Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[OH-].[NH4+:11]>C(O)C>[OH:9][C:3]1[C:4](=[O:5])[CH:6]=[CH:7][NH:11][C:2]=1[CH3:1]
Reactant: Cc1occc(=O)c1O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1O
Temperature: 66 °C
Yield: 24 %

Procedure:
A 500-mL high-pressure reaction vessel equipped with a magnetic stir bar and a thermometer was charged with maltol (20 g, 0.16 mol), ethanol (40 mL) and ammonium hydroxide solution (28.0-30.0%, 35 mL, 0.52 mol). The reaction vessel was sealed and heated at 66° C. for 2.5 h. HPLC analysis (HPLC Method 1, Example 24) indicated that only 26% of product (peak percent area) was formed. Another 30 mL of conc. ammonium hydroxide (28.0-30.0%, 0.45 mol) was added, and the resulting mixture was sealed and heated to 75° C. for overnight. Upon cooling, a solid separated, and it was collected by suction filtration (8.7 g). HPLC analysis of the solid indicated presence of the desired product and maltol in about 4/1 ratio. The solid was slurried in methanol (30 mL), and the resulting mixture was stirred. The solid 3-hydroxy-2-methyl-1H-pyridin-4-one was collected by suction filtration (4.8 g, 24% yield, HPLC purity (peak percent area): 99.7% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 11.6 (br s, 1H), 7.40 (d, J=6.8 Hz, 1H), 6.09 (d, J=6.8 Hz, 1H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15]([S:17][C:18]3[C@H:19]([CH3:49])[C@@H:20]4[C@@H:37]([C@H:38]([O:40][Si](C(C)(C)C)(C)C)[CH3:39])[C:36](=[O:48])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15]([S:17][C:18]3[C@H:19]([CH3:49])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:48])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCC(N)=O)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCC(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(carbamoylmethyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (428.6 mg, 0.6 mmol) (obtained as described in Reference Example 45(2)) in tetrahydrofuran (21 ml) were added acetic acid (0.11 ml, 1.9 mmol) and 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (1.8 ml, 1.8 mmol) in an ice bath and the mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate: methanol (8:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(carbamoylmethyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (310.5 mg, yield 85%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][CH3:24])[N:19]=1>CN(C=O)C>[CH2:23]([N:20]1[CH:21]=[CH:22][C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:19]1)[CH3:24]
Reactant: CCn1ccc(CBr)n1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc(CSc2nc(C)cc(O)n2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (341 mg, 2.4 mmol) was dissolved in anhydrous DMF (20 mL), then potassium carbonate (995 mg, 7.2 mmol) and 3-(bromomethyl)-1-ethyl-1H-pyrazole (590 mg, 3.1 mmol) were added. The mixture was stirred for 2.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 8% DCM in MeOH to afford 2-{[(1-ethyl-1H-pyrazol-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (235 mg, 39% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.34 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 4.07 (q, J=7.3 Hz, 2H), 4.32 (s, 2H), 5.99 (bs, 1H), 6.19 (d, J=2.2 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H); LRMS (ES+) m/z 251 (100%, M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>[Pd]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Yield: 72 %

Procedure:
The procedure described in Example 26 is repeated, but using 4.79 g (25 mmols) of 4-bromochlorobenzene and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 8 hours at 130° C., 3.79 g (18.0 mmols) of ethyl 4-chlorocinnamate are obtained, corresponding to a yield of 72% of theory (conversion figure 7200; Pd content 0.01 mol %).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[N:16]2[C:11]([CH:12]=[CH:13][C:14]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15]2)=[CH:10][C:9]=1[CH3:21])(C)(C)C.FC(F)(F)C(O)=O.C(C1NC=CN=1)(C1[NH:33]C=CN=1)=O>C(Cl)Cl>[CH3:19][N:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]2[N:16]([C:8]([CH2:7][C:6]([NH2:33])=[O:5])=[C:9]([CH3:21])[CH:10]=2)[CH:15]=1)[CH3:20]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1cc2ccc(CN(C)C)cn2c1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccc(CN(C)C)cn2c1CC(N)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.7 %

Procedure:
(6-Dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester (122 mg, 0.40 mmol) is dissolved in CH2Cl2 (10 ml) containing 5% of trifluoroacetic acid. The mixture is stirred for 14 hours at room temperature and then concentrated in vacuo. The residue is azeotroped twice with toluene, dissolved in N,N-dimethylformamide (2.0 ml) and treated with carbonyl diimidazole (76 mg, 0.44 mmol, 1.1 equiv). After 1 hour at room temperature, the volatiles are removed in vacuo, and the activated acid is taken up in concentrated aqueous ammonia (10 ml). The mixture is stirred for 30 minutes at room temperature and then concentrated in vacuo. The residue is purified via flash chromatography (CH2Cl2/MeOH 7:1) to afford the title compound (90 mg, 91%). 1H NMR (400 MHz, d6-DMSO): δ=7.31 (s, 1H), 7.27 (s, 1H), 6.75 (s, 1H), 6.61 (dd, J=9.3/1.5 Hz, 1H), 4.06 (s, 2H), 3.38 (s, 2H), 2.66 (s, 6H), 2.13 (s, 3H). MS (ES+): 246 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH3:13])(=O)=O)=CC=1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:12]([CH3:13])[CH2:11][N:36]2[CH2:37][CH2:38][C:33]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:34][CH2:35]2)=[CH:19][CH:18]=1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)c2ccc(C(=O)c3ccccc3)cc2)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CN1CCC2(CC1)OCCO2)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
Reaction of the 2-(4-benzoylphenyl)propyl p-toluenesulfonate described above with 1,4-dioxa-8-azaspiro[4,5]decane in DMF in the presence of anhydrous potassium carbonate affords 8-[2-(4-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:16]2[C:17](=[O:26])[C:18]([CH3:25])=[C:19]([CH3:24])[C:20](=[O:23])[C:21]=2[CH3:22])=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1>C(O)(=O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:16]2[C:17](=[O:26])[C:18]([CH3:25])=[C:19]([CH3:24])[C:20](=[O:23])[C:21]=2[CH3:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1
Reactant: CC1=C(C)C(=O)C(C(=CCCCCC(=O)O)c2cccnc2)=C(C)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2cccnc2)=C(C)C1=O
Reaction time: 2 h
Yield: 83.5 %

Procedure:
7-(3-pyridyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-heptenoic acid (2.5 g) was hydrogenated in the presence of 5% palladium-carbon (0.5 g) in acetic acid (20 ml) (the reaction completed in about 2 hours). The catalyst was removed, the solvent was concentrated, and water (10 ml) and methanol (40 ml) were added. This solution was neutralized by addition of a saturated solution of sodium hydrogen carbonate, and the hydroquinone derivative was oxidized by aeration. After completion of oxidation, the mixture was concentrated under reduced pressure and the product was extracted with chloroform. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and purified with silica gel column chromatography [ethyl acetate-ethanol(9:1)] and recrystallized from a mixture of ethyl acetate-isopropyl ether, to give 7-(3-pyridyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoic acid (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[C:19]([N:27]=1)=[N:20][CH:21]=[C:22]([N+:24]([O-])=O)[CH:23]=2.O.O.Cl[Sn]Cl>C(O)C>[NH2:24][C:22]1[CH:23]=[C:18]2[NH:17][C:16]([C:3]3[CH:4]=[C:5]([NH:8][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[O:10])[CH:6]=[CH:7][C:2]=3[Cl:1])=[N:27][C:19]2=[N:20][CH:21]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2nc3ncc([N+](=O)[O-])cc3[nH]2)c1)c1ccco1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)[nH]c2c1
Yield: 54.3 %

Procedure:
To a suspension of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)furan-2-carboxamide (3.9 g, 10.16 mmol, 1.00 equiv) in ethanol (50 mL) was added SnCl2.2H2O (3.4 g, 15.04 mmol, 1.48 equiv) and heated to reflux overnight. The reaction mixture was concentrated under vacuum and diluted with H2O. The pH value of the mixture was adjusted to 9 with sodium carbonate (sat.). The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/PE (3/1) to give 1.95 g (54%) of N-(3-[6-amino-1H-imidazo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide as a yellow solid. 1H-NMR: (CD3OD, 400 MHz): 8.16 (d, J=2.4 Hz, 1H), 7.97-8.10 (m, 2H), 7.78 (d, J=0.8 Hz, 1H), 7.65 (d, J=20.0 Hz, 1H), 7.31-7.41 (m, 2H), 6.68 (dd, J=3.6, 2.0 Hz, 1H. MS (M+H)+=354.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH3:41])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH3:41])=[O:39])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C

Procedure:
6.31 g of Z-Thr(tBu)-Gln-Asn-Phe-OCH3 and 700 mg of palladium carbon are hydrogenated together at room temperature in 600 ml of methanol in a shaking vessel. The substance gradually passes into solution. The amorphous evaporation residue is used for the next condensation as it is.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1c(C(=O)NNC(=O)C(O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1c(C(=O)NNC(=O)C(=O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
172 mg of N′-[2-(3,5-difluorophenyl)-2-hydroxyacetyl]-4-benzyloxy-2-ethyl-3-methylbenzohydrazide (C3) are dissolved in 0.9 ml of dimethyl sulfoxide and 28 ml of dichloromethane under a dry nitrogen atmosphere. 185 mg of triacetoxyperiodinane (Dens-Martin reagent) are subsequently added. The suspension is stirred at room temperature for 1 h. For work-up, 100 ml of dichloromethane and 30 ml of 0.5 M Na2S2O3 solution are added. The organic phase is subsequently extracted with 50 ml of sat. NaHCO3 solution, dried over Na2SO4, filtered off with suction and evaporated to dryness. The residue is purified by means of flash column chromatography on silica gel (solvent gradient: cyclohexane/0-30% by vol. of methyl tert-butyl ether), giving 163 mg of the title compound as amorphous solid; MS: 452.7 (2M+H+); TLC: Rf=0.37 (cyclohexane/ethyl acetate 2:1, parts by volume).
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O.O>C(O)C>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: O=C1CNC2(CCCCC2)N1
Reactant: CC(C)COC(=O)CC1CO1
Solvent: CCO
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 2 h

Procedure:
1 g of 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (8.76 mmoles) are heated at 165° C. (external temperature) for 1 h 30 min with 2 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (12.64 mmoles). 0.17 ml of water and 5 ml ethanol are added, and boiling is continued for a further 2 h. The mixture is cooled and filtered. Oxiracetam is obtained as a white crystalline powder, m.p. 167°-70° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(OCC)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:4]=1[Cl:3])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1cccc(Cl)c1Cl
Solvent: CCOCC
Product: O=C(CBr)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (2.54 g, 15.9 mmol) was slowly added dropwise to a solution of 1-(2,3-dichlorophenyl)ethanone (3.00 g, 15.9 mmol) in diethyl ether (60 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 2-bromo-1-(2,3-dichlorophenyl)ethanone as an oil quantitatively.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O.O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:31]#[C:30][CH2:29][OH:32])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-ethyliodobenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 12 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.10 g) as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:38])[C:14]2[C:15]([CH3:37])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53].C1CCN2C(=NCCC2)CC1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:38])[C:14]2[C:15]([CH3:37])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:35])[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)c1cn(Cc2ccccc2)nn1

Procedure:
A solution of 1-(4′-{4-[(1-benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (Enantiomer B) (0.100 g, 0.197 mmol), carbonyldiimidazole (0.080 g, 0.5 mmol), N,N-dimethylamino pyridine (0.002 g, 0.02 mmol) in THF (2 mL) was stirred at room temperature overnight. Added MeSO2NH2 (0.050 g, 0.5 mmol) and DBU (0.100 mL, 0.65 mmol) and the mixture heated to 100° C. in a capped vial for 4.5 hours. The solution was poured into sat. aqueous NH4Cl, then water and EtOAc was added. The organic layer was separated, dried (Na2SO4), concentrated and the resulting reside purified by preparative HPLC to yield the title compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH2:5])=[O:4].[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][S:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][S:19][CH2:18][C@H:14]1[C:15]([NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Deprotection of 500 mg of Boc-Gly-NH2 was performed similarly to that in Example 28 (Process 3), and the obtained product was dissolved in dichloromethane, and 0.39 ml of tri-ethylamine, 0.67 g of Boc-Thz-OH, 0.47 g of HOBt and 0.64 g of EDC hydrochloride were added under ice cooling and the mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 139 (Process 2) to give 0.54 g of the title compound as oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:16]#[N:17])[C:5]([CH3:15])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[F:8].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].Cl>N1C=CC=CC=1>[C:16]([C:4]1[C:3]([O:18][CH3:19])=[C:2]([NH:1][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH3:15])#[N:17]
Reactant: COc1c(N)c(F)c(-c2ccccc2)c(C)c1C#N
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(C#N)c(C)c(-c2ccccc2)c(F)c1NC(=O)C(C)(C)C
Reaction time: 20 h

Procedure:
5-Amino-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-236) (300 mg, 1.17 mmol) was dissolved in pyridine (3 ml), and under nitrogen atmosphere at 0° C., pivaloyl chloride (433 μl, 3.51 mmol) was dropwise added. After stirring at roam temperature for 20 hours, aqueous 1 M hydrochloric acid solution was added to the reaction liquid at 0° C. The solution was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([Cl:17])=[CH:10][C:7]=1C#N)(=[O:3])C.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:17][C:11]1[CH:10]=[C:7]2[C:6]([CH2:5][O:4][C:1]2=[O:3])=[CH:13][C:12]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)OCc1cc([N+](=O)[O-])c(Cl)cc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1OCc2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 2-acetoxymethyl-5-chloro-4-nitrobenzonitrile (19.5 g, 77 mmol) in MeOH:THF (600 mL, 2:1) was added a solution of 1M aqueous NaOH (100 mL, 100 mmol). After stirring at room temperature for 30 min. TLC showed no starting material remaining. The mixture was acidified with 6M aqueous HCl (100 mL, 0.6 mol), heated at 60° C. for 1 h, cooled to room temperature and stirred for 6 h. Volatile solvents were evaporated in vacuo. The residue was suspended in H2O and filtered. The solid collected was washed with H2O and dried under vacuum to give the title compound (14.5 g, 88%) as an orange-yellow solid. 1H NMR (CDCl3): δ 8.11 (s, 1H), 7.92 (s, 1H), 5.40 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[CH:3]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)CN(Cc1cncc(Br)c1)S(=O)(=O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CN(Cc1cncc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(5-bromo-pyridin-3-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-pyridin-3-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 492.9 ([M+H]+)