Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].C1CCN2C(=NCCC2)CC1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[NH:26][C:29](=[O:30])[O:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(Cc3cccc(-c4noc(=O)[nH]4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Under an argon atmosphere, to a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamidoxime (46.9 mg) in tetrahydrofuran (0.63 mL) were added 1,1′-carbonyldiimidazole (24.5 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (0.019 mL), and this mixture was stirred at room temperature for 3 hours. 1,1′-Carbonyldiimidazole (16.3 mg) was added thereto, followed by stirring for 80 minutes. Then, 1,8-diazabicyclo[5,4,0]-7-undecene (0.019 mL) was added thereto, followed by stirring for additional 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (43.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:19]=[C:20]([NH:21]C(=O)C(F)(F)F)[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.C(N(CC)CC)C>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:19]=[C:20]([NH2:21])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a suspension of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2,2,2-trifluoro-acetamide (106.65 mmol) in methanol (500 mL), triethylamine (150 mL) was added and the mixture was refluxed for 36 hours and then evaporated to dryness. The crude was treated with a mixture of diethylether (400 mL) and methanol (100 mL), stirred at room temperature for 30 min., filtered and washed with diethylether. After drying in vacuo the title compound was obtained as white solid (50.5 g, 86%).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>CS(C)=O.O>[C:9]1([CH3:8])[CH:16]=[CH:15][C:12]([CH:13]2[CH2:2][O:14]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Trimethylsulfonium iodide (1-1.2 equiv.) in DMSO is added sodium hydride 60% dispersion in oil (1-1.8 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 4-methylbenzaldehyde (1 equiv.) in DMSO is added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The reaction is monitored by TLC and the reaction mixture poured in water and extracted with EtOAc. The combined organic extract is washed with water, followed by brine, and dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-p-tolyloxirane as crude product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:15]3[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccc2c(c1)OCCO2
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: COCCOC
Product: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
1,4-benzodioxane-6-boronic acid (0.125 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.079 g in 75% yield.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](I)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C)C=O.O>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([C:20]#[N:21])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(=O)n2nc(SCc3ccccc3)sc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 120 ml of dimethylformamide, 9 g of 90% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved, and 3.05 g of cuprous cyanide and 1.57 g of sodium cyanide were added thereto. The reaction mixture was heated to 100° C. and stirred at that temperature for 1 hour. After the reaction was finished, the reaction mixture was cooled, diluted with water and extracted with chloroform. The organic layer was washed with water, and the chloroform was distilled off. Water was added to the residue and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the dried organic layer, and the organic layer was shaken well. After the Florisil® was separated, the solvent was distilled off, and thus 3.0 g of 2-benzylthio-7-cyano-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 50%. (Florisil® (a registered trademark of Floridin Company) is a highly selective magnesium silicate absorbent.)
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:15](=[O:16])[N:9]2[N:10]=[C:11](Cl)[CH:12]=[CH:13][C:8]2=[N:7]1)([OH:3])=[O:2].O.O.[SH-:19].[Na+].Cl.[OH-].[Na+]>O>[C:1]([CH2:4][CH2:5][N:6]1[C:15](=[O:16])[N:9]2[N:10]=[C:11]([SH:19])[CH:12]=[CH:13][C:8]2=[N:7]1)([OH:3])=[O:2]
Reactant: [SH-]
Reactant: O=C(O)CCn1nc2ccc(Cl)nn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCn1nc2ccc(S)nn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-carboxyethyl)-6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on (567 mg., 2.34 m.moles) and 70% sodium hydrosulfide dihydrate (924 mg., 7.02 m.mole) in water (10 ml.) was stirred at room temperature for 2 hours. The reaction mixture was adjusted successively to pH 1 with c. HCl, to pH 10 with NaOH and then to pH 1 with c. HCl. The resulting precipitate of 2-(carboxyethyl)-2,3-dihydro-6-mercapto-s-triazolo[4,3-b]pyridazin-3-on was collected by filtration and washed with water. Yield: 418 mg. (74%). M.p. 174°-176° C.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:12])[CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH3:5].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>N1C=CC=CC=1>[C:19]1([CH3:20])[CH:21]=[CH:22][C:16]([S:13]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:12])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCCCCOC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
17 g of 4-pentyloxypentanol was dissolved in 60 ml of pyridine, and under stirring, 22.4 g of tosyl chloride was added at below 10° C. in 40 min. The mixture was raised to 25° C. and stirred for 3 hours. After the reaction, cold water was added, and the product was extracted with ether, followed by successive washing with 5% hydrochloric acid and water and drying with anhydrous MgSO4. The solvent was distilled off to obtain 31.9 g of 4-pentyloxypentyl p-toluenesulfonate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[N:58]([CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])=[O:65])=[C:59]=[O:60]>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:59](=[O:60])[NH:58][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH2:68][Si:69]([CH3:70])([CH3:72])[CH3:71])=[O:65])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C[Si](C)(C)CCOC(=O)CCCN=C=O
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)NCCCC(=O)OCC[Si](C)(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 2 h

Procedure:
A solution of the FR-900506 substance (310 mg), 2-trimethylsilylethyl 4-isocyanatobutyrate (350 mg) and triethylamine (6 drops) in anhydrous benzene (4 ml) was heated at 50° C. with stirring for 2 hours. The reaction mixture was allowed to stand at room temperature overnight. The mixture was concentrated to dryness under reduced procedure to leave a residue, which was chromatographed on silica gel in chloroform. Elution was carried out with chloroform to give 17-allyl-12-[2-[3-methoxy-4-{3-(2-trimethylsilylethoxycarbonyl)propylcarbamoyloxy}cyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (99 mg). This product was treated with tetra(n-butyl)ammonium fluoride (0.12 m mole) in tetrahydrofuran (2.5 ml) at room temperature for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure to leave a residue, which was purified with preparative thin layer chromatography on silica gel. Elution with a mixture of chloroform and methanol (5:1) gave 17-allyl-12-[2-{4-(3-carboxypropylcarbamoyloxy)-3-methoxycyclohexyl}-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-]13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (18.1 mg).
Reaction SMILES: C1COCC1.CC(C)([O-])C.[K+].[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].Cl[C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[N:22][N:21]=1>O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:18][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[N:22][N:21]=1
Reactant: OCCCCCO
Reactant: Clc1nnnn1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCCOc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
10 ml of THF solution containing 225 mg of potassium t-butoxide was added with 0.6 g of 1,5-pentanediol and 0.36 g of 5-chloro-1-phenyl-tetrazole and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.4 g of the title compound (yield: 81%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([O:15][Si](C)(C)C)[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:21]([O:15][C@H:14]1[NH:13][C:12](=[O:20])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1O[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -35 °C
Reaction time: 21 h
Yield: 59 %

Procedure:
After 156 mg of (3R,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of ethyl acetate, the mixture was cooled to -35° C. and thereto 0.03 ml (concentration: 1.84% by volume) of acetic acid, 0.5 ml of acetic anhydride and then 30 mg (concentration: 1.36% by weight) of 4-dimethylaminopyridine were added. The mixture was stirred for 21 hours at -35° C. After completion of the reaction and the same treatment as in Example 16, it was analyzed by means of high performance liquid chromatography used in Example 16 to find 83 mg of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (yield: 59%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=C[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl.ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[CH:22][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: C=Cc1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C(=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
Combine 1,4-dibenzyl-2-vinyl-piperazine (200.0 mg, 0.68 mmol), styrene (142.5 mg, 1.37 mmol), bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (168.8 mg, 0.21 mmol), and dichloromethane (8 mL) and stir at reflux. After 24 hours, the reaction mixture was filtered and reduced to residue. The title compound was observed by LC/MS: mass spectrum (ion spray): m/z=369.1 (M+1); Rf=0.49 (hexanes/ethyl acetate (40:60)).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][C:3]=1[CH3:14].[Si](C=[N+]=[N-])(C)(C)[CH3:16]>CO.C1(C)C=CC=CC=1>[CH3:16][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([CH3:14])=[C:2]([F:1])[CH:10]=2)=[O:13]
Reactant: Cc1cc2cc(C(=O)O)[nH]c2cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(C)c(F)cc2[nH]1
Temperature: 25 °C

Procedure:
To a cooled solution of 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid in MeOH/toluene (1C) (200 mL, 1:1) was added TMS-diazomethane (2.0 M solution in diethylether, 1.05 eq.) dropwise and the reaction was allowed to warm up to room temperature over 1 h. The reaction mixture was concentrated and purified using triturating with CH2Cl2 and hexane and collecting the solids by filtration to obtain 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid methyl ester 1D (3.5 g). The concentrated filtrate was purified using chromatography over SiO2 using 0 to 40% ethyl acetate in hexanes to provide an additional amount of 6-Fluoro-5-Methyl-1H-indole-2-carboxylic acid methyl ester 1D (1.0 g). Overall yield (60%). 1H NMR (400 MHz, d6-DMSO): 2.26 (s, 3H), 3.83 (s, 3H), 7.07 (s, 1H), 7.08 (d, J=10.2 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 11.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=O)=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:30]P(Cl)(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([Cl:30])(=[O:29])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Yield: 17.1 %

Procedure:
3-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)propane-1-sulfonic acid (8.4 g) were dissolved in dichloromethane (70 mL). Pentachloro-λ5-phosphane (6.05 g, 29 mmol) were added at room temperature and the reaction mixture was heated under reflux for 3 h. The reaction mixture was poured on ice water and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated in vacuo (11 g). The crude product was used for the next step without further purification. For test purposes a sample of the crude product (3.8 g) was purified by flash chromatography (silica, methanol:acetonitrile=1:1) to yield a pale yellow foam (1.5 g).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3]O.C([O-])([O-])=O.[K+].[K+].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>ClCCCl>[S:21]([N@@:1]1[CH2:3][CH:2]1[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@@H](CO)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)[N@@]2CC2c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of the crude product from Step B (1.11 g, 5.45 mmol) in 1,2-dichloroethane (25 mL) at 0° C. are added K2CO3 (2.26 g, 16.4 mmol) and TsCl (2.60 g, 13.6 mmol). The reaction mixture is stirred at room temperature overnight. If reaction is not done at this point, additional K2CO3 (0.75 g, 5.45 mmol) and TsCl (1.04 g, 5.45 mmol) are added and the reaction mixture is stirred for another 24 h. After removal of the solvent, the residue is taken in cold saturated NaHCO3 aqueous solution (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (0˜35% EtOAc/Hexanes) to provide (R)-1-tosyl-2-(3-(trifluoromethyl)phenyl)aziridine (1.74 g, 94% yield); 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 2H), 7.54 (m, 1H), 7.43 (m, 3H), 7.36 (d, 2H), 3.81 (dd, 1H), 3.01 (d, 1H), 2.45 (s, 3H), 2.39 (d, 1H); HPLC-MS calculated for C16H14F3NO2S (M+H+) 342.1, found 342.1.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:18](O)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.N1C=CC=CC=1>[C:19]1([C:18]2[O:1][N:2]=[C:3]([N:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]3)[N:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (7 g, 28.6 mmol) in anhydrous DCM (150 mL) was added benzoic acid (3.49 g, 28.6 mmol) followed by diisopropyl carbodiimide (DIC, 3.6 g, 28.6 mmol). The reaction mixture was stirred at RT for 8 hours and filtered. The filtrate was evaporated and the residue obtained was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried and the solvent was evaporated. The residue was purified by chromatography using petrol ether/EtOAc (9/1) as eluent to afford 5 g (53%) of the title compound as a solid. TLC—Pet ether/EtOAc (9/1): Rf=0.7). HPLC purity: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17]O)=[N:9]2)=[CH:4][CH:3]=1.CO.C(Cl)(Cl)[Cl:25]>O=S(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][Cl:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 813 mg (2.75 mmol) of trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol in 40 ml of CHCl3, 1.0 ml of SOCl2 was added, followed by stirring at room temperature for 24 hours. A small amount of MeOH was added to the reaction mixture and the solvent was distilled off under reduced pressure, whereby trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride was obtained as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:22]=1
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A mixture of 4-bromo-6-fluoro-1H-indole (D16), (200 mg, 0.935 mmol), 4-benzyloxyphenylboronic acid (426 mg, 1.87 mmol), copper (II) acetate (332 mg, 1.87 mmol) and triethylamine (0.26 mL, 188 mg, 1.87 mmol) in dichloromethane (5 mL) was stirred in air at room temperature for 16 hours. The mixture was filtered through celite, concentrated and purified by chromatography on silica gel (elution with 0-20% ethyl acetate in hexanes) to give the title compound as a pink solid (D19), (205 mg).