Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8](Cl)=[CH:7][CH:6]=2.ClC1C=C2C(=CC=1)N=C([C:29](OCC)=[O:30])C(=O)N2>>[Cl:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:30][CH3:29])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2[nH]c1=O
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2nc1Cl
Product: CCOC(=O)c1nc2ccc(OC)cc2nc1Cl

Procedure:
In a similar manner, 3,6-dichloro-2-quinoxalinecarboxylic acid, ethyl ester, m.p. 63°-65°, was prepared from 6-chloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (Example 12a) (73%).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](=[C:12]1\[C@H:13]([CH3:32])[CH2:14][CH:15]2[C@:28]\1([CH3:29])[CH2:27][CH:26]=[C:25]1[CH:16]2[CH2:17][CH2:18][C:19]2[C@:24]1([CH3:30])[CH:23]=[CH:22][C:21](=[O:31])[CH:20]=2)/[O:7][Si](C)(C)C)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([C@:12]1([OH:41])[C@:28]2([CH3:29])[CH:15]([CH:16]3[C:25](=[CH:26][CH2:27]2)[C@:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][C@H:13]1[CH3:32])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(O[Si](C)(C)C)=C1\[C@H](C)CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@@]1(O)[C@H](C)CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reaction time: 4 h

Procedure:
(Z)-2-((10S,13S,16R)-10,13,16-trimethyl-3-oxo-7,8,12,13,15,16-hexahydro-3H-cyclopenta[a]phenanthren-17(6H,10H,14H)-ylidene)-2-(trimethylsilyloxy)ethyl acetate is dissolved in methylene chloride and the mixture is cooled to zero degrees Celsius. A solution of m-chloroperbenzoic acid in methylene chloride is added dropwise and the mixture is stirred for 4 hours. The organic phase was washed with aqueous acetic acid and then aqueous bisulfite. The organic phase was concentrated and chromatographed on silica gel to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Cl:19][C:20]([F:28])([F:27])[C:21]([Cl:26])([F:25])[CH2:22][CH2:23]I.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:26][C:21]([F:25])([C:20]([Cl:19])([F:28])[F:27])[CH2:22][CH2:23][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(Cl)C(F)(Cl)CCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(Cl)C(F)(F)Cl)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 9 h
Yield: 2.2 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.5 g of 1,2-dichloro-4-iodo-1,1,2-trifluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 9 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2-(3,4-dichloro-3,4,4-trifluorobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (67)).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:19][CH2:20][F:21])[CH:7]=1)=[O:5])C>Cl>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[F:18])[N:8]([CH2:19][CH2:20][F:21])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(CCF)c2cc(F)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(CCF)c2cc(F)c(F)cc2c1=O
Yield: 86 %

Procedure:
6,7-Difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (7.74 g, 25.9 mmol) was mixed with aqueous 1N hydrochloric acid solution (300 ml), and heated to reflux for 2 hours. The reaction mixture was cooled, filtered, and the precipitate was washed with water and dried under vacuum to provide the title product as a white solid, m.p. 249°-251° (6.07 g, 22.4 mmol, 86% yield).
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]#[CH:9].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH3:6])[C:3]([O:5][CH2:9][C:8]#[CH:7])=[O:4]
Reactant: C#CCO
Reactant: CC(O)C(=O)O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCOC(=O)C(C)O
Reaction time: 3 h
Yield: 45 %

Procedure:
52.99 g (0.50 mol) of an aqueous solution of 85% 2-hydroxypropionic acid and 45 mL of toluene were dissolved in 84.09 g (1.50 mol) of propargyl alcohol, and 1.0 mL of concentrated sulfuric acid was added thereto. Using a Dean-Stark device under normal pressure, the formed water was removed from the system, and this was further reacted under reflux under normal pressure. After 3 hours, the reaction liquid was analyzed through liquid chromatography, and the disappearance of the starting materials was confirmed. Then, the reaction liquid was neutralized with sodium acetate added thereto, filtered, and the filtrate was concentrated. The residue was purified through reduced pressure distillation to give 28.81 g (45% yield) of 2-propynyl 2-hydroxypropionate.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]#[N:18].C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C.CCC(C(O)=O)CC1C(I)=CC(I)=C(N)C=1I>C1COCC1>[C:1]1([CH2:7][CH:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:16][C:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])#[N:18]
Reactant: N#CCBr
Agent: CC(C)[N-]C(C)C
Agent: CCC(Cc1c(I)cc(I)c(N)c1I)C(=O)O
Agent: CCC(Cc1ccccc1)C(=O)OC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(CC#N)(Cc1ccccc1)C(=O)OC
Yield: 103.4 %

Procedure:
Methyl 2-phenylmethylbutyrate (9.60 g, 50 mmol) was reacted with bromoacetonitrile (7.20 g, 60 mmol) in the presence of lithium diisopropylamide in THF (150 mL) and HMPA (4.3 mL, 25 mmol), as described above in the preparation of Example 4, to give 12.08 g of the crude product as a dark colored liquid. Methyl 2-phenylmethylbutyrate was prepared as in Colombo M, De Amici M, De Micheli C, Pitre D, Carrea G, Riva S (1991) "Chemoenzymatic synthesis of the enantiomers of iopanic acid" Tetrahedron:Asymmetry, 2, 1021-1030. Column chromatography over silica gel (hexanes-CH2Cl2, 3:2) afforded 5.98 g (52%) of the nitrile as a colorless viscous liquid. Analytical sample was prepared by bulb-to-bulb distillation (pot temp. 105° C. (0.5 mmHg)). Lithium diisopropylamide was prepared by treating diisopropylamine (5.56 g, 55 mmol) with butyllithium in hexanes (2.5 M, 22 mL, 55 mmol).
Reaction SMILES: Cl.[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>>[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH2:27])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)C3CCCC3)ccc21
Yield: 89 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 89% of theory, C26H31N5O3 (461.6); EKA mass spectrum: (M+H)+=462; (M+H+Na)++=242.6; (M+Na)+=484; (M+2H)++=231.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]([CH3:19])([NH2:18])[CH3:17])=[CH:11][CH:10]=[C:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:8]=2)([O-:3])=[O:2].[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[CH:26]1([NH:32][C:33]([NH:18][C:16]([CH3:19])([CH3:17])[CH2:15][NH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:10][CH:11]=3)[N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Solvent: ClCCl
Product: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12)NC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (3.56 g, 10.6 mmol) in dichloromethane (100 mL) was cooled to 0° C. Cyclohexyl isocyanate (3.00 mL, 23.5 mmol) was added over the course of a day, and the reaction was stirred at ambient temperature for three days. The solvent was removed under reduced pressure. Xylenes (3 cx 100 mL) were added and removed under reduced pressure to provide N-cyclohexyl-N′-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]urea as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[N:26]=[C:25]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[O:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([CH:28]=[CH:27][C:25]2[O:24][N:23]=[C:22]([CH2:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[N:26]=2)[CH:34]=[CH:33][C:32]=1[O:35][CH3:36]
Reactant: COc1ccc(C=Cc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)no2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C=Cc2nc(CC3CCNCC3)no2)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Trifluoroacetic acid (5 mL) was added slowly into a solution of 4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidine-1-carboxylic acid tert-butyl ester (compound of Example 18; 4.5 g, 10.4 mmol) in dichloromethane (25 mL) and was stirred at 25° C. for 15 h. The solvent was evaporated and the residue was extracted into chloroform (2×25 mL). The combined organic layers were washed with saturated sodium carbonate solution (2×25 mL) and water (1×25 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to afford the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:41]2([CH3:42])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:35][OH:36])[CH2:21][CH2:22][C:23]([F:34])([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH2:9]1.[C:51]1([CH3:61])[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>N1C=CC=CC=1>[CH3:61][C:51]1[CH:56]=[CH:55][C:54]([S:57]([O:36][CH2:35][C@@H:20]([C@@H:19]2[C@:37]3([CH3:43])[C@H:16]([C@H:15]4[C@H:40]([CH2:39][CH2:38]3)[C@:41]3([CH3:42])[C:12]([CH2:11][C@@H:10]([O:44][CH:45]5[CH2:50][CH2:49][CH2:48][CH2:47][O:46]5)[CH2:9][C@@H:8]3[O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:13][CH2:14]4)[CH2:17][CH2:18]2)[CH2:21][CH2:22][C:23]([F:33])([F:34])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])(=[O:59])=[O:58])=[CH:53][CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 2.37 g (0.0033 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-ol, 7 mL of pyridine and 1.27 g (0.0067 mol) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield oily [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), [α]D20 +6° (c 1, CHCl3).
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5](=[O:20])[CH:6]([C:18]#[N:19])[CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[N:12][CH:11]=[CH:10][C:9]=2[C:8]1=O)[CH3:3]>C(O)(=O)C.C(OCC)C>[BrH:1].[CH2:2]([O:4][C:5]([C:6]1[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[C:8]=2[NH:19][C:18]=1[Br:1])=[O:20])[CH3:3]
Reactant: CCOC(=O)C(C#N)C1CCc2cnccc2C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Br)[nH]c2c1CCc1cnccc1-2
Yield: 89 %

Procedure:
To stirred, cold (4° C.) 33% HBr in acetic acid (27 mL), cyano-(5-oxo-5,6,7,8-tetrahydro-isoquinolin-6-yl)-acetic acid ethyl ester 8C (7 mmol), dissolved in acetic acid (22 mL) and diethyl ether (22 mL), was added dropwise. The mixture was stirred at rt for 15 h. The yellow precipitate was filtered and repeatedly washed with diethyl ether affording the title product in 89% yield. ESI (+) MS: m/z 322 (MH+). 1H NMR: 1.32 (t, J=7.19, 3H), 3.02-3.33 (m, 4H), 4.17-4.31 (m, 2H), 7.89 (d, J=6.22, 1H), 8.61-8.64 (m, 1H), 8.65-8.70 (m, 1H), 13.49 (bs, 1H).
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:3][CH:2]=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1=CCC=CC1
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1

Procedure:
To a solution of ethyl 3-{[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate (0.088 g, 0.140 mmol) and Pd(OH)2 (0.026 g, 0.036 mmol) in 1.5 mL of EtOAc and 0.75 mL of EtOH was added 1,4-cyclohexadiene (0.337 mL, 3.60 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, and then filtered through a Celite™ pad eluting with 100% EtOAc. The resulting filtrate was then concentrated in vacuo. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O) gave the title compound. LCMS: calculated for C27H24F2N2O3 462.49, observed m/e 462.9 (M+H)+484.9 (M+Na) (Rt 2.45/4 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11]O)[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1.CCN(C(C)C)C(C)C.O=S(Cl)[Cl:25]>C1COCC1.CCOCC>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][Cl:25])[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2c(Cl)cc(Cl)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: ClCc1cc2c(Cl)cc(Cl)cc2o1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of the product of Step E (0.24 g; 1.1 mmol) and DIPEA (0.2 ml; 1.11 mmol) in anhydrous THF (1 ml), SOCl2 (0.1 ml; 1.13 mmol) was added drop wise at 0° C. under N2 with stirring. The mixture was allowed to warm up to room temperature and stirred overnight, then diluted to 15 ml with Et2O and washed with 0.1N HCl, 5% NaHCO3, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.25 g; 96%), as a creamy syrup, which was used in the next step without further purification. 1H-NMR (CDCl3) 4.68 (s, 2H); 6.8 (s, 1H), 7.2 (s, 1H); 7.39 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][O:44][CH2:43]2)=[CH:38][C:37]=1[CH3:50].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(OCC2CCOC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCOC6)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (170 mg) and 3-((4-bromo-3,5-dimethylphenoxy)methyl)tetrahydrofuran (170 mg) and K3PO4 (290 mg) are suspended in tetrahydrofuran (10 mL). The mixture is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium (27 mg) is added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. After cooling to room temperature the mixture is diluted with diethylether and washed with saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→50:50) to give the title compound. Yield: 47 mg; LC (method 1): tR=1.48 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][O:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>N1C=CC=CC=1>[O:37]1[CH2:36][CH2:35][N:34]([C:10]2[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:19][CH2:20][N:21]([C:24](=[O:33])[CH2:25][O:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[CH2:22][CH2:23]4)=[CH:14][C:12]=3[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:42])[CH3:41])=[N:7][CH:6]=3)[N:9]=2)[CH2:39][CH2:38]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)COC5CCCCO5)CC4)cc3n2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)COC5CCCCO5)CC4)cc3n2)cn1

Procedure:
1-(4-((2-(6-Aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone (110 mg) was reacted with 80 μL acetic anhydride in 500 μL pyridine overnight at 40° C. to give N-(5-(4-morpholino-6-((4-(2-(tetrahydro-2H-pyran-2-yloxy)acetyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)acetamide. This intermediate was subjected to Procedure D to remove the THP protecting group and give 6.3 mg of 184 after purification. MS (Q1) 512.3 (M)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:23][O:24][C:25](=[O:44])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1>>[CH3:23][O:24][C:25](=[O:44])[CH2:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(F)ccc1Br
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-fluoro-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
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[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=12)=[O:33]>>[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:28]5[S:27][CH:31]=[CH:30][CH:29]=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)c3cccs3)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)c5cccs5)c4s3)[C@H](C)[C@H]12
Yield: 79.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiophen-2-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (815 mg) was prepared in the same manner as in step a) of Example 1, except that 640 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 923 mg of 7-(thiophen-2-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[F:31][S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([S:32]([F:31])(=[O:34])=[O:33])=[CH:36][CH:37]=3)[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)c1ccc(S(=O)(=O)F)cc1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(S(=O)(=O)F)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.100 mmol) (from Example 4 supra) and Et3N (14 μL, 0.100 mmol) in 5 mL of chloroform was cooled to −78° C. and then treated with 4-(fluorosulfonyl)benzoyl chloride (24 mg, 0.109 mmol) (Aldrich). The reaction mixture was stirred at −78° C. under a nitrogen atmosphere for 1 hr and then heated at reflux. The reaction mixture was allowed to cool to room temperature and then diluted with chloroform. The organic phase was then washed, in sequence, as follows: with a saturated aqueous sodium bicarbonate solution, with distilled water, with a 1N aqueous hydrochloric acid solution, and finally with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 30% ethyl acetate-hexanes elution) yielded pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-(fluorosulfonyl)benzamide (yield: 25.6 mg, 53%) as a yellow solid (mp: 148-151° C.).