Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=3)[C:19]3[C:24]([C:25]=2[CH:26]=1)=[CH:23][C:22]([C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=1)=[CH:21][CH:20]=3)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([N:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:11](=[O:13])[CH3:12])=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[C:22]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([S:1][C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:30][CH:29]=2)[CH:23]=3)=[CH:41][CH:40]=1)(=[O:44])[CH3:43]
Reactant: Sc1nc2ccccc2s1
Reactant: CC(=O)c1ccc(-n2c3ccc(C(C)=O)cc3c3cc(C(=O)c4ccc(F)cc4)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(-n2c3ccc(C(C)=O)cc3c3cc(C(=O)c4ccc(Sc5nc6ccccc6s5)cc4)ccc32)cc1

Procedure:
An analogous reaction as described in example 5.a by using 2-mercaptobenzothiazole and 1-{4-[3-acetyl-6-(4-fluoro-benzoyl)-carbazol-9-yl]-phenyl}-ethanone in the presence of potassium carbonate gives the product. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.74 (s, 3H), 2.75 (s, 3H), 7.35 (t, 1H), 7.47 (t, 2H), 7.52 (d, 1H), 7.72 (d, 2H), 7.77 (d, 1H), 7.86 (d, 2H), 7.92 (d, 2H), 7.96 (d, 1H), 8.03 (d, 1H), 8.15 (d, 1H), 8.28 (d, 2H), 8.71 (s, 1H), 8.81 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C=O.CN.[CH3:21][N:22]1[CH2:27]COC[CH2:23]1>CCO.O>[CH2:1]([N:3]1[CH2:23][N:22]([CH3:27])[CH2:21][N:6]([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[C:4]1=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: CN1CCOCC1
Agent: C=O
Agent: CN
Solvent: CCO
Solvent: O
Product: CCN1CN(C)CN(c2nc3c(s2)C(=O)CCC3)C1=O
Temperature: 60 °C
Yield: 100.9 %

Procedure:
To a suspension of N-ethyl-N′-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)urea (10.0 g, 41.79 mmol) in EtOH/H2O (1/1, 300 mL) were added formaldehyde (37 wt % in H2O, 20.4 g, 417.87 mmol), methylamine (40 wt % in H2O, 10.8 mL, 125.37 mmol) and N-methylmorpholine (11.8 mL, 83.6 mmol). The suspension was heated to about 60° C. for about 5 hrs, then a solution had been formed. The reaction mixture was pumped down in vacuo to give 12.41 g (quantitative yield) pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(N3CCCCC3)nncc2c1
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: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A mixture of 6-bromo-1-(piperidin-1-yl)phthalazine (0.12 g, 0.40 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) and 2M potassium carbonate (0.6 mL, 1.2 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was transferred directly to silica gel and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give the title compound (0.13 g) as yellow solid. Found MS (ES+): 387(M+H)+.
Reaction SMILES: N[C:2]1[C:14]([Br:15])=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[Br:16].CCOCC>CN(C=O)C>[Br:16][C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[C:14]([Br:15])[CH:2]=1
Reactant: Nc1c(Br)cc2oc3ccccc3c2c1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1cc(Br)c2c(c1)oc1ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.4 %

Procedure:
To a solution of t-butylnitride (0.89 ml, 7.2 mmol) dissolved in 10 ml of DMF at 50° C. was added dropwise a solution of 2-amino-1,3-dibromodibenzofuran 17 (1.0 g, 2.9 mmol) in 10 ml of DMF with nitrogen evolution. After stirring at 50° C. for 1 hour the reaction was diluted into ether and washed successively with H2O and saturated NaCl. Drying over MgSO4 and evaporation gave 1.1 g of a red solid which was purified by flash chromatography through 100 g of silica gel (20% methylene chloride:hexane) yielding 650 mg (68%) of the title compound as a pale orange solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[C:9]([CH:11]=O)[O:10][C:6]=2[CH:5]=1)[CH3:2].[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N+:25]1[C:34]2[C:29](=[CH:30][C:31]([S:35]([O-:38])(=[O:37])=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:39])=[CH:27][CH:26]=1)([OH:19])=[O:18].[CH3:40][N+:41]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH3:42]>CO.O>[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N+:25]1[C:34]2[C:29](=[CH:30][C:31]([S:35]([O-:38])(=[O:37])=[O:36])=[CH:32][CH:33]=2)[C:28](/[CH:39]=[CH:11]/[C:9]2[O:10][C:6]3[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])[CH:14]=[CH:13][C:7]=3[CH:8]=2)=[CH:27][CH:26]=1)([OH:19])=[O:18].[CH3:40][N+:41]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH3:42]
Reactant: CCN(CC)c1ccc2cc(C=O)oc2c1
Reactant: Cc1cc[n+](CCCCCC(=O)O)c2ccc(S(=O)(=O)[O-])cc12
Agent: C[N+](C)(C)CC(=O)O
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)c4ccc(S(=O)(=O)[O-])cc34)oc2c1

Procedure:
0.2 mmol 6-diethylamino-benzofuran-2-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-4-methyl-6-sulfonato-chinolinium betaine are converted according to the general directions given above. Column chromatography: SiO2 (RP18), eluent: methanol/water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[C:9](=O)[NH:8][C:5]2=[CH:6][CH:7]=1.COCCO[Al]OCCOC.[Na]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)Nc1ccc(F)cc12
Agent: COCCO[Al]OCCOC
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC2(CNc3ccc(F)cc32)C1
Temperature: 75 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a stirred solution of tert-butyl 5-fluoro-2-oxospiro[indoline-3,3′-piperidine]-1′-carboxylate (0.80 g, 2.5 mmol) in toluene (20 mL) was added dropwise a solution of sodium bis(2-methoxyethoxy) aluminium hybrid (Red-Al) in toluene (65% w/w, 1.1 mL, 3.5 mmol) at about 70° C. under N2. The reaction mixture was stirred at about 75° C. for 3 h. After cooling, the reaction mixture was quenched with EtOAc and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 3:1) to give tert-butyl 5-fluorospiro[indoline-3,3′-piperidine]-1′-carboxylate (0.18 g, 24%) as an oil. LCMS (APCI+) m/z 307 [M+H]+; Rt=3.66 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[C:24]([NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6].[CH3:37]I>>[ClH:2].[Cl:2][C:3]1[CH:25]=[C:24]([N:26]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[CH3:37])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1)OCc1ccccc1
Reactant: CI
Agent: Cl
Product: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
In a manner analogous to that described in Example 5, the 1-[2-chloro-4-(N-benzyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride obtained in accordance with Example 17 is methylated with 0.8 g of methyl iodide, yielding 1-[2-chloro-4-(N-benzyloxycarbonyl-N-methylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1.[Na+].[Cl-]>CN(C=O)C.O>[CH:1]1([CH2:4][O:5][C:11]2[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccnc(Cl)n1
Reactant: OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccnc(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (724 mg) was dissolved in DMF (4 mL) and treated with sodium hydride (401 mg, 60% in mineral oil) at 0° C. for 30 minutes. Then, a solution of 4-amino-2-chloro-pyrimidine (260 mg, CAS 7461-50-9 or made according to J. Am. Chem. Soc. 1930, 52, 1152-1157) in DMF (4 mL) was added drop by drop. The mixture was stirred at room temperature for 1 hour and then allowed to stir at 50° C. over night. The mixture was poured into water and the mixture was saturated with NaCl. The aqueous solution was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane as an eluant. The desired product was obtained as a light yellow oil (169 mg). MS (EI): 166.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(N)ccc21
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-Methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 0.6 g 2-methylsulfonylbenzenesulfonyl chloride is added portionwise to a solution, at a temperature in the region of 0° C. and under argon, of 0.83 g of 5-amino-3-phenethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole in 13 ml of pyridine. The reaction mixture is then stirred for 0.5 hours at a temperature in the region of 0° C. then 2 hours at a temperature in the region of 20° C., and is then diluted with 13 ml of water. After settling out, the aqueous phase is extracted with 3 times 30 ml of ethyl acetate. The organic extracts are pooled, washed with 2 times 15 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 70 g of silica (particle size 20-40 μm), eluting successively with pure cyclohexane then with a cyclohexane/ethyl acetate (80/20 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. 0.56 g of 2-methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide are obtained in the form of a brown-colored paste (Rf=0.32, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (70/30 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH:13]/[C:14](/[NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[N:15]\[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.I(O)(=O)(=O)=[O:32]>CC(C)=O.C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH:13]/[C:14](/[NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[N:15]\[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:24])=[O:32])[CH:18]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CSc1cccc(C(=O)/N=C(/NCC(C)C)Nc2cc(-c3ccc(F)cc3)n[nH]2)c1
Reactant: [O-][I+3]([O-])([O-])O
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(C)CN/C(=N/C(=O)c1cccc(S(C)=O)c1)Nc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 77 %

Procedure:
To an orange solution of (Z)—N-[[[3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino]-(isobutylamino)methylene]-3-methylsulfanyl-benzamide (500 mg, 1.175 mmol) and ferric chloride trihydrate (9.5 mg, 0.035 mmol) in acetone:acetonitrile (1:1) was added periodic acid (295 mg, 1.3 mmol) in one portion. After stirring the resulting mixture at room temperature for ca. 21 hr, the reaction was quenched by adding aqueous sodium thiosulfate. The product was extracted with DCM, and the organic layer was washed with brine and dried over MgSO4. The drying reagent was removed by filtration, and the filtrate was concentrated onto silica gel and purified by silica chromatography (50-90% EtOAc in hexanes) to provide the title compound (77% yield). MS (EI+) m/z: 442.17.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][N:5]1[N:9]=[N:8][C:7]([CH2:10][CH2:11][NH2:12])=[N:6]1.C(N(CC)CC)C.[F:20][C:21]1[CH:22]=[C:23]([C:31]2[S:35][C:34]([NH:36][C:37](N3C=CN=C3)=[O:38])=[N:33][C:32]=2[CH3:44])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>CN(C=O)C>[F:2][CH2:3][CH2:4][N:5]1[N:9]=[N:8][C:7]([CH2:10][CH2:11][NH:12][C:37]([NH:36][C:34]2[S:35][C:31]([C:23]3[CH:24]=[CH:25][C:26]([S:27]([CH3:30])(=[O:28])=[O:29])=[C:21]([F:20])[CH:22]=3)=[C:32]([CH3:44])[N:33]=2)=[O:38])=[N:6]1
Reactant: NCCc1nnn(CCF)n1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)NCCc2nnn(CCF)n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 2-[2-(2-Fluoro-ethyl)-2H-tetrazol-5-yl]-ethylamine hydrochloride (0.150 g, 0.0.77 mmol) in DMF (5 ml) was added triethylamine 0.243 ml, 0.1.74 mmol) followed by imidazole-1-carboxylic acid [5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (0.265 g, 0.7 mmol). After stirring at room temperature for 3.5 hours, the reaction mixture was filtered and water (3 ml) is added to the filtrate with vigorous stirring. The resulting solid was filtered and dried under high vacuum to yield the titled product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:14])[CH:3]=1.S(=O)(=O)(O)[OH:16]>>[NH2:1][C:2]1[C:11]([C:12](=[O:16])[NH2:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:14])[CH:3]=1
Reactant: COC(=O)c1cc(C#N)c(N)cc1O
Reactant: O=S(=O)(O)O
Product: COC(=O)c1cc(C(N)=O)c(N)cc1O
Temperature: 80 °C

Procedure:
Methyl 4-amino-5-cyano-2-hydroxybenzoate (J. Chem. Soc. Perkin I. 1979, 677; 4 g) was added to stirred concentrated sulphuric acid (6 ml) and the mixture was heated to 80° C. for 30 minutes. The mixture was cooled to ambient temperature and poured onto crushed ice. The resultant solid was filtered off, washed well with water and dried to give methyl 4-amino-5-carbamoyl-2-hydroxybenzoate (2.8 g); NMR Spectrum: (DMSOd6) 3.83 (s, 3H), 6.1 (s, 1H), 6.75 (br m, 2H), 8.08 (s, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[CH2:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][CH3:11].Cl>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:9][CH2:10][CH3:11])=[CH:13][C:14]=1[C:5](=[O:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: CCCc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1ccc(OC)c(C(C)=O)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A suspension of 10.6 g of AlCl3 in 150 mL of dichloromethane is cooled to −10° C. 5.7 mL of AcCl and 6 g of 4-propylanisole are added. The medium is stirred for 30 minutes at −10° C. and then poured into a beaker containing ice mixed with 35% HCl. After separation of the phases by settling, the aqueous phase is extracted 3 times with DCM and the combined organic phases are washed with water, with saturated NaCl solution, dried over MgSO4 and then evaporated to give 7.86 g of a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][F:20])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=3)[CH2:14][CH:15]2[CH2:19][F:20])[CH:28]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: O=C(c1ccc([N+](=O)[O-])c(F)c1)N1CCNC(CF)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])c(F)c3)CC2CF)c1
Temperature: 60 °C
Yield: 57.3 %

Procedure:
A stirred mixture of (3-fluoro-4-nitrophenyl)(3-(fluoromethyl)piperazin-1-yl)methanone (456 mg, 1.6 mmol), N-tert-butyl-3-(chloromethyl)benzamide (361 mg, 1.6 mmol), triethylamine (3.1 mmol, 341 mg) and sodium iodide (1.6 mmol, 240 mg) in acetonitrile (10 mL) was heated to 60° C. for several hours. The reaction was concentrated under reduced pressure. The residue was then dissolved in dichloromethane and extracted with water (×3). The organic phase was dried (sodium sulfate) and concentrated under vacuum. The crude material was purified using silica chromatography to give the title compound (435 mg). MS (ESI) m/z 475.7[M+H]+
Reaction SMILES: C(O)C1C=CC=CC=1.C1([Sn](C2CCCCC2)(C2CCCCC2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([OH:24])[CH3:23])CCCCC1.[Br:37]C1C=CC=CC=1CO>>[Br:37][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([OH:24])[CH3:23]
Reactant: CC(O)c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Reactant: OCc1ccccc1Br
Solvent: OCc1ccccc1
Product: CC(O)c1ccccc1Br
Yield: 75.1 %

Procedure:
17.2 g of o-[tri(cyclohexyl)]tin]benzylalcohol was obtained in the same manner as in the synthesis of tricyclohexyl[o-(1-hydroxyethyl)phenyl]tin of Example 1-(4), with the exception that 9.40 g of o-bromobenzylalcohol (50.2 mmol), prepared in the aforementioned example (1), instead of o-bromo-1-phenyl ethanol (yield=75.1%).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:13]=[C:14]([C:18]2[N:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[Cl:3][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:27])([F:26])[F:10])[CH:13]=2)=[N:23][CH:22]=1
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)nc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
911 mg (0.56 ml, 7.66 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 970 mg (3.83 mmol) [6-(3-Trifluoromethyl-phenyl)-pyridine-3-yl]-methanol in 30 ml dichloromethane, stirred for 5 min. at 0° C., and at r.t. for 1 h. The mixture is poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), and evaporated. Purification by chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 750 mg (72%) of 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine as light yellow crystals
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@H:15]2[CH3:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@H:15]2[CH3:20])[N:3]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(CN1CCC(C(C)(C)O)CC1)n2C
Reaction time: 17 h
Yield: 92.1 %

Procedure:
A mixture of 2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde (279 mg, 0.94 mmol), 2-piperidin-4-ylpropan-2-ol (149 mg, 1.04 mmol) and 4 Å powdered molecular sieves (700 mg) in DCE (15 mL) was stirred for 5.5 h before the addition of sodium triacetoxyborohydride (400 mg, 1.89 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite®, washing with MeOH. The resulting filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording the title compound as a pale yellow solid (366 mg, 92%). LCMS (method H): RT 2.11 min [M+H]+ 423.4
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([N:2]1[CH2:3][CH:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:12]=2)=[O:10])[CH3:7])[CH2:5]1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-azetidin-3-yl-ethyl)-amide hydrochloride (65 mg, 0.11 mmol) in CH2Cl2 (2 mL) at 0° C. was added triethylamine (47 μL, 0.33 mmol) followed by methanesulfonyl chloride (10 μL, 0.12 mmol). The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) to afford 35 mg (50%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide as a pale yellow solid.