Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:28][CH2:27][C:23]2([CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:26][C:23]4([CH2:27][CH2:28][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCC2(CC1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (72 mg, 0.254 mmol) in DCE (7 mL) was added 7-methyl-2,7-diaza-spiro[3.5]nonane (45 mg, 0.321 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (81 mg, 0.382 mmol) was added and stirring was continued for 3 h. To the reaction mixture was added water and the resulting solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH an concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow oil (31 mg, 30%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(OC(C)C)(=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (Intermediate A) (20 g, 87.0 mmol) in isopropyl acetate (240 mL) was added to a stirred solution of sodium carbonate (11.3 g, 106 mmol) in water (80 mL). After 10 min phenyl chloroformate (12.1 mL, 96 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (160 mL), the layers were separated and the organics were washed with water (2×80 mL), brine (80 mL), dried (MgSO4) and concentrated in vacuo. The resulting yellow solid was suspended in 10% ether/iso-hexane (320 mL) and stirred until a uniform suspension was obtained. The solid was collected by filtration and washed with iso-hexane to yield the subtitle compound phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate as a white powder (27.3 g, 88%); Rt 2.65 min (Method 1); m/z 350 (M+H)+ (ES+); 1H NMR δ:1.29 (9H, s), 2.37 (3H, s), 6.35 (1H, s), 7.10-7.23 (3H, overlapping m), 7.33-7.46 (6H, overlapping m), 9.99 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10]([C@H:14]1[C:44](=[O:45])[N:43]2[CH2:46][C@@H:40]([CH2:41][C@H:42]2[C:47]([NH:49][C@:50]2([C:55](=[O:64])[NH:56][S:57]([C:60]3([CH3:63])[CH2:62][CH2:61]3)(=[O:59])=[O:58])[CH2:52][C@H:51]2[CH:53]=[CH2:54])=[O:48])[O:39][C:26]2=[N:27][C:28]3[CH:29]=[C:30]([CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][C:33]=3[C:34]([OH:35])=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:65][C@H:18]2[O:17][C:16](=[O:66])[NH:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C@H:14]1[C:44](=[O:45])[N:43]2[CH2:46][C@@H:40]([CH2:41][C@H:42]2[C:47]([NH:49][C@:50]2([C:55](=[O:64])[NH:56][S:57]([C:60]3([CH3:63])[CH2:62][CH2:61]3)(=[O:59])=[O:58])[CH2:52][C@H:51]2[CH:53]=[CH2:54])=[O:48])[O:39][C:26]2=[N:27][C:28]3[CH:29]=[C:30]([CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][C:33]=3[C:34]([O:35][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:65][C@H:18]2[O:17][C:16](=[O:66])[NH:15]1)([CH3:12])([CH3:13])[CH3:11]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3cc(C(C)C)ccc3c1O)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: BrCCN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3cc(C(C)C)ccc3c1OCCN1CCOCC1)O2)C(=O)NS(=O)(=O)C1(C)CC1

Procedure:
The title compound was prepared using the same method as described in Example 42, using the 4-(2-bromoethyl)morpholine and (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo-14-(propan-2-yl)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxamide (synthesized in the same way as Example 120 but using intermediates A2, B10 and C9). LRMS (ES+) m/z 921.55 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:21]=[CH:20][C:10]2[N:11]=[C:12]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=2[CH:8]=1)(C)C.[OH-].[K+].Cl>CO.CCOC(C)=O>[C:6]([C:7]1[CH:21]=[CH:20][C:10]2[N:11]=[C:12]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=2[CH:8]=1)#[CH:5]
Reactant: CCNC(=O)Nc1nc2ccc(C#C[Si](C)(C)C)cc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2nc(NC(=O)NCC)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A mixture of 1-(6-trimethylsilylacetylenyl-2-benzothiazolyl)-3-ethylurea (0.0710 g, 0.22 mmol) and 1M aqueous KOH solution (1.22 mL, 1.22 mmol, 5.5 eq) in 1.5 mL MeOH was stirred at room temperature for about 2 hours. The mixture acidified with 1 M HCl, then taken up in 20 mL AcOEt, and the aqueous phase was extracted with 10 mL AcOEt. The combined organic portions were dried (MgSO4), concentrated, and purified by HPLC to give the desired compound 0.003 g (5%). LC/MS 246 (M+1); LC retention time 2.84 min.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[CH:1]([N:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Product: CC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from 1-benzhydryl-azetidin-3-ylamine and acetyl chloride by a procedure analogous to Example 70A. MS: 281 (MH+); HPLC Rf: 5.57 min; HPLC purity: 93%.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCCN2CCOCC2)cc1Cl
Reaction time: 18 h
Yield: 36.4 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), 2-morpholinylethylamine (59 mg, 0.45 mmol) and triethylamine (101 mg, 1 mmol). The reaction mixture was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(2-morpholinylethyl)pyrimidine-5-formamide (71 mg, 36.5% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:34]=[CH:33][C:20]2[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][O:25][C:19]=2[CH:18]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:34]=[CH:33][C:20]2[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:23][CH2:24][O:25][C:19]=2[CH:18]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(O)ccc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.253 ml, 1.498 mmol) was added to an ice cooled solution of 1,1-dimethylethyl 8-hydroxy-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 30) (0.265 g, 0.999 mmol) in pyridine (4 ml) and stirred for one hour. The reaction mixture was evaporated, dissolved in 40 ml of EtOAc and washed with 20 ml of 2M HCl and 20 ml of saturated sodium bicarbonate then dried (magnesium sulphate) and evaporated to give the title compound (399 mgs) as a yellow gum. MS (ES) C15H18F3NO6S requires 397; found 298 [M+H−100]+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[OH:41][C@@H:39]([CH3:40])[CH2:38][NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: C[C@H](O)CNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 93.6 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[CH3:20]O>Cl>[CH3:20][C:12]1[N:13]=[C:14]([NH2:16])[S:15][C:11]=1[S:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:10])=[O:9]
Reactant: CO
Reactant: CC(=O)Nc1ncc(S(=O)(=O)N2CCN(C)CC2)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1

Procedure:
A solution of N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide (1 g, 3.1 mmol) in methanol (5 mL) and 6 N hydrochloric acid (5 mL) was heated in a microwave oven (4×5 min at 80° C.). The reaction mixture was partly evaporated to remove most of the methanol, and the residue was washed with DCM (10 mL). The water phase was isolated, and the pH adjusted to 8-9. Extraction with DCM (3×25 mL), drying over anhydrous magnesium sulphate, and evaporation in vacuo gave white crystals of 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine. Yield: 0.53 g (61%). 1H-NMR (CDCl3): δ 5.46 (m, 2H); 3.18 (m, 4H); 2.51 (m, 4H); 2.45 (s, 3H); 2.31 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[N:47][CH:46]=[CH:45][N:44]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cnccn4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C
Yield: 43.9 %

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 (600 mg) was dissolved in 1,4-dioxane (11 ml). Added thereto were tri-n-butyl(pyrazinyl)tin 72 (720 mg), tetrakis(triphenylphosphine)palladium (0) (206 mg) and copper (I) iodide (51 mg), and the mixture was stirred under heating at 100° C. for 1.5 hours, under irradiation by a microwave (500 W). The mixture was diluted with ethyl acetate, the insoluble materials were filtered off, and the filtrate was washed with water. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-30:70), and crystallized from hexane-diethyl ether to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene 73 (263 mg) as pale yellow crystals. APCI-Mass m/Z 617/619 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([F:20])([F:18])[F:19])[CH:10]=1
Reactant: [H][H]
Reactant: O=c1ccn(CC(F)(F)F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=c1ccn(CC(F)(F)F)cc1O
Yield: 96.2 %

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (10.5 g, 42.7 mmol) was dissolved in sodium hydroxide solution (1.71 g, 42.7 mmol in 77 mL de-ionized water). 2,2,2-Trifluoroethylamine hydrochloride (23.1 g, 171 mmol) was added and the resulting suspension was stirred at 70° C. (oil-bath temperature) in the sealed flask for 17 hours. The reaction mixture was then filtered and the off-white solid was washed with de-ionized water (20 mL×5) to give 5-(benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (6.00 g). Yield=43%; 1H NMR (MeOD-D4, 90 MHz) δ 7.30 (s, 1H), 6.76-7.09 (m, 5H), 6.71 (s, 1H), 4.93 (d, J=8.4 Hz, 2H) and 4.65 (s, 2H); MS m/z 328 [M+1]+. (b) 5-(Benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (4.70 g, 14.4 mmol) was mixed with DMF (25 mL) and heated to 130° C. (bath temperature) for 3 hours. The mixture was concentrated under reduced pressure using a rotary evaporator and the residue was mixed with ethyl acetate (50 mL). It was then stirred for 2 hours at room temperature and filtered. The filtrate was concentrated to give 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (3.58 g). Yield=69%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.57-7.84 (m, 2H), 7.22-7.57 (m, 5H), 6.25 (br. s, 1H) and 4.69-5.28 (m, 4H); MS m/z 284 [M+1]+. (c) 3-(Benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (1.2 g, 4.2 mmol) was mixed with 10% Palladium on charcoal (wet, 0.12 g) in ethanol (70 mL). The resulting mixture was hydrogenated at 15 psi of hydrogen pressure for 1.5 hours. Palladium was removed by filtration through a layer of Celite™ and the Celite™ cake was washed with methanol (5 mL×3). The filtrate was evaporated to give 3-hydroxy-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.78 g) as white solid. Yield=95%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.60 (d, J=7.1 Hz, 1H), 7.46 (s, 1H), 6.23 (d, J=7.1 Hz, 1H) and 4.80-5.00 (m, 2H); MS m/z 194 [M+1]+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[O:19][C:13]3=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.C1C(=O)N([I:27])C(=O)C1.O>CN(C=O)C>[N:1]1[CH:2]=[C:3]([C:10]2[O:19][C:13]3=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:27])=[C:12]3[CH:11]=2)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2cc(-c3cnc4cnccn34)oc12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(I)c2cc(-c3cnc4cnccn34)oc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
2-(Imidazo[1,2-a]pyrazin-3-yl)furo[2,3-c]pyridin-7-amine (0.018 g, 0.072 mmol) was dissolved in DMF (1 mL). NIS (0.024 g, 0.11 mmol) was added and the mixture was brought to 40° C. After 4 h, the reaction was cooled to room temperature. Water was added and the resulting solid was filtered off. The solid was dissolved in 2:1 methanol:DCM (−30 mL). To this solution was added aqueous sodium thiosulfate (0.5 mL) and the mixture was then concentrated. Purification by ISCO chromatography (0 to 20% methanol:DCM) afforded 0.018 g (67%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.21 (dd, J=1.4, 4.7 Hz, 1 H), 9.17 (d, J=1.5 Hz, 1 H), 8.50 (s, 1 H), 8.14 (d, J=4.8 Hz, 1 H), 7.97 (s, 1 H), 7.27 (s, 1 H); MS (ESI): 378.14 [M+H]+.
Reaction SMILES: C(OC([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:82][Si](C(C)(C)C)(C)C)[CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:81])[C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([S:55]([C:58]4[CH:59]=[C:60]5[C:65](=[C:66]([CH3:68])[CH:67]=4)[N:64]=[CH:63][C:62]([C:69](=[O:71])[NH2:70])=[C:61]5[NH:72][C:73]4[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[CH:74]=4)(=[O:57])=[O:56])[CH:50]=3)=[CH:43][CH:42]=2)C(=O)OC(C)(C)C)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:82][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]([C:49]2[CH:50]=[C:51]([S:55]([C:58]3[CH:59]=[C:60]4[C:65](=[C:66]([CH3:68])[CH:67]=3)[N:64]=[CH:63][C:62]([C:69]([NH2:70])=[O:71])=[C:61]4[NH:72][C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[CH:74]=3)(=[O:56])=[O:57])[CH:52]=[CH:53][CH:54]=2)=[O:81])=[CH:43][CH:42]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OC(=O)OC(C)(C)C)c7[nH]c(=O)ccc67)C(=O)OC(C)(C)C)cc5)c4)cc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCOCCCCCCNC[C@H](O)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The concentrated reaction mixture containing Intermediate 159 was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (1 mL). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (1 mL) and treated with TBAF solution (1.0 M in THF, 1 mL) and glacial acetic acid (0.30 mL). The mixture was stirred overnight in a 40° C. oil bath, and then concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the trifluoroacetic acid salt of the title compound as a yellow powder (16 mg).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C)[C:5]=1[NH:11][S:12](C1C=CC(OC)=CC=1)(=[O:14])=[O:13].Cl.[N:25]1C=CC(CCl)=CC=1>>[N:25]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:5][NH:11][SH:12](=[O:14])=[O:13]
Reactant: ClCc1ccncc1
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: O=[SH](=O)NCc1ccccn1
Yield: 94 %

Procedure:
Following the procedure of Example 45, 0.750 g (2.239 mmol) of the product of Example 3 was alkylated with 4-picolyl chloride hydrochloride to give 0.897 g (94%) of the N-picolyl sulfonamide.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([NH:21][NH2:22])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CCOC(=O)c1ccc(N2CCC(N(C)C)C2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Temperature: 5 °C

Procedure:
A mixture of ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate (2.0 g), hydrazine hydrate (3.8 g) and ethanol (7 ml) was boiled under reflux for 15 hours. After cooling to 5° C., the resulting precipitate was filtered off with suction. The product with the molecular weight of 248.33 (C13H20N4O) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3][CH3:4].[NH2:7][C:8]([O:10][CH2:11][CH3:12])=O.S(=O)(=O)(O)O.C(O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][CH:8]=[N:7][C:1]([O:2][CH2:3][CH3:4])=[O:6])[CH3:12]
Reactant: CCOC(N)=O
Reactant: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC=NC(=O)OCC
Reaction time: 2 h
Yield: 32.4 %

Procedure:
In 40 ml toluene was dissolved 44.4 g (0.3 mol) of ethyl orthoformate, and while keeping the temperature at 110°-120° C., 18 g (0.2 ml) of urethane and 200 ml of a mixture of sulfuric acid with toluene were dropped thereto spending about 2 hours, during which produced ethanol was distilled out of the reaction vessel. After the dropping had been finished, toluene was removed by distillation. The intended product (9.5 g) was obtained by distillation of the residue; b.p. 72.4° C. (15 mmHg), yield 38.8%.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[OH:3].[OH-].[CH2:12]([N+:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>O.CC(O)C>[CH3:1][P:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[O-:4].[CH2:25]([N+:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][CH3:28]
Reactant: CP(=O)(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CP(=O)([O-])c1ccccc1

Procedure:
To a flask were added 2.0 g methylphenylphosphinic acid, 5.4 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 25 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, an oil was obtained.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:24](=[O:25])[N:12]2[C:13]([C:18]([O:20]CC=C)=[O:19])=[C:14]([CH2:16]O)[CH2:15][C@H:11]12)[CH3:9])=O)C=C.[S:26]1[CH:30]=[CH:29][N:28]2[CH:31]=[N:32][CH:33]=[C:27]12>>[OH:7][C@@H:8]([C@H:10]1[C:24](=[O:25])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH2:16][N:32]3[CH:33]=[C:27]4[S:26][CH:30]=[CH:29][N+:28]4=[CH:31]3)[CH2:15][C@H:11]12)[CH3:9]
Reactant: c1cn2cncc2s1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3)C[C@H]12
Yield: 12.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 43 mg of allyl (5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-carbapen-2-em-3-carboxylate and 31 mg of imidazo[5,1-b]thiazole were used, thereby obtaining 5.1 mg of the title compound.