Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4].Cl.[CH3:26][NH:27][O:28][CH3:29].C([Mg]Cl)(C)C>C1COCC1>[CH3:29][O:28][N:27]([CH3:26])[C:3]([C@H:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C@H:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]
Reactant: CNOC
Reactant: COCOc1ccc(OCOC)c(C2CC(C)CC2C(=O)OC)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COCOc1ccc(OCOC)c([C@@H]2C[C@H](C)C[C@@H]2C(=O)N(C)OC)c1
Yield: 95.8 %

Procedure:
Cool a suspension of 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methyl ester (2.4 g, 7.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.2 mmol) in anhydrous THF (60 mL) to −10° C. in an NaCl/ice bath. Add isopropyl magnesium chloride (2.0 M in THF, 14.2 mL, 28.4 mmol) and stir the reaction for 30 min. Quench the reaction with saturated ammonium chloride. Add EtOAc and wash with brine. Dry the organic solution (Na2SO4), filter and concentrate in vacuo to yield 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methoxy-methyl-amide 9a (2.5 g, 6.8 mmol, 96%) as a pale yellow oil. 1H NMR (δ, 400 MHz, CDCl3): 6.95 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=3.0 Hz), 6.79 (dd, 1H, J=8.8, 3.0 Hz), 5.16-5.03 (m, 4H), 3.80 (m, 1H), 3.64 (m, 1H), 3.50 (s, 3H), 3.46 (s, 3H), 3.43 (s, 3H), 2.74 (s, 3H), 2.13-2.05 (m, 2H), 1.95-1.79 (m, 3H), 1.19 (d, 3H, J=6.2 Hz). HRMS calcd. 368.2073; found (electrospray, M+1) 368.2065.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])C1C=CC=CC=1.C1CCCCC=1.Cl>C1COCC1.[C].[Pd]>[OH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)[C@@H](COCc1ccccc1)Cc1cccc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1=CCCCC1
Product: O=C(O)[C@@H](CO)Cc1cccc2ccccc12

Procedure:
(2R)-3-benzyloxy-2-(1-naphthylmethyl)propionic acid was dissolved in 6 ml of THF, and 3 ml of cyclohexene, 2.5 ml of 1N hydrochloric acid and 400 mg of 10% palladium carbon were added thereto. The mixture was refluxed under heating for 48 hours. After filtration, the solvent was distilled off under reduced pressure, and the residue was divided with ethyl acetate and a 4% sodium hydrogencarbonate aqueous solution. The aqueous layer was adjusted to pH2 with 1N hydrochloric acid under cooling with ice and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydride sodium sulfate to obtain 212 mg of (2R)-3-hydroxy-2-(1-naphthylmethyl)propionic acid as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([CH2:34]Br)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([CH2:34][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(CBr)cn1
Product: COC(=O)c1cnc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and 5-bromomethyl-pyrazine-2-carboxylic acid methyl ester [CAS Reg. No. 193966-70-0]. MS (m/e)=516.3 [MH+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CC(C)C(=O)c1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.9 %

Procedure:
2-Bromoethylbenzene (10.0 g, 0.0540 mol) is mixed with 6.6 g (0.062 mol) of isobutyryl chloride and 100 ml of 1,2-dichlorobenzene. The mixture is cooled internally to 0° C., and 9.4 g (0.070 mol) of aluminum chloride is added portion wise over 3 hours while keeping the reaction mixture at 0-5° C. The reaction mixture is stirred overnight, then poured into a mixture of ice and concentrated hydrochloric acid. After stirring for 30 minutes, the organic layer is washed with dilute hydrochloric acid, sodium bicarbonate solution, and water, then dried over sodium sulfate and concentrated to give 15.0 g of crude 1-[4-(2-bromoethyl)phenyl]-2-methylpropan-1-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22]([C:24]1[S:28][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[NH:35][CH2:36][CH2:37][N:38]=2)=[N:26][N:25]=1)=[O:23])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22]([C:24]1[S:28][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[NH:35][CH2:36][CH2:37][N:38]=2)=[N:26][N:25]=1)=[O:23])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1nnc(CCCCNC2=NCCN2)s1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](CNC(=O)c1nnc(CCCCNC2=NCCN2)s1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
t-Butyl 2(S)-benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate (100 mg, 0.18 mmol) was dissolved in CH2Cl2 containg 0.25 mL of TFA. The solution was stirred at rt for 24 hrs. Concentration gave the product(80 mg, 89% yield). 1H NMR(300 MHz, DMSO-d6)δ1.56(m, 2H), 1.86(m, 2H), 3.18(m, 4H), 3.54(m, 1H), 3.58(s, 4H), 3.66(m, 1H), 4.10(m, 1H), 5.00(s, 2H), 7.30(m, 5H), 7.76(d, 1H), 8.16(t, 1H), 9.10(t, 1H); MS(ESI) Calc. for (M+1)+ : 491. Found: 491.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)=[CH:3][CH:4]=2)[NH:8]1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Cc2ccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.5 %

Procedure:
6-bromoindolin-2-one (25.2 mg, 0.119 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (72.1 mg, 0.190 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.4 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3×10 ml) and EtOAc (6×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (7.1 mg, 16%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([Cl:11])[C:13]=2[F:20])/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: N#CCc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Br)cc1
Yield: 100.8 %

Procedure:
In a manner similar to the method described in Example 1b, 4-bromophenylacetonitrile (Aldrich) (4.5 g, 23 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.2 g, 33 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (150 mL) at 50° C. for 3 h to give (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (7.8 g, 100%).
Reaction SMILES: [O-2].[Mg+2].[CH:3](O)=[O:4].C(OC(=O)C)(=O)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]([OH:18])=O.C(O)(C)C>>[CH:3]([NH:13][C@@H:14]1[C:19](=[O:20])[O:21][C:16](=[O:18])[CH2:15]1)=[O:4]
Reactant: O=CO
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: O=CN[C@H]1CC(=O)OC1=O
Reaction time: 2.5 h

Procedure:
0.12 grams (0.003 mole) of magnesium oxide, a catalyst, was dissolved in 16 milliliters (ml) (0.405 mole) of 95% formic acid. 60.2 ml of acetic anhydride was then added to the aforementioned solution which was heated to 35°-40° C. for 10-15 minutes. Subsequently, 39.93 grams (0.3 mole) of L-aspartic acid was added and this mixture was stirred for 2.5 hours at 50°±2° C. At this point, an additional 8.6 ml of acetic anhydride was added and the reaction continued for an additional 2.5 hours at 50°±2° C. 9.2 ml (0.120 mole) of isopropyl alcohol was then added to the reaction mixture and heating was continued for an additional two hours. N-formyl-L-aspartic anhydride was formed at this point as shown by high performance liquid chromatography (HPLC).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=O)[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:64]([N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)([CH3:67])([CH3:66])[CH3:65]>>[C:64]([N:68]1[CH2:73][CH2:72][N:71]([C:22]([C:19]2[N:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:24])[CH2:70][CH2:69]1)([CH3:67])([CH3:66])[CH3:65]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ncc1OCC2
Reactant: CC(C)(C)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)N3CCN(C(C)(C)C)CC3)ncc1OCC2
Reaction time: 0.17 h

Procedure:
[2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carboxylic acid (0.140 g, 0.411 mmol) was dissolved in N,N-Dimethylformamide (3.18 mL, 0.0411 mol) at room temperature. N,N-Diisopropylethylamine (0.287 mL, 0.00164 mol) was added followed by N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.172 g, 0.452 mmol). The suspension was stirred for 10 minutes. 1-tert-butylpiperazine (0.0878 g, 0.617 mmol) was added and the reaction mixture was stirred for 1 hour. LCMS shows complete conversion to product. The reaction mixture was concentrated to dryness and was purified by reversed phase HPLC to give 203. 1H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.94 (s, 1H), 5.76 (dt, J=13.2, 6.6 Hz, 1H), 4.64 (s, 4H), 3.56 (br d, J=48.6 Hz, 8H), 1.49 (d, J=6.6 Hz, 6H), 1.02 (s, 9H). LCMS 465.3.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)(=O)C.[CH2:10]([C:12]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH2:30][N:31]([CH2:33][CH3:34])[CH3:32])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:35])[C:13]=1[OH:36])C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:33]([N:31]([CH2:30][C:25]1[CH:24]=[C:23]([C:21]2[O:20][N:19]=[C:18]([C:16]3[CH:15]=[C:14]([CH3:35])[C:13]([O:36][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[C:12]([CH3:10])[CH:17]=3)[N:22]=2)[CH:28]=[C:27]([CH3:29])[CH:26]=1)[CH3:32])[CH3:34]
Reactant: CCc1cc(-c2noc(-c3cc(C)cc(CN(C)CC)c3)n2)cc(C)c1O
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)Cc1cc(C)cc(-c2nc(-c3cc(C)c(OCCCCO)c(C)c3)no2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-bromobutyl acetate (186 mg, 936 μmol) was added to a suspension of 2-ethyl-4-(5-{3-[(ethyl-methyl-amino)-methyl]-5-methyl-phenyl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenol (114 mg, 312 μmol) and K2CO3 (129 mg, 936 μmol) in acetonitrile (2 mL). The mixture was stirred at 70° C. for 2 h before it was filtered. The filtrate was diluted with 25% aq. ammonia (0.5 mL) and a 32% aq. NaOH solution (300 μL) and the bi-phasic mixture was stirred at 70° C. for 2 h. The aq. phase was separated and 1N aq. NaOH (0.4 mL) was added. The now homogenous mixture was separated by prep. HPLC (XBridge 30×75 mm, eluting with a gradient of MeCN in water containing 0.5% of sat. aq. ammonia) to give the title compound as a white lyophilisate (53 mg). LC-MS: tR=0.65 min; [M+1]+=438.25; 1H NMR (D6-DMSO): δ 1.06 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.61-1.69 (m, 2H), 1.78-1.86 (m, 2H), 2.15 (s, 3H), 2.34 (s, 3H), 2.41-2.48 (m, 5H), 2.71 (q, J=7.5 Hz, 2H), 3.47-3.53 (m, 2H), 3.55 (s, 2H), 3.81-3.86 (m, 2H), 4.47 (br s, 1H), 7.47 (s, 1H), 7.80 (s, 2H), 7.90 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)C>[CH3:10][N:4]1[C:5]([N:24]2[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]2)=[C:6]([N+:7]([O-:9])=[O:8])[CH:2]=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])c(Cl)n1
Reactant: Oc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(O)CC1
Temperature: 130 °C
Yield: 104.6 %

Procedure:
To a solution of 3-chloro-1-methyl-4-nitro-1H-pyrazole (1.0 g, 6.17 mmol) in ethanol (10 mL) was added DIPEA (2 mL, 11.4 mmol) followed by 4-hydroxypyridine (686 mg, 6.79 mmol). The reaction mixture was heated at 130° C. in the microwave for 60 min before the solvents were removed under reduced pressure. Purification of the residue via silica gel column chromatography (75-100% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-ol as a bright yellow oil (1.46 g). To a solution of this oil (1.40 g, 6.17 mmol) in DCM (40 mL) was added portionwise Dess-Martin periodinane (3.1 g, 7.41 mmol). The reaction mixture was stirred at room temperature for 3 hr, diluted with DCM (100 mL) and washed with saturated aqueous sodium hydrogencarbonate (30 mL), followed by saturated aqueous sodium thiosulphate (30 mL), saturated aqueous sodium hydrogencarbonate (30 mL) and brine (30 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (50-75% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.32 g, 95% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 3.86 (s, 3H), 3.54 (t, J=6.0 Hz, 4H), 2.65 (t, J=6.0 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:27]=1.C1COCC1.[OH-].[K+].Cl>C(O)C>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH:27]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc2[nH]c(COc3cccc(OCC4CCOCC4)c3)c(C)c(=O)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)[nH]c2ccc(-c3ccccc3C(=O)O)cc2c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 68.9 %

Procedure:
To an ice-cold suspension of ethyl 3-methyl-4-oxo-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}-1,4-dihydroquinoline-6-benzoate (158 mg) in ethanol (5.0 mL)-THF (3.0 mL) was added dropwise a 4M aqueous potassium hydroxide solution (0.18 mL), and the mixture was stirred at 65° C. for 15 hours. The reaction mixture was ice-cooled, and adjusted to a pH of 7 by adding 1M hydrochloric acid. The resulting solid was collected by filtration, washed with water, and dried to obtain 3-methyl-4-oxo-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}-1,4-dihydroquinoline-6-benzoic acid (103 mg).
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=[O:10])[NH:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: O=c1[nH]sc2ncccc12
Product: CC1CCN(C(=O)Oc2nsc3ncccc23)CC1

Procedure:
In analogy to example 1, 60 mg (0.4 mmol) of isothiazolo[5,4-b]pyridin-3-one were reacted with 76 mg (0.47 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 29 mg (27%), M+H+: 278.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([CH2:14][O:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:11][C:10]1=[O:35].C(=O)(O)[O-].[Na+]>ClCCl.CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]1=[O:35]
Reactant: O=C1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Reaction time: 8 h
Yield: 44 %

Procedure:
Redissolve (3R,5S)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-trityloxymethyl-dihydro-furan-2-one in 30 mL of dichloromethane and 50 mL of methanol containing 0.5 mL of concentrate HCl. Stir the mixture overnight and neutralize with aqueous sodium bicarbonate. Most of the methanol and dichloromethane are removed. Extract the product with ethyl acetate. Wash the organic layers with water and then brine. Evaporate the solvent and chromatograph the product on flash silica gel using 5 to 25% acetone in methylene chloride. Evaporate the product containing fractions and recrystallize from ethyl acetate and heptane to afford 2.5 g (44% yield) of (3R,5S)-3-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxymethyl-dihydro-furan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](OC(OCC)OCC)C>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc(F)cc1
Product: Fc1ccc(-c2nnco2)cc1
Yield: 57 %

Procedure:
A stirred solution of 4-fluorobenzohydrazide (4.2 g, 27.2 mmol) in triethylorthoformate (27 mL) was heated at 140° C. for 5 h. The reaction was evaporated under reduced pressure. The crude was purified by silica gel column chromatography (100-200 mesh; using 12% ethyl acetate in hexane) to afford 2-(4-fluorophenyl)-1,3,4-oxadiazole [Polshettiwar, Tetrahedron Letters, 49:879-883 (2008)] as off-white solid (2.5 g, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.08 (dd, 2H), 7.19 (dd, 2H); LC-MS m/z calculated for [M+H]+ 165.04. found 165.00.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=3[S:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C1NCCc2scc(Br)c21
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2scc(-c3ccc(F)cc3)c21
Yield: 93.8 %

Procedure:
Using analogous reaction conditions and workup as described in Example 3, step 5, 3-bromo-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-15b: 300 mg, 1.293 mmol) was reacted with (4-fluoro-phenyl)-dihydroxy-borane (217.11 mg, 1.55 mmol), Pd(PPh3)4 (149.4 mg, 0.1293 mmol), toluene (20 mL) and water (3 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 300 mg of the product (47.02% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH2:38]([O:45][CH2:46][N:47]1[N:51]=[N:50][C:49]([Sn](CCCC)(CCCC)CCCC)=[N:48]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:49]3[N:50]=[N:51][N:47]([CH2:46][O:45][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:48]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn(COCc5ccccc5)n4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and (2-benzyloxymethyl-2H-tetrazol-5-yl)trin-butyltin (see Tetrahedron Lett. (2000) 2805) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene as colorless solid. APCI-Mass m/Z 727/729 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH2:29]2.C(O)(=O)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH:29]2[C:10](=[O:12])[C:7]1[S:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: COC(=O)c1csc(C(=O)O)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the procedure of Example 55. To a solution of 1.50 g (8.06 mmoles) of 4-methoxycarbonyl-2-thiophenecarboxylic acid (prepared as described in Example 9) in 15 ml of N,N-dimethylformamide was added 1.57 g (9.67 mmoles) of 1,1'-carbonyldiimidazole. After two hours the reaction contents were slowly added to 1.54 g (7.32 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 2.66 g (21.75 mmoles) of 4-(N,N-dimethylamino)pyridine in N,N-dimethylformamide. Acidic workup of this reaction followed by filtration, drying and trituration with hot acetic acid furnished 1.88 g (4.97 mmoles, 68% yield) of title compound as a yellow solid, m.p. 244°-246° C.