Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][CH2:37][C:36]1=[O:43]>C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[C:5](=[O:24])[O:6][C@H:7]([C@@H:9]([NH:10][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH2:11][N:38]2[CH2:37][C:36](=[O:43])[N:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH2:27][O:26][CH3:25])[CH2:40][C:39]2([CH3:42])[CH3:41])[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: COCOc1ccccc1N1CC(C)(C)NCC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Yield: 87.8 %

Procedure:
A solution of 214 mg of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (0.60 mmol) and 207 mg of 1-(2-methoxymethoxyphenyl)-5,5-dimethylpiperazin-2-one obtained in Example (12a) (0.78 mmol) in toluene (7 ml) was stirred at 110° C. for 45 minutes. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 326 mg of N-{(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}-2-nitrobenzenesulfonamide (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](/[CH:11]=[CH:12]/[C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc(/C=C/S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 68 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-methoxybenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 68-70% yield.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:29])=[C:18]([CH2:20][NH:21][C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH:19]=1)(OC(C)(C)C)=O.Cl.Cl.CCOCC.CO>O>[ClH:29].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:29])=[C:18]([CH2:20][NH:21][C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2ccco2)c1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: O=C(NCc1cc(OC[C@@H]2CCN2)cnc1Cl)c1ccco1
Yield: 64 %

Procedure:
The product of step 213a (0.20 g, 0.50 mmol) was deprotected and isolated as the free base in 64% yield according to the procedure of Example 20b, followed by conversion to the hydrochloride with HCl/Et2O. [α]D23 +21.67 (c 0.7, MeOH); 1H NMR (D2O, 300 MHz) δ 2.66 (dd, J=8.5, 16.5 Hz, 2H), 4.02-4.17 (m, 2H), 4.42 (d, J=4.0 Hz, 2H), 4.64 (s, 2H), 4.88 (m, 1H), 6.68 (dd, J=1.5, 5.5 Hz, 1H), 7.23 (dd, J=1.0, 3.5 Hz, 1H), 7.52 (d, J=3.0 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H); MS (CI/NH3) m/z 322 (M+H)+. Anal. Calcd for C15H16ClN3O3.1.2 HCl.0.2 H2O: C, 48.81; H, 4.81; N, 11.38. Found: C, 48.70; H, 4.76; N, 11.03.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[NH:17][C:18](=[N:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.[ClH:29].C(OCC)C>CO>[ClH:29].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-b 7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (9.0 g.) in methanol (90 ml.) was added concentrated hydrochloric acid (2.12 ml.) with stirring at room temperature, and the mixture was stirred for 7 hours at the same temperature. To the reaction mixture was gradually added diethyl ether till crystals started to precipitate. The mixture was allowed to stand for 30 minutes, and the precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give white crystals of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), (7.9 g.) The remaining filtrate was concentrated till the total volume became half. To the concentrated filtrate was gradully added diethyl ether till crystals started to precipitate, and the mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give further the same object compound (0.5 g.).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH:2]([NH2:1])[CH2:3][NH2:4])=[CH:12][CH:11]=1
Reactant: N#CC(N)CCc1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCC(N)CCc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of 2-amino-4-(4-chloro-phenyl)-butyronitril (0.425 g, 2.18 mmol) in tetrahydrofurane (4 ml) was added dropwise to a suspension of lithium aluminum hydride (0.331 g, 8.73 mmol) in tetrahydrofurane (4 ml) at 0° C. under argon atmosphere. The reaction mixture was allowed to reflux overnight. After cooling to 0° C. solid sodium sulphate decahydrate was added and stirring was continued for 1 hour. The grey suspension was filtered through Celite and the solvent was evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield a colorless oil (0.091 g, 21%); MS (ISP): 199.1 ((M+H)+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:17]O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: CC1CCCCC1n1ccc(Cl)c(C=NO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCCCC1n1ccc(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 102.7 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-(2-methylcyclohexyl)pyridin-2(1H)-one obtained in Step D (1.19 g) in acetonitrile (9.0 mL) was added phosphorus oxychloride (0.412 mL) at room temperature. The reaction mixture was heated at 90° C. for 30 min, and cooled to room temperature. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C1(C2C=CC=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:34]=[O:35])=[N:30][C:31]=1[O:32][CH3:33]>O1CCCC1.O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:34]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[OH:35])=[N:30][C:31]=1[O:32][CH3:33]
Reactant: COc1nc(C=O)ccc1Cl
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Agent: c1ccc(C2CC2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C(O)c2ccc(C3CC3)cc2)ccc1Cl
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.65 M, 3 mL) was added dropwise to a solution of the mixture of 4-bromo-1-cyclopropylbenzene and cyclopropylbenzene (976 mg) in tetrahydrofuran (20 mL) at −78° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. A solution of 5-chloro-6-methoxypyridine-2-carbaldehyde (732 mg) in tetrahydrofuran (9 mL) was added to the reaction solution at −78° C., and the mixture was stirred at the same temperature for three hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→1:10) to give (5-chloro-6-methoxypyridin-2-yl)(4-cyclopropylphenyl)methanol (765 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[C:8]1[O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:14])[CH2:12][N:13]=1.C(NC(C1[S:34]C=CC=1)=O)/C=C/C1C=CC=CC=1>>[C:15]1([CH:10]2[O:9][C:8]([C:3]3[S:34][CH:6]=[CH:7][CH:2]=3)=[N:13][CH2:12][CH:11]2[OH:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC/C=C/c1ccccc1)c1cccs1
Reactant: OC1CN=C(c2ccccc2F)OC1c1ccccc1
Product: OC1CN=C(c2cccs2)OC1c1ccccc1

Procedure:
(5RS, 6SR)-6-Phenyl-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazin-5-ol may be obtained in the following manner: working as described in Example 22 for the preparation of (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol, but starting with (E)-N-cinnamyl-2-thiophenecarboxamide (5 g), a 0.55 M solution (38 cc) of 3-chloroperbenzoic acid in dichloromethane and boron trifluoride etherate (3.2 g), and after recrystallization in dichloromethane, (5RS, 6SR)-6-phenyl-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazin-5-ol (2.9 g), m.p. 158° C., is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]=[C:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[N:15]([CH3:29])[C:16]=1[CH2:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=O)C>C1COCC1>[C:19]12([CH2:18][CH2:17][C:16]3[N:15]([CH3:29])[C:14]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[N:13][C:12]=3[CH2:10][OH:9])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: CCOC(=O)c1nc(-c2ccccc2C)n(C)c1CCC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc(CO)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (355 mg, 9.34 mmol) was added in small portions to an ice cooled solution of 5-(2-adamantan-1-yl-ethyl)-1-methyl-2-o-tolyl-1H-imidazole-4-carboxylic acid ethyl ester (Example 73, step a) (1.83 g, 4.67 mmol) in THF (20 ml). The suspension was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched sequentially with water (360 μl ), sodium hydroxide (2M, 360 μl) and water (3×360 μl), diluted with ethyl acetate (50 ml) and treated with magnesium sulfate. The suspension was filtered through celite, the solid residues were washed with ethyl acetate (20 ml) and chloroform (100 ml) and the filtrate was evaporated to afford white solid (2.15 g). 1H NMR (300 MHz, d6-DMSO/D2O) 7.34-7.24 (4H, m), 4.60 (2H, s), 3.32 (3H, s), 2.61 (2H, m), 2.40 (1H, br s), 2.20 (3H, s), 2.01 (3H, br s), 1.78-1.58 (12H, m), 1.32 (2H, m).
Reaction SMILES: Br[C:2]1[C:3]([C:16]#[N:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[C:3]([C:16]#[N:17])=[N:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(N)cc1
Reactant: N#Cc1ncc(Cc2ccc(F)cc2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C#N)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A dry 50 mL flask was charged with 3-bromo-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (55.3 mg, 0.190 mmol), cesium carbonate (87 mg, 0.266 mmol), palladium acetate (2.1 mg, 0.0095 mmol), rac-BINAP (8.9 mg, 0.0143 mmol), 4-(methyloxy)aniline (28 mg, 0.228 mmol) and toluene (5 mL). The mixture was refluxed for 5 hours, cooled to ambient temperature, filtered through Celite eluting with dichloromethane, and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes gradient elution) gave 5-[(4-fluorophenyl)methyl]-3-{[4-(methyloxy)phenyl]amino}-2-pyridinecarbonitrile (52.2 mg, 83% yield) as a white solid. 1H NMR (CDCl3) δ 7.88 (s, 1 H), 7.07-7.02 (m, 4 H), 6.98-6.88 (m, 5 H), 6.21 (br s, 1 H), 3.82 (s, 2 H); MS m/z 334 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:13])[N:3]=1.CC(C)([O-])C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:66][C:67]1[CH:72]=[CH:71][C:70]([S:73]([NH:76][CH3:77])(=[O:75])=[O:74])=[CH:69][CH:68]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:13][C:4]1[N:3]=[C:2]([NH:66][C:67]2[CH:72]=[CH:71][C:70]([S:73]([NH:76][CH3:77])(=[O:75])=[O:74])=[CH:69][CH:68]=2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: Clc1cc(N2CCCC2)cc(Cl)n1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCC3)cc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of 2,6-dichloro-4-pyrrolidino-pyridine (0.350 g, 1.62 mmol) in toluene (6 mL) were added potassium tert-butoxide (0.132 g, 1.18 mmol), palladium(II)-acetate (36.40 mg, 0.160 mmol), BINAP (32 mg, 0.514 mmol) and 4-amino-N-methyl-benzenesulfonamide (227 mg, 1.22 mmol) in a 10 mL reaction vessel. This reaction mixture was subjected the microwave irradiation, in which the microwave power was 250 W, to attain a reaction temperature of 150° C. After this reaction proceeded for 30 min, water (150 mL) was added to the reaction mixture and the reaction product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate concentrated under vacuum. The product was purified through column chromatography using 230-400 mesh silica gel (elution 20:80 acetone:petroleum ether) to afford the desired compound as a light brown solid (110 mg, yield 19%).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[O:24])[O:4][CH:3]1[C@H:25]([OH:57])[C@@H:26]([C:50]([O:52]C(C)(C)C)=[O:51])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:49])[C@H:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>FC(F)(F)C(O)=O>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:9]2=[O:24])[O:4][CH:3]1[C@H:25]([OH:57])[C@@H:26]([C:50]([OH:52])=[O:51])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:49])[C@H:33]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)O)[C@@H](O)[C@H]3O)c2=O)cc1
Yield: 94.8 %

Procedure:
A solution of tert-butyl (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (51 mg, 0.064 mmol, obtained from Example 51) in trifluoroacetic acid (6 ml) was stirred 5 hours at room temperature. The volatiles were removed in vacuo and the resulting residue was azeotroped with toluene to provide (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oic acid (45 mg, 95%) as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[C:13](=[O:20])[C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2sccc2-c2[nH]nc(-c3cccc(Cl)c3)c21
Temperature: 25 °C
Yield: 960 %

Procedure:
A mixture of 6-(3-Chloro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.27 g, 1.0 mmol) and Cs2CO3 (3.26 g, 10 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. After poured into ice water, aqueous wash, and evaporation of the solvent provided the corresponding 6-(3-Chloro-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one (2.75 g, 9.6 mmol) as orange solid in 96% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1>CN(C)C=O>[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62]([NH:16][C:14]3[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:12]([CH3:17])[N:13]=3)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1
Reactant: O=C(O)c1ccc(Cn2cccn2)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)c2ccc(Cn3cccn3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 136.8 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.47 g, 1.88 mmol), and N-methylmorpholine (0.23 mL, 2.08 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.42 g, 2.09 mmol) and 4-pyrazol-1-ylmethyl-benzoic acid (0.42 g, 2.09 mmol). The resultant solution was allowed to warm to ambient temperature over 18 h, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with methanol/dichloromethane (0/100 to 30/70) to afford the title compound (1.11 g); MS (ES+) m/z 432 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([N+:22]([O-])=O)[C:15]=2[C:25]#[N:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.NN>C(O)C.[Ni].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([NH2:22])[C:15]=2[C:25]#[N:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N)c(C#N)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To 370 mg (1.02 mmol) of 4-(2-cyano-5-methoxy-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 5 mL ethanol and 5 mL ethyl acetate was added a pipet of Raney nickel slurry in water followed by 64 μL (2 eq., 2.04 mmol) hydrazine. The mixture was stirred 30 minutes to completion, filtered through Celite and concentrated under reduced pressure to provide 300 mg of crude 4-(3-amino-2-cyano-5-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13][C:14]1[N:15]([CH2:21][C:22](O)=[O:23])[C:16]([Br:20])=[C:17]([Br:19])[N:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>O>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:22](=[O:23])[CH2:21][N:15]2[C:16]([Br:20])=[C:17]([Br:19])[N:18]=[C:14]2[Br:13])[CH2:3][CH2:2]1
Reactant: O=C(O)Cn1c(Br)nc(Br)c1Br
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(Br)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 mL 2-piperazin-1-yl-pyrimidine was added to a mixture of 17 g (2,4,5-tribromo-imidazol-1-yl)-acetic acid, 16.6 g TBTU, 7.3 mL TEA and 100 mL DMF. The reaction mixture was stirred for 2 h at RT and subsequently added to water. The precipitate was filtered to give 23 g desired product. Rt: 0.93 (method B), ESI+: 507
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:8][CH:9]=[N:10][N:11]=2)(=[O:37])=[O:36])[CH:34]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 73.9 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 5, 899 mg, 3.58 mmol) in tetrahydrofuran (6.0 mL) cooled to −78° C., was added lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 4.3 mL) dropwise. The reaction mixture was stirred for 35 minutes at ambient temperature, then cooled again to −78° C. before the dropwise addition of 5-chloro-2,4-difluorobenzenesulfonyl chloride (850 mg, 3.4 mmol). The reaction mixture was stirred at −78° C. for 1 hour then at ambient temperature for 4 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (0% to 10% ethyl acetate in hexanes gradient elution) to afford the title compound as a white solid (1.16 g, 73%).