Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:19]=[CH:20][C:21]([C@H:24]3[CH2:25][CH2:26][C@@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C3=CCC(C(C)(C)C)CC3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1

Procedure:
To a solution of 4-{(R)-2-[4-(4-tert-Butyl-cyclohex-1-enyl)-phenyl]-2-carboxy-ethyl}-benzoic acid tert-butyl ester (3.0 g) in ethyl acetate (100 mL) added 10% palladium on carbon (300 mg). The mixture was stirred under a balloon filled with hydrogen, until proton NMR indicated the disappearance of the olefinic signal. The reaction was filtered through a plug of celite, and the filtrate was concentrated under reduced pressure to give a mixture of cis/trans isomers (in a ratio of 1:1, based on 1H NMR). The cis1 and trans isomers were separated by reverse phase chromatography with the latter being cis (1.34 g, 2.9 mmol, 35%). 1H NMR (CDCl3): δ 0.95 (9H, s), 1.23-1.38 (4H, m), 1.58 (9H, s), 1.88-1.98 (4H, m), 2.39-2.56 (1H, m), 3.05-3.12 (1H, m), 3.19-3.50 (1H, m), 3.82-3.90 (1H, m), 7.19-7.22 (6H, m), 8.81 (2H, d).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:4]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1Nc1ccccc1

Procedure:
To a pressure reaction bottle was added 10 g 2-nitrodiphenylamine, 0.5 g 5% palladium on carbon and 100 ml 95% ethanol. The mixture was hydrogenated at 22 C and 40 psi hydrogen for 2 hours. Following filtration through celite and solvent removal, an oil was obtained that crystallized on standing.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([OH:31])=O)[CH:17]=2.C(=O)=O.[CH3:35][N:36]([CH3:41])[S:37]([NH2:40])(=[O:39])=[O:38].C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([NH:40][S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])=[O:31])[CH:17]=2
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CN(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1,1′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74%, >90% purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 38.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.34 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.42 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH:34]C=O)[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].Cl.CO>O1CCCC1>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]3[S:20][CH:21]=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.58 g.), conc. hydrochloric acid (0.405 g.), methanol (8.7 ml.) and tetrahydrofuran (5 ml.) was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.4 g.).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.O1CCCC1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44](=[O:47])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]([OH:47])([C:11]2[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=3)[N:10]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nc(-c3cccc(C(F)(F)F)c3)cn2COCC[Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a 100 mL round bottom flask (fitted with cooling bath, stir bar and nitrogen blanket) add 4-(3-Trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (0.995 g; 1.00 equiv; 2.91 mmoles; 995.00 mg), n-Butyl Lithium (2.8 mL; 1.54 equiv; 4.48 mmoles; 2.80 mL; 1.90 g), and Tetrahydrofuran (30 mL; 368.66 mmoles; 30.00 mL; 26.58 g) and cool the mixture to −78° C. with stirring on and hold for 30 min. Add N-T-Butoxycarbonyl-4-piperidone (0.706 g; 1.22 equiv; 3.54 mmoles; 706.00 mg) and allow the reaction to warm to room temperature. Dilute the reaction with CH2Cl2, wash with water, dry over Na2SO4, filter, and concentrate to dryness. Purify the crude mixture by flash chromatography on silica eluting with ethyl acetate/hexane from 10-50% EtOAc. Combine the appropriate fractions and concentrate to give 4-Hydroxy-4-[4-(3-trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (1.248 g; 0.79 equiv; 2.30 mmoles; 1.25 g; 79.29% yield).
Reaction SMILES: [CH2:1]([Se:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[CH2:1]([Se:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1[Se]Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2ccccc2)c1[Se]Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.37 g (0.0041 mol) 2-benzylseleno-3-methoxybenzoyl chloride (prepared from 2-benzylseleno-3-methoxybenzoic acid and α,α-dichloromethyl ether in dichloromethane at room temperature) in 10 ml pyridine at 0° C. is added with stirring a solution of 0.38 g (0.0041 mol-0.37 ml) aniline. After stirring at room temperature for 18 hours the contents of the flask are poured onto 150 g ice and 50 ml 25% HCl and extracted. The organic phase is washed with 50 ml 10% NaHCO3 and twice with 100 ml portions of dichloromethane and 200 ml water, dried over sodium sulfate and the solvent removed in vacuum.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:30](Cl)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a 0° C. solution of (R)-2-methylpiperazine (5.0 g, 50 mmol, 1.0 equiv) in dry DCM (200 mL) was added triethylamine (21 mL, 150 mmol, 3 equiv) by syringe. A solution of Boc2O (10.4 g, 47.4 mmol, 0.95 equiv) was then added as a solution in dry DCM (100 mL) over the course of an hour. After stirring for an addition 15 min at 0° C., the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then washed with aq. satd. NaHCO3 and brine. The resulting DCM solution was dried over sodium sulfate, filtered, and concentrated in vacuo, and used in the next step without further purification. The residue was dissolved in dry DCM (50 mL), and Et3N (21 mL, 150 mmol, 3 equiv) was added by syringe. To this room temperature solution was added CbzCl (8.4 mL, 60 mmol, 1.2 equiv) dropwise by syringe. After stirring at room temperature for 30 minutes, the mixture was quenched by the addition of aq. satd. NaHCO3. The solution was washed an additional time with aq. satd. NaHCO3, twice with aq. 1 N KHSO4, and twice with brine. The DCM layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (100 mL), and HCl (4 N in dioxane, 150 mL, 600 mmol, 12 equiv) was added dropwise by syringe. After 2 h, the reaction mixture was concentrated in vacuo. To the resulting solid was added EtOAc and 1 N NaOH. The aqueous layer was extracted twice with EtOAc, and the organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide (R)-benzyl 2-methylpiperazine-1-carboxylate (5.3 g, 45%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-3,5-dimethylphenol (3.5 g), 4-(dimethylamino)pyridine (212 mg) and triethylamine (2.7 mL) are stirred in dichloromethane (25 mL) at 0° C., then tert-butyldimethylchlorosilane (19 mL) is added dropwise. The reaction mixture is warmed to ambient temperature and stirred overnight. The reaction mixture is diluted with dichloromethane, washed with aqueous HCl (1 M, 25 mL) and then with saturated aqueous NaHCO3 (25 mL). The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 5.4 g
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[Cl:41][C:26]1[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[N:28][C:23]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: COCC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)COC)CC3(C)C)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-acetylamino)-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (40 mg, 38%) HPLC purity=99%, LCMS=572 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.72 (s, 1H), 9.40 (s, 1H), 9.34 (s, 1H), 8.51 (m, 1H), 8.18 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.31-7.27 (m, 2H), 7.16 (s, 1H), 7.10 (d, 1H), 4.23-4.21 (m, 1H), 3.82 (s, 2H), 3.33 (s, 3H), 2.73 (d, J=4.8 Hz, 3H), 2.22-2.18 (m, 1H), 1.92-1.88 (m, 1H), 1.33 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC(C)=O>[C:25]([O:24][C:22]([CH2:21][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC(=O)CCc1ccc(O)cc1

Procedure:
To a mixture of 3-(4-hydroxy phenyl) propionic acid (20 grams, 120.35 mmol) and triethyl amine (30 grams, 296.47 mmol) in acetone (150 mL) is added t-butyl chloroacetate (19.6 grams, 130 mmol) drop wise, later it is stirred under reflux for 10 hours. The resulting solids are filtered off, acetone is distilled off, and water (100 mL) is added. The crude 4 is extracted into chloroform, and is washed with 5% sodium bicarbonate (2×25 mL), water (2×25 mL), and the product is dried over sodium sulphate, and is distilled to give crude 4 which can be purified from an appropriate solvent.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.[F:34][C:35]([F:40])([F:39])C(O)=O>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])=[O:5]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCNC(=O)C(F)(F)F)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (27 mg, 0.060 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 1 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (3 mL), triethylamine (0.050 mL), and ethyl trifluoroacetate (2 mL), and the resulting mixture was refluxed for 16 h. After cooling to r.t., mixture was concentrated to dryness. 0.1 M HCl and EtOAc were added, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 16.4 mg of the title compound as a pale yellow solid. MS: (+) m/z 449.23 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][NH2:34].C(O)C>C(OCC)(=O)C>[CH3:33][NH:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:28])[F:30])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 40 mg, 0.08 mmol) and 8M methyl amine solution in ethanol (408 uL, 3.26 mmol) and was heated to 90° C. in a sealed tube for 48 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo to give a crude residue which was diluted with ethyl acetate and washed with water, sat. NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography using Amine-Silica to yield the desired product as a white solid (39 mg, 98%). MS (ESI): 485.2 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].O1CCCC1.[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[N:30][CH:31]=1)#[CH:25]>[Cu]I.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.C(N(CC)CC)C>[C:14]([O:13][C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:25]#[C:24][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:29]=[N:30][CH:31]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
Into the reaction flask was added tert-butyl (2-iodo-4-nitrophenyl)carbamate (1.5 g, 4.1 mmol) and copper(I) iodide (0.031 g, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine (0.63 mL). The mixture was stirred under bubbling N2 for 5 min, and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90 g, 4.1 mmol) was then added. The reaction mixture was stirred at 65° C. for 1 h. After concentration, the residue was diluted with EtOAc and water. The aqueous layer was extracted again with EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the crude was purified by silica gel column chromatography to give the desired product (1.6 g, 85%). LCMS for C23H27N4O6 (M+H)+: m/z=455.1.
Reaction SMILES: [CH2:1]([O:8]CC1C=CC=CC=1)[C:2]1C=CC=C[CH:3]=1.[O:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>[Pd]>[O:16]1[CH2:21][CH2:20][O:19][CH:18]1[CH2:17][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: C1COCCO1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [Pd]
Product: OCCCCC1OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Benzyl ether of step 3 (2.00 g, 8.46 mmol, 1.0 equiv) was dissolved under argon in 1,4-dioxane (20 mL). Pd/C (10% Pd, 50 mg, 2.5 weight-%) was added. The mixture was purged with argon, and subsequently with hydrogen. The mixture was stirred at room temperature for 16 h. The solution was filtered (GF/A glass microfiber) and concentrated under reduced pressure to give the resulting alcohol (1.24 g, 8.46 mmol, 100%) as clear, colourless oil which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ=4.86 (t, J=4.7 Hz, 1H), 4.00-3.91 (m, 2H), 3.90-3.80 (m, 2H), 3.65 (t, J=6.5 Hz, 2H), 1.74-1.66 (m, 2H), 1.66-1.58 (m, 2H), 1.56-1.46 (m, 2H), 1.40 (br s, 1H) ppm.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][NH:20][C:21](=O)[O:22]C1C=CC([N+]([O-])=O)=CC=1>N1C=CC=CC=1>[CH3:18][O:19][NH:20][C:21]([NH:17][C:14]1[CH:15]=[CH:16][C:10]2[C:11]([N:13]=1)=[N:12][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:8][N:9]=2)=[O:22]
Reactant: Nc1ccc2ncc(-c3ccccc3)nc2n1
Reactant: CONC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CONC(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
100 mg of 3-phenylpyrido[2,3-b]pyrazin-6-ylamine (0.45 mmol) were dissolved in pyridine and admixed with 191 mg of p-nitrophenyl N-methoxycarbamate (0.90 mmol). The mixture was heated under reflux for 4 h. For workup, the pyridine was removed under reduced pressure, and the residue was partitioned in ethyl acetate and distilled water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol eluent). A light beige solid was isolated.
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[CH:4].N1C=CC=CC=1>[H][H].[Pd]>[OH:1][C:2]([CH3:13])([CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4]
Reactant: [H][H]
Reactant: C#CC(C)(O)CCCCCCCC
Agent: [Pd]
Solvent: c1ccncc1
Product: C=CC(C)(O)CC=CCCCCC

Procedure:
A mixture of 20.0 g. of 3-hydroxy-3-methyl-undec-1-yne, 200 ml. of pyridine, and 500 mg. of 5% palladium on barium sulfate is shaken in hydrogen at an initial pressure of 45 lb./sq. in. The hydrogenation is stopped when the calculated amount for one mole uptake per mole of compound has been absorbed. The mixture is poured into water and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, aqueous sodium bicarbonate, dried, and evaporated under reduced pressure to give a residue which is distilled through a Vigreaux column to give a distillate comprising 3-hydroxy-3-methyl-1,5-undecadiene.