Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]C)=[O:18])[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.O[Li].O>O1CCOCC1.O>[C:13]([O:12][C:10]([N:9]1[CH2:8][CH2:7][C:4]2([CH2:5][CH2:6]2)[CH2:3][C:2]1([CH3:1])[C:17]([OH:19])=[O:18])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1(C)CC2(CCN1C(=O)OC(C)(C)C)CC2
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
6-tert-butyl 5-methyl 5-methyl-6-azaspiro[2.5]octane-5,6-dicarboxylate (D5) (320 mg, 1.13 mmol) was partitioned between dioxane/water (8/8 ml) prior addition of LiOH H2O (190 mg, 4.52 mmol). The mixture was stirred at RT for 18 hrs then heated at 150° C. under microwave irradiation 40 min (4 cycles of 10 min each). Organic solvent was evaporated off and the aqueous solution washed with EtOAc (2×10 ml), acidified to pH˜4 with citric acid sat. sol. and extracted with EtOAc (3×10 ml). The organic phases were washed with NaCl sat. sol, dried over Na2SO4 and evaporated to reduced pressure to afford the title compound (D6) (114 mg).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[N:16]([C:17](=[O:27])[C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[N:15]=[C:14]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[S:13]1.C1COCC1.CO.[Li+].[OH-]>C(OCC)(=O)C.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:14]2[S:13][CH:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:16]([C:17](=[O:27])[C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])[N:15]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
To a solution of {2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetic acid methyl ester (2.93 mmol) in 30 mL of a mixture of THF and MeOH (3:2), is added LiOH (1 M) (30 mL). After stirring for 12 hours the reaction is complete as determined by LC/MS. The reaction is diluted with ethyl acetate and water, washed with brine and dried over MgSO4 and the solvent is removed from the reaction mixture to yield {2-[5-(4-Fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-acetic acid: 1H NMR (400 MHz, acetone-d6) δ 7.66 (m, 3H), 7.39 (m, 1H), 7.3 (dd, J1=7.6 Hz, J2=1.6 Hz, 1H), 7.22 (m, 4H), 7.13 (m, 1H), 7.07 (t, J=7.6 Hz, 1H), 4.94 (s, 2H); LC/MS (ES+): 491.0 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[CH2:13])[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16].[N+](=[CH2:20])=[N-].C(OCC)(=O)C>C(OCC)C.CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:20][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16]
Reactant: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Temperature: 25 °C

Procedure:
A stirred, cooled (−30° C.) solution of 6-bromo-8-vinyl-2,2,4,4-tetramethyl chroman (Intermediate 31, 0.37 g, 1.26 mmol) in diethyl ether was treated with a solution of diazomethane in diethyl ether and catalytic amount of palladium (II)acetate (˜30 mg). The reaction mixture was allowed to warm to ambient temperature and subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear, pale yellow oil (0.376 g, 97%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.I[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CSc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: CSc1ccccc1-c1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
The mixture of 2-methylthiophenyl-dihydroxyborane (1.55 g) and 3-iodobenzoic acid (2.08 g) in water (30 ml) was stirred at room temperature, then sodium carbonate (2.67 g) and palladium(II) acetate (0.019 g) were added thereto. After stirring at 40° C. overnight, the reaction mixture was filtered and was washed with ether (2×20 ml). The aqueous layer was adjusted to pH 2 with 6N-hydrochloric acid. The crystalline was collected, washed with water, and dried to afford 3-(2-methylthiophenyl)benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH-].[NH4+:22]>C(O)(=O)C>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH2:22])=[O:17]
Reactant: [NH4+]
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N=Nc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride (1 g) was carefully warmed with 0.880 ammonium hydroxide (10 ml) for 10 minutes. The mixture was then acidified with glacial acetic acid and the amide removed by filtration. The product was crystallized from ethanol (0.60 g), 65%, m.p. 231°-3°, λmax (methanol)=352 nm.
Reaction SMILES: [Br:1][C:2]([C@H:5]1[C@H:9]([OH:10])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3].[CH:12](O)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]([C@H:5]1[C@H:9]([O:10][CH:12]([CH3:14])[CH3:13])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(Br)[C@@H]1CC(=O)O[C@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)O[C@@H]1OC(=O)C[C@H]1C(C)(C)Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.95 g of dl trans 4-(2-bromo-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one, 2 ml of isopropanol, 100 mg of p-toluene sulfonic acid and 30 ml of benzene was stirred at room temperature for 60 hours and was then washed with aqueous sodium bicarbonate solution. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure to obtain 2 g of dl trans 4-(2-bromo-prop-2-yl)-5-isopropyloxy-tetrahyrofuran-2-one as an oily product which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
Prepared from 4-chlorobenzyl chloride and 4-hydroxyphenyl acetone by the method of Example 2 (b).
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17](C(O)=O)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][CH:17]=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Solvent: C1CCOC1
Product: c1ccc(C2(c3ccc4ncsc4n3)CC2)cc1

Procedure:
A solution of 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-carboxylic acid (1.16 g, 3.91 mmol) in THF (78.0 mL) was stirred at 60° C. for 30 min. The reaction solution was then concentrated in vacuo, and the residue was chromatographically purified (silica gel, 0-45% EtOAc/Hexanes) to furnish 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a light-yellow solid. MS (ESI) m/z: Calculated: 252.1; Observed: 253.0 (M++1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:36])[CH2:21][NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[C:26]([O:34][CH3:35])[CH:27]=[CH:28][C:29]=3[O:32][CH3:33])[CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[ClH:37].C(OCC)C>CO.[Pd]>[ClH:37].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:36])[CH2:21][NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[C:26]([O:34][CH3:35])[CH:27]=[CH:28][C:29]=3[O:32][CH3:33])[CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: COc1ccc(OC)c2c1CC(NC[C@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(OC)c2c1CC(NC[C@H](O)c1ccc(O)c3[nH]c(=O)ccc13)C2
Reaction time: 4 h

Procedure:
(R)-8-Benzyloxy-5-[2-(4,7-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one (37 mg, 0.08 mmol) is dissolved in methanol (10 mL) and the compound is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 4 hours. The catalyst is filtered off, 1M HCl/diethyl ether (1.1 equivalent) is added and the solvent is removed in vacuo. TLC (silica, dichloromethane/methanol 10:1 Rf=0.15). ES+ MS m/e 397 (MH+).
Reaction SMILES: [Mg].Br[C:3]1[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>O1CCCC1.CCOCC.BrC(Br)C>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:26]1([OH:29])[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: Fc1ccccc1Cn1cccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2cccn2Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Yield: 72.3 %

Procedure:
To a suspension of magnesium turnings (2.2 g, 0.09 mole) in 60 ml tetrahydrofuran (THF) and 30 ml ether, was added a few drops of a solution of 2-bromo-1-(2-fluorobenzyl)pyrrole (20 g, 0.074 mole) in 60 ml THF. The reaction was initiated with a few drops of dibromoethane and heat, and reflux was maintained by the addition of the bromo compound. After stirring at reflux for 30 minutes, the mixture was cooled with an ice bath, then a solution of 1-benzyl-4-piperidone (11.2 g, 0.06 mole) in 75 ml THF was added. After stirring at ambient temperature for one hour, the mixture was poured into NH4Cl solution, then extracted with ethyl acetate. The ethyl acetate solution was washed with water, then dried over anhydrous MgSO4. After evaporation of the solvent, the resultant oil (25 g) was purified by HPLC, using ethyl acetate/hexane/diethylamine (30:70:0.5) as the eluent to give 15.8 g of 4-[1-((2-fluorophenyl)methyl)- 1H-pyrrol-2-yl]-1-benzyl-4-piperidinol, m.p. 112°-117° C.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[C@H:36]([OH:37])[C@@H:23]5[O:24][CH:25]([C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](Cl)=[S:46])=[CH:40][CH:39]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:45](=[S:46])([O:44][C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1)[O:37][C@@H:36]1[C@@H:23]2[O:24][CH:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[O:26][CH2:27][C@@H:22]2[CH2:21][C@H:20]1[N:17]1[C:13]2[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[C:12]=2[CH:19]=[CH:18]1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@H](O)[C@@H]3O2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol (4.00 g, 8.02 mmol) was dissolved in DCM (169 mL) under an atmosphere of argon and 4-(dimethylamino)-pyridine (2.94 g, 24.1 mmol) was added followed by phenyl chlorothionocarbonate (2.22 mL, 16.0 mmol). The mixture was stirred at rt for 1 hour. The solvent was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 20 to 100% EtOAc in hexanes on a column pre-treated with 1% TEA in hexanes to afford the title compound (5.00 g, 99%). LC/MS: Rt=2.34 min, ES+ 636 (AA standard).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[CH3:12][O:11][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C1COCCN1
Reactant: COc1ccc(CCl)cc1C#N
Solvent: C1CCOC1
Product: COc1ccc(CN2CCOCC2)cc1C#N
Yield: 98.9 %

Procedure:
To a solution of 5-chloromethyl-2-methoxy-benzonitrile (246 mg, 1.354 mmol, example 29) in tetrahydrofuran (10 mL) at room temperature was added morpholine (1.193 mL, 13.54 mmol). The reaction mixture was heated at reflux for 4 h. The reaction was concentrated in vacuo (with heating) to remove morpholine and tetrahydrofuran to afford 2-methoxy-5-morpholin-4-ylmethyl-benzonitrile as a yellow oil (311.2 mg, 99%). The crude product was used without further purification.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1.Cl.Cl[CH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[O-]S(C(F)(F)F)(=O)=O.[Fe+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:2][C@@H:3]1[CH2:7][N:6]([CH2:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1
Reactant: ClCc1ncccn1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: [Fe+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ncccn2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Temperature: 60 °C
Yield: 66.5 %

Procedure:
To a solution of 6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (7.75 g) (see preparation in step (a) of Example 73) in dimethylformamide (115 mL) was added iron triflate (900 mg), 2-(chloromethyl)pyrimidine hydrogen chloride (4.5 g), and cesium carbonate (22.2 g) and the reaction mixture was heated at 60° C. for 24 h. The reaction mixture was concentrated onto silica gel and purified by flash chromatography eluting with 0-15% methanoylethyl acetate/1% saturated ammonium hydroxide to provide the title compound (6 g). 400 MHz 1H NMR (CDCl3) δ 12.30 (brs, 1H), 8.63 (d, J=5.0, Hz, 2H), 8.03 (s, 1H). 7.20 (d, J=5.0, Hz, 1H), 4.84-4.79 (m, 1H), 4.30-4.27 (m, 1H), 4.14-4.08 (m, 2H), 3.87-3.82 (m, 1H), 3.63-3.55 (m, 2H), 3.47 (t, J=7.9 Hz, 1H), 3.29 (d, J=9.9 Hz, 1H), 2.88-2.86 (m, 1H), 2.60-2.56 (m, 1H), 2.46-2.24 (m, 4H), 1.93-1.84 (m, 2H), 1.24 (t, J=7.1 Hz, 3H). MS: (M+H m/z 396.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:17])[C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:17][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCC3)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.2 %

Procedure:
A solution of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (100 mg, 363 μmol) in DCM (5 mL), cooled to 0° C., was treated with oxalyl chloride (63.6 μL, 727 μmol), followed by a drop of DMF. The resultant mixture was stirred for 1 h at RT. The solvent was evaporated in vacuo and the residue dissolved in DCM (5 mL), and then treated with a solution of methyl 4-aminobenzoate (54.9 mg, 363 μmol) and DIPEA (190 μL, 1.09 mmol) in DCM (5 mL). The reaction mixture was stirred for 12 h at RT and then partitioned between DCM (20 mL) and aqueous HCl (20 mL, 1 M). The phases were separated and the organic phase was washed successively with water (2×20 mL), and brine (20 mL), dried over MgSO4, filtered and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002) (30 mg, 20%): m/z 406 (M−H)− (ES−). NMR (400 MHz, CDCl3) δ: 8.06 (2H, d), 7.85 (1H, br s), 7.82 (2H, s), 7.71 (2H, d), 5.05 (1H, m), 3.92 (3H, s), 2.10-1.90 (4H, m), 1.85-1.70 (2H, m), 1.70-1.60 (2H, m).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[O:8]=[C:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1>CO.C(Cl)Cl>[O:8]=[C:9]1[CH2:12][CH:11]([C:13]([O:15][CH3:1])=[O:14])[CH2:10]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyldiazomethane (21.0 mL of a 2 M solution in hexanes, 42.1 mmol) was added to a stirred solution of 3-oxocyclobutanecarboxylic acid (3.00 g, 26.3 mmol) in dry MeOH (11.1 mL) and dry CH2Cl2 (100 mL) at 25° C. under N2. The reaction was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford methyl 3-oxocyclobutanecarboxylate, as an oil. 1H NMR (500 MHz, CHCl3): δ 3.75 (s, 3H); 3.44-3.37 (m, 2H); 3.31-3.17 (m, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[NH:32][C:31]4[CH2:30][CH2:29][NH:28][CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[C:33](O)(=O)[CH3:34].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[NH:32][C:31]4[CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CC(=O)O
Reactant: O=C(c1cc2c([nH]1)CCNC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCN1CCc2[nH]c(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Reaction time: 0.25 h
Yield: 103.8 %

Procedure:
In methylene chloride (3.0 ml), 2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (149 mg) was suspended, followed by the addition of methanol (0.6 ml), triethylamine (82.5 μl), acetic acid (51.0 μl, 891 μmol), acetaldehyde (19.5 μl) and sodium triacetoxyborohydride (74.0 mg) at room temperature. The resulting mixture was stirred for 15 minutes. To the reaction mixture, a saturated aqueous solution (30 ml) of sodium bicarbonate and methylene chloride (15 ml) were added to separate the water layer. The resulting water layer was extracted with methylene chloride (2×10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (30 g of silica gel, methylene chloride:methanol=10:1). The resulting white solid was dissolved in a 1N aqueous hydrochloride in ethanol (10 ml). After concentration of the resulting solution, water (30 ml) was added to the concentrate and the mixture was concentrated again, whereby the title compound (81.7 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:10]1[C:11]2[CH:18]=[CH:17][N:16]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]=2[N:13]=[CH:14][N:15]=1)[CH:3]1[CH2:9][O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:29][C:30]1[CH:31]=[C:32]([NH:37][CH2:38][C:39](O)=[O:40])[CH:33]=[C:34]([Cl:36])[CH:35]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:29][C:30]1[CH:31]=[C:32]([NH:37][CH2:38][C:39]([N:5]2[CH2:4][CH:3]([N:2]([CH3:1])[C:10]3[C:11]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:9][O:8][CH2:7][CH2:6]2)=[O:40])[CH:33]=[C:34]([Cl:36])[CH:35]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CNCCOC4)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4COCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-methyl-N-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-amine ((0.114 g (0.283 mmol) 107.5, (3,5-dichloro-phenylamino)-acetic acid (0.0685 g (0.311 mmol) 107.b, and 1-hydroxybenzotriazole hydrate (9 mg (0.057 mmol) were dissolved in DMF (4 mL). The resulting solution was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (60 mg, 0.311 mmol) and DIEA (100 uL (0.566 mmol) and stirred at rt for 24 hr. The mixture was diluted with H2O and extracted with EtOAc (2×) and 1:1 EtOAc/THF (2×). The combined organics were washed with 10% citric acid and brine, dried over MgSO4, filtered, and concentrated, absorbing onto 3 g SiO2. Purification by flash column chromatography (ISCO 12 g SiO2, 40% EtOAc/hex then gradient to 100% EtOAc) afforded (2-(3,5-dichlorophenylamino)-1-(6-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1,4-oxazepan-4-yl)ethanone (0.179 g) 107.6 as a white solid. LCMS (ESI) m/z: 603.20 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2].[CH:28]([OH:31])([CH3:30])[CH3:29]>[OH-].[Na+].C([C@@H]1OC1)Cl.CC(=O)OCC>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:28]4[CH2:30][O:31]4)=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CC(C)O
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Agent: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (1.49 g, 3.87 mmol) in isopropanol (70 mL) and 3 N aq. NaOH (19 mL), (R)-epichlorohydrine is added. The mixture is stirred at rt for 41 h. The mixture is diluted with EA and washed with 1 M aq. NaOH. The washing is extracted back with EA. The organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge C18, 50×50 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of concentrated aq. ammonia) to give diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (990 mg) as a pale yellow resin; LC-MS: tR=0.65 min; [M+1]+=442.09. b) A solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (450 mg, 1.02 mmol) in 7 N NH3 in methanol is stirred in a sealed vessel at 65° C. for 16 h. The solvent is evaporated and the crude product is purified by prep. HPLC. The product containing fractions are filtered over Amberlyst A21. The filtrate is concentrated and dried to give the title compound (381 mg) as a yellow resin; LC-MS: tR=0.44 min; [M+1]+=459.10; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.73 (q, J=7.5 Hz, 2H), 2.88 (dd, J=12.8, 9.0 Hz, 1H), 3.10 (dd, J=12.5, 3.0 Hz, 1H), 3.73 (s, 2H), 3.81 (d, J=5.3 Hz, 2H), 4.04-4.12 (m, 1H), 7.75 (s, 2H), 7.80 (s, 1H).