Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[CH:32]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[C:36]=2[CH:35]=[CH:34][N:33]=1>O>[CH:32]1[C:41]2[C:36](=[C:37]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3cccc4cnccc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.5 mL of a sonicated and degassed solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 740 mg, 2 mmol), potassium carbonate (830 mg, 6 mmol), bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 70 mg, 0.1 mmol), dioxane (41 mL) and water (4.1 mL) was added to a reaction vial containing 5-isoquinolineboronic acid (available from Frontier Scientific, Inc., Logan, Utah; 104 mg, 0.6 mmol). The solution was sonicated and degassed. The mixture was heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica, and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added. The solvents were removed in the Genevac and then 50% aqueous methanol (2 mL) was added. The vial was centrifuged and the solvent removed. This process was repeated and then the same was dried overnight in the oven to give 3-(4-isoquinolin-5-yl-phenoxymethyl)-benzoic acid. Mass spectrum MH+=356.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH2:13][C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]=2[O:43][CH3:44])=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCl>[C:17]1([CH:23]([O:30][C:31]([C:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH:41][C:14](=[O:15])[CH2:13][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C@H:37]3[S:36][CH2:35][C:34]=2[O:43][CH3:44])=[O:32])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CCl
Solvent: c1ccncc1
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
1 ml of pyridine and 0.5 ml of phenylacetic acid chloride are added at 0° C, under a nitrogen atmosphere, to a suspension of 0.250 g of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of methyl chloride and the mixture is stirred for 30 minutes at this temperature. The reaction mixture is evaporated under reduced pressure; the residue is stirred for 10 minutes with 20 ml of a 1:1 mixture of dioxane and water and diluted with methylene chloride. The aqueous phase is separated off and extracted with methylene chloride. The combined organic phases are washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product is purified by means of preparative thin layer chromatography using, as the solvent, a 1:1 mixture of toluene and ethyl acetate. The zone visible under ultraviolet light of λ = 254 mμ (Rf~0.35) is eluted with a 4:1 mixture of acetone and methanol and gives 3-methoxy-7β-(α-phenylacetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester which is identical with the product obtainable by the process of Example 9.
Reaction SMILES: [OH:1][C:2]12[C:14](=[O:15])[C:10](=[CH:11][CH2:12][CH2:13]1)[CH:9]([OH:16])[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]2.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:16][CH:9]1[C:10]2[C:14](=[O:15])[C:2]([OH:1])([CH2:13][CH2:12][CH:11]=2)[C:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C2=CCCC1(O)C#CC=CC#CC2O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)OC1C#CC=CC#CC2(O)CCC=C1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (product of Example 4, 32 mg, 0.149 mmol) in 1 ml of pyridine Was added dimethylaminopyridine and 1 eq of acetic anhydride (14 ul, 0.149 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then pyridine was stripped off on rotovap and on high vacuum. This residue was purified on a silica gel column using 10% and 20% ethyl acetate/hexane mixture as the solvent system. The title compound was obtained as light yellow foam in 85% yield (32.4 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.N1C(=O)CC[C@H]1C(O)=O.C(Cl)Cl>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(-c2cc3cc(OC(=O)C(C)(C)C)ccc3o2)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of 75 (8.2 g, 36.3 mmol) in CH2Cl2/Pyr was treated with pivaloyl chloride (9.63 g, 79.9 mmol) and stirred at rt until TLC indicated that the reaction was complete. The reaction was worked up by diluting with additional CH2Cl2 and washing with 2 N HCl aq. The CH2Cl2 layer was washed with satd NaHCO3 aq, brine and dried over MgSO4. Filtration and concentration yielded 9.3 g of the crude solid that was used as is for the next reaction.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([F:33])[F:32])[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([F:32])[F:33])[CH2:25][N:1]1[CH:2]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: O=Cc1ccc(OC(F)F)c(Cl)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-chloro-4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 427.96 g/mol.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:33]1[O:34][C:35]([CH3:38])=[N:36][N:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][N:26]([C:33]5[O:34][C:35]([CH3:38])=[N:36][N:37]=5)[CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC1CNCCC1Nc1nc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccn2n1
Reactant: Cc1nnc(Br)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cccn4n3)C(F)C2)o1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 269b, 68 mg, 152 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) and diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) dissolved in dry dioxane (2 mL) was stirred at 70° C. for 12 hours and then at 110° C. for 1 hour. Further diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) were added and heated to 110° C. for another hour. The solvent was evaporated and the residue directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as colorless oil (46 mg, 57%) as a mixture of cis- and trans-isomers.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:11].[Se](=O)=[O:13]>O1CCOCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH:11]=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1nc2cnccc2n1C
Solvent: C1COCCO1
Product: Cn1c(C=O)nc2cnccc21
Temperature: 130 °C
Yield: 73 %

Procedure:
To a solution of 1,2-dimethyl-1H-imidazo[4,5-c]pyridine (500 mg, 3.40 mmol) in dry 1,4-dioxane (7.5 mL) was addedhttp://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.int Value&query=structure._structureID%3D4635571 &target=entry&action=PowerSearch&onclick=1 &from=0 &history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3COOH%22+ or +catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D%3F+elsor+entry.catalogID%3D%3 selenium dioxide (665 mg, 5.10 mmol). The mixture heated by microwave at 130° C. for 5 min. Then the mixture was filtered and concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether:DCM 10:1 to 1:1) to give the title compound (400 mg, yield 28%). LC-MS (ESI) m/z: 162 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.61 (s, 3H), 5.91 (s, 1H), 7.67-7.70 (d, J=5.6 Hz, 1H), 8.39-8.41 (d, J=5.6 Hz, 1H), 8.93 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:34][C:35]([CH:37]1[CH2:39][CH2:38]1)=[NH:36]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]3[O:18][N:36]=[C:35]([CH:37]4[CH2:39][CH2:38]4)[N:34]=3)=[CH:14][N:13]=2)[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cn2)CC1
Reactant: N=C(NO)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(C4CC4)no3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 380 %

Procedure:
To a solution of 6-(1-tert-butoxycarbonylamino-cyclopropyl)-nicotinic acid (0.10 g, 0.10 mmol) in DMF (5 mL) was added CDI (0.16 g, 0.10 mmol). The mixture was stirred at room temperature for 3 h. N-hydroxy-cyclopropanecarboxamidine (0.28 g, 0.10 mmol) was then added and the reaction mixture heated at 100° C. for 24 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, satd aqueous NaHCO3, brine and dried with MgSO4. The mixture was filtered and concentrated to give {1-[5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (0.13 g, 0.38 mmol) as a yellow oil, m/z 343.7 [M+H]+.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:34])([F:33])[S:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[C:17](=[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:16]=2[CH:32]=1)(=[O:11])=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:29]1[CH2:30][CH2:31][C:26](=[C:17]2[C:16]3[CH:32]=[C:12]([S:9]([C:8]([F:34])([F:7])[F:33])(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]=3[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=3)[CH2:27][CH2:28]1)[CH3:2]
Reactant: O=S(=O)(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Reactant: C1CO1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide of 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.55 g. of 4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give (±)-1-hydroxyethyl-4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 141°-144° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:7]([N:5]1[CH:6]=[C:2]([NH:1][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=[CH:4]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4-amino-1-tritylimidazole (0.30 g, 0.92 mmol) in dichloromethane (4 ml) were added sequentially triethylamine (0.19 ml, 1.37 mmol) and benzoyl chloride (0.13 ml, 1.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then diluted with dichloromethane and washed sequentially with water, saturated aq. NaHCO3 solution, water and saturated brine. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane 0:100 to 10:90) to yield the title compound as an orange solid (0.36 g, 92%); MS (ISP): 430.3 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:40])[CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][CH:23]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:41])(=[O:3])[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:40])[CH:12]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:41])(=[O:3])[NH2:2]
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc(C(N)=O)c(F)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc(C(N)=O)c(F)c1)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E337) in THF under N2 at 0° C. was added TBAF, and the solution was stirred for 30 min at 0° C. The reaction was warmed to room temperature and stirred another 3.5 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropylcarbamate (E337-1)
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:34][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]\[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(=CBr)c1cccc(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 40 mg as the TFA salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.22 (d, 1H), 7.18 (s, 1H), 7.10 (m, 2H), 6.85 (t, 1H), 6.70 (s, 1H), 6.62 (d, 2H), 4.65 (d, 1H), 4.05 (d, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.80 (s, 3H), 2.60 (m, 1H), 2.42 (s, 3H), 2.38 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([O:15][CH3:16])[C:12](O)=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([C:12]([Cl:19])=[O:13])[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COC(C(=O)O)C(=O)OCc1ccccc1
Product: COC(C(=O)Cl)C(=O)OCc1ccccc1

Procedure:
A solution of Benzyloxycarbonyl methoxy-acetic acid (40 g) and Thionyl Chloride (80 ml) was stirred at reflux temperature for 3 hours. Excess Thionyl Chloride was distilled off and to the residue was added Toluene (100 ml). The solvent was distilled off completely to get chlorocarbonyl methoxy-acetic acid benzyl ester (40 g) as a light brown liquid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(OC)=O)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4].[Cl-].[Li+].O>CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1Cc2cccc([N+](=O)[O-])c2C1
Temperature: 160 °C
Yield: 67.7 %

Procedure:
A mixture of dimethyl-4-nitroindane-2,2-dicarboxylate (4.84 g, 0.0167 mol), lithium chloride (0.84 g, 0.0198 mol), 1.1 mL water, and 18 mL dimethylsulfoxide was heated to 160° C. under nitrogen for two hours. It was then allowed to cool and the dimethylsulfoxide was removed under high vacuum. The residue was purified on silica (10%-100% CH2Cl2 in hexanes) to give 2.5 g white solid (65%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[OH:25][CH2:26][C:27](O)=[O:28].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:28][CH2:27][C:26]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)CO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a solution of 3.0 g of tert-butyl piperidin-4-ylcarbamate in 60 ml of methylene chloride, were added 2.5 ml of triethylamine, 2.4 g of HOBt, 1.3 g of hydroxyacetic acid and 3.5 g of WSCD hydrochloride, and the reaction mixture was stirred at room temperature for 18 hours. 1 M hydrochloric acid was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, water and brine. This was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform/MeOH=50/1) to obtain 2.8 g of tert-butyl [1-(hydroxyacetyl)piperidin-4-yl]carbamate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[C:5]([F:27])=[CH:4][N:3]=1.[CH3:28][O-:29].[K+]>CN1C(=O)CCC1>[F:27][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:7][C:2]([O:29][CH3:28])=[N:3][CH:4]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3nc(Cl)ncc3F)CC2)CC1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(F)c(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The tert-butyl 1′-(2-chloro-5-fluoropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (40 mg, 0.10 mmol) was added to NMP (1 mL), and then potassium methoxide (8.1 mg, 0.11 mmol) was added to the mixture. The reaction was stirred for 30 min at r.t. and was quenched with ammonium chloride solution (5 mL), extracted with ethylacetate (10 mL). The organic phase was washed with brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% acetone: hexane to yield the title compound.
Reaction SMILES: [O-:1]I(=O)(=O)=O.[Na+].[CH3:7][C:8]([CH3:29])([Si:10]([CH3:28])([CH3:27])[O:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9]>O.CO>[CH3:9][C:8]([CH3:29])([Si:10]([CH3:28])([CH3:27])[O:11][CH2:12][CH2:13][CH2:14][S:15](=[O:1])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH3:26])([CH3:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCSCCCO[Si](C)(C)C(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of sodium (meta)periodate (7.751 g, 1.1 eq) in water (40 mL) was slowly poured into a solution of 2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane (12.32 g, 1 eq) in methanol (150 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered through a pad of celite and silica gel which was washed with methanol. The filtrate was concentrated under reduced pressure at a temperature below 25° C. The residue was diluted with brine and extracted a couple of times with chloroform. All organic solvents were combined, dried with anhydrous sodium sulfate, and concentrated to give the title compound as a clear oil (12.84 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][S:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:6]
Reactant: COC(=O)CSCCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CS(=O)CCCl
Reaction time: 0.5 h

Procedure:
3-Chloro-peroxybenzoic acid (81%, 4.7 g, 0.022 mole) was added to the title compound of Example 10 (3.7 g, 0.022 mole) in cold (5° C.) methylene chloride (75 ml) stirred for 30 minutes and cooled in a refrigerator for 48 hours. After removing the solid by filtration, a saturated solution of sodium thiosulfate (30 ml) was added and the mixture stirred for 15 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate (2×50 ml), dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was crystallized from ethyl acetate and hexane to give a white solid which was identified as the title compound by its NMR and IR spectra.