Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([O:25][CH2:26][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:24])([CH2:20][CH2:21]3)[O:16][CH2:15]4)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cn4)cc3)(CC1)CO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: Nc1ccc(-c2ccc(C34CCC(CC(=O)OCc5ccccc5)(CC3)OC4)cc2)nc1
Temperature: 130 °C
Yield: 43 %

Procedure:
To a mixture of methyl 2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (286 mg, 0.812 mmol) in neat benzyl alcohol (6 mL, 57.9 mmol) was added titanium(IV) isopropoxide (1.5 mL, 5.12 mmol) and 4 A molecular sieves (5 g, 0.812 mmol). The reaction mixture was heated at 130° C. overnight. The reaction was quenched by saturated NaHCO3 and was extracted with EtOAc. The combined organic layer was filtered and washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (15 to 90% ACN-water (0.1% NH4OH) with X-bridge C18 column) to give the title compound after drying (150 mg, 43% yield). LC/MS, ESI-MS(+): 429.1, RT: 1.41 (Condition E).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:4]([CH2:27][CH3:28])[N:3]=1.OS(O)(=O)=O.C(OCC)(OCC)O[CH2:36][CH3:37].C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:36][CH3:37])=[O:25])=[C:4]([CH2:27][CH3:28])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1OCCCOc1ccccc1OCCCC(=O)O
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccccc1OCCCOc1c(N)nc(N)nc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 2,4-diamino-6-ethyl-5-(3-(2-(3-carboxypropoxy)phenoxy)propoxy)pyrimidine (0.3904 g, 1 mmol) and a catalytic amount of con. H2SO4 in EtOH (4 mL) was added triethyl orthoformate (2 mL) and the solution was left stirring at 25° C. for 8 hours. The reaction mixture was neutralized with K2CO3 and evaporated to dryness. The crude product was diluted with water and extracted with CH2Cl2. Evaporation to dryness gave the desired ester as white semi-solid (0.2720 g, 65%). 1H NMR (500 MHz, DMSO-d6): 0.99 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.1 Hz), 1.93 (2H, m), 2.13 (2H, m), 2.33 (2H, q, J=7.5 Hz), 2.45 (2H, t, J=7.3 Hz), 3.78 (2H, t, J=6.0 Hz), 3.95 (2H, t, J=6.3 Hz), 4.03 (2H, q, J=7.1 Hz), 4.13 (2H, t, J=6.0 Hz), 5.54 (2H, s), 6.07 (2H, s), 6.87-6.90 (2H, m), 6.95-7.01 (2H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=[C:25]([CH:31]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])O1.[F-].[Cs+]>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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[C:23]([CH:22]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[C:23]([CH:22]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)OCC)c1
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccc3ccc(-c4cc(C(=O)OCC)cc(C(=O)OCC)c4)cc3c2)c1
Yield: 76 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromonaphthalene (2.00 g, 6.99 mmol), diethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (6.09 g, 17.48 mmol), CsF (4.00 g) and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen. 160 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen for 2 days. The solvent was removed on a rotary evaporator. 120 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was washed with acetone and then hexane (3×20 mL for each) to give a pure product with a yield of 76% (3.02 g) based on 2,7-dibromonaphthalene. 1H NMR (300 MHz, DMSO-d6): δ 1.39 (t, 12H), 4.42 (q, 8H), 7.90 (d, 2H), 8.11 (d, 2H), 8.45 (s, 4H), 8.52 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O>CO>[CH2:15]([O:14][C:10]([CH:11]=[N:9][NH:8][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:13])[CH3:16]
Reactant: NNc1ccc(Cl)nn1
Reactant: CCOC(=O)C=O
Solvent: CO
Product: CCOC(=O)C=NNc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of compound 3-chloro-6-hydrazinylpyridazine (8.85 g, 0.061 mol) and ethyl glyoxalate (6.16 g, 0.061 mol) in 50 mL of methanol containing about 30% acetic acid was stirred at room temperature for 2 h. The yielded solid was collected by filtration and washed with methanol to give product 1-ethoxycarbonylmethylene-2-(6-chloro-3-pyridazinyl) hydrazine as a white solid (9.5 g, 68%). LRMS (M+H+) m/z: calcd 229.03; found 229. 1H NMR (300 MHz, CDCl3): δ 12.40 (s, 1H), 7.80-7.31 (d, J=9.6 Hz, 1H), 7.60-7.56 (d, J=9.3 Hz, 1H), 7.50 (s, 1H), 4.25-4.23 (q, 2H), 1.31-1.26 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([C:23](O)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([N:3]1[CH:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])=[O:24]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CC1CCCC(CCOc2ccccc2)N1
Product: CC1CCCC(CCOc2ccccc2)N1C(=O)c1ccccc1-c1ccccc1

Procedure:
The title compound was prepared according to general procedure A using 2-methyl-6-(2-phenoxyethyl)piperidine and biphenyl-2-carboxylic acid. MS (ESI) 400 (M+H).
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]2[C:3]1=O.[C:21]([NH2:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>O>[C:22]1([C:21]2[S:28][C:2]3[CH2:19][CH2:18][C:5]4=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]4[C:3]=3[N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCCSc1sc(C(=O)OCC)c2c1C(=O)C(Br)CC2
Solvent: CCO
Solvent: O
Product: CCCSc1sc(C(=O)OCC)c2c1-c1nc(-c3ccccc3)sc1CC2
Yield: 34.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (9.43 g), thiobenzamide (6.86 g) and ethanol (190 ml) was refluxed under heating for 4 hours, after which it was poured over water (600 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:10, v/v) to yield ethyl 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylate (3.63 g, 34.9%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 125-126° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1.[Br:19]Br>ClCCl>[Br:19][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:18][C:8]=2[C:9]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCc1ccc2occ(-c3ccccc3)c2c1
Reactant: BrBr
Solvent: ClCCl
Product: OCCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Temperature: 15 °C

Procedure:
The product from step A is dissolved in 200 ml. of dichloromethane, the solution is cooled to 5° C., and 9.16 g. (0.0573 mole) of bromine in 50 ml. of dichloromethane is added dropwise. The solution is allowed to warm to 15° C., then evaporated to provide a green residue of 2-bromo-5-(2-hydroxyethyl)-3-phenylbenzofuran. The structural assignment is confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:10]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:10])=[O:8]
Reactant: [NH4+]
Reactant: O=C1CCCCCO1
Agent: [OH-]
Product: NC(=O)CCCCCO

Procedure:
ε-Caprolactone was charged to a flask equipped with a mechanical stirrer and thermometer and cooled in an ice bath to below 5°C. A pre-cooled 30% solution of ammonium hydroxide was added and the reaction temperature was maintained below 5° C. until all ε-caprolactone was consumed as indicated by gas chromatography. The water and excess ammonia were vacuum stripped at 50° C. at the completion of which the acid value was measured to be 2300. The acid by-product was removed via flocculation by addition of lithium hydroxide hydrate in methanol solution and ethyl acetate followed by isopropanol until clarified. A second portion of ethyl acetate was added and the flocculated acid was filtered. All solvents were stripped under reduced pressure at 50° C. to yield 6-hydroxycaproamide (2750 g) as a pale yellow oil which crystallized upon standing at room temperature. Gas chromatographic and NMR spectral data indicated greater than 95% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][CH2:18][CH:17]([OH:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccccc1C1CO1
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC

Procedure:
Similarly a mixture of 13.6 g. (0.0753 mol) of 3,4-dimethoxyphenethylamine and 10.1 g. (0.753 mol) of o-methylstyrene oxide is stirred at 100° C. under argon for 16 hours to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-methylphenyl)ethylamine, m.p. 91°-94° C.
Reaction SMILES: [N+:1](/[C:4](/[CH3:13])=[CH:5]/[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6](/[CH:5]=[C:4](/[N+:1]([O-:3])=[O:2])\[CH3:13])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C/C(=C\c1cccc(O)c1)[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C(=C\c1cccc(OCc2ccccc2)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 1 (23.68 g, 0.13 mol) in dimethylformamide (175 mL) was slowly added sodium hydride (60%, 5.29 g, 0.13 mol). The mixture was stirred at room temperature for 1 hour. Then benzyl bromide (15.72 mL, 0.13 mol) was added into the mixture and was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The title compound was obtained (26.46 g, 74%) and was used in the next step without further purification. MS (M+): 270.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O:12][B:13](OCC)[O:14]CC)C.S(=O)(=O)(O)O.O>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:14])[OH:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOB(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether were added dropwise at reflux under an inert gas atmosphere to a suspension of 1.3 g of Mg turnings in 5 ml of anhydrous diethyl ether, and the mixture was refluxed for 2 hours. The mixture was then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled to -70° C. After stirring for one hour at -70° C., then for one hour at ambient temperature, the solution was poured into a mixture of 11 ml of sulfuric acid and 50 g of ice and water and stirring was carried out for one hour. The organic phase was extracted with 100 ml of a saturated aqueous solution of sodium bicarbonate and the aqueous phases were combined and reacidified with 6 N hydrochloric acid, followed by extraction with ether, drying and evaporating under reduced pressure to obtain 3.9 g of the expected product.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[CH2:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH:1]=[CH2:2])[CH2:6][CH2:7]1)(=[O:16])=[O:15]
Reactant: C=COCC1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=COCC1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
4-[(Vinyloxy)methyl]cyclohexylmethanol (2.0 g, 0.010 mol) was dissolved in chloroform (20 mL), cooled to 0° C., and then methanesulfonyl chloride (0.85 mL, 0.011 mol) and triethylamine (1.5 mL, 0.011 mol) were added. The reaction was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate, and the extracts were washed with water, brine, and then dried over MgSO4 and concentrated. The product was purified via column chromatography on silica gel (40% ethyl acetate, 60% hexanes), to give 1.53 g of the desired product as a 3:1 mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.36-6.41 (m, 1H), 4.04-4.10 (m, 2H), 3.94-3.96 (m, 2H), 3.39-3.43 (m, 2H), 2.92 (s, 3H), 0.90-1.80 (m, 10 H) (major diastereomer).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[I:26]C1C=C(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)C=CC=1>>[I:26][C:22]1[CH:21]=[C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CSc1ncnc2sc(-c3c(-c4cccc(I)c4)ncn3C)cc12
Product: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(3-iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 54) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Yellow solid (220 mg, 68%);
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)(Cl)Cl>[CH3:31][S:32]([O:28][CH2:27][C@H:24]1[CH2:23][CH2:22][C@@H:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:30])([CH3:29])[CH3:1])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:26][CH2:25]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CO)CC4)c3)ncnc21
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanol was dissolved in chloroform (3.00 mL) and was cooled to 0° C. To the reaction was added TEA (0.10 mL, 0.00072 mol) and methanesulfonyl chloride (0.05 mL, 0.0006 mol) and this mixture was stirred at 0° C. for 2 hours at which time LCMS analysis showed mainly the product present in the mixture. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. LC/MS (M+H)+: 506
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#C)[CH2:15]2)=[N:6][CH:7]=1.C(Cl)(=[O:38])C>>[C:22]([N:14]1[CH2:13][CH:12]2[CH2:21][CH2:20][CH:16]([C:17]3[C:11]2=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:19][CH:18]=3)[CH2:15]1)(=[O:38])[CH3:23]
Reactant: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Reactant: CC(=O)Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)=O)C2)ncc1Cl

Procedure:
2-[2-(10-Acetyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide and acetyl chloride in an analogous manner to Example 282. Product isolated as a yellow foam (30 mg, 91%). LCMS (m/e) 491 (M+1); 1H-NMR (CDCl3, 400 MHz,) major rotomer δ 11.08 (s, 1H), 8.61 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.56-7.38 (m, 3H), 7.32-7.21 (m, 1H), 7.13-7.01 (m, 2H), 6.95 (s, 1H), 6.26 (bs, 1H), 4.34-4.20 (m, 1H), 3.80-3.69 (m, 1H), 3.43-3.30 (m, 1H), 3.28-3.18 (m, 1H), 3.15-2.99 (m, 2H), 3.03 (d, 3H, J=1.9 Hz), 2.07 (s, 3H), 2.02-1.92 (m, 2H), 1.84-1.67 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-methoxyphenylboronic acid 66 mg, sodium carbonate 69 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 31 mg at room temperature, and it was stirred under application of pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was stirred under application of pressure at 180° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was stirred under application of pressure at 200° C. for 5 minutes. After the reaction mixture was cooled to room temperature, it was stirred under application of pressure at 220° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 0.5 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL and ethanol 4.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour and 30 minutes. 0.7 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(4-methoxyphenyl)benzoic acid 19 mg of pale yellow solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]12[CH2:16][S:15][CH:12]([S:13][CH2:14]1)[S:11][CH2:10]2)[CH2:7][CH3:8].Cl[CH2:18][O:19][CH2:20][CH2:21][C:22]#[CH:23].O>O1CCCC1>[CH2:20]([O:19][CH2:18][C:12]12[S:11][CH2:10][C:9]([CH2:6][CH2:7][CH3:8])([CH2:16][S:15]1)[CH2:14][S:13]2)[CH2:21][C:22]#[CH:23]
Reactant: CCCC12CSC(SC1)SC2
Reactant: C#CCCOCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#CCCOCC12SCC(CCC)(CS1)CS2
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.3 ml,1.6M solution in hexane) was added to a solution of 4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane (0.1 g) in dry tetrahydrofuran (5 ml) at -70°, under nitrogen. The solution was stirred for 30 minutes and but-3-ynyl chloromethyl ether (0.058 g) in dry tetrahydrofuran (2.0 ml) was added and the reaction mixture was allowed to warm to 20°. Water (10 ml) was added and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina, eluting with 1:10 dichloromethane:hexane saturated with ammonia. 1-(But-3-ynyloxy-methyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane was obtained as a waxy solid (0.032 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:12]([O-])=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>O.Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[C:9]([OH:11])=[N:12][NH:5]2
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1n[nH]c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a mixture of 3-bromo-2-carboxyaniline (6.6 g, 30.6 mmol, see Aust. J. Chem., 1999, 52, 1061) in H2O (28 ml) and HCl (conc., 6 ml) was added a solution of NaNO2 (2.11 g, 30 mmol) in H2O (5 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes then a solution of Na2SO3 (10.4 g, 82.5 mmol) in H2O (28 ml) was added slowly. The mixture was stirred at room temperature for 2 hours and HCl (conc., 9 ml) was slowly added. The resulting mixture was stirred at room temperature for additional 18 hours, then at 80° C. for 4 hours, and finally cooled to room temperature. The reaction mixture was basified to dissolve the precipitate and then reacidified. The precipitated 4-Bromo-1H-indazol-3-ol CLXXXIII was filtered and dried in vacuo (yellow powder, 3.19 g, 49% yield).
Reaction SMILES: B(O)(O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20](Cl)[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[CH:17]=[N:16][C:15]=2[CH:26]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[C:17]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[N:16][C:15]=2[CH:26]=1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Reactant: OB(O)c1ccncc1
Product: Clc1ccc2c(c1)N=C(c1ccncc1)c1ccccc1N2
Yield: 30.4 %

Procedure:
4 pyridyl-4-boronic acid (14 mg, 0.12 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (26 mg, 0.1 mmol) were reacted according GP11 to give 9.3 mg of the title compound (160FE69A). MS (ESI) 306 (MH+). Purity for MH+ (UV/MS) 98/95.