Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C@H:4]1[C@@H:8]([C@:9]([NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH3:10])[CH2:7][O:6][CH2:5]1)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:18][C@@:9]([C@H:8]1[CH2:7][O:6][CH2:5][C@H:4]1[OH:3])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10]
Reactant: C[C@@](N)(c1ccccc1F)[C@H]1COC[C@H]1OC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@](N)(c1ccccc1F)[C@H]1COC[C@H]1O
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of (3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazole (16.72 g, 72.9 mmol) in ethanol (300 ml) was treated with ammonium formate (36.8 g, 583 mmol) and palladium (5% on carbon; 7.76 g). The reaction mixture was stirred at room temperature for 18 hours, then filtered and the filtrate evaporated at reduced pressure. The crude product was triturated with diisopropyl ether (50 ml) and filtered. The filtrate was evaporated at reduced pressure and the (3S,4S)-4-[(S)-rel-1-amino-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (8.69 g, 48% yield) was obtained as a thick colorless oil. MS (ISP): m/z=226.2 [M+H]+. The solid material obtained after filtration, the rel-(3S,4S)-4-[(S)-1-amino-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol formate (8.21 g, 42% yield), was treated with a saturated solution of sodium hydrogencarbonate (100 ml) and with dichloromethane (100 ml) and stirred for 1 hour. The aqueous layer was separated and extracted with dichloromethane, then the combined organic layers were dried over sodium sulphate and evaporated. An additional amount of the rel-(3S,4S)-4-[(S)-1-amino-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (5.6 g, 31% yield) was obtained as a thick colorless oil. MS (ISP): m/z=226.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][C:9]([Cl:13])=[N:10]2)=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)C>[N:21]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][C:9]([Cl:13])=[N:10]2)=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(-c2cc(Cl)nc3cc(CBr)ccc23)cc1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1

Procedure:
A solution of 7-(bromomethyl)-2-chloro-4-(4-fluorophenyl)quinoline (1.0 g, 2.9 mmol) and sodium azide (204 mg, 3.1 mmol) in ethanol (40 mL) was refluxed for 16 h. The solution was concentrated and dichloromethane was added. The mixture was filtered, and concentrated to give the title compound. MS (+ESI): 313 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:14]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2Cc3ccc(-c4ccc(Cl)cc4Cl)cc3[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2ccc3c(c2)[C@H]2CNCC[C@H]2C3)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of cis-6-(2,4-dichloro-phenyl)-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid tert-butyl ester in CH2Cl2-(1.6 mL) was added trifluoroacetic acid (0.4 mL). The reaction mixture was stirred for 2 h at 20° C. then concentrated in vacuo. The residue was basified with NH4OH then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (20 mg, 0.06 mmol): MS (ES) 318.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[C:18]([O:24][CH2:25]Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:18]([O:24][CH2:25][N:10]1[C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][N:4]=2)[C:8]([C:11](=[O:12])[NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a stirred mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in DMF (5 mL) was added chloromethyl pivalate (225 mg, 1.5 mmol) followed by K2CO3 (276 mg, 2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1, v/v) to give (2-bromo-7-(tert-butylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (140 mg, 34% over two steps) as white solid. MS: (M+H)+=411; 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.33 (s, 1H), 7.80 (s, 1H), 6.20 (s, 2H), 1.52 (s, 9H), 1.15 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][OH:24])=[C:14]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[CH:32][CH:31]=3)=[O:27])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1.C(Cl)Cl>[CH3:46][S:47]([O:24][CH2:23][CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:13][C:14]=1[NH:25][C:26]([C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([O:37][CH3:38])=[CH:32][CH:31]=2)=[O:27])(=[O:49])=[O:48]
Reactant: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCO)cc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCOS(C)(=O)=O)cc2c1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (0.4 g, 0.78 mmol) and triethylamine (0.44 mL, 3.14 mmol) in THF (20 mL) was added methanesulfonyl chloride (0.24 mL, 3.14 mmol) with ice bath and stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (10 mL) and saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica-gel column (30% AcOEt-Petroleum ether) to yield as a yellow foam 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethyl methanesulfonate (0.28 g, 61%): mp 160° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 9.09 (brs, 1H), 8.36 (brs, 1H), 7.89 (d, 9.0, 1H), 7.87 (d, 9.0, 1H), 7.57 (t, 8.5, 1H), 7.48 (d, 7.5, 2H), 7.40 (t, 7.5, 2H), 7.34 (m, 2H), 7.17 (s, 1H), 7.13 (s, 1H), 7.00 (d, 8.5, 1H), 7.00 (d, 9.0, 1H), 4.70 (brs, 2H), 4.61 (t, 6.0, 2H), 4.50 (s, 2H), 3.88 (s, 3H), 3.54 (t, 6.0, 2H), 2.84 (s, 3H); ); FABMS (NBA) m/z 543 (M−CO2+), IR (neat) νmax 3400, 1643, 1591, 1530, 1479, 1453, 1351, 1231, 1213, 1173, 1142, 1076, 1031, 974, 947, 841, 805, 761, 734, 699 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[O-]CC.[Na+:12].[Cl-]>C(O)C>[Na:12][CH2:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6]
Reactant: [Na+]
Reactant: COC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Cl-]
Solvent: CCO
Product: CC(=O)CC(=O)OC[Na]
Reaction time: 3 h

Procedure:
Sodiomethylacetoacetate was prepared by adding an excess of methylacetoacetate (74.3 g, 0.64 mole) to a solution of sodium ethoxide (31.3 g, 0.46 mole) in 150 mls. absolute ethanol at 25°. The reaction mixture was cooled to 0° and then the crude chloride prepared above was added dropwise over a 25-minute period and stirring was continued at 0° for an additional 3 hours. After this period, the temperature was allowed to rise to ambient over a 40-minute period. A portion of the ethanol (78.0 g) was distilled at this point by stirring the reaction mixture at 60°-65° for 2 hours under a slight vacuum. After cooling to 30°, 550 mls. of 10% aqueous NaOH was added over a 15-minute period and the reaction mixture was stirred at 70° for 4 hours. After settling, the layers were separated and the aqueous layer was saturated with NaCl and extracted with three 200-ml. portions of pentane. The combined oils were washed once with 1 liter H2O and once with 1 liter saturated NaCl to yield, after solvent removal, 139.2 g of crude 6,10,14-trimethylpentadeca-5,9-dien-2-one. Gas chromotographic analysis indicated 53.2% purity which represents an estimated theory yield from 10,11-dihydrofarnesene of 78.8%.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.CCOCC.O>C(Cl)Cl>[CH3:21][C:2]1([CH3:1])[O:30][CH:3]1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)NCCOc1ccc(OCC2OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl}carbamate (0.46 g, 1.6 mmol) in 10 ml of methylene chloride at 5° is added m-chloroperbenzoic acid (0.29 g, 1.7 mmol) in portions over 15 min. The mixture is stirred at 5° for 1 hour, then allowed to warm to RT and stirred for 1.5 hours longer. Ether is added to the reaction mixture and it is poured into water and washed with 10% sodium sulfite, with saturated sodium bicarbonate, with water until neutral and with brine. The organic layer is dried over calcium sulfate, filtered and rotoevaporated and the residue is purified by column chromatography to give ethyl N-{2-[4-(3-methyl-2,3-epoxybutoxy)phenoxy]ethyl}carbamate (compound 27, Table A).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]=[C:11](B3CC(C)(C)C(C)(C)O3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](OS(C(F)(F)F)(=O)=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[Li+].[Cl-]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:11]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[O:9][CH:10]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1cccc2c(B3CC(C)(C)C(C)(C)O3)coc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12
Temperature: 150 °C
Yield: 104.7 %

Procedure:
To a solution of 2-(7-methoxybenzo[b]furan-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane (1.10 g, 4.0 mmol) in dimethoxyethane (1 mL) was added CsCO3 (0.650 g, 2.0 mmol), H2O (1 mL), 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.480 g, 1.45 mmol), LiCl (0.10 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0.05 mmol). The reaction was heated in the microwave for 5 min at 150° C. The solvent was removed in vacuum, the residue taken up in 300 mL of methylene chloride, washed with 200 mL portions of saturated aqueous sodium carbonate and 1 N NH4OH (aq), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was filtered through 150 mL of silica gel with 15% ethyl acetate/hexane as eluant to give 0.50 g of the title compound. 1 H NMR (300 MHz, CDCl3); δ 1.5 (s, 9H), 2.51 (t, 2H), 3.66 (t, 2H), 4.04 (s, 3H), 4.12 (dd,2H), 6.24 (brs, 1H), 6.91 (d, 1H), 7.17 (t, 1H), 7.39 (d, 1H), 7.59 (s, 1H), MS (ES) m/z (relative intensity): 330 (M+H,100).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])=[CH:4][C:5](=O)[CH3:6].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:12]([CH3:13])[C:11]2[C:5]([CH:4]=1)=[CH:6][CH:14]=[CH:15][CH:10]=2
Reactant: Brc1ccccc1
Reactant: COC(C)=CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C)c2ccccc2c1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of 5-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was added dropwise to a suspension of NaNH2 (84.4 g, 2.2 mmol) in dry THF (480 mL) under nitrogen. The resulting mixture was heated for 2 h at 40-45° C. After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C. The resulting mixture was stirred at 45° C. for 2 h. A solution of bromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and the mixture was stirred at 55° C. for 6 h. The mixture was allowed to cool to room temperature overnight. The mixture was poured into ice, acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, and the residue was diluted with acetone (480 mL) and stirred with conc. HCl solution (24 mL) for 10 min. The mixture was diluted with EtOAc (200 mL) and washed with saturated brine (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (700 g silica gel with dry-loading, eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)[CH:18]=2)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59]>CN(C=O)C>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][C:23]([NH:22][C:19]2[CH:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[O:21][N:20]=2)=[O:28])[CH2:64][CH2:65]1)=[O:59]
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cc(-c2ccc(F)cc2)on1
Reaction time: 0.03 h
Yield: 28.5 %

Procedure:
DIPEA (57 mg, 0.078 mL, 0.45 mmol) was added dropwise to N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid (40 mg, 0.15 mmol) in DMF (2 mL) followed by EDCI (35 mg, 0.18 mmol) and HOBT (24 mg, 0.18 mmol). After 2 minutes, (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (55 mg, 0.18 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched with cold water and was then extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by preparative HPLC afforded 22 mg (28.27% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-3-oxo-propionamide. LC/MS [M+H]+: 515.07, 96.02%. 1H NMR (300 MHz, DMSO-d6): δ 11.4-11.2 (m, 1H), 7.8 (m, 2H), 7.6 (d, 1H), 7.4-7.2 (m, 5H), 7.1 (t, 2H), 6.6 (d, 1H), 4.1-3.9 (m, 2H), 3.8-3.2 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+].[ClH:19]>C(O)C.O1CCCC1>[ClH:19].[Br:1][C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1nc2cccc(C)n2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(=O)O)c(Br)n12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 3-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate (0.62 g, 2.2 mmol) in ethanol (3.3 mL) and tetrahydrofuran (3.3 mL) was treated with 1 M sodium hydroxide (6.5 mL, 6.5 mmol) and stirred at 20° C. for 2 h. The reaction mixture was concentrated and the resultant solid was diluted with water, cooled to 0° C., and treated with 1 M hydrogen chloride (8.7 mL, 8.7 mmol) dropwise. The aqueous mixture was concentrated to a solid that was diluted with acetonitrile and reconcentrated (2×) to give the desired product which contained sodium chloride. This material was used without further purification. LCMS for C9H8BrN2O2 (M+H)+: m/z=255.0, 257.0.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14]CC3C=CC([N+]([O-])=O)=CC=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35](=[NH:38])[CH2:36][SH:37])[CH2:31][C:30]1=[O:39]>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35](=[NH:38])[CH2:36][S:37][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]3[C:7]=2[C:12]([OH:14])=[O:13])[CH2:31][C:30]1=[O:39]
Reactant: CN1CCN(C(=N)CS)CC1=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCN(C)C(=O)C3)[C@H](C)[C@H]12
Yield: 9.1 %

Procedure:
The procedure of Example 1(3) was repeated, except that 100 mg of p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 90 mg of 2-(4-methyl-3-oxopiperazin-1-yl)-2-iminoethylmercaptan hydrochloride were used. After hydrogenation and filtration over "Celite" (Trade Mark) filter aid, the filtrate was extracted twice with 20 ml portions of diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure, and the residue was purified by chromatography through a Lobar column (Merck "LiChloprep RP-8", size B, two columns), eluted with 2% aqueous methanol, to give 10 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>CN(C)C=O>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH:46][C:47]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)=[O:48]
Reactant: O=C=Nc1ccccc1F
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)Nc5ccccc5F)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (220 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (143.2 mg, 1.1 mmol) followed by o-fluorophenylisocyanate (75.4 mg, 0.55 mmol). The resulting mixture was stirred at room temperature overnight, concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (92.6 mg, 0.12 mmol, 22%). (m/z): [M+H]+ calcd for C30H39FN6O2 535.32. found 535.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=2.09 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: C1CCNC1
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 86.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), pyrrolidine (0.084 mL, 0.998 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (172 mg, 0.433 mmol, 87% yield). 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H); 7.89 (dd, J=8.33, 2.34 Hz, 1H); 6.74 (d, J=8.92 Hz, 1H); 6.67 (s, 1H); 3.94 (s, 3H); 3.50 (s, 4H); 1.95 (s, 4H). m/z (ESI, +ve ion) 398.0 (M+H)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH:11]=[CH:10][CH:7](C=O)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)CC.[CH3:17][C:18](=[CH:21]C1CCC=C(C(C)(C)C)C1)[CH:19]=[O:20]>>[CH3:21][C:18](=[CH:17][CH:10]1[CH2:7][CH2:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:12][CH2:11]1)[CH:19]=[O:20]
Reactant: CC(C)(C)C1CC=CC(C=O)C1
Reactant: CC(C=O)=CC1CCC=C(C(C)(C)C)C1
Solvent: CCC=O
Product: CC(C=O)=CC1CC=C(C(C)(C)C)CC1
Yield: 80 %

Procedure:
A mixture of Δ3 -4-tert.-butyl- and Δ3 -3-tert.-butyl-tetrahydrobenzaldehyde prepared according to instructions B is condensed with propionaldehyde in a conventional manner. An 80% yield of 2-methyl-(4-tert.-butyl-cyclohex-3-enyl)-prop-2-en-1-al and 2-methyl-(3-tert.-butyl-cyclohex-3-enyl)-prop-2-en-1-al in a ratio of about 70:30 is obtained. Boiling point: 153° C./30 mbar.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[SH:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1.Cl>[OH-].[Na+]>[CH2:1]([S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCI
Reactant: Oc1cc(O)nc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCSc1nc(O)cc(O)n1

Procedure:
An amount of 184.1 g of n-butyliodide is added to 144.2 g of 2-mercapto-4,6-dihydroxy-pyrimidine dissolved in 1000 ml of 2-n aqueous sodium hydroxide solution, and the whole heated for 2 hours at 85°-90°C. After cooling, the reaction mixture is rendered acid, to a congo-red indicator, with ice and concentrated hydrochloric acid. The 2-n-butylthio-4,6-dihydroxy-pyrimidine obtained as a precipitate is separated and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1>O1CCOCC1>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: c1ccc2c(CCN3CCOCC3)c[nH]c2c1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
Morpholine (2.33 g, 2.33 ml, 26.8 mmol) was dissolved in abs. dioxane (50 ml), and 3-(2-bromo-ethyl)-1H-indole (3.00 g, 13.4 mmol) was added at RT. The solution was stirred at 70° C. for 14 h and concentrated i. vac., the residue was taken up in CHCl3 (100 ml) and the mixture was washed with water (2×30 ml). The organic phase was dried over Na2SO4, filtered and concentrated i. vac. The residue obtained was recrystallized from aqueous methanol.