Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:15]1[C@@H:20]([OH:21])[C@@H:19]([OH:22])[C@H:18]([OH:23])[CH2:17][C@@:16]1([C:25]([OH:27])=[O:26])[OH:24].C1[C@:34](O)([C:35]([OH:37])=[O:36])CC(=O)[C@@H](O)[C@@H]1O>>[CH2:15]1[C@@H:20]([OH:21])[C@@H:19]([OH:22])[C@H:18]([OH:23])[CH2:17][C@@:16]1([C:25]([OH:27])=[O:26])[OH:24].[C:35]([O-:37])(=[O:36])[CH3:34]
Reactant: O=C1C[C@@](O)(C(=O)O)C[C@@H](O)[C@@H]1O
Agent: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(=O)[O-]
Reaction time: 60 h

Procedure:
QP1.1/pKD12.112 was cultured for 60 h under fed-batch fermentor conditions at 37° C., pH 7.0, dissolved oxygen at 10% of saturation and an initial glucose concentration of 23 g/L. Extracellular accumulation of quinic acid began in early to mid log phase of microbial growth as represented by the open boxes in FIG. 2. The dry cell weight is represented by the solid line and closed circles. 3-Dehydroquinate was efficiently converted to quinic acid as there was never a build-up of the intermediate (solid bars in FIG. 2). After 60 hours of cultivation with Kc=0.1, E. coli QP1.1/pKD12.112 synthesized 60 g/L of quinic acid in 23% yield along with only 2.6 g of 3-dehydroquinate. Quinic acid was isolated from the fermentation broth by ion-exchange chromatography on AG1-x8 (acetate form) and DOWEX 50 (H+ form) columns. Purified quinic acid was obtained by further recrystallization.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([NH:20][C:18](=[O:19])[C:17]3[C:16](=[CH:24][CH:23]=[C:22]([Br:25])[CH:21]=3)[NH:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
N-benzyl 4-piperidone (1.76 g, 9.3 mmol) and concentrated H2SO4 (2 drops) were added to a solution of 2-amino-5-bromo-benzamide (2 g, 9.3 mmol) dissolved in acetic acid (15 ml). The mixture was stirred at RT for 2 h, then poured into ice water and brought to a pH value of 8-9 with saturated NaHCO3. The white precipitate was filtered off and washed with water, giving 1-benzyl-6′-bromo-3′,4′-dihydro-spiro[piperidine-4,2′(1′H)-quinazoline]-4′-one (1.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22](O)=[O:23])[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27]>C1COCC1>[CH2:25]([NH:28][C:22]([CH:20]1[CH2:19][CH2:18][C:17]2[C:10]3[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:15][C:16]=2[CH2:21]1)=[O:23])[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: O=C(O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Solvent: C1CCOC1
Product: C=CCNC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 15 mL round-bottom flask were added 50 mg (0.124 mmol, 1 equiv) of 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid, 1, 20 mg (0.124 mmol, 1 equiv) of CDl and THF (1.25 mL). The reaction was stirred for 4 h at rt and then 0.01 mL (0.186 mmol, 1.5 equiv) of allyl amine was added via syringe and the reaction was allowed to stir at rt overnight. The reaction was stopped and THF was concentrated in vacuo and the crude solid was re-dissolved in CH2Cl2 (5 mL). This solution was poured into a separatory funnel and washed with satd NaHCO3 (1×5 mL), water (1×5 mL), and brine (1×5 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield a white solid. The compound was triturated with diethyl ether to yield pure material, 56, as a white solid (36 mg, 66%). 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.31 (s, 1H), 8.19 (t, 1H), 7.86 (m, 1H), 7.63 (m, 1H), 7.25 (m, 2H), 5.82 (m, 1H), 5.08 (m, 2H), 3.75 (t, 2H), 3.21 (m, 2H), 2.97 (d, 2H), 2.69 (m, 1H), 2.15 (m, 1H), 1.82 (m, 1H); LCMS RT=2.78 min; [M+H]+=444.
Reaction SMILES: N[C@@:2]1(/[CH:15]=[N:16]\[O:17][C:18](=O)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[N:30]1C=CC=CC=1>>[OH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]2[O:17][N:16]=[C:15]([C@@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:30]=2)=[CH:22][CH:23]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(N)/C=N\OC(=O)COc1ccc(CO)cc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CO)cc2)n1

Procedure:
tert-Butyl (Z)-(2S)-2-amino[(2-[4-(hydroxymethyl)phenoxy]acetyloxy)imino]methyl-1-piperidinecarboxylate (see Preparation 12] (2.94 g) was dissolved in pyridine (30 ml) and heated under reflux for 18 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50 changing to 0:100 (in 10% increments), by volume, hexane:ethyl acetate to afford tert-butyl (2S)-2-(5-[4-(hydroxymethyl)phenoxymethyl]-1,2,4-oxadiazol-3-yl)-1-piperidinecarboxylate (1.06 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].[N:21]1([C:26]2[CH:27]=[C:28]([C:32]3[O:37]C(C)(C)[O:35][C:34](=O)[CH:33]=3)[CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH:19][C:34](=[O:35])[CH2:33][C:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:27]=1)=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (1.37 g, 5.0 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) (1.28 g, 4.75 mmol) according to the general procedure M. Obtained as a light brown foam (1.78 g).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]2=[N:20][CH:19]=1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ccncc4)c3F)cnc2n1

Procedure:
2-Fluoro-3-(pyridin-4-yl)benzeneboronic acid was coupled with 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 70% yield by a similar procedure to that described in Example 3, step f, to afford the title compound as a yellow solid: mp 221-223° C. (CH2Cl2-EtOAc-MeOH); 1H NMR (400 MHz, DMSO-d6) δ 1.57 (6H, s), 5.79 (1H, s), 7.55 (1H, t, J 7.8 Hz), 7.66 (2H, m), 7.73 (1H, m), 8.15 (1H, m), 8.29 (1H, d, J 2.3 Hz), 8.71 (2H, m), 9.02 (1H, s); MS (ES+) m/z 350 [M+H]+. Anal. Found: C, 65.06; H, 4.62; N, 19.91%. Required for C19H16FN5O: C, 65.32; H, 4.62; N, 20.05%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:4]2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:74]1([NH2:79])[CH2:78][CH2:77][CH2:76][CH2:75]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)C>[CH:74]1([NH:79][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:10]([C:11](=[O:13])[CH3:12])=[C:4]3[CH:3]=2)[CH2:78][CH2:77][CH2:76][CH2:75]1
Reactant: COc1ccc(-c2nn3ccc(Cl)cc3c2C(C)=O)cc1
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(C)=O)cc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 55.5 %

Procedure:
To a solution of 1-[5-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (1.77 g, 5.88 mmol) in toluene (60 mL) was added successively racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (220 mg, 0.35 mmol), cesium carbonate (2.88 g, 8.83 mmol), cyclopentylamine (2.9 mL, 29.4 mmol), and palladium (II) acetate (53 mg, 0.24 mmol). The resulting mixture was stirred at 95° C. for 3 days, at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and diethyl ether and water were added to the reaction mixture. The phases were separated, and the aqueous phase again extracted with diethyl ether. The combined organic phases were dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (3:2 hexanes:ethyl acetate) to give 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (1.14 g, 56%) as a yellow solid. 1H NMR (CDCl3): δ 8.19 (d, 1H), 7.52 (d, 2H), 7.45 (d, 1H), 7.03 (d, 2H), 6.35 (dd, 1H), 4.15 (broad s, 1H), 3.98 (m, 1H), 3.91 (s, 3H), 2.21–2.15 (m, 2H), 2.11 (s, 3H), 1.79–1.54 (m, 6H); MS m/z 350 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[Cl:34][C:30]1[CH:29]=[C:28]([C:7]2[N:8]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][C:18]([CH2:20][N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)=[CH:19][C:14]=4[N:13]=[CH:12]3)[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-n2cnc3cc(CN4CCN(C)CC4)ccc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc3c(c2)ncn3-c2nc(-c3cccc(Cl)c3)c(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 0.25 g (0.5 mmole) of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.2e) in 10 mL of tetrahydrofuran and 10 mL of water was added 0.12 g (5 mmole) of lithium hydroxide. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure, 40 mL of water was added and the pH adjusted to 6-7 by the addition of 1M hydrochloric acid. The precipitate was collected by filtration to give 0.120 g of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.3a) as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([NH2:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[O:1]([CH2:8][CH2:9][CH2:10][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CCOc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
A solution of 3-phenoxy-propionamide (1.0 g, 6.0 mmol) in diethyl ether (30 mL) was cooled to 0 C. Lithium aluminum hydride (0.46 g, 12 mmol) was added in portions to the stirring amide solution. The resulting slurry was allowed to warm to rt and stirred for 20 h. The mixture was cooled to 0° C. and carefully quenched by the sequential addition of 0.5 mL of water, followed by 0.5 mL of 3 N sodium hydroxide and 1.5 mL of water. The mixture was stirred for 15 min, then filtered to remove the aluminum salts. The filtrate was collected and the volatile material was removed by a rotary evaporator to give 3-phenoxy-propylamine (0.55 g) as a pale green oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.C(O)(C)C.CO.[BH4-].[Na+]>O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][CH:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: Cn1c2c(c3cc(O)ccc31)CCC2NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a stirred solution prepared from 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (16.0 g), isopropanol (200 ml) and methanol (50 ml) was added sodium borohydride (4.8 g) and the mixture was stirred under nitrogen at ambient temperature for 3 hours. The mixture was cooled to 0° C., water was slowly added and the mixture was stirred 0.5 hour. The mixture was extracted with CH2Cl2 (2×200 ml), and the CH2Cl2 extracts were dried (Na2SO4), Concentrated and chromatographed on silica gel eluting with 2:1 hexanes/acetone. The product-containing fractions were combined to give 4.25 grams of 4-methyl-3-(phenylmethylamino)-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]#[N:21].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:19][C:20]#[N:21])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Br)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A solution of ethyl 6-bromoindole-2-carboxylate (4.4 g, 16.4 mmol) in DMF (20 mL) was added dropwise over ˜2–3 min to a stirred suspension of sodium hydride (60%, 1.0 g, 25 mmol) in DM (20 mL) at 0° C. under Ar. The reaction was stirred at 0° C. for 45 min then chloroacetonitrile (2.1 mL, 33 mmol) was added in one portion. The reaction was then heated to 75° C. and stirred for 1 h. After allowing to cool to room temp the mixture was poured into water (150 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with brine (75 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude solid which was purified by flash column chromatography (SiO2; ethyl acetate) to give the product as a yellow solid (4.8 g, 95%). IR νmax (Nujol)/cm−1 3320, 3089, 2925, 2855, 1898, 1705, 1609, 1530, 1521, 1470, 1449, 1427, 1400, 1394, 1377, 1367, 1336, 1308, 1265, 1205, 1151, 1134, 1108, 1054, 1027, 993, 950, 90, 873, 841, 832, 802, 792, 762, 736, 663, 615 and 589; NMR δH (400 MHz; CDCl3) 7.61 (1H, s), 7.57 (1H, d, J 8.5 Hz), 7.37 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5 Hz, 1.5 Hz), 5.57 (2H, s), 4.45 (2H, q, J 7.2 Hz), 1.42 (3H, t, J 7.2 Hz).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1)[CH3:25]>C(#N)C>[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33]([N:10]3[CH2:11][CH2:12][C:6]4([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]4)[CH2:9]3)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CN1CCC2(CCNC2)C1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCN(C)C4)C3)c(F)c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.1 %

Procedure:
A suspension of 0.64 g (3.0 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 40 ml acetonitrile was treated with 1.33 g (9.0 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.81 g (3.0 mmol) 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added. The mixture was stirred 45 minutes at room temperature, refluxed 1.5 hours, and stirred at room temperature overnight. The precipitate was filtered and washed with acetonitrile and ether to afford 0.87 g of the title compound, mp 229°-231° C. (dec).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:22]([Cl:23])=[CH:21][N:20]([CH3:24])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:23][C:22]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[C:31]([OH:33])=[O:32])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([C:41]5[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=5)=[CH:35][CH:34]=4)[C:11]=3[CH:12]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: Cn1cc(Cl)c(COc2ccc3nc([C@@H]4CCCC[C@@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(-c5ccc(C(F)(F)F)cc5)cc4)c3c2)n1

Procedure:
The title compound was prepared using analogous conditions described in Example 144 using (1S,2R)-2-(1-(4-bromobenzyl)-6-((4-chloro-1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. for C33H30ClF3N4O3, 623.08; m/z found, 623.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.81 (d, J=8.3, 2H), 7.76-7.67 (m, 5H), 7.63 (s, 1H), 7.34-7.23 (m, 4H), 5.90 (d, J=17.4, 1H), 5.84 (d, J=17.4, 1H), 5.09-4.99 (m, 2H), 3.75 (s, 3H), 3.70-3.61 (m, 1H), 3.00-2.89 (m, 1H), 2.42-2.28 (m, 1H), 2.25-2.17 (m, 1H), 2.14-2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.88-1.63 (m, 2H), 1.64-1.43 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:17]2[C:13]([S:14][C:15]([C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[CH:16]2)=[CH:12][N:11]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([C:15]3[S:14][C:13]4=[CH:12][N:11]=[C:10]([CH2:9][OH:8])[N:17]4[CH:16]=3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(CO[Si](C)(C)C(C)(C)C)ncc4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(CO)ncc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 799 mg of 4-nitrobenzyl (1S,5R,6S)-2-(5-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 20 ml of THF were added 1.1 ml of acetic acid and 6.5 ml of 1 M solution of tetra-n-butylammonium fluoride in THF under the atmosphere of argon, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and diluted with 100 ml of ethyl acetate, 100 ml of aqueous saline and a saturated aqueous sodium hydrogen carbonate solution to adjust pH to 7.8. The organic layer was separated, washed with aqueous saline, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 619 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>CC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][N:7]([C:25]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:27][N:28]=[C:23]([Cl:22])[N:24]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred clear colourless solution of Ethyl3-(cyclopentylamino)-2,2-dimethyl-propanoate (US 2004/0176380 A1; 29.8 g, 139.7 mmol) in the acetone (700 mL) at room temperature was added potassium carbonate (21.3 g, 153.7 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 29.81 g, 153.7 mmol). The reaction mixture was stirred vigorously at room temperature overnight. Potassium carbonate (7.75 g, 56 mmol) was added stirring continued for a further 4 hours. The reaction mixture was concentrated in vacuo to low volume and partitioned between Ethyl Acetate (600 mL) and water (400 mL). Phases were separated and the aqueous phase re-extracted with Ethyl Acetate (1×200 ml, 1×100 ml). The combined organic extracts were dried using MgSO4 and evaporated to dryness The residue was dissolved in DCM (150 mL) and purified in two batches using a Biotage Flash 75 system with 400 g Si column, conditioned with 10% Ethyl Acetate in isohexane and eluted with 10% Ethyl Acetate in isohexane. Product containing fractions were combined and evaporated giving the title compound as a yellow oil which solidified on standing in a freezer (27.90 g 54%)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28]>CN1C(=O)CCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: NCC(N)=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(NCC(N)=O)cc1OCC2
Temperature: 85 °C
Yield: 8 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and glycinamide hydrochloride salt in NMP were heated at 85° C. for 20 h. The reaction mixture was cooled and loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol and appropriate fractions concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% 2M ammonia in methanol in DCM). The solid was recrystallised from methanol to give 404 as a white solid (19 mg, 8%). LCMS: RT=2.14 min, [M+H]+=369. 1H NMR 400 MHz (DMSO-d6) δ: 9.01 (1 H, s), 7.90 (1 H, d, J=0.63 Hz), 7.82 (1 H, s), 7.32 (1 H, br, s), 7.01 (1 H, br, s), 6.11 (1 H, s), 5.97-5.88 (1 H, m), 4.49-4.48 (4 H, m), 3.84 (2 H, d, J=4.26 Hz), 1.48 (6 H, d, J=6.60 Hz)