Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:20][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:14][CH:13]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)NCc1nccs1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ncc(Br)s1

Procedure:
A solution (2 L) of 1.33 kg of 2-t-butoxy carbonylaminomethylthiazole in ethyl acetate was added to an aqueous solution (20 L) of 8.6 kg of sodium acetate, and the mixture was stirred. Bromine (1.35 L) was added dropwise to this solution (internal temperature: 19 to 24° C.) over a period of 3.5 hr, and the mixture was stirred at an internal temperature of 25.5±5° C. for 14 hr. Sodium sulfite pentahydrate (180 g) was added thereto, the mixture was then extracted with 3 L of ethyl acetate, and the organic layer was washed with 1 L of water and 1.53 L of a 6 M aqueous sodium hydroxide solution. The aqueous layer was then extracted with 3 L of ethyl acetate. The organic layers were combined, were dried over anhydrous magnesium sulfate, and were filtered. The solvent was removed from the filtrate by evaporation under the reduced pressure, followed by substitution concentration twice with 2 L of ethanol to give 944 g of 5-bromo-2-t-butoxy carbonylaminomethylthiazole.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1([CH2:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([CH2:18][CH2:19][CH2:20][O:21][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-toluenesulfonyl-chloride (1.33 g, 6.98 mmol), portionwise, to a mixture of 3-piperidin-1-yl-propan-1-ol (1 g, 6.98 mmol), triethylamine (1.41 g, 13.9 mmol) and dichloromethane (6 mL). Stir the resulting suspension vigorously overnight at room temperature. Add water, separate the organic layer, and extract the aqueous layer with dichloromethane, twice. Combine the organic layers and wash with water, dry with sodium sulfate and evaporate the solvent to give the final, desired compound. The final compound may be purified by chromatography.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:27]#[C:28]Br>C1C=CC=CC=1>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]#[N:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CBr
Reactant: c1ccc(NCCCCCCCCOc2cccc3ccccc23)cc1
Solvent: c1ccccc1
Product: N#CN(CCCCCCCCOc1cccc2ccccc12)c1ccccc1

Procedure:
4.5 g of 1-(1-naphthyloxy)-8-(phenylamino)octane and 1.4 g of cyanogen bromide were heated in 150 ml of benzene at 55° for 2 hours. The benzene was then evaporated from the solution, affording 1-(1-naphthyloxy)-8-(phenylcyanoamino)octane which was employed in Step B (below) without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36]COCC[Si](C)(C)C)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2cc(O)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl)-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][C:23](=[O:25])[CH2:22][C@H:21]([CH3:26])[O:20]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3([OH:25])[CH2:22][C@@H:21]([CH3:26])[O:20][C@@H:19]([CH3:18])[CH2:24]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Product: C[C@@H]1CC(O)(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one. Brown solid. MS (m/e): 338.4 ([M+H]+, 100%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[O:16].Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccsc1
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of 5-Bromo-1-methyl-imidazole (18.8 g, 117 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 38.9 mL, 117 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-methoxy-N-methylthiophene-3-carboxamide (20.0 g, 117 mmol) was added dropwise. The mixture was stirred for 3.5 h at room temperature. The mixture was worked-up by addition of water (400 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (3×100 mL), the organic layers were washed with water (100 mL) then dried over MgSO4 and concentrated in vacuo. Purification of the residue on silica gel afforded (1-methyl-1H-imidazol-5-yl)(3-thienyl)methanone [11.6 g, yield 41%; HPLC/MS: m/z=193 (M+H); log P(HCOOH)=0.43].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH2:4]Cl.C[O:15]CCO>O.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH2:4][OH:15]
Reactant: O=[N+]([O-])c1cc(Cl)c(CCl)c(Cl)c1
Reactant: COCCO
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(CO)c(Cl)c1

Procedure:
A suspension of silver carbonate (560 mg), 2,6-dichloro-4-nitrobenzylchloride (440 mg) in 2-methoxyethanol (9 cm3) and water (9 cm3) were heated at reflux for 18 h. After this time the hot reaction mixture was filtered and the filtrate diluted with dichloromethane (30 cm3) and water (20 cm3). The heterogeneous mixture was shaken, separated and the aqueous phase extracted with dichloromethane (30 cm3). Combined organic extracts were washed with saturated brine, dried and evaporated to leave an orange oil which was purified by chromatography over silica gel with an ethyl acetate--petroleum ether gradient. The title compound was obtained as a cream solid, m.p. 111°-114° C.
Reaction SMILES: [O:1]=[C:2]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[N:25]=[CH:24][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:22]=4)[CH:19]=3)[N:14](C3CCCCO3)[N:13]=2)[CH:7]=1)=[O:4]>Cl.O1CCOCC1>[NH:23]1[CH:24]=[N:25][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2](=[O:1])[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:11]=[CH:10][CH:9]=2)=[N:22]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
2-Oxo-N-(3-{1-perhydro-2H-pyran-2-yl-5[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-2-phenylacetamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 4 h. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.014 g, 14% yield over 2 steps): 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.39 (t, 1H), 8.21 (m, 2H), 8.13 (d, 1H), 7.94 (dt, 1H), 7.89 (dt, 1H), 7.82–7.69 (m, 3H), 7.64–7.57 (m, 3H); ES-MS (m/z) 409 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH:11]=1)=[O:5])[CH3:2].[CH3:21][Si](C)(C)N[Si](C)(C)C.[K].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]([CH3:21])[C:9](=[O:13])[N:10]([CH3:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)C1=CN(C)C(=O)NC1c1ccc(F)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1=CN(C)C(=O)N(C)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (1.0 g, 3.6 mmol) was dissolved in 10 mL DMF and cooled to 0°. Potassium hexamethyldisilazane (8 mL, 4 mmol of 0.5M toluene solution) was added and the reaction mixture was stirred at 0° for 5 minutes. CH3I (0.3 mL, 4.8 mmol) was added and the mixture was allowed to warm to room temperature and stir for 2 hours. The solution was poured into cold aqueous pH 2 buffer and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 0-30% ethyl acetate/hexane to yield 700 mg of 4-(4-fluoro-phenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl>CC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(c2cccnc2F)CC1
Temperature: 45 °C

Procedure:
To a solution of 2-fluoro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine (7.88 g, 33.2 mmol) in acetone (350 mL) was added aqueous hydrochloric acid (39.9 mL, 39.9 mmol, 1N). The mixture was heated to 45° C. for 5 h, then cooled to room temperature. Most of the organic solvent was removed in vacuo and ethyl acetate (200 mL) was added. The resulting solution was washed with saturated aqueous sodium bicarbonate (2×), water (1×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 4-(2-fluoropyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 194.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:23](OCCO)[N:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>C(O)(=O)C.O1CCOCC1.[C].[Pd]>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[C:19]([NH:18][S:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)(=[O:17])=[O:16])=[N:20][CH:21]=[N:22][CH:23]=2)=[CH:30][CH:29]=1
Reactant: O=S(=O)(Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncncc1-c1ccc(Cl)cc1)c1ccc(O)cc1

Procedure:
A solution of 512 mg of p-(benzyloxy)-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]benzene-sulfonamide in 30 ml of glacial acetic acid was treated with 2 ml of 4N HCl in dioxane and 100 mg of 10% palladium-carbon. The mixture was hydrogenated while stirring, thereafter the solution was suction filtered, evaporated under reduced pressure and the residue was recrystallized from isopropyl ether and again from CH3CN. There was obtained N-[5-(p-chlorophenyl)-4-pyrimidinyl]-p-hydroxybenzenesulfonamide, melting point 231°-232° C.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:37])[F:38])=[CH:31][CH:32]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of N-dodecyl-4-formyl-benzamide (Example 10, step a) (1.00 g, 3.115 mmol), acetic acid (0.227 g, 3.78 mmol) and 4-trifluoromethyl-phenylamine (0.609 g, 3.78 mmol) in DCE (25 mL) was added at once NaBH(OAc)3 (0.801 g, 3.78 mmol). The resulting mixture was stirred overnight at 70° C. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a colorless oil. This crude product was purified by column chromatography over silica gel (4/1 c-Hex/AcOEt to 3/1 in about 0.5 h) to give the title compound as a colorless oil (0.824 g, 63%). 1H NMR (CD3OD, 300 MHz) δ 7.74 (d, 2H, J=8.3 Hz), 7.43 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.7 Hz), 6.63 (d, 2H, J=8.3 Hz), 4.42 (s, 2H), 3.35 (m, 2H), 1.58 (m, 2H), 1.27 (m, 18H), 0.88 (m, 3H). M+(LC/MS(ESI)): 463.0; M−(LC/MS(ESI)): 461.3. HPLC (Condition A), Rt: 6.84 min (HPLC purity: 98.5%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:14]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]#[N:25])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cccc(C#N)c2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2noc([C@@H]3CCCN3)n2)c1
Yield: 73.1 %

Procedure:
(S)-3-(5-Pyrrolidin-2-yl-[1,2,4]oxadiazol-3-yl)-benzonitrile (360 mg, 73%) was prepared according to the procedure in Example 39 from (S)-2-[3-(3-cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (697 mg, 2.05 mmol) in dichloromethane (15 mL) and trifluoroacetic acid (2.4 mL) at room temperature for 2 h. 1H NMR (CDCl3), δ(ppm): 8.39 (s, 1H), 8.32 (d, 1H), 7.78 (d, 1H), 7.60 (t, 1H), 4.58 (dd, 1H), 3.22 (m, 1H), 3.13 (m, 1H), 2.34 (m, 1H), 2.14 (m, 1H), 2.00 (m, 3H).
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:25][CH:26]([NH:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl>[CH3:25][CH:26]([N:32]([CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)[C:7](=[O:9])[CH2:6][S:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC(C)NCc1cccnc1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(C)N(Cc1cccnc1)C(=O)CSCCCC

Procedure:
N-(1-methylhexyl)-N-[(3-pyridyl)methyl]-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 3.6 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide with 5.0 g. of N-(1-methylhexyl)-[(3-pyridyl)methyl]amine in 200 ml. of dichloromethane. Oil.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][S:27][CH3:28])[CH:20]([NH:29][C:30](=[O:60])[C:31](=[N:57][O:58][CH3:59])[C:32]1[N:33]=[C:34]([NH:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:35][CH:36]=1)[C:19]2=[O:61])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.O>C(O)=O>[NH2:37][C:34]1[S:35][CH:36]=[C:32]([C:31](=[N:57][O:58][CH3:59])[C:30]([NH:29][CH:20]2[C:19](=[O:61])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][S:27][CH3:28])=[C:17]3[C:15]([OH:16])=[O:14])=[O:60])[N:33]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSC)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSC)CSC12)c1csc(N)n1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
2-Benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-3-(2-methylthiovinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, mixture of E- and Z-forms) (1.26 g) is dissolved in formic acid (35 cc), water (13 cc) is added and the mixture is heated at 50° C. for 15 minutes. It is then allowed to cool, filtered and concentrated to dryness under reduced pressure (20 mm Hg at 20° C.). The residue is triturated in diethyl ether (20 cc), filtered off, washed with ether (20 cc) and dried. 7-[2-(2-Aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-3-(2-methylthio-vinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, mixture of E- and Z-forms) (0.63 g) is obtained as a solvate with formic acid, in the form of a cream-coloured powder.
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[F:7][C:8]([F:19])([F:20])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Ic1ccc[se]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ccc[se]2)cc1

Procedure:
A mixture of 15.1 g (58.7 mmol) of 2-iodoselenophene, 13.9 g (67.7 mmol) of 4-trifluoromethoxyphenylboronic acid, 3.90 g (3.38 mmol) of tetrakis(triphenylphosphine)palladium(0) and 150 ml of 2 N sodium carbonate soln. in 400 ml of toluene/ethanol (1:1) is heated under reflux for 23 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with MTBE. The combined organic phases are washed with 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→1:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-trifluoromethoxyphenyl)selenophene is obtained as a yellowish solid.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:19][CH:18]2[C:14]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)([N:15]([C:20](=[S:30])[NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:16][CH2:17]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+]>[Zn].O>[C:22]([NH:21][C:20]([NH:15][C:14]1([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH:18]([CH2:17][OH:16])[CH2:19][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:13]1)=[S:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2cccs2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cccs2)C1
Temperature: 40 °C
Reaction time: 7 h
Yield: 32 %

Procedure:
Acetic acid (104 mL) is added to tert-butyl-1-(benzoylcarbamothioyl)-6a-(2-thienyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate followed by powdered zinc (17.1 g, 261 mmol) and the resulting suspension is vigorously stirred at 40° C. for 7 hours followed by an additional hour at 45-50° C. The reaction is concentrated under reduced pressure. To the crude reaction mixture is added diatomaceous earth and water, followed by a saturated solution of sodium bicarbonate. The mixture is filtered and washed with ethyl acetate. The filtrate is extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (3.8 g, 32%). ES/MS (m/e): 460 (M−1).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(S(C)(=O)=O)cc3)c2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (17 mg, 0.044 mmol) in Acetonitrile (0.4 mL) was treated with Cs2CO3 (57.9 mg, 0.178 mmol), 4-methylsulfonylbenzyl bromide (44.3 mg, 0.089 mmol), and stirred at 70° C. for 1.5 hours. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-1-(4-(methylsulfonyl)benzyl)-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (22 mg, 0.040 mmol, 90% yield) as yellow oil. The ester intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with 2M LiOH (0.120 mL, 0.24 mmol), and stirred at 60° C. for 2 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (9.3 mg, 0.017 mmol, 37.6 yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.00 (s, 9H), 2.44 (s, 3H), 3.02 (s, 3H), 3.64 (s, 3H), 5.47 (s, 1H), 5.81 (d, J=15.7 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.43 (m, 3H), 7.47-7.58 (m, 1H), 7.89 (d, J=8.4 Hz, 2H). LCMS (m/z) ES+=537 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+].CCCCCC>CN(C)C=O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:16]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)CN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.1 %

Procedure:
Into a solution of isoindoline (1.788 g, 15 mmol) and ethyl bromoacetate (2.756 g, 16.5 mmol) in N,N-dimethylformamide (20 mL), was added Cs2CO3 (5.376 g, 16.5 mmol) under N2. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the resulting mixture was subjected to silica gel chromatography, eluting with 33:66 ethyl acetate:hexane to afford Intermediate 200(a) (1.14 g, 5.56 mmol) as a yellow oil in 37% yield.