Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1.CCCCCCC=CCCC>C1COCC1.C(OCC)(=O)C>[Br:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCNC1
Agent: CCCC=CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1CCN(c2cccc(Br)n2)C1
Temperature: 25 °C

Procedure:
A mixture of 2,6-dibromopyridine (2.37 g, 0.01 mol), pyrrolidin-3-ol (1.0 g, 0.01 mol), 1,8-diazabicclo[5.4.0)-7-undecene (1.5 mL) in 10 mL of THF was heated at 70° C. under a nitrogen atmosphere for 11 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL). The resulting solution was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:19]2[CH2:18][CH2:17][N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=3)[CH2:21][CH2:20]2)[N:4]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: Cc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CN2CCN(c3cccc(Br)c3)CC2)cs1

Procedure:
A mixture of 4-chloromethyl-2-methylthiazole (7.4g; 0.05 mole), 1-(3-bromophenyl)piperazine (12.05g; 0.05 mole) and anhydrous sodium carbonate (10g) was suspended in absolute ethanol (150 ml). The mixture was stirred and boiled under reflux for 8 hours. The solvent was then evaporated to dryness and water added (100 ml). The emulsion thus formed was extracted with dichloromethane, the organic extracts being dried over magnesium sulphate and evaporated to an oil. This was dissolved in hot benzene, treated with decolourising charcoal and filtered. The filtrate was evaporated to give the title compound as an oil which crystallised completely, m.p. 82° C. (ether).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17].P(Cl)(Cl)(Cl)=O>O>[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:2]([CH3:1])[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])=[O:23])=[CH:20][CH:19]=1)#[N:17]
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(N(C)C(=O)c2ccc(C#N)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 13.1 g of methyl 4-methylamino-3-nitro-benzoate, 10.3 g of 4-cyano-benzoylchloride and 75 ml of phosphorusoxychloride is stirred for 8 hours at 100° C. After cooling, the mixture is decomposed with water and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are washed with soda solution and concentrated by evaporation. The residue is dissolved in a little acetone and ether is slowly added. The quantities precipitated initially (about 1.2 g) are discarded. After further ether has been added the desired substance is precipitated. Yield: 10.2 g (48% of theory), Rf value: 0.54 (silica gel; ethyl acetate/petroleum ether =7:3)
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@:5]2([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]23)[CH2:4]1.[OH-].[NH4+:29]>CN(C=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]3[C@@:5]3([CH2:4][C@H:3]3[CH2:2][NH2:29])[N:11]=2)=[CH:17][CH:16]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CBr)c1nnc(C)n1-2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CN)c1nnc(C)n1-2
Reaction time: 9 h
Yield: 4 %

Procedure:
To a solution of (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro-[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine](350 mg, 0.758 mmol) in DMF (4 mL) was added ammonium hydroxide (3 mL, 77 mmol) at rt. After 9 h at rt, silica gel was added, and the solvent was removed under vacuum. The dry silica gel was packed, and the product was purified by chromatography (Hexane/EtOAc 5:5 to 0:10 then DCM/MeOH 10:0 to 9:1). A second (EtOAc/toluene/MeOH 4:4:2) and a third chromatography were performed (2-propanol 100%) to give a tan solid (12 mg). LRMS (M+H)+: 398 m/z.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2].C(N(CC)CC)C.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C(Cl)Cl>[P:1]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([S:3][CH2:4][CH3:5])=[S:2]
Reactant: O=Cc1ccccc1O
Reactant: CCCSP(=S)(Cl)SCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSP(=S)(Oc1ccccc1C=O)SCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-ethyl S-propyl chlorotrithiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 2-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-ethyl S-propyl O-(2-formylphenyl)trithiophosphate.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:8][O:17]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: C[S+](C)C
Reactant: COc1ccc(C=O)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C2CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])(OCC)=O)C.[H-].[Na+].[NH2:20][C:21]1[C:35]([Cl:36])=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=O)=[CH:23][C:22]=1[Cl:37].O>O1CCCC1>[NH2:20][C:21]1[C:22]([Cl:37])=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])=[CH:34][C:35]=1[Cl:36]
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 5.3 g (0.02 mol) of diethylphosphonoacetic acid morpholide in 100 ml of dry tetrahydrofuran was slowly added dropwise, while stirring, to a suspension of 1 g of sodium hydride (0.02 mol, 50% in oil) in 50 ml of dry tetrahydrofuran. Slight heating and strong foaming occurred. After all had been added, the mixture was stirred for 10 minutes more. A solution of 3 g (0.01 mol) of 4-amino-3,4',5-trichlorobenzophenone in 20 ml of dry tetrahydrofuran was added dropwise to the resulting clear solution, and the mixture was heated for 16 hours at reflux temperature. After cooling, the solution was poured into water, and the aqueous mixture was extracted exhaustively with methylene chloride. The methylene chloride phase was dried with sodium sulfate and evaporated by evaporation in vacuo. The residue was crystallized from isopropanol/petroleum ether. The colorless crystals thus obtained, melting point 150°-155° C., contained the cis/trans isomers in a ratio of 1:3.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:37]([NH:44][C@@H:45]([C:50](O)=[O:51])[CH2:46][CH2:47][S:48][CH3:49])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37](=[O:38])[NH:44][C@@H:45]([C:50]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:51])[CH2:46][CH2:47][S:48][CH3:49])([CH3:43])([CH3:41])[CH3:42]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Yield: 68 %

Procedure:
Following general amide formation method 1, 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined with BOC-D-Methionine (51 mg, 0.205 mmol, 1.0 eq) which gave ((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-3-methylsulfanyl-propylycarbamic acid tert-butyl ester (105 mg) in 68% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.56 (m, 14H) 1.63 (br. s., 2H) 1.68-1.82 (m, 3H) 1.82-1.99 (m, 4H) 1.99-2.18 (m, 10H) 2.48-2.68 (m, 5H) 3.18 (s, 7H) 3.73 (dd, J=10.36, 6.82 Hz, 1H) 4.51 (br. s., 1H) 4.69 (br. s., 3H) 4.77-4.89 (m, 2H) 5.28 (t, J=10.11 Hz, 1H) 6.51 (s, 1H) 7.80 (d, J=6.57 Hz, 1H) 8.36 (br. s., 1H) 8.42 (d, J=2.02 Hz, 1H) 8.59 (br. s., 1H) 8.80 (s, 1H). HRMS m/z, (M+H)+: 720.3682.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1.[NH4+].[Cl-]>C1COCC1>[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1CC(C=C2SCCCS2)C(OC)O1
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
According to a procedure described in Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050-4055, to a solution of 2-trimethylsilyl-1,3-dithiane (1.2 mL, 6.3 mmol) in dry THF (40 mL) at 0° C. was added n-butyllithium (4 mL of 1.6 M in hexanes). After 15 minutes at 0° C. and 20 minutes at 4 mL of 1.6 M ambient temperature, a solution of 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde (1.00 g, 6.00 mmol) in dry THF (10 mL) was added dropwise. After 17 hours at ambient temperature, the resultant mixture was treated with saturated aqueous NH4Cl (10 mL) and partitioned between EtOAc and H2O. The layers were separated and the aqueousueous phase extracted with EtOAc:hex (1:1) two times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford a residue which was purified via flash column chromatograpy with 10% EtOAc/hex as eluant to yield 1.06 g (70%) of a mixture of diastereomeric 2-(2,5-dimethoxy-tetrahydrofuran-3-yl-methylidene)-1,3-dithiane as a yellow oil, which was used without any further purification. 1H NMR: δ 6.00 (d, 1H, J=9.6 Hz), 5.93 (d, 1H, J=9.6 Hz), 5.77 (d, 1H, J=9.6 Hz). Anal. Calculated for C11H18O3S2: C, 50.35; H, 6.92; S, 24.44. Found: C, 50.07; H, 7.00; S, 24.33.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][CH2:15][C:14](=[O:16])[C:8](=[N:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOCCON=C(C(=O)CCl)C(=O)OCC
Yield: 88.7 %

Procedure:
ethyl 2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer 56 g.), sulfuryl chloride (32.7 g.) and acetic acid (56 ml.) were treated in a similar manner to that of Example A-(2) to give ethyl 4-chloro-2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer, 57.1 g.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][CH2:14]1>>[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@@H](OCc3c(Cl)cccc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(Cl)c1CO[C@@H]1CCC[C@H](Cn2ccnc2)O1
Yield: 107 %

Procedure:
Using 103 mg of imidazole, 66 mg of 55% sodium hydride and 161 mg of cis-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, the procedure described in Example 1(b) was repeated to give 132 mg of the title product in the form of a colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([CH3:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].[OH:20]O>C(O)(=O)C.O[W](O)(=O)=O>[C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([CH3:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])(=[O:20])=[O:16])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2]
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(S(C)=O)cc1
Reactant: OO
Agent: O=[W](=O)(O)O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
The above 4-(methylsulfonyl)phenyl compound also was prepared from the corresponding 4-(methylsulfinyl)phenyl compound as follows: to a stirred warm solution containing 0.8 g of 3-cyano-6-methyl-5-[4-(methylsulfinyl)phenyl]-2(1H)-pyridinone in 30 ml of glacial acetic acid was added 500 ml tungstic acid and to the resulting stirred solution was added dropwise over a period of 2 minutes a solution containing 0.102 g of hydrogen peroxide in acetic acid (32.97 mg/ml/3.1 ml) and the resulting reaction mixture was stirred at room temperature for 1 hour and then heated occasionally over a period of 1 hour. After tlc analysis indicated a small quantity of methylsulfinyl compound still present, and additional 3 ml of said hydrogen peroxide solution was added and heating as above was continued for 1 hour. The hot reaction mixture was filtered thru diatomaceous earth to remove the tungstic acid, the filter pad washed with warm acetic acid and the filtrate stripped, first in vacuo and then under high vacuum. The remaining solid residue was slurried in about 75 ml of hot absolute ethanol and the mixture cooled slightly. The solid was collected, washed with ethanol and dried at 65° C. in vacuo to yield 0.7 g of 3-cyano-6-methyl-5-[4-(methylsulfonyl)phenyl]-2(1H)-pyridinone, m.p. 311°-313° C.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14](N)=[CH:15][CH:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[I:31]I>CC(O)=O.O.Cl>[I:31][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([CH:1]=[CH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:10][N:11]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 113.7 %

Procedure:
To a solution of 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine (1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl (1.67 mL) cooled to 2° C. was added a solution of NaNO2 (304 mg, 4.4 mmol) in water (0.5 mL) over 5 min. The resulting dark red solution was stirred at 2° C. for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) and I2 (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keep the internal temperature below 5° C. After 2 h at 2° C. the reaction was allowed to stir at 23° C. for 17 h. The reaction was quenched with 3 N NaOH (aq), diluted with EtOAc (50 mL) and H2O (15 mL), the phases were separated and the aqueous was extracted 2×15 mL EtOAc. The pooled organic phase was washed 3×20 mL 5% NaHSO3, brine (15 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (eluting with 1:1 hexane:EtOAc) to give 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a white solid (1.3 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.30–7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, J=6.0 Hz), 0.96 (t, 2H, J=6.0 Hz), 0.0 (s, 9); 13C NMR (75 MHz, CDCl3) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4, 119.6, 119.5, 92.9, 78.1, 66.9, 18.0, −1.2. Anal. Calc'd: C, 52.94; H, 5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:21]([CH3:34])=[CH:20]2.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:21]([CH3:34])=[C:20]2[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: COc1ccc2c(c1)cc(C)n2CCN1CCOCC1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C(=O)c1ccc(C)c3ccccc13)c(C)n2CCN1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (84 mg, 0.41 mmol) and 4-(2-(5-methoxy-2-methyl-1H-indol-1-yl)ethyl)morpholine (120 mg, 0.44 mmol) in 8 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.5 mL, 0.90 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give CBX001 (107 mg, 0.24 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.37 (s, 3H), 2.42-2.55 (m, 4H), 2.66 (t, J=6.9 Hz, 2H), 2.78 (s, 3H), 3.59 (s, 3H), 3.68 (t, J=4.2 Hz, 4H), 4.17 (t, J=6.9 Hz, 2H), 6.84 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 7.41-7.50 (m, 2H), 7.55 (t, J=7.2 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 13.14, 20.21, 41.74, 53.90, 54.49, 55.80, 57.81, 67.29, 103.91, 110.33, 112.67, 115.61, 124.69, 125.76, 126.30, 126.59, 126.91, 128.42, 130.86, 131.35, 133.25, 136.92, 139.50, 145.98, 156.28, 193.91. MS m/z 443.4 [M+H]+.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>C(O)(C)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][N:35]([CH2:20][CH:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5]1)[CH2:34][CH2:33]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)CN1CCC(c3noc4cc(F)ccc34)CC1)CC2
Reaction time: 8 h
Yield: 11 %

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine (3.2 g, 11.6 mmol), K2CO3 (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153°-154° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>C(OCC)C>[CH2:11]([O:13][C:14](=[O:19])[C:15]([F:17])([F:16])[O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
A suspension of 60% of NaH in oil (3.84 g, 96 mmol) was washed three times with hexanes and the solid was suspended in dry DMF (80 ml). 4-Fluorophenol (8.96 g, 80 mmol) was slowly added over a period of 5 min and the reaction mixture was stirred at rt for about 10 min. The reaction mixture was cooled at 0° C. and 2-bromo-2,2-difluoroacetic acid ethyl ester (16.24 g, 80 mmol) was slowly added. The reaction mixture was heated at 90° C. for 20 h. After allowing the reaction to reach room temperature, ethyl ether (300 ml) was added and the suspension was washed with water and brine. After drying the organic layer over sodium sulfate for 15 min, the solvent was evaporated and the crude was purified by flash chromatography, using a mixture of ethyl acetate/hexanes (1/10) to give 2,2-difluoro-2-(4-fluorophenoxy)acetic acid ethyl ester as an oil (11.0 g, 59%).