Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CCCCN
Agent: Cl
Product: CCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 17.1 mg (0.23 mmol) of n-butylamine are reacted together by general method E. 15.2 mg (26.2% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:24]=[C:23]([O:25][CH:26]3[CH2:44][CH:43]4[N:28]([C:29](=[O:58])[N:30]([CH2:49][C:50]5[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=5)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]5[C:40]([C:46](O)=[O:47])([NH:41][C:42]4=[O:45])[CH2:39]5)[CH2:27]3)[C:22]3[C:17](=[C:18]([CH3:61])[C:19]([O:59][CH3:60])=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:24]=[C:23]([O:25][CH:26]3[CH2:44][CH:43]4[N:28]([C:29](=[O:58])[N:30]([CH2:49][C:50]5[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=5)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH:38]5[C:40]([C:46]([NH:7][S:4]([CH:1]6[CH2:3][CH2:2]6)(=[O:6])=[O:5])=[O:47])([NH:41][C:42]4=[O:45])[CH2:39]5)[CH2:27]3)[C:22]3[C:17](=[C:18]([CH3:61])[C:19]([O:59][CH3:60])=[CH:20][CH:21]=3)[N:16]=2)=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4nc(-c5ccc(F)cc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4nc(-c5ccc(F)cc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Yield: 33 %

Procedure:
Cyclopropanesulfonamide (99 mg, 0.8 mmol) was coupled to the acid 102 (200 mg. 0.27 mmol) as described in example 21. Purification by HPLC gave the title compound (75 mg, 33%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:13][CH:12]=1)C>C(O)C>[C:17]1([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:25])=[O:5])=[CH:16][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CCOC(=O)CCCOc1ccc(C2=CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1ccc(C2=CCCCCCC2)cc1

Procedure:
50 ml of 2 N sodium hydroxide solution are added to a solution of 21 g of crude 4-[p-(1-cyclooctenyl)-phenoxy]-butyric acid ethyl ester in 300 ml of ethanol, whilst stirring, and the mixture is stirred for 48 hours and evaporated to dryness under reduced pressure. The evaporation residue is distributed 3 times between 200 ml of ether and 200 ml of water in each case and the water phases are acidified to pH = 2 with concentrated hydrochloric acid and extracted with 3 times 200 ml of ether. The resulting organic phases are combined, washed until neutral, dried over sodium sulphate and evaporated under reduced pressure. The evaporation residue, after treatment with active charcoal and crystallisation from ether-petroleum ether, gives 4-[p-(1-cyclooctenyl)-phenoxy]-butyric acid in the form of white needles of melting point 110° -111° C.
Reaction SMILES: C([O:9][CH2:10][C:11]1([CH2:17][CH3:18])[O:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[OH-].[Na+]>CO.O>[CH2:17]([C:11]1([CH2:10][OH:9])[O:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:18]
Reactant: CCC1(COC(=O)c2ccccc2)OCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(CO)OCCCO1
Temperature: 25 °C
Reaction time: 11 h
Yield: 92.9 %

Procedure:
A mixture of (2-ethyl-1,3-dioxan-2-yl)methyl benzoate (4.33 g, 17.3 mmol), potassium carbonate (4.95 g, 35.9 mmol), tetrahydrofuran (50 ml), and water (20 ml) was stirred at room temperature for 11 hours. A 5N aqueous sodium hydroxide solution (2 ml) was added to the mixture, which was stirred at room temperature for 7 hours and then methanol (50 ml) was added thereto, which was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in heptane/ethyl acetate and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=2/1→1/1) to obtain the title compound (2.35 g, 92.9%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1>C(CN)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:9][CH2:4][CH2:3][OH:2])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: NCCO
Product: COc1ccccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 118.1 %

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.2 mmol) was dissolved in ethanolamine(5.0 ml), and reacted at the same condition of Step 3 in the Example 38 to obtain 307 mg of desired compound as solid in 58% of yield.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:16]1[O:18][C@H:17]1[CH2:19]Cl>>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C@@H:17]2[CH2:16][O:18]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-(1,1,3,3-tetramethyl-butyl)-phenol and R-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][C:27]1[C:28]([C:34]([CH:36]2[CH2:38][CH2:37]2)=O)=[N:29][CH:30]=[CH:31][C:32]=1[Cl:33]>C1COCC1>[CH:36]1([C:34]([C:28]2[C:27]([CH3:26])=[C:32]([Cl:33])[CH:31]=[CH:30][N:29]=2)=[CH:2][O:3][CH3:4])[CH2:38][CH2:37]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(Cl)ccnc1C(=O)C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C(c1nccc(Cl)c1C)C1CC1
Temperature: 40 °C
Yield: 82.1 %

Procedure:
A solution of methoxymethyl triphenylphosphonium chloride (17.9 g, 52.3 mmol) in dry THF (80 mL) was treated with NaH (2.79 g, 69.8 mmol) at 0° C. for 3 h. To this mixture was added a solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanone (6.82 g, 34.9 mmol) in dry THF (20 mL). The reaction mixture was heated at 40° C. overnight. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound (6.41 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[C:16](=[O:19])[NH:17][N:18]=[C:10]3[C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[C:16](=[O:19])[N:17]([CH2:32][C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=4)[N:18]=[C:10]3[C:9]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-5-(methylthio)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.27 mmol) in DMF (2 mL) at room temperature under argon was added 4-trifluoromethylbenzyl bromide (77.7 mg, 0.33 mmol), followed by K2CO3 (74.5 mg, 0.54 mmol). The resulting mixture was stirred at room temperature for 5 h. Insoluble material was filtered off and the filtrate was purified by silica gel column chromatography eluted with ethyl acetate-hexanes, then lyophilized from 1,4-dioxane, to obtain the title compound (112 mg) as an off-white lyophilate. HPLC/MS: retention time=4.50 min, [M+H]30 =527.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C>>[C:26]([NH:30][C:31]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([F:25])[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)[CH:5]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Yield: 24 %

Procedure:
The title compound was prepared from the reaction of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride with tert-butylisocyanate in the presence of excess diisopropylethylamine as described in Example 19, with the exception that hydrochloride salt formation was not carried out. The desired material was obtained in 24% yield as a white solid.
Reaction SMILES: FC1C=CC(CBr)=CC=1.CC1C=CC(S(O[CH2:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)(=O)=O)=CC=1.[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[NH:35][N:34]=[CH:33]2)[S:29][C:28]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH:23]1([CH2:22][CH2:21][N:35]2[C:36](=[O:37])[N:32]([C:30]3[S:29][C:28]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:27]([CH3:26])[CH:31]=3)[CH:33]=[N:34]2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Agent: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)cc1C
Yield: 80 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with 2-cyclopropylethyl 4-methylbenzenesulfonate to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 6.94 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 3.94 (t, J=7.1 Hz, 2H), 1.72-1.63 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 0.77-0.63 (m, 1H), 0.49-0.41 (m, 2H), 0.08-0.01 (m, 2H); MS (ES+) m/z 322.3 (M+1).
Reaction SMILES: [H-].[Na+].ClC1C=C(N)C(I)=CN=1.S(OC[C@@H]1OCCN(C(OC(C)(C)C)=O)C1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41](I)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:66][O:67][C:68]1[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=1>CN(C=O)C.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41]([C:71]2[CH:72]=[CH:73][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2cc(Cl)ncc2I)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Nc1cc(Cl)ncc1I
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cnc(Cl)cc2NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h before further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for a further 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate and hexane (2/4), to give an an inseparable mixture of starting material and product. LC-MS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as colorless oil (0.036 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:31])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[C@H:18]([F:31])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Solvent: ClCCl
Solvent: O
Product: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](F)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile obtained in example 21 (400 mg, 1.14 mmol) in DCM (10 mL) at 0° C. was added DAST (0.18 mL, 1.34 mmol) and stirred at room temperature for 1 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was diluted with DCM, water and extracted, organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 30% EtOAc in Hexane) provided the title compound (215 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[C:7]([C:20]#[N:21])=[N:8][N:9]([CH3:19])[C:10]=1[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:5].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH:4]([OH:5])[C:6]1[C:7]([C:20]#[N:21])=[N:8][N:9]([CH3:19])[C:10]=1[C:11]1[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Cn1nc(C#N)c(C(=O)c2ccc(F)cc2Cl)c1-c1c(F)cccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1nc(C#N)c(C(O)c2ccc(F)cc2Cl)c1-c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(2-chloro-4-fluorobenzoyl)-5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carbonitrile (i.e. the product of Example 10) (0.05 g, 0.13 mmol) in ethanol (2 mL) was added sodium borohydride (0.005 g, 0.13 mmol). The reaction was stirred for 30 minutes, and then hydrochloric acid (1 N) (0.5 mL) was added and the mixture was concentrated under reduced pressure. The resulting material was diluted with methylene chloride (5 mL) and filter through a Celite® (diatomaceous earth) extraction tube rinsing with methylene chloride (15 mL). The filtrate was concentrated under reduced pressure and the resulting material purified by flash chromatography on a silica gel, Varian Bond Elute SI® column (10 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.03 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([N+:12]([O-])=O)[S:10][CH:11]=1)(=[O:4])=[O:3]>[Pd].O1CCCC1>[NH2:12][C:9]1[S:10][CH:11]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]=1[S:15]([NH2:18])(=[O:16])=[O:17]
Reactant: CS(=O)(=O)NCc1csc([N+](=O)[O-])c1S(N)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1csc(N)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Palladium on carbon (12 g, 10%, activated, Aldrich) was added to a solution of 4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (prepared as described in Example 1g; 15 g, 47.6 mmol) dissolved in tetrahydrofuran (150 mL). The flask was degassed and backfilled with hydrogen gas. The mixture stirred under an atmosphere of hydrogen gas (balloon) for 20 h at 25° C. and then was filtered through Celite. The filtrate was concentrated in vacuo to afford 2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide as a thick golden oil. The oil was dissolved in N,N-dimethylformamide (150 mL) and 3,3-diethoxy-acrylic acid ethyl ester (10.62 g, 56.4 mmol) was added. A slow stream of nitrogen gas was applied to the atmosphere above the reaction mixture and the solution stirred at 70° C. for 5 h. Triethylamine (19 g, 188 mmol) was added directly to the reaction mixture and the solution continued to stir for 1 h. Upon cooling, the solution was concentrated in vacuo to reduce the total volume to 25 mL. The mixture was diluted with ethyl acetate (150 mL) and washed with 1.0 M aqueous hydrochloric acid solution (1×50 mL) followed by saturated aqueous brine solution (1×50 mL). The aqueous phase was back extracted with ethyl acetate (1×25 mL). The organic phases were combined, passed through a plug of silica gel (Merck silica gel 60, 40-63 μm) and concentrated in vacuo to afford a thick oil. The oil was dissolved in ethyl acetate (30 mL) and was stored at 25° C. for 16 h. The resulting solid was collected by vacuum filtration (10.75 g). The filtrate was concentrated in vacuo to afford a thick oil. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40-100% ethyl acetate in hexanes) to afford a solid (3.23 g) which was combined with the solid from above followed to afford [7-(methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid ethyl ester (13.98 g, 36.7 mmol, 77%) as a beige powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=4)[CH2:17][CH2:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CCCCCC.CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:22]=4)[CH2:17][CH2:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
Sodium hydride (0.626 g, 15.64 mmol, 60% suspension in mineral oil) was washed under dry conditions under nitrogen atmosphere with n-hexane. Dimethylformamide (20 mL) was added followed by 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (2.1 g, 7.11 mmol) under stirring. After the exothermic reaction had ceased stirring was continued at room temperature for 1 h before tert-butyl (2-bromoethyl)carbamate (4.78 g, 21.33 mmol) was added dropwise as a solution in dimethylformamide (10 mL). The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. Ice water was added (60 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and the solvent was evaporated in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:51][C@@H:52]1[CH2:56][CH2:55][NH:54][C:53]1=[S:57]>C(#N)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:51][C@@H:52]2[CH2:56][CH2:55][NH:54][C:53]2=[S:57])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: S=C1NCC[C@H]1S
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CCNC3=S)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
(1R, 5R, 6S)-6-[(1R)-1-Hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylic acid 4-nitrobenzyl ester (8.3 g) is dissolved in anhydrous acetonitrile (50 ml), and thereto are added dropwise diisopropylethylamine (4 ml) and diphenylphosphoryl chloride (4.8 ml) in this order under nitrogen gas below 0° C. After stirring the mixture at the same temperature for 30 minutes, a solution of (3R)-3-mercaptopyrrolidine-2-thione (4 g) and diisopropylethylamine (4 ml) in anhydrous acetonitrile (50 ml) is added dropwise to the reaction mixture below -15° C. The mixture is stirred at the same temperature for 1.5 hour, and water (50 ml) is added to the reaction mixture. The mixture is concentrated under reduced pressure to remove acetonitrile. The residue is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (eluent, chloroform:methanol=99:1) to give (1R, 5S, 6S)-2-[(3R)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (4.3 g) as an amorphous powder.