Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ncccc4C(F)(F)F)cc3)C2=N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of 5-chloro-3-(4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyridin-2-amine (450 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 246 mg) and 2-chloroethanesulfonyl chloride (602 mg) in THF (dry) (10.0 mL) at room temperature. The mixture was stirred at 70° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (315 mg) as a white solid. The solid was crystallized from CH3CN—IPE to give a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([O:13]C(=O)C(C)=C)[CH2:9][CH:10](C)C)[C:3]([O:5][CH2:6]C)=[O:4].CO.[C:22](=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[F:19][C:2]([F:1])([CH:8]([OH:13])[CH:9]([CH3:10])[CH3:22])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C([O-])O
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(F)(F)C(O)C(C)C
Yield: 85 %

Procedure:
To a mixture of 50 g of Intermediate 2 (Example 2), 200 g of methanol and 250 g of benzene was added 0.3 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with hexane. The hexane solution was washed, dried, and concentrated, obtaining 45.78 g (yield 85%) of methyl 2,2-difluoro-3-hydroxy-4-methylpentanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:16][CH2:15][C:12]2[N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[O:14][N:13]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NCc1noc(-c2cc3cnccc3o2)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNCc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 72 h

Procedure:
A solution of C-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)methylamine (Preparation 14, 50 mg, 0.23 mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (59 mg, 0.27 mmol) in anhydrous CH2Cl2 (5 mL) was stirred for 45 min. Na(AcO)3BH (78 mg, 0.37 mmol) was added, then the mixture was stirred for 3 d. Standard aqueous work-up, followed by column chromatography (EtOAc), gave the title compound: RT=2.18 min; m/z (ES+)=414.1 [M+H]+.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)C=C.CCCCC.C([Li])(C)(C)C.[CH:22]([C:24]1[CH:33]=[CH:32][C:27](C(OC)=O)=[CH:26][C:25]=1O)=[O:23].[Cl-].[NH4+]>O1CCCC1.O>[C:24]1([CH:22]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[OH:23])[CH:33]=[CH:32][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Reactant: C=CCOc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 108.8 %

Procedure:
To a solution of 1-allyloxy-4-bromobenzene (3.1 g) in tetrahydrofuran (70 mL) was added 1.45 mol/L tert-butyllithium n-pentane solution (11 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 5 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.89 g) in tetrahydrofuran (15 mL) was added to the reaction mixture. After the mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give a diphenylmethanol compound (0.99 g). The obtained diphenylmethanol compound (0.99 g) was dissolved in methanol (10 mL), and 10% palladium-carbon powder (0.30 g) was added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate (0.50 g).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[ClH:14].[NH2:1][C@H:2]([C:9]([O:11][CH3:16])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: COC(=O)[C@@H](N)Cc1c[nH]cn1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution (ice-bath) of L-histidine (38.75 g, 240 mmol) in methanol (500 ml), thionyl chloride (27.2 ml, 375 mmol) was added in drops. After fifteen minutes the ice bath was removed and the reaction mixture was stirred at room temperature for one hour. Then after refluxing for 48 hours, it was concentrated in vacuo. The separated crystals were filtered using methanol for washing (48.93 g). The methanolic solution on dilution with ether afforded additional 10 g of the title K compound, m.p. 208°-209°.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCOc1ccc2c(c1)[nH]c1ccccc12)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.1 mmol) was reacted with 2-hydroxy-9H-carbazol (0.3 g, 1.1 mmol) in the presence of potassium carbonate (0.15 g, 1.1 mmol) and DMF as solvent to give 8-(9H-carbazol-2-yloxy)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.1 g, 20%; purified by column chromatography using silica gel and ethyl acetate as eluent). MS (M+H+)=483.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH2:34][CH2:35][CH3:36])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CCCNCC
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.84 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.82(s, 1H), 3.32-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]3[CH2:35][C@H:34]4[C@:36]5([CH2:40][N:39]([CH2:41][C:42]([F:45])([F:44])[F:43])[S:38](=[O:47])(=[O:46])[NH:37]5)[C@H:31]([CH2:32][CH2:33]4)[CH2:30][C:29]=3[CH:48]=2)O1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:5]2[CH:6]=[C:2]([C:25]3[CH:26]=[CH:27][C:28]4[CH2:35][C@H:34]5[C@:36]6([CH2:40][N:39]([CH2:41][C:42]([F:45])([F:44])[F:43])[S:38](=[O:46])(=[O:47])[NH:37]6)[C@H:31]([CH2:32][CH2:33]5)[CH2:30][C:29]=4[CH:48]=3)[N:3]=[CH:4]2)=[CH:10][CH:9]=1
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(Cl)cc4)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 4-chlorophenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2. δ (1H, 500 MHz, CDCl3) 1.34-1.42 (2H, m), 1.68-1.75 (2H, m), 2.42-2.50 (2H, m), 2.70-2.82 (2H, m), 3.20-3.28 (2H, m), 3.44 (2H, s), 3.68 (2H, q, J=8.7 Hz), 4.68 (1H, s), 7.12 (1H, d, J=7.8 Hz), 7.38 (2H, d, J=8.7 Hz), 7.47-7.51 (3H, m), 7.56 (1H, d, J=7.8 Hz), 7.62 (1H, s), 7.86 (1H, s). MS (ES+) 537, 539 ([MH]+).
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-].[Cl-].[Ca+2].C(Cl)Cl>C(O)CCC.O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]=[C:10]1[C:9]2[C:3](=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=2[OH:12])[C:1](=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:2]1
Reactant: Nc1ccccn1
Reactant: N#Cc1c(O)ccc(O)c1C#N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCCCO
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(O)c2c1C(=Nc1ccccn1)NC2=Nc1ccccn1
Temperature: -40 °C
Reaction time: 480 h

Procedure:
A solution of 1.0 g (6.24 mmol) 2,3-dicyanohydroquinone, 1.23 g (13.11 mmol) 2-aminopyridine and 0.14 g (1.3 mmol) CaCl2 in 20 ml 1-butanol was refluxed under N2. Despite the presents of fluorescent blue 2,3-dicyanohydroquinone starting material, as observed by TLC (CH2Cl2), the reaction was discontinued after 20 days. The reaction mixture was poured into 500 mL of H2O. The precipitate was collected by filtration and was washed with water until no blue fluorescents was observed from the filtrate. The precipitate was then dissolved in boiling CH2Cl2 and then cooled to −40° C. overnight. Precipitate was then collected by filtration and washed with MeOH. 0.485 g (24%), yellow needles. MS (Maldi-TOF): m/z=331.85. HRMS-FAB (m/z): [M+H]+ calcd for C18H14N5O2, 332.1142; found, 332.1136. 1H NMR (400 MHz, CDCl3), δ 13.3 (s, 1H), 8.57 (ddd, J=4.8, 2.0, 0.8 Hz, 2H), 7.75 (ddd, J=8.0, 7.6, 2.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.11 (ddd, J=7.6, 4.8, 0.8 Hz, 2H), 7.00 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 159.3, 154.9, 149.0, 147.9, 147.9, 138.1, 122.4, 121.4, 120.4, 116.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C([C:32](=[N:38]OC(N(C)C)=[N+](C)C)[C:33](OCC)=[O:34])#N.C(CN)O>CN(C)C=O>[OH:34][CH2:33][CH2:32][NH:38][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: NCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCCO

Procedure:
Ethyl 3-[2-(2-hydroxyethylcarbamoyl)phenyl]-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine and 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide, and a second solution consisting of 306 mg (5.0 mmol) of ethanolamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.14 g of ethyl 3-[2-(2-hydroxyethylcarbamoyl)phenyl]-2-methacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>C(Cl)Cl>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:10]([C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 15 h
Yield: 81.9 %

Procedure:
To a stirring anhydrous DCM (3.5 mL) solution of trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.096 ml, 0.56 mmol), which is commercially available from, for example, Sigma-Aldrich Corporation (P.O. Box 14508, St. Louis, Mo. 63178), under an argon (g) atmosphere was added the 1-isopropylpiperazine (0.167 ml, 1. 17 mmol), which is commercially available from, for example, Sigma-Aldrich, in one portion at ambient temperature, wherein the reaction was allowed to stir for ca. 15 h before being washed with dilute aq. K2CO3 (1×2 mL), H2O (2×2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting gum was subjected to flash chromatography (basic alumina-24 g; gradient elution: 30-10% EtOAc/Hexane over 14 min at 30 mL/min) to give 125 mg title compound as a colorless tacky solid (82% yield). m/z (ES+) M+1=273.2; HPLC tR=1.44 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7. 10 (d, J=7.0 Hz, 2H), 3.68-3.55 (m, 4H), 2.70 (ddd, J=12.9, 6.7, 6.6 Hz, 1H), 2.54-2.43 (m, 5H), 1.96 (ddd, J=8.4, 5.3, 4.3 Hz, 1H), 1.65 (ddd, J=9.2, 5.3, 4.3 Hz, 1H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 1.03 (d, J=6.7 Hz, 6H).
Reaction SMILES: O.[C:2]1(C)[CH:7]=CC(S(O)(=O)=O)=C[CH:3]=1.O.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.CC(C)=O>C1C=CC=CC=1>[CH3:3][C:2]1([CH3:7])[C:22]2=[CH:23][CH:24]=[CH:25][N:21]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Oc1ccccc1-n1cccc1
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)Oc2ccccc2-n2cccc21

Procedure:
p-Toluenesulfonic acid monohydrate (110 mg) is dissolved in 70 ml of dry benzene and the solution heated at reflux with a water-separator for about 10 minutes. A solution of 1-(o-hydroxyphenyl)-pyrrole (1.1 g) in dry benzene (80 ml) is added, followed by 10 ml of acetone. The reaction mixture is heated at reflux with the water-separator for 15 hr, cooled, and washed with a solution of NaHCO3. The benzene solution is evaporated to dryness. The residue is subjected to chromatography on silica gel, using chloroform as eluent. Evaporation of the first portion of the eluate gives the title compound, m.p. 38° - '° C, νmaxCHCl3 1600, 1510, 1345 cm-1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=O.CCOCC>ClCCl>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CNc1ccccc1N
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(F)cc2F)nc2ccccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
N-methyl-benzene 1,2-diamine (1.22 g, 10 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was then added, and the mixture was cooled to 0° C. 2,4-Difluoro-benzoyl chloride (1.77 g, 10 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2,4-difluoro-phenyl)-1-methyl-1H-benzoimidazole (yield=1.97 g, 81%).
Reaction SMILES: CC#N.O[Li].O.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:18]([NH:20][C:21]2[S:22][C:23]([C:26]([O:28]CC)=[O:27])=[CH:24][N:25]=2)=[O:19])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>C1COCC1.O>[CH3:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[C:18]([NH:20][C:21]2[S:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][N:25]=2)=[O:19])=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ethyl 2-aminothiazole-5-carboxylate (2.21 g, 12.8 mmol) was condensed with 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 41, 1.00 g, 3.2 mmol), using the procedure described for EXAMPLE 65, to give ethyl 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylate: m/z (ES+)=508.3 [M+MeCN+H]+. LiOH.H2O (410 mg, 9.8 mmol) was added to a solution of this ester (1.44 g, 3.1 mmol) in THF—H2O (3:1, 30 mL). The mixture was stirred at 20° C. for 16 h and then at 55° C. for 24 h. The solvents were removed in vacuo, then the residue was dissolved in H2O (50 mL). The aqueous solution was washed with EtOAc (20 mL), before being acidified to pH 1 with 2M HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give a solid that was recrystallised (EtOAc-MeOH) to give the title compound: RTA=2.95 min; m/z (ES+)=480.2 [M+MeCN+H]+.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]2[C:32]3[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=3)[CH2:26][CH2:25][O:24]2)[CH2:17][CH2:16]1)[CH3:7].[C:34](Cl)(=[O:38])C(Cl)=O.[Cl-].[NH4+:41]>C1COCC1.CN(C=O)C>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]2[C:32]3[C:27](=[CH:28][C:29]([C:34]([NH2:41])=[O:38])=[CH:30][CH:31]=3)[CH2:26][CH2:25][O:24]2)[CH2:17][CH2:16]1)[CH3:7]
Reactant: [NH4+]
Reactant: CCOc1ccccc1N1CCN(CCC2OCCc3cc(Br)ccc32)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccccc1N1CCN(CCC2OCCc3cc(C(N)=O)ccc32)CC1
Reaction time: 0.08 h

Procedure:
A dry 25 ml round bottom flask is charged with THF (2 ml) and cooled to -78°. t-butyllithium in hexanes (1.6 M, 1.18 ml, 2 mmol) is added at once via syringe and stirred for 5 min. A solution of 1-(2-ethoxyphenyl)-4-[2-(6-bromoisochroman-1-yl)-ethyl]piperazine (CXXVI, EXAMPLE 126) in THF (3 ml) is added via canula, and stirred for another 10 min. Dry carbon dioxide gas is bubbled through the reaction mixture for 10 min, while maintaining the dry ice/acetone cooling bath. The reaction mixture is warmed to 20-25°. When the gas evolution stopped, oxalyl chloride (0.13 ml, 1.5 mmol) is added dropwise via syringe, followed by DMF (4 drops). After two hours of stirring, the reaction mixture is poured into ammonium chloride (40 ml), extracted two times with equal volumes of methylene chloride (which are combined), dried with sodium sulfate, filtered and concentrated. The concentrate is purified by flash chromatography (silica gel, 25 g; eluting with methanol/ethyl acetate (10/90) to give the impure product. The impurity is removed by triturating with methylene chloride and hexane to leave an oil which is converted into the hydrochloride salt using ethereal hydrochloric acid to give the title compound, mp 208-210°; HRMS Calcd for C24H31N3O3 =409.2365, found=409.2364.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O-:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:19])#[N:2].[Li+].Cl.[NH2:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([OH:38])[CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[C:24]1=[O:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH:22][C@@H:23]3[CH2:27][CH2:26][N:25]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([OH:38])[CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:39])=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)[O-])cc1F
Reactant: N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CC(=O)N[C@@H]2CCN(c3cccc4ccc(O)cc34)C2=O)cc1F

Procedure:
A mixture of lithium [1-(4-cyano-3-fluorobenzyl)-1H-imidazol-5-yl]acetate, as described above in Step D, (46 mg, 0.18 mmol), (R)-3-amino-1-(7-hydroxynaphthalen-1-yl)-2-oxopyrrolidine hydrochloride, as described in Example 10A (45 mg, 0.16 mmol), HOBT (24 mg, 0.18 mmol), EDC (35 mg, 0.18 mmol), and N,N-diisopropylethylamine (0.084 mL, 0.48 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (1 mL) and CHCl3 (2 mL). The aqueous layer was extracted further with CHCl3 (2×2 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of EtOAc—10% MeOH—1% NH4OH to EtOAc—15% MeOH—1.5% NH4OH to yield the titled product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([NH:10][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=2[F:18])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](NCc2ccc(F)cc2F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2 mmol, 1 equvi) was dissolved in dry DCM (20 ml) cooled to 0 centigrade was added 2,4-difluorobenzaldehyde (1.05 equiv), then NaBH(OAc)3 (2 equiv) and 5 drops of HOAc. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM, washed with brine, and dried over anhydrous sodium sulfate. After removal of solvent, the crude product was used for the next step without further purification. MS m/e=371.4 [M+H]+.