Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2].[OH-].[K+].C([OH:25])(C)(C)C>O>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:25])[NH2:2]
Reactant: CC(C)(C)O
Reactant: N#CCc1c(-c2ccccc2)[nH]c2ncccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1c(-c2ccccc2)[nH]c2ncccc12
Temperature: 25 °C

Procedure:
3-(Cyanomethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.37 g, 1.39 mmol), powdered KOH (0.82 g), and t-butanol (5 ml) were heated to reflux under argon for 3 h. The reaction mixture was then cooled to room temperature and diluted with deionized water (6.5 ml) to give a precipitate. The suspension was extracted with methylene chloride and filtered. The filter cake consisted of pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Li])[CH:7]=[CH:6]2.[CH3:15][C:16]([NH:19][Si:20](Cl)([CH3:22])[CH3:21])([CH3:18])[CH3:17]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Si:20]([CH3:22])([CH3:21])[NH:19][C:16]([CH3:18])([CH3:17])[CH3:15])[CH:7]=[CH:6]2
Reactant: [Li]C1C=Cc2cc(OC)c(OC)cc21
Reactant: CC(C)(C)N[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C([Si](C)(C)NC(C)(C)C)C=C2
Reaction time: 18 h
Yield: 94.2 %

Procedure:
(5,6-Dimethoxy-1H-inden-1-yl)lithium (2.5 g, 13.73 mmol) slurried in 40 mL of THF was added to a solution of N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine (3.185 g, 19.22 mmol) in 100 mL of THF over a 25 min period. After stirring for 18 h, the volatile components were removed under reduced pressure. The residue solution was extracted with hexane (40 mL). After filtration the volatile components were removed in under vacuum to give 3.95 g, 94 percent yield of the desired product as a light yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:34][O:33][C:30]([C:28]1[CH:29]=[C:24]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:25]=[N:26][CH:27]=1)([CH3:32])[CH3:31]
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Reactant: COC(C)(C)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(C)(C)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 90 °C

Procedure:
To a sealed tube which contained the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 mL 1,4-dioxane, 0.78 mmol) is added 3-bromo-5-(1-methoxy-1-methyl-ethyl)-pyridine (216 mg, 0.937 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (0.5 mL). The mixture is bubbled with Ar for 5 min. Then PdCl2(DPPF) (57 mg, 0.078 mmol) is added. The mixture is then bubbled with Ar for 5 min. The cap is sealed and the mixture is heated at 90° C. for 1 h and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtration is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is separated by flash silica gel column (MeOH/DCM 0 to 5% gradient, then 5%) and then separated by C-18 prep HPLC ((MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 65% gradient over 10 min run). The resulting material is further purified by C-18 HPLC (31% CH3CN in 2.5 mM NH4HCO3 aqueous solution, isocratic for 15 min plus 5 min wash at 17 ml/min) to obtain 66 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:38])[N:27]=[C:28]([NH2:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:38])/[N:27]=[C:28](/[NH2:37])\[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:36][C:5](=[O:7])[C@H:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[CH:33][CH:34]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccc(C(N)=NC(=O)OCc2ccccc2)cc1
Reactant: CCO[C@@H](C(=O)O)c1ccc(OC)cc1F
Agent: Cl
Product: CCO[C@@H](C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1ccc(OC)cc1F

Procedure:
According to general procedure B (R)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid was reacted with [amino-(4-aminomethyl-phenyl)-methylene]-carbamic acid benzyl ester hydrochloride 1:2 (prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429) to give [1-amino-1-(4-{[(R)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-phenyl)-meth-(E)-ylidene]-carbamic acid benzyl ester (96.5% ee). Off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:15][CH2:13][C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)=[O:14]
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 16.6 g (0.074 mol) of 1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanone in 150 ml of dry tetrahydrofuran, were added portionwise at room temperature 27.8 g (0.074 mol) of phenyltrimethylammonium tribromide. The solution was stirred for 3 hours at room temperature. The formed solid was removed by filtration and the mother liquors were concentrated under vacuum. The resulting orange oil (32.7 g) was purified by flash chromatography on silica gel (eluent:heptane/dichloromethane 3:1) to give 2-bromo-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanone: 10.4 g (46%) as a yellow oil.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH:16]=[CH:17][C:18](=[N:20][OH:21])[CH3:19])(OCC1C=CC=CC=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:19][C:18]1[CH:17]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[CH3:1])[O:21][N:20]=1
Reactant: CC(C=C[C@@H]1CCCN1C(=O)OCc1ccccc1)=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2CCCN2C)on1

Procedure:
The Cbz-protected compound of step 23d is reacted with LAH in THF at 0° C. as described in Example 24 below, and the title compound is isolated in pure form by extraction with ethyl acetate and distillation under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH2:64][C@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][C@@H:65]1[CH2:64][OH:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC[C@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3CO)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-hydroxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: C(O)C.[BH4-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[N:18]1[C:22](=[N:23][CH:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)Cl)[CH:21]=[C:20]([C:32]#[N:33])[NH:19]1.O>C(OCC)(=O)C>[Cl:17][C:9]1[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=[C:7]([Cl:6])[C:8]=1[N:18]1[C:22]([NH:23][CH2:24][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:20]([C:32]#[N:33])=[N:19]1
Reactant: N#Cc1cc(=NC(Cl)c2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: N#Cc1cc(NCc2cnccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To an ethanol (2 ml) suspension of 85 mg (2.2 mmol) of sodium borohydride was gradually added 0.5 g (1.1 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylchloromethylimino)pyrazole-3-carbonitrile at 20° C. or less. After 1 hour of stirring at room temperature, the mixture was gradually poured into 40 ml of water to precipitate crystals. After 30 minutes of stirring, the crystals were filtrated and washed with water until the pH of the filtrate became 6. The crystals thus obtained were dissolved in ethyl acetate and the solution was extracted after the addition of saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated. The resulting crystals were filtrated, washed with a small amount of hexane and ethyl acetate, and dried to obtain 0.42 g (yield 92%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylmethylamino)pyrazole-3-carbonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[N:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[N:2]1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: c1cnc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2cccnc21
Temperature: 70 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 7-aza indazole (250 mg, 2.1 mmol) and ethyl bromoacetate (0.47 mL, 4.2 mmol) in DMF (8 mL) was added K2CO3 (1.16 gm, 8.4 mmol) and the resulting mixture stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×5 mL), brine (5 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography eluting with EtOAc:hexane 10:90 to afford the title compound as an off-white solid in 49% yield, 210 mg.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:17]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:1]1([C:16]2[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: C1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCCCCC1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
Azepane (0.113 mL; 1.00 mmol) and triethylamine (0.277 mL; 2.00 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL). The reaction vessel was sealed and heated at 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.092 g (98%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([N:9](C2C=CC(OC)=C(OC3CCCC3)C=2)[C:10](=O)C)[C:3]=1[OH:27].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:27]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: COc1ccc(N(C(C)=O)c2cc(Cl)cc(Br)c2O)cc1OC1CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2ocnc2c1
Reaction time: 1 h
Yield: 261.2 %

Procedure:
A suspension of 32.9 g (72.4 mmol) of 2-bromo-4-chloro-6-(3-cyclopentyloxy-4-methoxy-phenyl-acetylamino)-phenol in 400 ml of toluene and 39.7 ml (434 mmol) of phosphorus oxychloride was refluxed for 1.5 hours. Some solid material was filtered off and the filtrate evaporated to dryness in vacuo. The honey-like residue was suspended in 200 ml of sodium bicarbonate solution for 1 hours. The solid was collected, washed and dried at 25° C. to give 22.53 g (71.2%) of crude benzoxazole.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][CH2:24][OH:25])[CH:7]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCO
Reactant: Fc1cc(Nc2ccc(Oc3ccccc3)cc2)ccn1
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1cc(Nc2ccc(Oc3ccccc3)cc2)ccn1
Temperature: 25 °C
Yield: 89 %

Procedure:
53 mg of 2-fluoro-N-(4-phenoxyphenyl)pyridin-4-amine in 80.6 mg of ethanolamine were heated in a screw cap vial under argon at 150° C. for 3 days. The mixture obtained was cooled to r.t. and 5 mL of 2N NaOH were added. The mixture obtained was extracted with 15 mL of EtOAc for three times. From the mixture obtained organic solvent was evaporated off. 2-(4-(4-Phenoxyphenylamino)pyridin-2-ylamino)ethan-1-ol was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1Cl)[C:5]([NH2:7])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S-:20])=[CH:16][CH:15]=1.[K+]>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:10]2[C:9]([Cl:12])=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=2[Cl:1])=[CH:16][CH:15]=1
Reactant: [S-]c1ccc(Cl)cc1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
A solution of 3,4,5-trichlorobenzamide (25.0 g, 111 mmol) and potassium 4-chlorothiophenolate (29.0 g, 159 mmol) in dimethylformamide (220 ml) was stirred for 3 days at ambient temperature under nitrogen atmosphere, poured into ice water (2.2 L), and filtered. The solid was washed with water, partially dried under vacuum, suspended in diethyl ether (200 ml), filtered, and washed with diethyl ether (2×75 ml). The residue was triturated with diethyl ether (75 ml), filtered, again triturated with diethyl ether (75 ml), filtered, and dried under vacuum to provide 21.2 g (57%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzamide, m.p. 171°-174° C.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.C([Li])(CC)C.[Cl:38]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>C1COCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[N:6]1[C:14]2[C:9](=[C:10]([Cl:38])[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)Oc1ccc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1ccc2c(ccn2[Si](C)(C)C(C)(C)C)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diethyl-carbamic acid 1-(tert-butyl-dimethyl-silanyl)-1H-indol-5-yl ester (9.26 g, 26.7 mmol) is dissolved in THF (250 mL), flushed with nitrogen and cooled to −78° C. TMEDA (5 mL, 33.1 mmol) is then added followed by sec-butyllithium (24.8 mL, 34.7 mmol) and the reaction is stirred for 30 minutes. Hexachloroethane (12.73 g, 53.8 mmol) in 50 mL of THF is added over 10 minutes to the reaction. The reaction is allowed to warm to room temperature overnight (15 hours). The reaction is cooled using an ice bath and a saturated ammonium chloride (aq) solution is added (150 mL). The mixture is then extracted with ethyl acetate, dried (sodium sulfate) and concentrated to obtain the title compound as an oil that is used without further purification. MS (ESI) m/z 381.1 (M+1).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][CH:9]=1.S(=O)(O)[O-].[Na+]>ClCCCl>[Cl:3][C:4]1[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][C:9]=1[Br:1]
Reactant: BrBr
Reactant: CSc1cccc(Cl)c1-c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CSc1ccc(Br)c(Cl)c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 3.3 g (20 mmol) of bromine dissolved in 10 mL of 1,2-dichloroethane was added dropwise with stirring to a solution of 4.0 g (17 mmol) of 3-chloro-2-phenyl(methylthio)benzene in 50 mL of 1,2-dichloroethane containing 3.1 g (19 mmol) of ferric chloride. The resulting mixture was allowed to react for another 1.5 hour and then another about 1 g of bromine was added. After 15 min, aqueous sodium bisulfite was added and the mixture was allowed to stand overnight. The organic phase was recovered, washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica eluting with a 5:1 mixture of hexane and dichloromethane to obtain 2.7 g (51 percent of theory) of the title compound as a colorless liquid.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4].[Li]C(C)(C)C.[I:15][C:16]1[C:24]2[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=2)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH2:35]C)([CH2:33]C)[CH2:31]C)[N:17]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[I:15][C:16]1[C:24]2[C:19](=[CH:20][C:21]([C:3]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH2:4])=[CH:22][CH:23]=2)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:35])[N:17]=1
Reactant: C=CC1(Br)C=CC=CC1
Reactant: CC[Si](CC)(CC)CCOCn1nc(I)c2ccc(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1ccc2c(I)nn(COCC[Si](C)(C)C)c2c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 69.5 %

Procedure:
1-Bromostyrene (26 μL, 0.20 mmol, 2.0 equiv) was dissolved in THF (0.75 mL), cooled to −78° C. and was treated with t-BuLi (235 μL, 0.40 mmol, 1.70 M, 4.0 equiv). The mixture was allowed to warm to 42° C. for 10 min and was added to freshly dried zinc chloride (34 mg, 0.25 mmol, 2.5 equiv). The resulting solution was allowed to warm to 23° C. with stirring for 25 min. This mix was added to a mixture of neat 3,6-Diiodo-1-[2-(triethyl-silanyl)-ethoxymethyl]-1H-indazole (50 mg, 0.10 mmol, 1 equiv) and Pd(PPh3)4 (5 mg, 0.004 mmol, 0.04 equiv). After 10 min the reaction was determined to be complete by TLC monitoring and was quenched with saturated sodium bicarbonate. Organic material was extracted into ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (5:95 ethyl acetate-hexane) provided 3-Iodo-6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (33.1 mg, 70%): Rf sm 0.39, p 0.36 (ethyl acetate-hexane 1:9); 1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.33 (m, 5H), 7.22 (dd, 1H, J=1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1H, J=1.0 Hz), 5.57 (d, 1H, J=1.0 Hz), 3.58 (t, 2H, J=8.2 Hz), 0.88 (t, 2H, J=8.2 Hz), −0.09 (s, 9H); HRMS (FAB) [m+H]/z Calc'd 477.0859, found 477.0866.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>O1CCOCC1.[Pd]>[CH3:1][C:2]1([CH3:35])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1
Reactant: COc1ccc2c(c1)C(=CCOC1CCCCO1)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(CCOC1CCCCO1)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
2,2-Dimethyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1-[2-(tetrahydro-2-pyranyloxy)ethylidene]-1,2,3,4-tetrahydronaphthalene (151 g), dissolved in 1100 ml of dioxan is submitted to a catalytic hydrogenation at atmospheric pressure and roomtemperature, the catalyst being 10 g of 5% palladium on charcoal. After some 80 percent of the calculated amount of hydrogen has been consumed, the hydrogen uptake tends to slow down and an additional quantity of 2 g of catalyst is needed to bring the reduction to an end. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The residue does not tend to crystallize. It contains a mixture of two stereoisomers of the title product and it is applied without purification in the next synthesis.
Reaction SMILES: [I-].[K+].C[N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[S:12]([CH3:15])(=[O:14])=[O:13].O.[CH3:17]N(C)C=O>>[CH3:17][N:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[N:4]=[C:5]1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: Cn1c([N+](=O)[O-])cnc1S(C)(=O)=O
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Cn1cc([N+](=O)[O-])nc1S(C)(=O)=O
Temperature: 160 °C

Procedure:
Potassium iodide (4.8 g) and 1-methyl-2-methylsulfonyl-5-nitroimidazole (5.0 g) were combined in N,N-dimethylformamide (30 ml) and the reaction mixture heated to 160° C. for 2 hours. Upon cooling, the reaction mixture was added to 150 ml of a water and ice mixture. The product precipitated and was filtered and dried affording 4.4 g of 1-methyl-2-methylsulfonyl-4-nitroimidazole.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1N(C2C=C(C#N)SC=2)N=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[Cl-].[C:23]([C:25]1[S:29][C:28]([NH2+:30][NH2:31])=[CH:27][CH:26]=1)#[N:24]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:30]([C:28]2[S:29][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[N:31]=[C:8]([C:18]([F:19])([F:20])[F:21])[CH:7]=1
Reactant: N#Cc1ccc([NH2+]N)s1
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Agent: [Cl-]
Product: N#Cc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Yield: 37 %

Procedure:
Following the same procedure as described for compound 14 (step 4, scheme 2, example 1c) except using 21 (278 mg, 1.58 mmol) instead of 13 to afford 22 (182 mg, 37%) as a beige solid. LRMS (ESI): calc. 309.1; found 310.1 (MH)+.