Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20][Si:21]([CH3:29])([CH3:28])[O:22][CH2:23][CH2:24]OCI.CN(C)[CH:32]=[O:33]>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:32][O:33][CH:23]([O:22][Si:21]([CH3:20])([CH3:28])[CH3:29])[CH3:24])[C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)OCCOCI
Reactant: CCc1nc(C)[nH]c1Sc1cc(C)cc(C)c1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc(C)n(COC(C)O[Si](C)(C)C)c1Sc1cc(C)cc(C)c1
Reaction time: 0.08 h

Procedure:
To a solution of 500 mg of 5-(3,5-dimethylphenylthio)-ethyl-2-methylimidazole (2 mmol) in 5 ml of dry dimethylformamide is added 120 mg of 60% oil suspension of sodium hydride (3 mmol) under ice cooling and allowed to stand for 5 minutes. After the addition of 820 mg of iodomethyl trimethylsilyloxyethyl ether (3 mmol) [Tetrahydron Letters, No. 35, pp. 3263-3264, 1979],the mixture is allowed to stand for 15 minutes, when it is poured onto ice water and extracted with ethyl ether. The extract is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (2:1) to give 170 mg of 5-(3,5-dimethylphenylthio )-4-ethyl-2-methyl-1-trimethylsilyloxyethoxymethyl-imidazole 4 as an oil. Yield, 21%.
Reaction SMILES: Cl.ClC[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][NH2:11].[CH3:12]CO>>[CH3:10][N:11]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:12]
Reactant: CCO
Reactant: ClCc1ccccn1
Reactant: CN
Agent: Cl
Product: CN(C)c1ccccn1
Yield: 20 %

Procedure:
Using 2-chloromethyl-pyridine hydrochloride salt and 33% methylamine/EtOH the title compound was obtained as a colourless liquid (0.1 mm Hg, 47-48° C.) (20% yield), MS: m/e=93.1 (M—NHCH3).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#N.CC(C[AlH]CC(C)C)C.C(Cl)Cl.C1C[O:36]CC1>>[F:20][C:4]1[C:3]([CH:1]=[O:36])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(NC(=O)OCc2ccccc2)c1F
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1cccc(NC(=O)OCc2ccccc2)c1F
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a slightly tan, homogeneous solution of benzyl 3-cyano-2-fluorophenylcarbamate (4.45 g, 16.47 mmol) in THF (211 mL) in a −78° C. bath under nitrogen was syringed DIBAL-H (65.9 mL, 65.9 mmol)/CH2Cl2 dropwise over 75 min. The reaction was stirred for 30 min. The cold bath was removed, and the reaction was stirred to room temperature. After 4 hr, the solution was added to ice-cold water (300 mL) over 50 minutes; heavy emulsion ensued. After stirring for another 30 min, the organic layer was separated, and the aqueous layer/emulsion was filtered, and the insoluble materials were rinsed with CH2Cl2 (200 mL). The organic layers were combined and concentrated in vacuo. The residue was dissolved in CH2Cl2 (300 mL) and washed with brine (75 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (4.0253 g, 11.78 mmol, 71.6% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: OCCCc1c[nH]c2ccc(F)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a stirred solution of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (2.90 g, 15.0 mmol) in pyridine (15.0 mL) was added p-toluenesulfonyl chloride (7.1 g, 37.5 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was poured to 200 mL of ice water. The aqueous was extracted with ethyl acetate and the combined organic extracts were washed with 1N HCl, brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane, 3/7) to give 4.1 g (79%) of the title compound as a solid: mp 74° C. (Lit. mp 99° C.; EP 464604 A2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.C1C(=O)N([Br:24])C(=O)C1.O.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:24][C:5]1[S:1][C:2]([C:6]2([OH:16])[CH2:7][CH2:8][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
The product of Step 1 (60.5 g, 251 mmol) was diluted with DMF (5 mL). To this solution, NBS (49.1 g, 276 mmol) was added. The reaction was heated to 50° C. for 2 h. The reaction was cooled to 45° C. and H2O (600 mL) containing Na2SO3 (15.8 g, 125 mmol) was added drop wise. The reaction was stirred at room temperature for 1 h then filtered and washed with H2O (2×, 300 mL). The filtrate was dried under nitrogen to afford 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (68.15 g, 213 mmol, 85% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:2].N1C(C)=CC=CC=1C.[Cl:22][C:23]([Cl:28])([Cl:27])[C:24](Cl)=[O:25].O>C(Cl)(Cl)Cl>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:24](=[O:25])[C:23]([Cl:28])([Cl:27])[Cl:22])[CH3:13]
Reactant: CCOC(Cn1cccc1)OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(Cn1cccc1C(=O)C(Cl)(Cl)Cl)OCC
Temperature: 25 °C
Yield: 60 %

Procedure:
To a refluxing solution of 1-(2,2-diethoxyethyl)pyrrole (31.6 g, 172.5 mmol) and 2,6-lutidine (20.3 g, 189.8 mmol) in 90 mL of chloroform over a period of 16 hours was added trichloroacetyl chloride (34.5 g, 189.8 mmol) in 90 mL of chloroform. The reaction mixture was refluxed for an additional 4 hours. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of water and chloroform (1:1). The phases were separated, washed with a saturated solution of NaCl, dried over MgSO4, and then evaporated. Purification of the product by column chromatography [hexane:ether (9.9:0.1)] gave the title compound, 1-(2,2-diethoxyethyl)-2-trichloroacetylpyrrole, in 60% yield, ms 327 (M+).
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[S:18][C:17]([Cl:19])=[N:16][C:15]=2[CH3:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:19][C:17]1[S:18][C:14]([C:13]2[C:12](=[O:21])[NH:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[C:3]=2[OH:4])=[C:15]([CH3:20])[N:16]=1
Reactant: COC(=O)c1nccnc1NC(=O)Cc1sc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cl)sc1-c1c(O)c2nccnc2[nH]c1=O
Temperature: 25 °C

Procedure:
3-[2-(2-Chloro-4-methyl-thiazol-5-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (Example 2.2) (1.020 g) was heated to 110° C. with potassium carbonate (1.08 g) in dry N,N-dimethylformamide (30 ml) for 3 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and the mixture extracted with ethyl acetate. The aqueous fraction was acidified to pH 3 by addition of concentrated hydrochloric acid (36% by weight in water) and then extracted again with ethyl acetate. The organic fraction was washed with water, dried over magnesium sulfate, and concentrated to give Compound No. B1 of Table B (0.61g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12](Cl)(Cl)=[O:13].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1>>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:12]([NH:1][C:2]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=4)=[O:13])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: COC(=O)c1ccc(NC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)nc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from methyl 6-aminonicotinate (Aldrich, Cat. #648736), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=503.2.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].Br[CH:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=O.[OH-].[Na+].[CH:37]([NH2:39])=O>C1C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:39]=[CH:37][S:2][C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1
Reactant: NC=O
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(-c2ncsc2-c2ccc(OC)cc2)cc1

Procedure:
7 g of phosphorus pentasulphide in 20 ml of formamide are added to a solution of 7 g of 2-bromo-1,2-bis-(p-methoxyphenyl)-ethanone in 20 ml of benzene and the mixture is heated at the boil for 1 hour. It is allowed to cool, neutralised with 10% strength sodium hydroxide solution and extracted by shaking with chloroform. The organic phase is removed, washed with water, dried over magnesium sulphate and concentrated by evaporation. 4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 98°-99° is obtained, which can be used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26](/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([Cl:43])[CH:42]=2)[C:5](=[O:6])[NH:4][CH2:3]1.ClN1C(=[O:52])CCC1=O>COCCOC.O>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:52][CH:29]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([Cl:43])[CH:42]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)/C=C/c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)/C=C/c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl

Procedure:
Likewise, cryptophycin 3 (about 40 mg, 0.063 mmol) is put into 2:1 DME/H2O (about 6 mL) and N-chlorosuccinimide (0.075 mmol) is added and is heated at about 60-70 C for about 24 hours. A further quantity of NCS (8 mg) is added and continue heating for about another 24 hours. The solvent is removed and the residue subject to HPLC (35% H2O/CH3CN 6 mL/min) to give the desired cryptophycin compounds. The resulting mixture is further purified by HPLC using methanol/water (about 4:1) to obtain the desired purified cryptophycin compounds.
Reaction SMILES: [Cl-].Br[C:3]1[S:7][C:6]([N:8](C)[C:9](=O)C)=[N:5][CH:4]=1.[CH2:13]([O:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:14].[F-].[Cs+].CO[CH2:41][CH2:42][O:43]C>>[C:42]([CH2:9][NH:8][C:6]1[S:7][C:3]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH3:20])=[O:18])=[CH:27][CH:26]=2)=[CH:4][N:5]=1)(=[O:43])[CH3:41]
Reactant: COCCOC
Reactant: CC(=O)N(C)c1ncc(Br)s1
Reactant: CCO[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Product: CCO[C@@H](Cc1ccc(-c2cnc(NCC(C)=O)s2)cc1)C(=O)OC
Temperature: 80 °C
Yield: 37 %

Procedure:
0.2 g (0.3 mmol) of diphenylphosphinoferrocenepalladium chloride (PdCl2dppf) is added to a solution of 1 g (4.5 mmol) of N-(5-bromothiazol-2-yl)-N-methylacetamide, 1.8 g (6.8 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate and 1 g (6.8 mmol) of caesium fluoride in 50 ml of ethylene glycol dimethyl ether, degassed beforehand. The reaction medium is heated at 80° C. for 18 hours. After cooling, water is added and the reaction medium is extracted with ethyl acetate. The ethyl acetate phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 and then 60/40 heptane/ethyl acetate mixture. 0.6 g (37%) of methyl 3-{4-[2-(acetylmethylamino)thiazol-5-yl]phenyl}-2(S)-ethoxypropanoate is obtained in the form of a beige-colored solid with a melting point of 123° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: BrCC1CCCO1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CCCO2)c1
Yield: 29.7 %

Procedure:
The procedure for Example 1 was followed using sodium hydride (60% in mineral oil, 12 mg), N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (Intermediate 3, 45 mg) and 2-(bromomethyl)tetrahydrofuran (26 mg) in DMF (5 ml) to give the title compound as a colourless glass (17 mg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>C(#N)C>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Product: Cc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)s1
Temperature: 4 °C
Yield: 37.8 %

Procedure:
The procedure is identical to that described in Example 1, but starting with 5-methylthiophene-2-carboxylic acid (4.1 g), N,N'-carbonyldiimidazole (5.6 g) and 2-amino-7-chloro-1,8-naphthyridine (4.85 g). The product produced (3.8 g; m.p. 220° C.) is dissolved in boiling acetonitrile (150 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.066 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-methylthiophene-2-carboxamide (3.1 g) is produced, m.p. 222° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH3:8][S:9]([O:7][CH2:1][CH2:2][CH2:3][CH:4]=[CH:5][CH3:6])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC=CCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=CCCCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
This example illustrates a synthesis of 1-(4,5-Oxohexyl)-3,7-dimethylxanthine (inventive compound no. 1555). To a solution of 4-hexen-1-ol (1.22 g, 12.2 mmol) and methanesulfonyl chloride (1.04 mL, 13.4 mmol) in dichloromethane (15 mL), cooled in an ice bath, was added triethylamine (2.55 mL, 18.3 mmol) dropwise. After 5 minutes, the cooling bath was removed and the mixture stirred for an additional 45 minutes and then treated with saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic layers were dried over magnesium sulfate and the solvents evaporated under vacuum, yielding 1-methanesulfonyloxy-4-hexene as a viscous oil.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:13]([N:15]=[C:16]=NCCCN(C)C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][C@H:37]([OH:39])[CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CNC>O1CCCC1>[CH3:13][N:15]([CH3:16])[C:33]([C@@H:32]1[CH2:36][C@@H:37]([OH:39])[CH2:38][N:31]1[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
24.9 g of 1-hydroxybenzotriazole monohydrate and 24.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added under ice cooling to a 250 mL tetrahydrofuran solution of 25.1 g of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 15 minutes. 10.7 g of a 50% dimethylamine aqueous solution was added dropwise over a period of 10 minutes to the reaction mixture, and the reaction mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, after which 100 mL of a saturated sodium hydrogencarbonate aqueous solution was added and extraction was performed with chloroform (50 mL×2). The extract was dried with anhydrous sodium sulfate, the drying agent was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: chloroform/methanol=20/1 to 9/1; v/v) to obtain 26.2 g of the titled compound (colorless solid).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC[C@H](C)CBr
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 3.01 g of (S)-(+)-1-acetoxy-3-bromo-2-methyl-propane (15.7 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. Stirring was continued for 2 h at 95-105° C. The dimethylformamide was removed by evaporation under reduce pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give the crude product as a brownish oil (5.81 g).
Reaction SMILES: [C:1]([Li:5])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][C:15]1(C)CC=C(OS(C(F)(F)F)(=O)=O)[C:21]2[CH:20]=[C:19](/[CH:33]=[CH:34]/[C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH:18]=[CH:17][C:16]1=2>CCCCC.C1COCC1.[Cl-].[Cl-].[Zn+2].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>[Li:5][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:2][C:1]1([CH3:4])[CH2:14][CH:15]=[C:16]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:17]2[CH:18]=[C:19](/[CH:33]=[CH:34]/[C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH:20]=[CH:21][C:3]1=2
Reactant: [Li]C(C)(C)C
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Product: [Li]c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-lithiotoluene was prepared at -78° C. by the addition of 130.7 mg of t-butyllithium (2.04 mmol; 1.20 ml of a 1.7M solution in pentane) to a solution of 374.5 mg (2.20 mmol) of 4-bromotoluene in 2.5 ml of THF. After 30 minutes a solution of 313.4 mg (2.30 mmol) of ZnCl2 in 2.0 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 1.25 hour and then added via canula to a solution of 285.0 mg (0.590 mmol) of ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethenyl]benzoate (Compound P) and 29.0 mg (0.025 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF. The resulting solution was stirred at room temperature for 1 hour and then at 55° C. for 2 hours. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the combined extracts were washed with 5% aqueous NaOH, saturated aqueous NaCl, and dried over Na2SO4 before being concentrated under reduced pressure. The title compound was isolated by column chromatography (10% EtOAC/hexanes) as a colorless solid. 1H NMR (CDCl3): δ 7.96 (2H, d, J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.43-7.16 (7H, m), 7.07 (1H, d, J=16.3 Hz), 6.93 (1H, d, J=16.3 Hz), 5.97 (1H, t, J=4.7 Hz), 4.39 (2H, q, J=7.0 Hz), 2.41 (3H, s), 2.33 (1H, d, J=4.7 Hz), 1.38 (3H, t, J=7.0 Hz), 1.33 (6H, s).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(-c3cccc4cc(C(=O)N[C@@H]5CN6CCC5CC6)oc34)c2)CC1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 23.5 mg (0.23 mmol) of N-methylpiperazine are reacted together by general method E. 9.2 mg (15.4% of theory) of the title compound are obtained.