Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9]1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:11][NH:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1

Procedure:
A solution of (S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 81, Step 9, 1.44 g, 3.26 mmol) in ethyl acetate (25 mL) and absolute ethanol (50 mL) was added to 10% Pd/C (1.0 g) and hydrogenated at 30 psi for 7 hr. Filtration and evaporation gave the title compound as a white glassy solid. FAB-HRMS: theory 308.1410 (M+1); meas. 308.1408.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][C@@H:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@H](CO)CC1CCCCC1
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@H](CO)CC1CCCCC1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The process is performed as in Example 3, starting with 8.1 g of (+)-(2S)-2-amino-3-cyclohexyl-1-propanol and 9.8 cm3 of tert-butyl isothiocyanate in 79 cm3 of ethanol. The reaction medium is stirred for 72 hours at a temperature in the region of 20° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 50° C., the oil obtained is taken up in 110 cm3 of cold petroleum ether. The crystals are filtered off and dried under reduced pressure (10 Pa) at a temperature in the region of 60° C. 11.1 g of N-(tert-butyl)-N′-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea are obtained in the form of a white solid melting at 97° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:19]([O-])=O)[N:3]=1>CO.[Pd]>[NH2:19][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cc(Oc2ccc(N)nc2C)ccn1
Yield: 93.9 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.44 g, 1.526 mmol) in MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.162 g, 0.153 mmol) and hydrogenated (1 atm) at RT for 24 h. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate concentrated to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (370 mg, 94%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1 H), 8.10 (d, J=5.7 Hz, 1 H), 7.53 (d, J=2.3 Hz, 1 H), 7.13 (d, J=8.7 Hz, 1 H), 6.53 (dd, J=5.7, 2.4 Hz, 1 H), 6.32 (d, J=8.7 Hz, 1 H), 5.91 (s, 2 H), 2.02 (s, 3 H), 2.01 (s, 3 H); MS (ESI) m/z: 259.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[CH:3][CH:4]=3)[C:16]=12
Reactant: Nc1ccc(-c2nn([C@@H]3CCOC3)c3ncnc(N)c23)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.075 g, 0.25 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.035 mL, 0.25 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD68. ESI-MS m/z [M+H]+ found 469.4, calculated 469.2.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([CH3:30])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:22]1[CH:21]=[C:20]([NH:19][CH:2]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:29]=[CH:28][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)cc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-2-methylbenzoate (1.1 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 33%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:17])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine (product of Example 3C,50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated to 90° C. for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic extraction was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 1.08 (m, 1H), 1.19 (m, 1H), 1.32 (d, J=6 Hz, 3H), 1.42 (m, 1H), 1.63 (m, 1H), 1.99 (m, 3H), 2.20 (m, 1H), 2.65 (m, 1H), 2.94 (m, 1H), 3.07 (m, 1H), 3.34 (dd, J=9 Hz, J=6 Hz, 1H), 3.51 (m, 1H), 7.24 (d, J=9 Hz, 2H), 7.60 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33])=[O:10])C1C=CC=CC=1.C(O)=O>CN(C)C=O.[Pd]>[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33])([OH:10])=[O:8]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=CO
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Reaction time: 24 h
Yield: 88.5 %

Procedure:
A solution of methyl 4-(5-benzyloxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (41.0 g) and formic acid (40 mL) in N,N-dimethylformamide (600 mL) was treated with 10% (w/w) palladium on carbon (10 g) and shaken under hydrogen (3.45 bar) for 24 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate evaporated to give an amber solid. The solid was triturated with warm diethyl ether and filtered to afford methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate as a light gray solid (28.9 g, 88%); mp 249°-251° C.; partial NMR (250 MHz, DMSO-d6): 3.78 (s, 3H, NCH3), 3.64 (s, 3H, CO2CH3), 3.93 (s, 3H, OCH3), 4.09 (s, 2H, CH2), 7.12 (s, 1H, indole-H(2)), 8.16 (s, 1H, indole-H(4)), 12.44 (br, 1H, CO2H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][N:15]([CH:16]([CH3:18])[CH3:17])[C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(CCNC(C)C)cc1OC
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCN(C(=O)C(Cl)Cl)C(C)C)cc1OC
Reaction time: 2 h

Procedure:
In a sulfuration-flask, there is added while stirring 20 ml of 20% aqueous sodium hydroxide to 22,3 g of N-(3,4-dimethoxyphenylethyl)-N-isopropyl amine. The reaction-mixture is then cooled in CO2 alcohol-cooling-bath to a temperature of -10° to -15°, to which is then added dropwise, while stirring a solution of 14.7 g of dichloroacetylchloride in 10 ml toluene. After everything has been added, the cooling-bath is removed and the reaction mixture is stirred for another 2 hours until it reaches room-temperature. It is then poured into an ice/water mixture and the organic material is extracted with toluene. The toluene extracts are washed once with diluted sodium hydroxide and with diluted hydrochloric acid and twice with water dried over sodium sulfate and concentrated in a rotatory evaporator. The title product is thus obtained as viscous oil in a yield of 28.4 g.
Reaction SMILES: BrC1C2N(N=C(Cl)N=2)C=CC=1.FC1C=CC(C(F)(F)F)=CC=1B(O)O.[Cl:26][C:27]1[N:43]=[C:30]2[C:31]([C:35]3[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:32][CH:33]=[CH:34][N:29]2[N:28]=1.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[Cl:26][C:27]1[N:43]=[C:30]2[C:31]([C:35]3[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:32][CH:33]=[CH:34][N:29]2[N:28]=1.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([C:57]2[CH:62]=[CH:61][C:60]([NH:63][C:27]3[N:43]=[C:30]4[C:31]([C:35]5[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=5)=[CH:32][CH:33]=[CH:34][N:29]4[N:28]=3)=[CH:59][CH:58]=2)[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: COc1ncccc1-c1cccn2nc(Cl)nc12
Agent: Clc1nc2c(Br)cccn2n1
Agent: OB(O)c1cc(C(F)(F)F)ccc1F
Product: COc1ncccc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
2-Chloro-8-(2-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-fluoro-5-trifluoromethylphenylboronic acid in a manner analogous to Example 2c (0.47 g, 84%). MP=218-219° C. MS=261 (MH)+. 271b) [4-{4-[8-(2-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-Chloro-8-(2-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.25 g, 50%). MP=101-103° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 8.80 (d, J=6.58 Hz, 1H), 8.25 (m, 1H), 8.05 (d, 1H), 7.75 (m, 1H), 7.55 (m, 2H), 7.02 (m, 4H), 4.05 (m, 2H), 3.90 (s, 3H), 2.6-2.8 (m, 3H), 1.65 (m, 2H), 1.40 (m, 11H). MS=501 (MH)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:11]([CH2:16][C:17]([OH:19])=[O:18])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH2:31][CH2:32][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: CC(C)CN(CC(=O)O)S(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), [(4-fluoro-benzenesulfonyl)-isobutyl-amino]-acetic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=140-143° C.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O.C(O)(=O)C>CS(C)=O>[F:1][C:2]1[C:20]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2c(F)cc3cc4c(=O)c(C(=O)O)cn(C)c4nc3c2F)CC1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
A suspension of 4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 60 cm3 of dimethyl sulphoxide and 3 g of 1-methylpiperazine is heated at 80° C. for 1 hour and a half. After cooling to about 20° C., 150 cm3 of water are added. 18 cm3 of 10% acetic acid are added to the solution obtained. The precipitate formed is drained, washed with 3 times 50 cm3 of water and recrystallized from 50 cm3 of dimethylformamide. 4 g of 7,9-difluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 316° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:21]([NH:23][C@@H:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]=1[Cl:20]>C(O)=O>[NH2:1][C@@H:2]([C:21]([NH:23][C@@H:24]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[C:5]=1[Cl:20]
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1c(Cl)n(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=CO
Product: CCCC[C@@H](NC(=O)[C@H](N)Cc1c(Cl)n(C(=O)OC(C)(C)C)c2ccccc12)C(=O)OC(C)(C)C
Yield: 46.6 %

Procedure:
A solution of Boc-DTrp(1-Boc,2-Cl)-DNle-OtBu (252 mg, prepared in (3)) in formic acid (10 ml) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with sat. aq. NaHCO3 (50 ml×2) and sat. brine (50 ml) successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (98 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]([C:18](=[O:31])[CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]C=C)[CH2:6][C:7]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH2:8].CS(C)=O>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]1[CH2:6][C:7]([C:9]([CH3:16])([CH3:17])[O:10][SiH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][CH2:20][CH:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:18]1=[O:31]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N(CC(=C)C(C)(C)O[SiH2]C(C)(C)C)CC(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CN1CC(C(C)(C)O[SiH2]C(C)(C)C)=CCC(NC(=O)OC(C)(C)C)C1=O
Reaction time: 12 h
Yield: 96 %

Procedure:
Super Grubbs catalyst (2 g) is added to a solution {(2-tert-butoxycarbonylamino-pent-4-enoyl)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-allyl]-amino}-acetic acid methyl ester, 16, (4.1 g, 8.7 mmol) in CH2Cl2(100 mL). The solution is refluxed for 1 hour then DMSO (10 mL) is added and stirring is continued for another 12 hours at room temperature. The solvent is removed in vacuo and the residue purified over silica (EtOAc/hexane) to afford 3.7 g (96% yield) of the desired product. 1H NMR (CDCl3) δ 5.80–5.78 (d, J=6.3 Hz, 1H), 5.65 (bs, 1H), 5.03–4.96 (m, 1H), 4.56–4.48 (m, 2H), 3.98 (s, 2H), 3.98–3.92 (d, J=17.4 Hz, 1H), 3.73 (s, 3H), 3.44–3.38 (d, J=17.7, 1H), 2.74–2.67 (d, d, J=18, 3.3 Hz, 1H), 2.30–2.18 (m, 1H), 1.45 (s, 9H), 0.89 (s, 9H), 0.06 (s, 6H); 13C (CDCl3) δ 172.9, 169.6, 155.2, 135.6, 124.6, 79.7, 66.9, 60.5, 52.4, 50.0, 49.8, 47.6, 33.1, 28.5, 26.0, 18.4,14.4, −5.0; MS 442 (M+H)+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=1>C(O)C.[H][H].[C].[Pd]>[C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(C)c(-c2ncccc2[N+](=O)[O-])c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(-c2ncccc2N)c(C)c1
Yield: 106.5 %

Procedure:
Palladium-carbon (10%, 0.6 g) was added to a solution of 2-mesityl-3-nitropyridine (5.99 g, 23 mmol) in ethanol (120 mL), followed by stirring for one day in hydrogen atmospher. The mixture was filtered through Celite and evaporated, to give the title compound (5.2 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[CH:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([CH2:19]Cl)[CH:12]=1.Cl>N1C=CC=CC=1>[Cl:18][C:14]1[CH:15]=[C:16]([Cl:17])[CH:11]=[CH:12][C:13]=1[CH2:19][S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc(Cl)cc2Cl)c(=O)o1
Temperature: 90 °C
Yield: 56 %

Procedure:
4-Hydroxy-3-mercapto-6-methyl-2-pyrone (47.5 g., 0.300 mole) and α2,4-trichlorotoluene (58.6 g., 0.300 mole) were dissolved in pyridine (250 ml.). The temperature rose from 20° to 43°C. The solution was then heated at 90°C. for two hours, cooled and poured onto ice and 500 ml. of concd. hydrochloric acid. The resulting mixture was extracted with methylene chloride. The extract was dried (MgSO4) and the solvent removed by evaporation. The residue was mixed with hexane, filtered and dried, giving 53.3 g. (56 percent) of the desired product. Recrystallization from benzene gave the pure product as a white solid, m.p. 163°-164°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([CH:14]=O)[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([CH:14]=[CH:24][N+:21]([O-:23])=[O:22])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: C[N+](=O)[O-]
Reactant: COc1c(C=O)cc2c(c1OC)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1c(C=C[N+](=O)[O-])cc2c(c1OC)CCC2

Procedure:
In a 2 liter 3-necked flask fitted with a condenser and thermometer and magnetically stirred, 126.7 g (0.613 mole) of 4,5-dimethoxy-6-indanaldehyde, 29.3 g (0.380 mole) of ammonium acetate, 127 ml (2.82 mole) of nitromethane and 390 ml of acetic acid were heated at 112°C for 45 minutes. After cooling in the refrigerator and scratching with a glass rod the solution crystallized. After filtering and washing with cold acetic acid the product was dried under vacuum overnight and recrystallized from methanol yielding 104.4 g (68%) of 4,5-dimethoxy-6 -nitrovinylindane as yellow needles, m.p. 103.5°-104.5°C. Anal. Calcd. for C13H15NO4 : C, 62.64; H, 6.06; N, 5.62. Found: C, 62.45; H, 6.17; N, 5.84.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[C-:12]#[N:13].[Na+]>CN(C)C=O>[C:12]([C:7]1[C:2]([Cl:1])=[C:3]([F:11])[N:4]=[C:5]([F:10])[C:6]=1[Cl:9])#[N:13]
Reactant: [C-]#N
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)c(F)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
To a mixture of 40.4 g (0.200 mole) of 3,5-dichloro-2,4,6-trifluoropyridine in 50 ml of dimethylformamide that had been cooled to 0° C. was added slowly 10 g (0.20 mole) of sodium cyanide. After addition was complete the reaction was stirred at 0° C. for two hours and at room temperature of two hours. The dimethylformamide was distilled from the reaction mixture under reduced pressure, and the black residue was mixed with 200 ml of water. This mixture was extracted with ethyl acetate. The extracts were combined, and the ethyl acetate was evaporated, leaving a black residue weighing approximately 15 g. This residue was distilled, yielding approximately 10 g of 4-cyano-3,5-dichloro-2,6-difluoropyridine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.[N:27]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:26]=[C:9]1[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:12][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:35])[CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:7][CH:6]=1
Reactant: O=C(O)CN1CCCCC1
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Product: O=C(CN1CCCCC1)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with piperidin-1-ylacetic acid as described in example 217. The product with the molecular weight of 468.56 (C28H28N4O3); MS (ESI): 469 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.