Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH:26]=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:36]([O:40][C:41](=[O:55])[NH:42][S:43]([CH2:46][CH2:47][CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][NH:52][CH3:53])(=[O:45])=[O:44])([CH3:39])([CH3:38])[CH3:37].[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:18]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH3:25])[CH:16]([CH2:26][N:52]([CH3:53])[CH2:51][CH2:50][N:49]([CH3:54])[CH2:48][CH2:47][CH2:46][S:43](=[O:44])(=[O:45])[NH:42][C:41](=[O:55])[O:40][C:36]([CH3:39])([CH3:37])[CH3:38])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)N(C)c1ccccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)N(C)c1ccccc1-3
Reaction time: 0.08 h

Procedure:
Methyl 13-cyclohexyl-6-formyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in MeOH (0.08 M) and HOAc was added. Tert-butyl[(3-{methyl[2(methylamino)ethyl]amino}propyl)sulfonyl]carbamate (1.5 eq. prepared as described in Example 15, Steps 1-3) was added and the mixture was stirred for 5 min. NaCNBH3 (1.5 eq.) was added and the mixture was stirred for 6 h. All volatiles were evaporated and the residual material was dissolved in EtOAc. The solution was extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. A yellow amorphous solid was obtained which was used without further purification in the next reaction (60%). (ES+) m/z 711 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[CH:12][CH3:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[O:17])[CH3:16]>CN(C)C=O.O>[C:15]([NH:18][C:19]1[S:20][CH:2]=[C:3](/[C:4](=[CH:12]/[CH3:13])/[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[N:21]=1)(=[O:17])[CH3:16]
Reactant: CC=C(C(=O)CCl)C(=O)OC(C)(C)C
Reactant: CC(=O)NC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C(\C(=O)OC(C)(C)C)c1csc(NC(C)=O)n1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
The crude product of a 2.2 mol batch of tert.-butyl 4-chloro-2-ethylidene-3-oxobutyrate, dissolved in 100 ml of dimethylformamide, is added to a solution, warmed to 85° C., of 236 g (2 mol) of acetylthiourea in a mixture of 360 ml of water and 720 ml of dimethylformamide. The mixture is stirred at 85° C. for two hours and concentrated, the residue is taken up in ethyl acetate and the solution is extracted three times with water. After drying and concentrating, by-products are precipitated with ether.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH2:11])[C:9]#[CH:10]>O1CCCC1>[O:7]=[C:1]([NH:11][CH2:8][C:9]#[CH:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: C#CCN
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: C#CCNC(=O)CCC(=O)O

Procedure:
1.6 g (16 mmol) Succinic anhydride and 1.06 g (19.2 mmol) propargylamine in 10 ml tetrahydrofuran were stirred over night at room temperature whereat a solid precipitated. The reaction mixture was taken up with methyl-t-butyl ether (MTBE) and the insoluble crystals were filtered off and dried in a stream of nitrogen. 2 g (80% of theory) of the title compound were obtained which were used in the next reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:31][CH:32]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH:32]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)piperidine-1-carboxylate (1.5 g, 2.6 mmol) in dichloromethane (8 mL) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (30 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 3-10% methanol in dichloromethane) to give the title compound as a white solid (1.1 g, 2.3 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1 H), 7.74 (d, J=8.4 Hz, 1 H), 7.47 (d, J=1.9 Hz, 1 H), 7.25-7.21 (m, 1 H), 7.16-7.13 (m, 1H), 7.04 (s, 1 H), 6.86 (d, J=8.4 Hz, 1 H), 6.00-5.93 (m, 2 H), 4.29-4.07 (m, 2 H), 3.86-3.66 (m, 2 H), 3.30-3.26 (m, 1 H), 2.82-2.50 (m, 3 H), 1.99 (d, J=7.0 Hz, 3 H), 1.97-1.52 (m, 8 H); MS: (ES) m/z calculated for C26H29Cl2N4O [M+H]+483.2, found 483.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:34])=[CH:15][N:14]=1)[CH3:7])C.[BH4-].[Li+].C1COCC1.Cl>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:18]2[C:13]([C:9]3[N:8]([CH:6]([CH3:7])[CH2:5][CH2:4][OH:3])[CH:12]=[N:11][N:10]=3)=[N:14][CH:15]=[C:16]([Cl:34])[CH:17]=2)(=[O:21])=[O:22])=[CH:24][C:25]=1[C:30]([F:32])([F:31])[F:33]
Reactant: CCOC(=O)CC(C)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCO)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{3-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-butyric acid ethyl ester (27 mg, 0.05 mmol), lithium borohydride (2.0M, 0.14 ml, 0.28 mmol), 1.5 ml of THF and 0.02 ml of methanol was stirred at room temperature for 2 hours. The mixture was mixed with diluted HCl (1.0M), extracted with ethyl acetate, and the extracts were combined and washed with brine and dried. After concentration the residue was purified by prep TLC to afford title compound as a white solid. 1H NMR: (DMSO-d6, ppm): 9.03 (s, 1H), 8.30 (m, 1H), 8.11 (m, 1H), 8.02 (m, 1H), 7.91 (m, 1H), 7.83 (m, 1H), 3.28 (m, 1H), 3.19 (m, 2H), 1.91 (m, 2H), 1.42 (d, 3H). MS (ES) [M+H]+ expected 510.0. found 510.0.
Reaction SMILES: C1C(N2C(=O)COCC2)=CC=C(N2C(=O)O[C@@H](CNC(C3SC(Cl)=CC=3)=O)C2)C=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][C:38]2=[O:43])=[CH:33][CH:32]=1.[O:44]1[CH2:46][C@@H:45]1[CH2:47][N:48]1[C:56](=[O:57])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]1=[O:58]>>[OH:44][C@H:45]([CH2:46][NH:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][C:38]2=[O:43])=[CH:35][CH:36]=1)[CH2:47][N:48]1[C:49](=[O:58])[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:56]1=[O:57]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
WO 01/47919, application disclosed the Rivaroxaban with applications for prevention and treatment of various thromboembolic diseases. Further this patent describes a method for preparation of Rivaroxaban of formula (I), wherein 4-(4-aminophenyl)morpholin-3-one is reacted with 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione, in presence of solvent to obtain 2-[(2R)-2-hydroxy-3-{[4(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione which is further converted to 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione by phosgene equivalent. Departing of the pthalamide group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one, which is finally coupled with 5-chlorothiophene-2-carbonyl chloride to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide i.e. Rivaroxaban of formula (I) as shown in scheme-1;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:20][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:3][C:2]=1[CH3:1])=[O:10]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)CBr
Temperature: 110 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A mixture of 1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (5.66 g, 22 mmol), pyridinium tribromide (10.63 g, 33.0 mmol), and glacial acetic acid (60 mL) was stirred at 110° C. for 3 h. The reaction mixture was cooled to 0–5° C., and the precipitated product was collected by filtration and washed with small amounts of water, ethanol, and diethyl ether. The crude material was purified by flash chromatography (5:95 ethyl acetate/hexane) to give 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid (4.33 g, 59% yield). HPLC ret. time 3.63 min; 1H NMR (CDCl3) δ: 2.63 (s, 3H), 2.25 (s, 2H), 7.52–7.58 (m, 2H), 7.72–7.83 (m, 3H), 8.32 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>O>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:14](=[O:15])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:32]3[CH2:33][C@@H:28]4[CH2:34][C@H:31]3[CH2:30][O:29]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:23]([F:26])([F:25])[F:24]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1ccncc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccncc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 120 °C
Yield: 74.2 %

Procedure:
140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 126 μl (0.90 mmol) of triethylamine are added. The tube is sealed and heated at 120° C. in an oil bath for 2 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.[N+]([O-])([O-])=O.[NH4+]>C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:21]
Reactant: CCCCCCCCCC=O
Reactant: CCOC(OCC)OCC
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCCCCCCC(OCC)OCC

Procedure:
Decanal diethyl acetal was prepared by reacting 316 g decanal with 354 g triethyl orthoformate in the presence of 7.6 g ammonium nitrate dissolved in 20 ml. ethanol at a temperature of 50° C. for a period of time of 4 hours. The resulting product was quenched with 32 g sodium methoxide and distilled at 170° C. at 8.0 mm Hg pressure. Then, into a 2 liter reaction flask equipped with stirrer, thermometer, heating mantle, addition funnel, vacuum apparatus, and reflux condenser the following ingredients are added at 20°:
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)(=O)=O.[OH2:18]>>[CH:8]([CH:7]=[CH:6][C:5]([OH:4])=[O:18])=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 80 °C

Procedure:
A 2 l reactor with stirrer and reflux condenser was charged with 433 g of deionized water, and 3 grams of lauryl sulfate (30% strength solution), this initial charge then being heated to 80° C. with stirring under a nitrogen atmosphere.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][CH:16]([CH3:26])[CH2:17][O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(O)C>[CH3:15][CH:16]([CH3:26])[CH2:17][O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: CC(C)COc1ccccc1N
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (50 g) and 2-(2-methylpropoxy)aniline (45 g) is heated with stirring at 120° C. for 2 hours. After cooling, ethanol (300 ml) is added to the reaction mixture and the solid is pulverized, and then the product is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (57 g). M.p. 188°-190° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[C:9]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=3)=[O:14])[CH:10]=[C:9]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1
Reactant: Cc1ccc(N)nc1
Reactant: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 2-(methoxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylic acid (130 mg, 0.345 mmol) in DMF (5 mL) was added HATU (263 mg, 0.691 mmol) and DIEA (89.3 mg, 0.691 mmol). After stirring the solution at 0° C. for 15 minutes, 2-amino-5-methylpyridine (74.7 mg, 0.691 mmol) was added. The solution was warmed gradually to room temperature and stirred for 14 h. The reaction was concentrated under high vacuum, and the product was purified by reverse phase HPLC to give the title compound (88 mg, 55%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.36 (s, 3 H) 3.07 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.59 (s, 1 H) 7.07-7.18 (m, 2 H) 7.53 (d, J=1.32 Hz, 1 H) 7.74 (dd, J=8.67, 1.32 Hz, 1 H) 7.85-7.95 (m, 2 H) 8.00 (s, 1 H) 8.09 (s, 1 H) 8.22 (d, J=8.67 Hz, 1 H) 9.10 (s, 1 H). LCMS m/z 467.20 (M+H)+.
Reaction SMILES: O=[C:2]([CH3:8])[C:3](=O)[C:4]([OH:6])=[O:5].CC[O-].[Na+].[CH3:13][S:14][C:15](=[NH:17])[NH2:16]>>[CH3:13][S:14][C:15]1[N:17]=[C:3]([C:4]([OH:6])=[O:5])[CH:2]=[CH:8][N:16]=1
Reactant: CSC(=N)N
Reactant: CC(=O)C(=O)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Product: CSc1nccc(C(=O)O)n1

Procedure:
In step a of scheme 1, reaction of the ketone with diethyl oxalacetate in the presence of a base, such as sodium ethoxide, and an organic solvent such as ethanol, provides the dioxobutanoic acid. Refluxing the dioxobutanoic acid, in step b, in the presence of a base, such as EtONa, and 2-methylisothiourea followed by and organic extraction and acid wash provides the 2-(methylthio)pyrimidine-4-carboxylic acid. In step c, the carboxylic acid is converted to the amide using standard amine coupling methodologies, such as with PyBOP or EDC, in the presence of the appropriate amine, e.g., NHRcRd. In step d, oxidation of the thiol with an oxidizing agent such as m-CPBA or H2O2 in CH3CO2H provides the sulfinyl or sulfonyl compound. In step e, reaction of the sulfinyl or sulfonyl compound with the appropriate amine, HNRaRb, in an organic solvent such as dioxane provides the compound of formula I.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>CN1C(=O)CCC1>[F:8][C:7]1[C:2]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: Fc1cc(I)cnc1F
Reactant: CC(C)(O)CN
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(C)(O)CNc1ncc(I)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
2,3-Difluoro-5-iodopyridine (500 mg, 2.07 mmol) was dissolved in NMP (500 μL) and pyridine (201 μl, 2.49 mmol, 1.2 equiv.) and 1-amino-2-methylpropan-2-ol (555 mg, 6.22 mmol, 3 equiv.) were added at room temperature. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (590 mg, 1.9 mmol, 91.7% yield) was obtained as a colorless oil, MS: m/e=311.0 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)C(F)(F)F.[O:11]=[C:12]1[O:18][C@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[C:15]([OH:16])=[C:13]1[OH:14].[CH2:23]1[O:31][CH:24]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[OH:31][CH2:23][CH:24]([O:16][C:15]1[C@@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[O:18][C:12](=[O:11])[C:13]=1[OH:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C1O[C@H]([C@@H](O)CO)C(OC(CO)c2ccccc2)=C1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Under an argon atmosphere, 4 ml of 1,1,1,3,3,3-hexafluoro isopropanol and 10 ml of acetonitrile were added to L-ascorbic acid (1.00 g), and further, styrene oxide (1.37 g) was added. The mixture was heated up to 70° C. and stirred for 48 hours, then, concentrated under reduced pressure, and 2.73 g of the resultant residue was subjected to silica gel column chromatography. Thereafter, it was eluted with chloroform/methanol/water(volume ratio:20/3/0.3) to obtain two elution fractions (first eluted fraction: 225 mg, later eluted fraction: 228 mg). Based on the measurement results of high resolution mass analysis, infrared absorption spectrum, 1H-NMR, 13C-NMR and specific optical rotation on the resultant elution fractions, it was confirmed that these are two 3-O-(2-hydroxy-1-phenylethyl) ascorbic acids which are in mutual stereoisomerism and both of them are represented by the following structural formula.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[S:27]1[C:31]([C:32]([C:34]2[N:35]=[CH:36][N:37]3[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=23)=[O:33])=[CH:30][N:29]=[CH:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([C:32]([C:31]5[S:27][CH:28]=[N:29][CH:30]=5)=[O:33])[N:35]=[CH:36][N:37]4[CH:41]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncs3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncs5)c4s3)[C@H](C)[C@H]12
Yield: 85.2 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (244 mg) was prepared in the same manner as in step a) of Example 1, except that 179 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 260 mg of 7-(thiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=3)[C:15]([O:17]C(C)(C)C)=[O:16])[O:9][N:8]=2)[CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=3)[C:15]([OH:17])=[O:16])[O:9][N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Reaction time: 1 h

Procedure:
A solution of the product of Example 45 (180 mg, 0.56 mmol) in methylene chloride (5 mL) was stirred with trifluoroacetic acid (1 mL) at room temperature for 4 hours. It was then concentrated and the residue was stirred in water (15 mL) for 1 hour. The precipitate was collected by filtration and dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 8.28 (ddd, J=8.0, 1.5, 1.2 Hz, 1H), 8.42-8.51 (m, 2H), 8.70 (t, J=1.6 Hz, 1H), 8.83 (dd, J=5.0, 1.8 Hz, 1H), 9.28 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 268 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.Cl.C(O)(=O)CCC(O)=O>N1C=CC=CC=1.O>[C:12]([C:11]1[CH:10]=[C:9]([N:8]([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=2)[C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:17]=[CH:16][CH:15]=1)([OH:14])=[O:13]
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: O=C(O)CCC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 150 °C
Yield: 47.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3.0 g (0.0088 mole) of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid and 9.0 g (0.090 mole) of succinic anhydride was heated at 150° C. for 15 minutes. The reaction mixture was diluted with pyridine (50 ml) and water, and was poured into cold dilute hydrochloric acid. The resulting precipitate was recrystallized from a mixture of 14 ml of ethanol and 22 ml of water to give a white solid. This solid was heated in 70 ml of water to dissolve any succinic acid, and was collected and heated in 40 ml of ethyl acetate. The ethyl acetate solution was filtered to remove a small amount of insoluble material. The ethyl acetate filtrate was concentrated to 20 ml, and was then diluted with 10 ml of hexane. The resulting precipitate was collected and dried to give 1.85 g of white solid N-(3-carboxyphenyl)-N-(3,5-di-t-butyl-4-hydroxyphenyl)succinamic acid, m.p. 182°-183° C. Analysis: Calculated for C25H31NO6 : % C, 68.0; % H, 7.1; % N, 3.2; Found: % C, 68.2; % H, 7.1; % N, 3.0.