Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([N:22]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[CH3:28])[C:20]=2[CH3:21])[CH:11](O)CS(C)(=O)=O)[C:4]([CH3:7])=[CH:5][CH:6]=1.C[O-].[Na+].[NH:32]([CH2:39][CH2:40][C:41]#[N:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CS(C)=O>[NH:32]([CH:39]=[C:40]([CH2:11][C:10]1[CH:18]=[C:19]([N:22]2[C:23]([CH3:28])=[CH:24][CH:25]=[C:26]2[CH3:27])[C:20]([CH3:21])=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:9]=1)[C:41]#[N:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(-n2c(C)ccc2C)cc(C(O)CS(C)(=O)=O)cc1-n1c(C)ccc1C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(-n2c(C)ccc2C)cc(CC(C#N)=CNc2ccccc2)cc1-n1c(C)ccc1C

Procedure:
A mixture of 4.95 g. of 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methyl-α-[(methylsulfonyl)methyl]benzyl alcohol, 0.95 g. of sodium methylate and 2.16 g. of β-anilinopropionitrile in 13 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 100 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with ethyl acetate and recrystallization from ethyl acetate, there was obtained α-(anilinomethylene)-3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methylhydrocinnamonitrile, having a melting point of 252° C.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH2:5][NH:4][C:3]1=[O:7].CN(C=O)C.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:3](=[O:7])[CH:2]([CH3:1])[S:6][CH2:5]1
Reactant: CC1SCNC1=O
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1SCN(CCCCBr)C1=O
Reaction time: 3.5 h

Procedure:
To 12.35 g of 5-methyl-4-thiazolidinone placed in a 500 ml round bottom flask was added 210 ml of DMF and the mixture stirred for 3.5 h. An additional 30 ml of DMF was added and the mixture stirred for 10 minutes and thereafter 11.8 g of KOH was added all at once. The resultant solution was stirred for 0.5 h at room temperature and thereafter 38 ml of 1,4-dibromobutane was added rapidly. The mixture was stirred at room temperature overnight. After 24 hours of stirring at room temperature, the reaction mixture was poured into 600 ml of water and the resultant mixture extracted with EtOAc (2×175 ml). The combined EtOAc layers were washed successively with water (200 ml) and brine (150 ml), dried over MgSO4 and concentrated in vacuo to 49.68 g of oil. After removal of DMF by vacuum distillation, the residual oil was purified by flash chromatography (silica gel column) to obtain the desired product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: CN(C)c1cccc(CO)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(N(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [3-(dimethylamino)phenyl]methanol (95 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (119 mg, yield: 76%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C@H:10]4[CH2:14][CH2:15][CH2:16][C@@H:9]34)=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Reactant: C#Cc1cccc(F)c1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2cccc(F)c2)cn1
Yield: 96 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (107 mg, 0.326 mmol) (Example 1, step 6) and 1-ethynyl-3-fluorobenzene to yield 100 mg (96%) of the title compound as a viscous yellow oil; MS: m/e=321.2 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@H:15]3[CH2:22][CH2:21][C:18]4([CH2:20][CH2:19]4)[CH2:17][C@@H:16]3[C:23]([OH:25])=O)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.NO.F[P-](F)(F)(F)(F)F.[N:36]1([O:45][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:45][NH:36][C:23]([C@@H:16]1[C@@H:15]([C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:14])[CH2:22][CH2:21][C:18]2([CH2:19][CH2:20]2)[CH2:17]1)=[O:25]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NO)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
The product from step 9 (36 mg, 0.105 mmole), and hydroxylamine hydrochloride (22 mg, 0.315 mmole) were dissolved in DMF (0.70 ml). To the solution, BOP (49 mg, 0.11 mmole) was added with stirring at r.t. for 10 min. DIEA (61 mg, 0.47 mmole) was added. The mixture was stirred at r.t. for 2 hours. The product was purified with preparative HPLC providing 22 mg of (5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5) octane-5-carboxamide. Yield: 44%. MS: M/Z 358.2 (M+H)+; 380.2 (M+Na)+; 737.2 (2M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:16]([C:18]#[N:19])[Na].C(C(O)=O)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:18]([NH2:19])=[O:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Nc2ccc(F)cc2)cc1
Reactant: N#CO[Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Di(p-fluorophenyl)amine (102.5 g., 0.5 mole) and NaOCN (65 g, 1.0 mole) were stirred in 700 ml CH2Cl2 at 16° C. F3CCOOH (84.5 ml, 117 g, 1.025 mole) was added as a thin stream over 5 minutes, during which the reaction mixture exothermed to 28° C. The exotherm peaked at 32° C. shortly after addition was complete. The reaction mixture was stirred at 23°-25° for 21 hours, diluted with 350 ml H2O and stirred 0.5 hour. The organic layer was separated and stirred 0.25 hour with 40 g NaOH in 500 ml H2O. The layers were separated, and the aqueous layer back washed with 100 ml CH2Cl2. The combined organic layer and back wash was dried (MgSO4), concentrated to 600 ml, diluted with 600 ml isopropanol, reconcentrated to 600 ml, rediluted with 600 ml of fresh isopropanol, reconcentrated to 800 ml, rediluted with 400 ml fresh isopropanol and again reconcentrated to 800 ml. The mixture was cooled to room temperature (product began to crystallize) and then to 0°-5° C. Title product was recovered by filtration, 104.9 g, m.p. 150°-153° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([O:23]CC)=[O:22])[C:5]2=[O:26].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)c(C)c2c1=O
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 69.5 %

Procedure:
A solution of 0.76 g (2.00 mmol) of ethyl 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 0.69 g (8.00 mmol) of anhydrous piperazine, and 30 ml of acetonitrile was refluxed for 18 hours, cooled, and concentrated. The residue was dissolved in 20 ml 6N hydrochloric acid and refluxed for three hours. The suspension was cooled, concentrated by half and filtered, and the solids were washed with water. The crude product was suspended in water which was made basic (pH 12), filtered, and neutralized to pH 6.8. The precipitate was filtered and neutralized to pH 6.8. The precipitate was filtered, washed with water, and dried to give 0.58 g of the title compound, mp 198°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 75.5 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl4-hydroxy-phenyl)-methanone (0.203 g, 0.448 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.319 g,1.34 mmol). Purification on Dynamax C18 (85% CH3CNIH20) gave 0.221 g (49%) of the title compound as a brown solid, mp 188-192° C. 1H NMR (DMSO-d6) δ1.26-1.32 (m, 2 H), 1.49-1.57 (m, 2 H), 1.64-1.74 (m, 4 H), 1.77 (s, 3 H), 2.18 (s, 3 H), 2.96 (quintet, 1 H), 3,79 (s, 2 H), 6.96 (d, 2 H), 7.23 (d, 1 H), 7.36 -7.43 (m, 4 H), 7.53-7.56 (m, 2 H), 8.00 (d, 1 H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 651 (M−H). Anal. Calcd. for C32H29BrO8S: C, 58.81; H, 4.47; N, 0.00. Found: C, 58.45; H. 4.54; N, 0.07.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[Cl:32][C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[C:38]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[CH:12]=[C:13]([O:15][S:16]([C:19]([F:22])([F:20])[F:21])(=[O:17])=[O:18])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 26, step (c)) under the conditions described in Example 26, step (d-f)) using 4-chloro-5-trifluoromethylphenylboronic acid in step (d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I.O>CN(C)C=O.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
To the solution of 52 g of ethyl 4-nitrophenylacetate in 350 ml dimethylformamide-toluene (1:1), 9.5 g of 50% sodium hydride in mineral oil are added portionwise while stirring and cooling, After 11/2 hours stirring at room temperature, 26 g methyl iodide are added dropwise and the mixture is stirred overnight at room temperature. The mixture is carefully combined with water, extracted with diethyl ether, the extract dried, filtered and evaporated. The residue is taken up in 100 ml ethanol, the solution seeded with a few crystals starting material and allowed to stand in the cold. The precipitate formed is filtered off and the filtrate evaporated, to yield the ethyl α-(4-nitrophenyl)-propionate.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]([CH2:14][CH2:15][CH3:16])[C@H](O)C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-:25].[Na+].[C:27]([O:30]CC)(=[O:29])[CH3:28].CCCCCC>>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:14][CH2:15][CH3:16])[C@H:28]([OH:25])[C:27]([OH:30])=[O:29])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC[C@@H]([C@H](O)C#N)N(Cc1ccccc1)Cc1ccccc1
Reactant: [OH-]
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Product: CCC[C@@H]([C@H](O)C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 100 °C
Yield: 96 %

Procedure:
To (2S,3S)-3-(dibenzylamino)-2-hydroxyhexanenitrile (93.0 g; 0.301 mol) was added 12N hydrochloric acid (465 mL). The resulting mixture was heated to reflux (100° C.) for 3 hours, monitoring progress of the reaction by TLC analysis (ethyl acetate/hexane, 1:1). After TLC analysis indicated that the reaction was complete, the reaction mixture was cooled, and the pH was adjusted to 6-7 using 6N aqueous sodium hydroxide solution (930 mL). The product was extracted with two portions of dichloromethane (2×700 mL), and the combined organic phases were dried over sodium sulfate. After filtration the solvent was removed under reduced pressure, to give 95.0 g (96%) of (2S,3S)-3-(dibenzylamino)-2-hydroxyhexanoic acid as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:45])[NH:31][CH:32]([C:34](=[O:44])[NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([NH2:43])[N:37]=1)[CH3:33])([CH3:28])([CH3:27])[CH3:26].[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52](O)=[O:53].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:45])[NH:31][CH:32]([C:34](=[O:44])[NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([NH:43][C:52]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][N:46]=2)=[O:53])[N:37]=1)[CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(N)n1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (180 mg, 0.47 mmol) is added to a mixture of tert-butyl-N-{1-[(6-amino-4-chloropyridin-2-yl)carbamoyl]ethyl}carbamate J8 (100 mg, 0.32 mmol), pyridine-2-carboxylic acid (60 mg, 0.49 mmol) and DIPEA in NMP (1.5 ml) and the mixture is stirred at RT for 2 h and stirring continued at 50° C. for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 27 mg (20%). HPLC-MS: M+H=420 (Method—2).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:15])([F:14])[CH:8]([OH:13])[C:9](F)([F:11])[F:10].Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23].Cl.[OH-:25].[Na+]>CCCCCC.O1CCCC1>[F:10][C:9]1([F:11])[C:18]2([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]2[O:13][C:8]1([C:7]([F:15])([F:14])[F:6])[OH:25]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: [OH-]
Reactant: O=C1CCCCC1Br
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC12CCCCC1OC(O)(C(F)(F)F)C2(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
In a nitrogen atmosphere at −5° C., 260 ml of 2.6M n-butyllithium in hexane was added to a mixture of 58 g of 1,1,1,3,3,3-hexafluoro-2-propanol and 260 g of tetrahydrofuran, followed by one hour of stirring at 5° C. Then 59 g of 2-bromocyclohexanone was added at 5° C. The mixture was stirred for 10 hours, after which dilute hydrochloric acid was added to quench the reaction and neutralize the reaction mixture. Then 310 g of a 10% aqueous solution of sodium hydroxide was added to the reaction mixture, from which an aqueous layer was separated. It was made acidic by adding 150 g of 20% dilute hydrochloric acid and combined with 250 g of toluene, after which separatory operation was performed to separate an organic layer. The organic layer was concentrated and purified by recrystallization from hexane, obtaining 58 g of the product (yield 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:40][OH:41]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:40][OH:41])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Yield: 66.2 %

Procedure:
(3R)-3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from (3R)-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (3.48 g, 9.79 mmol), carbonyldiimidazole (1.91 g, 11.8 mmol) and hydroxylamine hydrochloride (0.95 g, 13.7 mmol) in tetrahydrofuran (10 mL) to afford (3R)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide as a white solid (2.4 g, 69% yield): mp, 183.5–184.5° C.; 1H NMR (DMSO-d6) δ 1.29 (t, J=6.9 Hz, 3H, CH3) 2.81–2.86 (m, 2H, CH2), 3.72 (s, 3H, CH3), 3.96–4.04 (m, 2H, CH2), 4.13 (d, J=17.5 Hz, 1H, CHH), 4.54 (d, J=17.5 Hz, 1H, NCHH), 5.73 (t, J=7.9 Hz, 1H, NCH), 6.84–6.92 (m, 3H, Ar), 7.43–7.68 (m, 4H, Ar), 8.83 (br.s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.68, 35.04, 46.22, 51.20, 55.44, 63.73, 111.85, 112.19, 119.21, 122.78, 123.43, 127.83, 131.29, 131.85, 132.27, 141.67, 147.85, 148.42, 165.99, 166.82. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C, 64.82; H, 5.95; N, 7.47.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=O.Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C=CC=CC=1>C(O)C>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][N:23]=[C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=2)[CH3:1])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1F
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(C)=NOCc2ccc([N+](=O)[O-])cc2)cc1F
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A solution of 3-fluoro-4-methoxyacetophenone (0.064 g, 0.380 mmol), O-(4-nitrobenzyl)hydroxylamine hydrochloride (0.111 g, 0.552 mmol) and pyridine (0.14 ml, 1.73 mmol) in ethanol (7 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a yellow oil which was diluted with water/dichloromethane. The suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a yellow oil. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a yellow oil which was triturated with petrol, and the resultant off white solid was further washed with petrol to give 3′-fluoro-4′-methoxyacetophenone-O-4-nitrobenzyloxime (CP9-123) as a white solid (0.079 g, 65%), m.p. 67-68°.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:56][CH2:57][CH3:58])=[CH:46][C:47]=3[O:49][CH2:50][C@H:51]3[CH2:55][CH2:54][CH2:53][NH:52]3)[N:42]=[CH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[F:37].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CS(C)=O>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][C:45]([O:56][CH2:57][CH3:58])=[CH:46][C:47]=2[O:49][CH2:50][C@H:51]2[CH2:55][CH2:54][CH2:53][N:52]2[C:1](=[O:5])[CH2:2][OH:3])[N:42]=[CH:41][N:40]=1
Reactant: O=C(O)CO
Reactant: CCOc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 16 h
Yield: 39 %

Procedure:
Glycolic acid (22 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 110 mg) were added sequentially, each in one portion, to a stirred solution of N-(3-chloro-4-fluorophenyl)-7-ethoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (81 mg) and N,N-diisopropylethylamine (68 μl) in DCM (2.5 ml) at room temperature. The reaction mixture was stirred for 16 hours and then concentrated in vacuo to leave a brown residue. The residue was taken up in a 7:2:1 mixture of DMSO:acetonitrile:water, filtered and then purified by reverse phase HPLC. The fractions containing the required product were combined, basified by the addition of potassium carbonate and then extracted with DCM. The organic layer was dried (MgSO4) and then concentrated in vacuo to give the title compound as a white solid (36 mg, 39%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.50-3.40 (m, 2H), 2.10-1.85 (m, 4H), 1.40 (t, 3H); Mass spectrum MH+ 475.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[C:29]([O:33][C:34](=[O:38])[C@H:35]([CH3:37])[NH2:36])([CH3:32])([CH3:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:36][C@@H:35]([CH3:37])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:38]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: C[C@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (105.5 mg, 0.282 mmol) and L-alanine tert-butyl ester hydrochloride (51.2 mg, 0.282 mmol) according to Reference R and the general procedure for reductive amination to give (S)-tert-butyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)propanoate as a yellow-orange solid. MS (ESI) m/z: Calculated: 503.2; Observed: 503.8 (M++1).