:34]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[C:31]2[CH:30]=[CH:29][N:28]=[C:27]([NH2:26])[CH:32]=2)=[CH:18][C:17]=1[F:24])(=[O:14])=[O:15])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1cc(-c2cc(F)ccc2O)ccn1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(F)cc2-c2ccnc(N)c2)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 60 mg, 0.15 mmol) was added to a mixture of 2-(2-aminopyridin-4-yl)-4-fluorophenol (Preparation 21, 30 mg, 0.1 mmol) and potassium carbonate (41 mg, 0.29 mmol) in dimethylsulfoxide (2 mL) and stirred at ambient temperature for 24 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane, concentrated onto diatomaceous earth, and purified by automated silica gel flash chromatography (100% hexanes to 20% methanol in ethyl acetate, gradient elution) to afford tert-butyl({4-[2-(2-aminopyridin-4-yl)-4-fluorophenoxy]-5-chloro-2-fluorophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate as a light brown oil, which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([C@H:32]([OH:37])[C@H:33]([OH:36])[CH2:34]O)[CH:30]=[O:31].[BH4-].[Na+]>CO.C(O)(=O)C>[CH:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][CH2:34][C@H:33]([OH:36])[C@@H:32]([OH:37])[C@H:29]([OH:28])[CH2:30][OH:31])[N:15]=2)=[CH:23][C:20]=1[C:21]#[N:22])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NC[C@H](O)[C@@H](O)[C@H](O)CO)no2)cc1C#N
Temperature: 50 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
Prepared using General Procedure 13. To a solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (50.mg, 0.14 mmol) in MeOH (10 mL) was added (2S,3R,4R)-2,3,4,5-tetrahydroxypentanal (20.71 mg, 0.14 mmol) and acetic acid (2 drops) with stirring at 50° C. for 18 h. The reaction was cooled to room temperature and sodium borohydride (52.2 mg, 1.38 mmol) was added slowly with stirring for 2 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3 aqueous (10 mL) and extracted with EA (3×10 mL). The organic layers were washed with brine and dried over Mg2SO4. The product was purified by preparative HPLC to give 8.68 mg (25%) of 2-isopropoxy-5-(3-((S)-1-(((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 119 as a solid. LCMS-ESI (m/z) calculated for C26H30N4O6: 494.5; found 495.2 [M+H]+, tR=2.42 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (56 mg) and 4-bromo-1-butanol (62 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (19 mg, yield 35%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9](=[O:18])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2N[C@H]1Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3S)-3-benzyl-3,4-dihydro-2(1H)-quinoxalinone (19) (4.66 g, 19.6 mmol) as a suspension in toluene (200 mL) was added DDQ (4.45 g, 1 equiv.) and the mixture stirred at room temperature overnight. The grey solid was collected by filtration and crystallized from ethanol/ water to afford the required compound (I10) (3.02 g, 65%).