Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[S:16][C:17]([C:19]3[C:28]([CH2:29][CH3:30])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:31][CH3:32])[N:20]=3)=[CH:18][C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:29]([C:28]1[C:19]([C:17]2[S:16][C:13]3[N:14]([CH3:15])[C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH:18]=2)=[N:20][C:21]([O:31][CH3:32])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])[CH3:30]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(CO[Si](C)(C)C(C)(C)C)n(C)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(CO)n(C)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To solution of methyl 6-(5-((tert-butyldimethylsilyloxy)methyl)-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-5-ethyl-2-methoxynicotinate (0.594 g, 1.25 mmol) in THF (8 mL) was added solution of TBAF (1M THF, 1.50 mL, 1.50 mmol). Reaction mixture was stirred at room temperature for 30 min and THF was then concentrated. Residue was loaded directly on the column and product was isolated eluting with EtOAc/hexanes gradient (0-50%). Methyl 5-ethyl-6-(5-(hydroxymethyl)-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-methoxynicotinate (0.233 g, 26% 2 steps) was obtained as solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[NH:8][CH:9]=1)=[O:13]
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c2ncc(Br)nc12
Yield: 43 %

Procedure:
To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.527 g, 2.18 mmol) in 50 ml, of methanol was added H2SO4 (1.5 mL) slowly at room temperature. The reaction mixture was stirred at reflux for 16 h. The solvent was evaporated at 40° C. under reduced pressure then the residue was suspended in 5 mL of water and treated with solid NaHCO3 until pH=7. The solution was extracted with ethyl acetate (90 mL), then the organics were washed with water (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was evaporated at 40° C. under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid methyl ester (0.24 g, 43%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[N:22]1.C(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:22]2[N:23]=[CH:24][CH:25]=[N:21]2)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cc1cccc(I)c1
Agent: CC(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cc1cccc(-n2nccn2)c1

Procedure:
(S)-2-(3-[1,2,3]Triazol-2-yl-benzyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from (S)-2-(3-iodo-benzyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 1H-1,2,3-triazole in analogy to the procedure described for A-13. LC-MS A: tR=0.97 min; [M+H-tBu]+=273.16.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:19]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:17]=3[C:33]3[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[N:19]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:17]=3[C:33]3[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc(-c2c(-c3ccc(F)cc3)nc(C(F)(F)F)nc2N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Product: Nc1ccc(N2CCN(c3nc(C(F)(F)F)nc(-c4ccc(F)cc4)c3-c3cccc(S(N)(=O)=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-1-yl}-4-[4-fluorophenyl]-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.13 g, 0.22 mmol) was taken in concentrated hydrochloric acid (1.5 ml) and to this tin (II) chloride dihydrate (0.145 g, 0.65 mmol) was added and the reaction mixture was stirred for 24 hours at room temperature. Subsequently the reaction mixture was poured onto crushed ice, neutralized with sodium bicarbonate, and extracted with ethyl acetate. Evaporation of the solvent yielded the required product. 1H-NMR (DMSO-d6) δ: 3.13 (m, 4H), 3.30 (m, 4H), 4.58 (br, 2H, D2O exchangeable), 6.57-6.59 (m, 1H), 6.88 (d, 1H), 7.04-7.09 (m, 2H), 7.12-7.14 (m, 2H), 7.39 (br, 2H, D2O exchangeable), 7.41 (d, 1H), 7.50-7.55 (m, 2H), 7.73-7.77 (m, 2H); MS m/z: 574.1 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH:19]1([CH2:18][N:9]2[C:8]3[CH:25]=[CH:26][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=[C:10]2[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc2c(c1)nc(Cc1cccs1)n2CC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)nc(Cc1cccs1)n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To 13.60 g of 1-Cyclohexylmethyl-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester in 25 ml of methanol and 100 ml of THF were added 37 ml of 2 M aqueous sodium hydroxide solution. The reaction stirred at rt for 6 h. The reaction mixture was adjusted to pH 4 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (silica, heptane/ethyl acetate) to yield 11.1 g (85%) of 1-Cyclohexylmethyl-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19].C(N(CC)CC)C>COCCOCCOC>[F:13][C:12]([F:15])([F:14])[C:9]1[C:10]([NH:16][CH2:17][C:18]([NH:20][CH:21]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)=[O:19])=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[N:4][N:3]=[CH:2]2
Reactant: FC(F)(F)c1ccc2cnnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2c(C(F)(F)F)ccc3cnncc23)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 1-chloro-7-(trifluoromethyl)phthalazine (prepared as described in the previous step, 1.5 g, 6.47 mmol, 1.00 equiv) in 2-methoxyethyl ether (10 mL), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step E) (1.5 g, 6.55 mmol, 1.22 equiv) and triethylamine (1.95 g, 19.31 mmol, 2.99 equiv). The reaction mixture was stirred overnight at 100° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with CH3CN:H2O (3:1). The title compound was obtained as a white solid.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:14])[CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>ClCCl>[Br:1][CH:5]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:4](=[O:3])[CH3:14]
Reactant: BrBr
Reactant: CC(=O)Cc1ccc(C#N)cc1
Solvent: ClCCl
Product: CC(=O)C(Br)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Bromine (5.28 g) in dichloromethane (80 ml) was, added dropwise at 25° C. over 1 hour to 4-(2-oxopropyl) benzonitrile in dichloromethane (85 ml). The reaction mixture was stirred for 1/2 hour after the addition was complete. The mixture was washed with brine (50 ml), dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a pale red oil (7.55 g, 96%).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[CH2:33]([Sn](CCCC)(CCCC)C#CC)[CH2:34][CH2:35]C>CCOC(C)=O>[C:33]([C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)#[C:34][CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC#Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
To a microwave vial containing (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate (500 mg, 1.159 mmol) and a stir bar was added 1,4-dioxane (6 mL). To this solution was added tetrakis(triphenyl-phosphine)palladium(0) (67.0 mg, 0.058 mmol, 0.05 eq) and tributyl(prop-1-yn-1-yl)stannane (458 mg, 1.391 mmol, 1.2 eq). The vial was capped and irradiated in a microwave at 120° C. for 20 min. The vial was allowed to cool, diluted with hexanes (5 mL) and loaded directly to a normal phase silica gel column (80 g ISCO, 0 to 40% EtOAc in hexanes) to provide (S)-tert-butyl ((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]>>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: COCCCCCCl
Reactant: O=C1CCNCC1
Product: COCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Methoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-methoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])C#N.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+]>O.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:12]([OH:13])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C#N)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)cc1F
Yield: 90 %

Procedure:
3-Fluoro-4-methoxybenzonitrile (2.0 g, 13.2 mmol) in water (5 mL) and concentrated sulphuric acid (5 mL) was heated at 110° C. for 4 hours. The solution was then cooled to room temperature and neutralized with solid sodium carbonate. Acidification with glacial acetic acid leads to a white precipitate, which was collected by filtration and dissolved in dichloromethane. The resulting solution was dried over sodium sulfate, filtered, and concentrated to give the product as a beige-colored solid (2.03 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: ClCc1ccccc1Cl
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(N(Cc3ccccc3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:13][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:12])([CH3:13])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-bromoisatin (255 mg, 1.13 mmol) in THF (3.0 mL) was added methylmagnesium bromide (1.12 mL, 3.39 mmol, 3M in ether). The solution was stirred at room temperature for 2 hours. The solution was cooled to 0° C. and was quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted with EtOAc (3×), washed with brine, dried over MgSO4, filtered and concentrated to afford 6-bromo-3-hydroxy-3-methylindolin-2-one 7.45. The solid was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.15 (dd, J=7.9, 1.8 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 5.94 (s, 1H), 1.34 (s, 3H).
Reaction SMILES: Br[N:2]1C(=O)CC[C:3]1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH3:18]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][C:3]#[N:2]
Reactant: COc1ccc(C)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CC#N)c(C)c1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Under argon atmosphere, a mixture of N-bromosuccinimide (17.8 g) and 2,2′-azobisisobutyronitrile (492 mg) was added to a solution of 1,2-dimethyl-4-methoxybenzene (13.6 g) in carbon tetrachloride (200 ml). The mixture was refluxed for 6.5 hours. The reaction mixture was cooled with ice-bath. An insoluble matter was removed by filtration, and washed with carbon tetrachloride. A combined filtrate was concentrated. The residue was dissolved into N,N-dimethylformamide (100 ml) and sodium cyanide (9.86 g) was added to the mixture. The mixture was stirred over night at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:6→1:4) to give the title compound (11.78 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:46]([CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[C:47]=[O:48]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][N:42]([C:47]([NH:46][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[O:48])[CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Reactant: O=C=NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCN(C(=O)NC2CCCC2)C1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 43% yield. LCMS for C29H33ClN7O2 (M+H)+: m/z=546.2.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[NH:12][C:9]2=[CH:10][N:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:24]([C@H:18]([NH:17][C:15]([C:13]1[NH:12][C:9]2=[CH:10][N:11]=[C:6]([Cl:5])[CH:7]=[C:8]2[CH:14]=1)=[O:16])[C@@H:19]([OH:23])[C:20](=[O:22])[NH:4][CH2:1][CH2:2][CH3:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCN
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
n-Propylamine (16 μL, 0.19 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydroxy-4-phenylbutyric acid (EXAMPLE 44, 40 mg, 0.11 mmol), HOBt (16.4 mg, 0.11 mmol), DIPEA (41 μL, 0.24 mmol) and EDCI (25 mg, 0.13 mmol) in DMF (3 mL). After stirring for 72 h at room temperature the solvent was removed in vacuo and the remaining residue was purified by preparative LCMS to give the title compound as colourless solid. m/z (ES+)=415.34 [M+H]+; RT=3.10 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]([C@@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])[CH2:23][CH2:22][CH2:21]2.CNCCNC.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CO.[Cu]I.CN1C(=O)CCC1>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]([C@@H:28]1[CH2:32][CH2:31][N:30]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]4[S:13][CH:14]=[CH:15][N:16]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)[C:29]1=[O:33])[CH2:23][CH2:22][CH2:21]2
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Reactant: O=C1NCC[C@H]1N1CCCc2cc(Cl)ccc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: O=C1[C@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 200 °C

Procedure:
Prepared using general procedure 64. 4-Bromo-N-(thiazol-2-yl)benzenesulfonamide (54 mg, 0.17 mmol), (R)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one (50 mg, 0.20 mmol), copper(I) iodide (3.8 mg, 10 mol %), N,N′-dimethylethylenediamine (4.2 μL, 20 mol %), and K2CO3 (94 mg, 0.68 mmol) were combined in a microwave vial and set under nitrogen. NMP (0.4 mL) was added, and the reaction mixture was heated to 200° C. for 30 min. using microwave irradiation. After cooling to RT, the reaction mixture was diluted with DMSO/MeOH (1:1, 0.6 mL) and purified via reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give (R)-4-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=489.3; tR=3.27 min.
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18](=[O:40])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CC(C)=O>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH2:20])[C:18](=[O:40])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reaction time: 16 h

Procedure:
Methyl 3-benzyl-7-tritylamino-3-cephem-4-carboxylate (111 mg) was dissolved in acetone (1.5 ml.) and the solution cooled to -20°. p-Toluene sulphonic acid (40 mg) in acetone (0.5 ml) was added dropwise over a few minutes and the solution left at 0° for 16 hours. Thin layer chromatography (TLC) still showed some unchanged starting material was present. A further quantity of p-toluene sulphonic acid (10 mg) was added and the solution left at room temperature for 4 hours. Ethyl acetate was added and the solution washed with dilute aqueous sodium bicarbonate and brine. Evaporation of the dried organic layer afforded methyl 3-benzyl-7-amino-3-cephem-4-carboxylate contaminated with trityl alcohol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:10][CH2:9][C@@H:8]([C:11]([O:13]CC3C=CC=CC=3)=[O:12])[CH2:7]2)[C:5](=[O:21])[NH:4][C:3]1=[O:22]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]1[C:6]2([CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]2)[C:5](=[O:21])[NH:4][C:3]1=[O:22]
Reactant: CN1C(=O)NC(=O)C12CC[C@@H](C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1C(=O)NC(=O)C12CC[C@@H](C(=O)O)C2
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To (7R)-benzyl 1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxylate (from step A, 0.1 g, 0.331 mmol) in ethyl acetate (10 mL) was added Pd—C (0.035 g, 0.033 mmol) under a nitrogen atmosphere. The contents were hydrogenated at 20 psi for 1 hour. The reaction mixture was filtered over a Whatman filter (FN MB 25 MM 0.45 uM) paper and washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure to yield an oil (0.05 g, 0.236 mmol, 71.2%) which was used in the next step without further purification. MS m/z 211.3 (M−H)+
Reaction SMILES: [H-].[Na+].[CH:3]1C=CC=CC=1.[CH3:9][C:10]([OH:19])([CH2:12][CH2:13][CH:14]=[CH:15][C:16]([CH3:18])=[CH2:17])[CH3:11].CI>O>[CH3:3][O:19][C:10]([CH3:9])([CH2:12][CH2:13][CH:14]=[CH:15][C:16]([CH3:18])=[CH2:17])[CH3:11]
Reactant: c1ccccc1
Reactant: C=C(C)C=CCCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: C=C(C)C=CCCC(C)(C)OC

Procedure:
4.8 g (0.11 mol) of a 50% suspension of sodium hydride in paraffin oil are mixed with 120 ml of benzene in a three-necked flask provided with a thermometer, stirrer, reflux condenser and dropping funnel. 16.9 g of 2,7-dimethyl-5,7-octadien-2-ol are slowly added dropwise thereto. The reaction is completed by heating the mixture at reflux for 2 hours. 28 g (0.2 mol) of methyl iodide are then added dropwise at 30° C. After completion of the addition, the mixture is heated at reflux for 2 hours. After cooling, 50 ml of water are cautiously added. The benzene layer is separated and washed neutral with water. The solvent is distilled off and the residue fractionally distilled. There are obtained 13.7 g of 2-methoxy-2,7-dimethyl-5,7-octadiene of boiling point 72° C/3 mm Hg; nD20 = 1.4670; IR n° 24872 (s 1085 cm-1); NMR n° 23421 (3.17 ppm, 3 H, S, --O--CH3). Odor: natural, fresh, reminiscent of lavender; suitable in combination with esters.
Reaction SMILES: [CH3:1][N:2]([CH2:20][P:21]([O:33]CC)([CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].C[Si](Br)(C)C>ClCCl>[CH3:1][N:2]([CH2:20][P:21]([OH:33])([CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4]
Reactant: CCOP(=O)(CCCCc1ccccc1)CN(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)CCCCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 1-[[methyl[[ethoxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester, dry dichloromethane, and trimethylsilylbromide is stirred under argon at room temperature for several hours. The dichloromethane and excess trimethylsilylbromide are removed in vacuo and the residue is partitioned between ethyl acetate/water. The organic phase is washed with brine, dried, and evaporated to give 1-[[methyl[[hydroxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester.