Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[OH:23][CH2:22][C:17]1([NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: NC1(CO)CCCC1
Product: O=C(NC1(CO)CCCC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-amino-cyclopentanemethanol (CAN 10316-79-7) as starting materials and isolated (40 mg, quant.) as white solid; MS (ESI, m/z): 325.1 (MH+).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.[CH2:15]([N:17]([CH2:28][CH3:29])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O)[CH3:16]>>[CH2:28]([N:17]([CH2:15][CH3:16])[C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=3)[N:14]=2)[CH:24]=[C:25]([CH3:27])[N:26]=1)[CH3:29]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CCCOc1ccc(C(=N)NO)cc1
Product: CCCOc1ccc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-4-propoxy-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=1.41*min; [M+1]+=367.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Cl:15]C1C=C(Cl)C=CC=1C=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:15])[CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: Cc1cccc(-c2ccc(Cl)cc2Cl)n1

Procedure:
6-(2,4-dichlorophenyl)-2-methylpyridine was prepared substantially according to the procedures of Example 1 for preparing 6-(2-chlorophenyl)-2-methylpyridine except 2,4-dichlorobenzaldehyde was used to afford 6-(2,4-dichlorophenyl)-2-methylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:40](B(O)O)[CH:41]([CH3:43])[CH3:42]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: CC(C)CB(O)O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(CC(C)C)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and isobutylboronic acid replacing phenylboronic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOCC>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred mixture of 3-morpholinyl-phenol (3.8 g; 21.2 mmol) and powdered K2CO3 (4.4 g; 31.8 mmol) in dry DMF (15 mL) was added iodomethane (1.45 mL; 23.3 mmol) via syringe at room temperature under nitrogen atmosphere. The resulting mixture was allowed to stir at room temperature for 22 hours. The reaction was diluted with ether (150 mL) and washed successively with water (2×40 mL) and brine (40 mL), then dried (MgSO4), filtered and concentrated in vacuo to provide the desired ether as a yellow oil (2.51 g; 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH2:10][N:9]=1.O1CCCC1.O.O.O.C([O-])(=O)C.[Na+].N>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][OH:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[CH2:10][N:9]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NO)ccc21

Procedure:
A mixture of 16 g. (0.05 mol) of 1,3-dihydro-5-(2-fluorophenyl)-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one, 500 ml. of tetrahydrofuran, 250 ml. of methanol, 68 g. of sodium acetate trihydrate and 56 g. of stannous chloride dihydrate was stirred under nitrogen for 6 hours. 25 ml. of concentrated ammonia was added and the inorganic salts were removed by filtration through celite. The filtrate was washed well with 2 l. of tetrahydrofuran. The filtrate was evaporated and the solid residue was dissolved in ethanol/tetrahydrofuran. The solution was again filtered with celite and concentrated. The separated crystals were collected to leave light yellow product. For analysis it was recrystallized from ethanol/tetrahydrofuran, m.p. 228°-230° dec.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:5][N:4]=1.C[Si](I)(C)C>ClCCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[O:22][N:21]=[C:20]([C:16]2[CH:15]=[C:14]([CH3:29])[C:13]([O:12][CH2:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=3)=[C:18]([CH3:19])[CH:17]=2)[N:24]=1
Reactant: COc1ccc(CCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)cn1
Agent: C[Si](C)(C)I
Solvent: ClCCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(=O)[nH]c1
Yield: 34.5 %

Procedure:
A solution of 3.0 g (7.36 mmol) of 2-methoxy-5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine and 3.6 ml (3.4 eq) of trimethylsilyl iodide in 60 ml of 1,2-dichloroethane was refluxed under nitrogen for 1 h. The above red solution was quenched with methanol, poured into water, and diluted with methylene chloride. The organic layer was washed with sodium bisulfite, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from isopropyl acetate to afford 1 g (34.5%) of 5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-2(1H)-pyridone, as a white, flaky solid, m.p. 128.5°-130.5° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([Br:35])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Br:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:30][CH:31]=1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: Nc1cnc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionic acid (310 mg, 1.0 mmol) in methylene chloride (5 mL) was treated with oxalyl chloride (0.175 mL, 2.0 mmol) and N,N-dimethylformamide (1 drop). The solution was stirred at 25° C. for 45 min. The reaction mixture was concentrated in vacuo, and the residue was suspended in toluene. The toluene was further concentrated in vacuo. The resulting residue was dried in vacuo. The waxy material was dissolved in methylene chloride (5 mL), cooled to 0° C., and then treated with a solution of 2-amino-5-bromopyrazine (1.74 g, 1.0 mmol) and pyridine (0.121 mL, 1.5 mmol) in methylene chloride (5 mL). The mixture was stirred at 0° C. for 20 min and then stirred at 25° C. for 3 h. The solution was extracted with methylene chloride and water. The organic layer was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/2 ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (391 mg, 84%) as a fluffy solid.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=O>>[C:2]1([C:1]2[S:8][CH:11]=[C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2csc(-c3ccccc3)n2)cc1
Yield: 68 %

Procedure:
In the same manner as in Example 74, thiobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-(2-phenyl-4-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 68%. Pale yellow prisms. Melting point: 72 to 73° C.
Reaction SMILES: [C:1]([O:9][CH:10]([C:18](=[O:21])[CH2:19][CH3:20])[C:11](=[O:17])[CH:12]=[CH:13]N(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:18](=[O:21])[CH:19]=[CH:20][O:17][C:11]=1[CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCC(=O)O
Solvent: O=CO
Solvent: CC(=O)O
Product: CCc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-dimethylamino-1-heptene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-ethyl-4-pyrone, and,
Reaction SMILES: O.[C:2]([S:6]([CH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Ca+2].[OH-]>CS(C)=O>[C:2]([S:6]([CH2:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)C(C)(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)S(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 56.9 %

Procedure:
550 ml of water are placed in a sulphonation flask having a mechanical stirrer, pH control as well as a dropping funnel and treated while stirring vigorously with 4.85 g (16.36 mmol) of ethyl (RS)-α-[[(RS)-t-butylsulphinyl]methyl]hydrocinnamate (see EPA 0 236 734) in 15 ml of dimethyl sulphoxide. The reaction solution is thereafter adjusted to pH 7.5, treated with 200 mg of α-chymotrypsin and the pH is held constant with 0.037N calcium hydroxide solution. After 220 ml of this calcium hydroxide solution have been consumed (about 45 hours) the unreacted ester is extracted with ethyl acetate, the aqueous phase is adjusted to pH 2 with 30% sulphuric acid and extracted with ethyl acetate. The extracts are washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated, whereby there are obtained 2.50 g of (S)-α-[[(RS)-t-butylsulphinyl]methyl]hydrocinnamic acid, MS: 269 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][C:18]1[N:17]=[C:16]([N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[O:20][N:19]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(CNc2nc(C)no2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(CN(C(=O)C2CC2)c2nc(C)no2)cc1

Procedure:
Cyclopropane carboxylic acid chloride (3.45 g, 0.033 mole) was added dropwise to a solution of 5-(4-methylphenyl)methylamino-3-methyl-1,2,4-oxadiazole (6.1 g, 0.03 mole) and triethylamine (3.45 g, 0.03 mole) in dry benzene keeping the temperature below 10° C. After the addition the temperature was allowed to reach room temperature and then refluxed overnight. On cooling the reaction mixture was washed twice with 2N HCl and twice with a saturated solution of NaHCO3 and dried over Mg SO4 and charcoaled. The product was purified by column chromatography-silica gel (110 g) eluting with petroleum ether 40°-60° C. increasing polarity to 10% ether in petroleum ether. The title compound was recrystallised from petroleum ether 60°-80° C. as white needles. m.p. 49.5°-50.5° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[CH:43])[CH:37]=1>C1COCC1.CN(C=O)C.O>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[CH:43])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: CC#CC(=O)O
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CC)cc23)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Dissolved 370 mg (4.40 mmol) 2-butynoic acid in 20 ml THF under N2 and chilled to 0° C. Added 484 1 (4.40 mmol) N-methylmorpholine and 572 μl (4.40 mmol) isobutyl chloroformate and stirred for 10 minutes. Added a solution of 500 mg (1.76 mmol) 6-amino-4-[(3-ethynylphenyl)amino]-quinoline-3-carbonitrile in 1 ml DMF and ml THF. Removed ice bath at 15 minutes and stirred overnight at 25° C. Stripped solvent, slurried residue with water, collected solids, and dried in vacuo. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 494 mg of yellow solid: mass spectrum (electrospray m/e): M+H=350.9.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[CH3:22][O:23][C:24]1([O:31][CH3:32])[CH2:29][CH2:28][O:27][CH2:26][C:25]1=[O:30]>C1COCC1>[CH3:22][O:23][C:24]1([O:31][CH3:32])[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]1[OH:30]
Reactant: COC1(OC)CCOCC1=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: COC1(OC)CCOC[C@@H]1O
Temperature: 40 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A 5-L 4-neck round bottom flask equipped with an overhead air stirrer, addition funnel with nitrogen inlet adapter, condenser, and a thermocouple was charged with (R)-(+)-2-methyl-CBS-oxazaborolidine (34 g, 0.12 mol) and THF (1.2 L). The mixture was warmed under nitrogen to 40° C. then Me2S—BH3 (63 mL, 0.67 mol) was added to the THF-catalyst mixture via syringe. An addition funnel was charged with 4,4-dimethoxydihydro-2H-pyran-3(4H)-one (as prepared in Intermediate 1, Step B, 96 g, 0.59 mol) in THF (1.2 L) was added drop wise over an 8 h period. After addition, the reaction was allowed to stir for 18 h at 40° C. The reaction was chilled to 10° C. in an ice-acetone bath and quenched by slow addition of MeOH (600 mL) over 45 min. The cooling bath was removed and the mixture allowed to warm to room temperature for 3 h. After the gas evolution ceased, the mixture was concentrated on a rotary evaporator to give 132 g. Purification on silica gel using a mixture of EtOAc and heptanes afforded the title compound (80.5 g, 83%, chiral GC 95% ee) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:28])[CH2:17][S:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[NH:21][CH:22]=[N:23]4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([O:28][C:36](=[O:38])[CH3:37])[CH2:17][S:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[NH:21][CH:22]=[N:23]4)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 70 h
Yield: 65 %

Procedure:
To a solution of 6-[1-[1-[bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-hydroxy-3-propanylthio]purine (1.0 g, 0.002 mol) in CH2Cl2 (7 mL), acetic anhydride (0.2 mL, 0.002 mol) in Et3N (0.2 mL, 0.002 mol) was added dropwise over 5 min at room temperature under nitrogen. After 70 h, CH2Cl2 (50 mL) was added and the solution was extracted with saturated NaHCO3 (2×100 mL), H2O (1×100 mL), and saturated brine (1×100 mL); the organic layer was dried over Na2SO4. Solvent removal of the dried organic layer gave a solid which was dried in vacuo at 40° C. to give pure product (0.7 g, 64.8%), mp 105°-109° C. (dec). DCI/MS (M+1) 539. 400 MHz 1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.2 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 5.3 (m, 1H), 4.2 (s, 1H), 3.4 and 4.0 (m, 2 H), 2.65 (m, 2H), 2.6 (m, 4H), 2.4 (m, 4H), 2.0 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]1)C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]1
Reactant: O=C1CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CN(c2ccc(CCCc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
A solution of 5-[2-benzyloxy-4-((E)-3-phenylpropenyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (74 mg, 0.17 mmol) in 6 mL of EtOH/HOAc (4:2) is hydrogenated at 50 psi over 10% Pd/C (70 mg) for 18 h. The catalyst is filtered, the solvent is removed under reduced pressure and the residual oil purified by preparative HPLC to give the title compound as a solid: (M−1)−=345.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]([C:18]([NH2:20])=[O:19])=[N:13][CH:14]=[C:15](Cl)[N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[C@@H:30]1([NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH2:36].C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]([C:18]([NH2:20])=[O:19])=[N:13][CH:14]=[C:15]([NH:36][C@@H:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]4[NH2:37])[N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: NC(=O)c1ncc(Cl)nc1Nc1ccc2[nH]ncc2c1
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc2[nH]ncc2c1
Temperature: 150 °C

Procedure:
To 3-(1H-indazol-5-ylamino)-5-chloropyrazine-2-carboxamide (˜100 mg) in ˜3 mL NMP was added 6 equivalents of DIEA and 20 equivalents of racemic cis-1,2-cyclohexanediamine. The mixture was heated at 150° C. in a sealed tube overnight. The reaction mixture was cooled, acidified with TFA, diluted with water and prepped via rpHPLC to give the title compound. MS found for C18H22N8O as (M+H)+367.2.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH2:34][CH:35]([F:37])[F:36])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2C(OCC)=O)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NCC(F)F)C(C)=N4)=CC=2C(O)=O)CC1.Cl.NC1(C2NC(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=CC=2C(O)=O)CC1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[F:36][CH:35]([F:37])[CH2:34][NH:33][C:25]1[C:26]([CH3:32])=[N:27][C:28]2[C:23]([N:24]=1)=[C:22]([C:14]1[NH:13][C:12]3[C:9]4([CH2:10][CH2:11]4)[NH:8][C:6](=[O:7])[C:16]=3[CH:15]=1)[CH:31]=[CH:30][CH:29]=2
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Agent: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NCC(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NCC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(34(2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (331b) (378 mg, 0.73 mmol) was converted to 2-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (331c: m/z (ESI, +ve) 388.1 (M+H)+) in a fashion similar to that described for Intermediate 324c. This material was used as crude. A suspension of 2-(1-aminocyclopropyl)-5-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (331c) in DMF (5 mL) and DCM (5 mL) at 0° C. was treated with DIEA (0.76 mL, 4.38 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (456 mg, 0.87 mmol). The ice bath was removed and the resulting mixture was stirred at RT for 18 h. It was treated with 20 G of ice, the yellow solid was filtered, washed sequentially with 5 mL of water, 5 mL of 0.5 N NaOH, 5 mL of water and 2×5 mL of DCM. The yellow solid was dried in a vacuum oven at 45° C. for 5 h to give 2′-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (331) (179 mg, 0.48 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br.), 7.83 (1H, d, J=8.0 Hz), 7.65 (2H, m), 7.58 (1H, br.), 7.40 (1H, t, J=7.5 Hz), 6.85 (1H, s), 6.43 (0.25; H, m), 6.29 (0.5; H, m), 6.14 (0.25; H, m), 3.92 (2H, m), 2.57 (3H, s), 1.42 (2H, m), 1.38 (2H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −120.48. m/z (ESI, +ve) 370.1 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([OH:18])[C@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6]([S:14][CH2:15][CH2:16][NH2:17])=[C:7]2[C:11]([OH:13])=[O:12].[OH-].[Na+].Cl.[CH:22](=[NH:25])OC.Cl>P([O-])([O-])([O-])=O>[CH3:1][C@@H:2]([OH:18])[C@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6]([S:14][CH2:15][CH2:16][N:17]=[CH:22][NH2:25])=[C:7]2[C:11]([OH:13])=[O:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCCN)C[C@H]12
Reactant: COC=N
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCCN=CN)C[C@H]12
Reaction time: 0.17 h

Procedure:
Thienamycin (517 mg) is dissolved in pH 7 0.1 N phosphate buffer (25 ml) and cooled in an ice bath with magnetic stirring. The solution is adjusted to pH 8.5 using 2.5 N sodium hydroxide solution dispensed from an automatic burette. While maintaining a pH of 8.5, methyl formimidate hydrochloride (711 mg) is added portionwise over a 2-3 minutes. After an additional 10 minutes, the pH of the solution is brought to 7.0 using 2.5 N hydrochloric acid. The solution is chromatographed on a column of XAD-2 resin (150 cc) which is eluted with water. The N-formimidoyl Thienamycin derivative elutes in 1.5-2.0 column volumes (200-300 cc) and is lyophilized to a white solid (217 mg). UV (pH 7 0.1 N phosphate buffer)λmax 297 nm (8,590). ir (Nujol mull) 1767 cm-1 (β-lactam) nmr (D2O)δ1.37 (d, J=6 Hz, CH3 --CH), 3.0-3.75 (m, --CH2 --), 4.2-4.8 (m, C5H, C6H, C7H), 7.86 ##STR76##