Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][O:6][C:7](=[O:40])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][C@H:14]1[C:18](=[O:19])[CH:17]=[CH:16][C@@H:15]1/[CH:20]=[CH:21]/[C@@H:22]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:23][CH2:24][C:25]1[S:26][C:27]([CH3:31])=[C:28]([Br:30])[CH:29]=1>C1COCC1.[Cu]I>[CH3:5][O:6][C:7](=[O:40])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][C@H:14]1[C:18](=[O:19])[CH2:17][CH:16]([CH:1]=[CH2:2])[C@@H:15]1/[CH:20]=[CH:21]/[C@@H:22]([O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[CH2:23][CH2:24][C:25]1[S:26][C:27]([CH3:31])=[C:28]([Br:30])[CH:29]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reactant: C=C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC1CC(=O)[C@H](C/C=C\CCCC(=O)OC)[C@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Vinylmagnesium bromide (1.25 mL, 1.25 mmol, 1 M/THF) was added to a 0° C. mixture of CuI (158 mg, 0.83 mmol) in 2 mL THF. The dark mixture was stirred for 5 min. and then was cooled to −78° C. A solution of Enone 7 (169 mg, 0.28 mmol) in 1 mL THF was added by cannula, rinsing with 0.25 mL THF. The mixture was stirred for 1.5 h and then 20 mL saturated NH4Cl was added. The resulting mixture was stirred for 20 min. and then was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (7.5% ethyl acetate/hexanes) gave the title ketone (138 mg, 0.22 mmol, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:26]O>>[CH3:26][O:19][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=S(=O)(O)O
Product: COC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reaction time: 12 h
Yield: 56 %

Procedure:
A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.1011 mole), methanol (100 ml) and concentrated sulfuric acid (3 ml) was refluxed overnight under a Dean-Stark trap. Another 2 ml of concentrated sulfuric acid and methanol (50 ml) was added and reflux continued for 12 hr. The methanol was evaporated, water (50 ml) was added, and sodium bicarbonate (solid) added until basic. The mixture was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extracts were washed with water (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (2.5 g) was combined with a sample obtained previously and recrystallized from isopropyl ether-isopropyl alcohol to give 3.0 g (56%) of white needles, mp 198°-200° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:12][N:13](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.[C-]#N.[C-]#N.[Zn+2]>[Cl:11][C:9]1[CH:10]=[C:2]([C:12]#[N:13])[C:3]2[CH:4]=[N:5][NH:6][C:7]=2[CH:8]=1
Reactant: Clc1cc(Br)c2cn[nH]c2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Cl)cc2[nH]ncc12
Temperature: 120 °C
Yield: 86.9 %

Procedure:
A mixture of 4-bromo-6-chloro-1H-indazole (3.0 g, 12.9 mmol), Pd(PPh3)4 (2.24 g, 1.94 mmol), and Zn(CN)2 (9.22 g, 25.8 mmol) in DMF (50 mL) under nitrogen was heated at 120° C. for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL×5). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 6-chloro-1H-indazole-4-carbonitrile as white solid (2.0 g, 86.9%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[C:8]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:9]([C:13]([NH:15][NH2:16])=[O:14])[S:10][C:11]=1[CH3:12])#[N:6]>O.Cl>[C:5]([C:7]1[C:8]([S:17](=[O:18])(=[O:19])[NH2:20])=[C:9]([C:13]([N:15]=[N+:16]=[N-:1])=[O:14])[S:10][C:11]=1[CH3:12])#[N:6]
Reactant: O=N[O-]
Reactant: Cc1sc(C(=O)NN)c(S(N)(=O)=O)c1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1sc(C(=O)N=[N+]=[N-])c(S(N)(=O)=O)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of sodium nitrite (0.47 g) in 5 ml of water was added dropwise to a stirred solution of 4-cyano-2-hydrazinocarbonyl-5-methyl-thiophene-3-sulfonamide (1.6 g) in 38 ml of 1 M hydrochloric acid at 0° C. The resulting mixture was stirred for 30 min at 0° C. and then filtered. The filter cake was washed with water and dried in vacuum to give 1.35 g of the title compound; 1H-NMR (DMSO-d6), δ(ppm): 7.75 (br, 1H, NH2), 2.75 (s, 1H, CH3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOCC>[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([O:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: OC(CCCCCCCCCCCCOCc1ccccc1)CCCCCCCCCCCCOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(CCCCCCCCCCCCOCc2ccccc2)CCCCCCCCCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
First, 3 g of bis(12-benzyloxydodecyl)methanol and 20 ml of pyridine were placed in a 100 ml flask. Then, 1.15 g of p-toluenesulfonylchloride was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ether. The diluted mixture was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and water in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from acetone to obtain 1.6 g of bis(12-benzyloxydodecyl)methyl p-toluenesulfonate (Y: 42%). The compound thus obtained had a purity of 98.5% by HPLC.
Reaction SMILES: C1(C2ON=C([C:9]3[N:13]4[C:14]5[C:19]([C:20](=[O:25])[N:21]([CH:22]6[CH2:24]C6)[C:12]4=[CH:11][N:10]=3)=[C:18](Cl)[CH:17]=[CH:16][CH:15]=5)N=2)CC1.C1([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34]C=CC=3Cl)[NH:32][C:31]2=O)CC1.C1(C2ON=C(C[N+]#[C-])N=2)CC1>>[CH:38]1([C:39]2[O:40][N:32]=[C:31]([C:11]3[N:10]=[CH:9][N:13]4[C:14]5[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20](=[O:25])[N:21]([CH2:22][CH3:24])[C:12]=34)[N:30]=2)[CH2:33][CH2:34]1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)n1C1CC1
Reactant: O=c1c2c(Cl)cccc2n2c(-c3noc(C4CC4)n3)ncc2n1C1CC1
Agent: [C-]#[N+]Cc1noc(C2CC2)n1
Product: CCn1c(=O)c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl-4,5-dihydro-4-cyclo-propyl-5-oxo-6-chloro-imidazo(1,5-a)quinazoline. M.p. 232°-235° C. by reaction between 3-cyclopropyl -5-chloro-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[N:10][C:9]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=5)[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH2:28]([O:30][CH2:31][CH2:32]Br)[CH3:29].C1COCC1.[H-].[Na+]>CCOCC.O.CN(C=O)C>[CH2:28]([O:30][CH2:31][CH2:32][N:1]1[CH:5]=[C:4]([C:6]2[N:11]=[N:10][C:9]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=5)[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH:3]=[N:2]1)[CH3:29]
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(-c4cn[nH]c4)nn3)CC1)CC2
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 1-(1-(6-(1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline (55 mg, 0.15 mmol, 1.0 equiv) and 2-ethoxyethylbromide (0.17 mL, 1.5 mmol, 10 equiv) was added THF (2 mL) and DMF (0.5 mL). NaH (30 mg, 60% in mineral oil, 0.75 mmol, 5 equiv) was then added. The resulting mixture was stirred at room temperature for 1.5 h and then poured into Et2O/H2O (20 mL/20 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield 1-(1-(6-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[S:27][C:20]=23)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[CH:25]=[C:26]([C:28]([OH:30])=[O:29])[S:27][C:20]=23)=[CH:17][CH:18]=1)=[O:11]
Reactant: COC(=O)c1cc2nccc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccnc4cc(C(=O)O)sc34)cc2)c1
Temperature: 70 °C

Procedure:
To a stirred solution of methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate (20 mg, 0.046 mmol) in THF/MeOH (5 ml/5 ml) was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 70° C. for 30 minutes, cooled to room temperature and poured into 50 ml of water. 1M HCl was added until pH=4 and the resulting precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 43.5 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (0.500 g), 4-(piperaziny-1-yl)benzamide (Example 3, Step 1; 0.536 g), triethylamine (0.477 g), and ethylene glycol (6 mL) give 0.40 g of the title compound after chromatography on silica gel using methanol/dichloromethane (8/92) and crystallization from methanol/dichloromethane; mp 240-241° C.; IR (mineral oil) 1612, 1646, 1331, 3359, 1501 cm-1. 1H NMR (DMSOd6) δ2.60, 3.25, 3.66, 6.92, 7.04, 7.25, 7.54, 7.72, 7.73, 7.84, 8.80.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[N:15]1[CH:14]=[C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])[CH:18]=[N:17][CH:16]=1
Reactant: Brc1cncnc1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccccc1-c1cncnc1
Temperature: 150 °C
Yield: 59.7 %

Procedure:
A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 5-bromo-pyrimidine (316 mg, 2.0 mmol) and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 100 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide a crude material, which was purified by ISCO to give 220 mg of 2-pyrimidin-5-yl-benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[N:15]=[N+]=[N-].CCO.CO.[NH4+].[Cl-].C1COCC1>C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[NH2:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1N=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c(Cl)c1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 4.4 g (16.19 mmol) of 4-amino-2-azido-3-chloro-5-nitro-benzoic acid methyl ester in 161 mL of a mixture EtOH:MeOH 2:1 (v/v), 161 mL of a saturated NH4Cl aqueous solution is added followed by the addition of 88 mL of THF. Then 5.2 g (81 mmol) of powdered zinc is added and the reaction is stirred at ambient temperature during 5 h. The suspension is diluted with CH2Cl2 and the organic phase is washed with brine (2 times) and then dried on Na2SO4. After filtration and evaporation 3.2 g (14.84 mmol, 92%) of a dark violet-red solid were obtained and used directly in the next step without more purification. LC/MS: 216/218 (M+1)+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=[C:3]1[CH2:35][C:36]([O:38]CC)=[O:37].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[O:12])=[C:3]1[CH2:35][C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)Cc1c(C(=O)N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)c2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CC(=O)O)c(C(=O)N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)c2ccccc21
Yield: 39 %

Procedure:
A solution of ethyl (1-methyl-3-{[4-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-1-piperazinyl]carbonyl}-1H-indol-2-yl)acetate (E60) [54 mg] in methanol [6 ml] and water [0.8 ml] was treated with 2N sodium hydroxide [0.46 ml] and was heated under reflux for 2 h. The reaction mixture was quenched with hydrochloric acid [10 ml] at room temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was dried and concentrated in vacuo to give the title compound (20 mg). LCMS RT=2.35 min, 518 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:8]([CH3:9])[CH:7]=[CH:6][S:5]1.C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][CH:4]1[N:8]([CH3:9])[CH:7]=[CH:6][S:5]1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: CN1C=CSC1CCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCC1SC=CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of 2-(2-hydroxyethyl)-3-methylthiazole (0.70 mol.), 71 g of triethylamine (0.70 mol.), 500 g of chloroform and 3 g of phenothiazine. Next, 63 g of acryloyl chloride (0.70 mol.) was slowly added to the reaction over 1.5 hour via the addition funnel. The reaction was stirred for 2 hours at room temperature. The reaction mixture was extracted with NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was evaporated with a rotoevaporator to yield 113 g (82%) of a dark brown liquid. The compound was confirmed by IR and 13C NMR.
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH2:10][CH2:9][S:8][CH:7]=[C:6]1[CH2:11][C:12]([OH:14])=O.[NH2:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH2:28][S:29][C:30]1[N:34]([CH3:35])[N:33]=[N:32][N:31]=1)=[C:21]2[C:25]([OH:27])=[O:26].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CC(C)=O.O>[C:25]([C:21]1[N:22]2[CH:17]([S:18][CH2:19][C:20]=1[CH2:28][S:29][C:30]1[N:34]([CH3:35])[N:33]=[N:32][N:31]=1)[CH:16]([NH:15][C:12](=[O:14])[CH2:11][C:6]1[S:5][CH2:10][CH2:9][S:8][CH:7]=1)[C:23]2=[O:24])([OH:27])=[O:26]
Reactant: O=C(O)CC1=CSCCS1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
Thionyl chloride (8.7 g.) is added to a solution of (5,6-dihydro-1,4-dithiin-2-yl)acetic acid (6.45 g.) in benzene (120 cc.). The mixture is heated under reflux until gas ceases to be evolved and is then concentrated to dryness under reduced pressure (20 mm.Hg). The brown oil thus obtained is dissolved in acetone (50 cc.) and the resulting solution is added dropwise, over the course of one hour, to a solution of 7-amino-2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (12 g.) and sodium bicarbonate (7.35 g.) in water (200 cc.) and acetone (100 cc.) kept at 3° C. Stirring is continued for a further hour at 3° C. and then for 2 hours at about 20° C. The mixture is concentrated to dryness under reduced pressure (20 mm.Hg), water (150 cc.) is added and the slight amount of insoluble matter is filtered off. The solution is washed twice with ethyl acetate (300 cc.) and brought to pH 2.2 by addition of 4 N hydrochloric acid in the presence of ethyl acetate (300 cc.). The solution is filtered through "Supercel" and decanted, and the aqueous phase is extracted with ethyl acetate (300 cc.). The organic phases are combined and washed with water (200 cc.), dried over magnesium sulphate and treated with decolourizing charcoal. The mixture is filtered and the filtrate is concentrated to a volume of 100 cc. Diethyl ether (700 cc.) is then added and the mixture is cooled to about 0° C.; the resulting precipitate is filtered off and washed with diethyl ether (100 cc.). 2-Carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (4.4 g.) is obtained in the form of a cream powder.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1N)([O-])=O.Cl.N([O-])=O.[Na+]>O>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[C:4]3[C:5](=[CH:7][CH:8]=[C:9]([OH:11])[CH:10]=3)[NH:1][C:4]=2[CH:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)[nH]c1ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
2-Nitro-4-methoxyaniline (16.8 g) was added to water (30 ml) and concentrated hydrochloric acid (160 ml), and stirred at room temperature for 20 minutes and then at 70° C. for 75 minutes. The reaction mixture was cooled with ice and an aqueous solution (30 ml) of sodium nitrite (11.5 g) was dropwise added so that the temperature of the reaction solution did not exceed 5° C. After addition, the mixture was stirred for 1 hour while the temperature was maintained at 10° C. The reaction mixture was filtered and the residue was washed with water (50 ml). The filtrate was cooled with ice, to which an aqueous solution (120 ml) of sodium hydrogencarbonate (123 g) and 1,4-benzoquinone (12.3 g) was dropwise added over 1 hour. After addition, the reaction mixture was stirred for 4 hours while ice cooling and then filtered. The crystal was washed with water and dried. The resulting crystal was dissolved in methanol (200 ml) and acetic acid (20 ml), and 10% palladium/carbon (1.0 g) was added thereto and stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered and the residue was washed with methanol (30 ml). Under ice cooling, concentrated aqueous ammonia (50 ml) was dropwise added to the filtrate over 5 minutes. After addition, the mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was filtered and the crystal was washed with water and dried in vacuo. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 0/1) to yield the titled compound (2.71 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[C:26]([F:34])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1Cl.[OH2:35]>CC(C)CO.C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:34])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1[O:35][CH2:13][CH:14]([CH3:19])[CH3:15]
Reactant: COC(=O)c1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F
Reactant: O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)CO
Product: CC(C)COc1ncc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide (700 μL; 1 M; 0.70 mmol) was added to a solution of methyl 4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-fluorobenzoate, obtained in step 1 (73.63 mg; 0.20 mmol) in 2-methyl-1-propanol (3 mL) and THF (2 mL). The resulting mixture was stirred at RT for 1 h. Water (500 uL) was added and the mixture was stirred at RT for 3 h, saponification was complete. The reaction mixture was then diluted with EtOAc and washed with HCl 1N, NaCl sat. solution and dried over magnesium sulfate. After evaporation of the solvents, the crude was purified by HPLC prep to afford the title compound as a slightly yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.94 (d, J=2.2 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 8.01 (dd, J=8.1, 1.5 Hz, 1H), 7.94 (dd, J=11.1, 1.5 Hz, 1H), 4.27 (d, J=6.5 Hz, 2H), 2.16-2.07 (m, 1H), 1.01 (d, J=6.6 Hz, 6H). LC/MS (Method B): 390.3 (M−H)−, 392.2 (M+H)+. HPLC (Method A) Rt 5.49 min (Purity: 98.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]([Se]C1C=CC=CC=1)[C:6]2=[O:9].N1C=CC=CC=1.OO>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH:7]2[CH2:8][CH:3]1[CH:4]=[CH:5][C:6]2=[O:9]
Reactant: CC1(C)C2CC([Se]c3ccccc3)C(=O)C1C2
Agent: OO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C2C=CC(=O)C1C2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
6,6-Dimethyl-3-phenylselanyl-bicyclo[3.1.1]heptan-2-one, pyridine (8.71 mL), and methylene chloride (650 μL) were combined in a round bottom flask. The temperature of the flask was dropped to 0° C. 67.5 μL of H2O2 was added to the flask and allowed to stir at room temperature for 5 hours at 0° C. Next, the reaction was stirred at room temperature overnight. 5 mL of methylene chloride was added to the solution, and the mixture was washed with water, NaHSO3, and CuSO4, dried with NaSO4, and concentrated. The concentrate was purified via column chromatography to afford final product (70:30, Hexane: EtOAc). 1H NMR (500 MHz, CDCl3): δ (ppm) 1.485 (s, 3H), 1.517 (s, 3H), 2.145 (d, 3H), 2.2.616 (m, 1H), 2.724 (m, 1H), 2.849 (m, 1H), 5.958 (d, 1H), 7.526 (dd, 1H). (ESI, Pos) m/z 159.0 (M+23).