Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:28]([N:11]([CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2ncc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (30 mg) in N,N-dimethylacetamide (0.6 mL) were added benzyl bromide (13 mg) and cesium carbonate (26 mg). The mixture was stirred overnight at r.t. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 1:1) to give N-benzyl-2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 534.8 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[CH:21]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3C=CCCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg, 1.29 mmol), 3-bromocyclohexene (0.17 mL, 1.42 mmol), and cesium carbonate (462 mg, 1.42 mmol) were added to an oven-dried flask, followed by DMF (4.3 mL). The reaction mixture was stirred at 90° C. overnight then cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(cyclohex-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (500 MHz, CD3OD) δ 7.82 (s, 1H), 7.69 (s, 1H), 5.81-5.62 (m, 2H), 4.15-4.09 (m, 1H), 2.24-1.41 (m, 6H), 1.31 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Cl)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28]([O:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:27][C:26]([Cl:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: COc1ccc(CO)cn1
Product: COc1ccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)cn1

Procedure:
Prepared by the method of Example 31 using (6-methoxy-3-pyridinyl)methanol (0.3 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:17])([CH3:16])[CH3:15])[C:11]([OH:13])=O)=[C:5]([CH3:18])[C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:17])([CH3:15])[CH3:16])[C:11]([NH:31][NH:30][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:33][CH:32]=2)=[O:13])=[C:5]([CH3:18])[C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Reactant: NNC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
(R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoic acid (500 mg, 1.58 mmol) and 4-fluorobenzohydrazide (244 mg, 1.58 mmol) were mixed together in THF (20 mL) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (214 mg, 1.58 mmol), TEA (0.33 mL, 2.37 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (454 mg, 2.37 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete, ethyl acetate (50 mL) was added and the solution was washed with 5% citric acid (2×40 mL), 5% NaHCO3 (2×40 mL) followed by water (40 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (660 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.81 (br s, 1H), 8.02-7.95 (m, 2H), 7.69-7.63 (m, 1H), 7.27-7.21 (m, 2H), 7.01-6.95 (m, 1H), 5.54 (d, J=7 Hz, 1H), 4.14 (d, J=8 Hz, 1H), 2.38 (s, 3H), 1.47 (s, 3H) and 1.43 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[CH3:8].IC1C=CC=CC=1CCN.CC(OC(C)=O)=O>O1CCOCC1>[I:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:8]
Reactant: CC(=O)NCCc1ccccc1I
Agent: NCCc1ccccc1I
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC1=NCCc2c(I)cccc21
Temperature: 25 °C

Procedure:
N-(2-iodophenethyl)acetamide. A solution of 2-(2-iodophenyl)ethanamine (13.5 g, 54.6 mmol) and Ac2O (10.3 mL, 109 mmol) in 1,4-dioxane (200 mL) was heated to 100° C. for 45 min. The reaction was then allowed to cool to RT and concentrated in vacuo. The resulting residue was taken up in DCM and washed with a saturated aq. solution of NaHCO3— gas formation! The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow oil (16.2 g) which was used as it is in the next step. UPLC-MS: MS 290.3 (M+H+); UPLC rt 0.96 min.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18](Br)[CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([F:6])([F:5])[F:4].Br[Zn][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)[CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([F:6])([F:5])[F:4]
Reactant: Cc1ccc([Zn]Br)nc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(N)C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(N)C(F)(F)F)c2)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-(1-amino-2,2,2-trifluoroethyl)-5-bromobenzoate (1.4 g, 3.95 mmol) in dioxane (20 mL) was added bis(tri-t-butylphosphine)palladium(0) (0.06 g, 0.12 mmol). The mixture was degassed with nitrogen and bromo(5-methylpyridin-2-yl)zinc (0.5 M in THF; 23.7 mL, 11.9 mmol) was added. The mixture was heated to 70° C. After 1 h, the mixture was cooled to ambient temperature and filtered with Celite. The filtrate was concentrated to remove dioxane and saturated NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→60% dichloromethane/ethyl acetate) gave the title compound (1.39 g). MS 367.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:21][CH:20]=1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Sc1ccc(Br)cc1
Product: O=c1ccc2cc(OCCCCSc3ccc(Br)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 4-bromo-thiophenol.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][CH:6]=2)[N:8]=1)(=[O:15])[CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1nc(-c2ccccc2)cs1
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Temperature: 25 °C

Procedure:
N-(4-Phenyl-thiazol-2-yl)-acetamide was added to chlorosulfonic acid (5 eq) at 0° C. and allowed to warm to room temperature. The mixture was heated at 70° C. for 1 h and carefully poured into ice. The solid was filtered, washed with water and dried under vacuum to give 4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl chloride. Characterized by derivatization as N-[4-(4-Isobutylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide, 1H NMR (400 MHz, CD3OD) 8.08 (d, 2H), 7.85 (d, 2H), 7.58 (s, 1H), 2.66 (d, 2H), 2.22 (s, 3H), 1.7 (m, 1H), 0.87 (d, 6H). LCMS (m/z): 354.
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]#[N:9]>O>[OH:7][C@@H:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]#[N:9]
Reactant: C#N
Reactant: CCCCCC=O
Solvent: O
Product: CCCCC[C@H](O)C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
1.33 mmol of hexanal (133 mg) were dissolved in 3 ml of water-saturated diisopropyl ether. 1.1 ml of aqueous hydroxynitrile lyase solution (900 IU/ml) were added at room temperature and the mixture was stirred at room temperature for 5 min. 300 μl of anhydrous hydrocyanic acid (7.88 mmol) were then added and the reaction vessel was sealed pressure-tight. After stirring at room temperature for 1.5 hours, the phases were separated, the aqueous phase was extracted three times with 5 ml of diisopropyl ether each time and the combined ether phases were dried using anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude cyanohydrin obtained in this way was subjected to purification by column chromatography. 140 mg of (S)-2-hydroxyheptanenitrile were obtained (83% isolated yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][C@@H:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:7]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([F:33])[CH:24]=2)[CH:5]=1.[NH2:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1>>[F:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:31])=[O:30])[O:22][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH:11]([CH3:21])[CH2:12][OH:13])[CH:7]=1)[C:3]([NH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1)=[O:2]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reactant: Nc1nccs1
Product: CC(CO)Oc1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)cc(C(=O)Nc2nccs2)c1

Procedure:
The compound of Production Example 42 was obtained as a colorless oil using the obtained 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(3-fluoro-4-methanesulfonyl-phenoxy)-benzoic acid methyl ester and 2-amino-thiazole, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([CH2:14][NH2:15])[OH:13].[BH4-].[Na+].O>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:15][CH2:14][CH2:12][OH:13])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(CNCCO)c1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
500 mg of 3-nitrobenzaldehyde and 202 mg of ethanol amine were dissolved in 10 mL of ethanol, followed by stirring at 80° C. To this was added 125 mg of sodium borohydride, followed by stirring for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 594 mg (yield 92%) of a title compound as a yellow solidified product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].CCN(C(C)C)C(C)C.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:4]3[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[F:12])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 33.5 %

Procedure:
To a solution of 1,2,3-trifluoro-4-nitrobenzene (3.2 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 21 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:2). Recrystallization from EtOAc (10 ml) and hexanes (˜100 ml) gave the title compound as red crystals (1.5 g, 33%). NMR (400 MHz) 11.90 (s, 1H), 8.78 (s, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.08 (q, J=8.7 Hz, 1H), 5.60 (s, 1H), 1.83 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:19][C:20]([N:22]2[C:28](=[O:29])[C@@H:27]([CH2:30][C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[CH2:26][NH:25][C:24](=[N:40][N:41]([CH3:43])[CH3:42])[CH2:23]2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].Cl.C1(C)C=CC=CC=1>C(O)(=O)C>[NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:19][C:20]([N:22]2[C:28](=[O:29])[C@@H:27]([CH2:30][C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[CH2:26][NH:25][C:24](=[N:40][N:41]([CH3:43])[CH3:42])[CH2:23]2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCC[C@@H](NC(=O)N1CC(=NN(C)C)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC[C@@H](NC(=O)N1CC(=NN(C)C)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To the compound 21 (16 mg), 1 M hydrochloric acid in acetic acid solution was added, and the mixture was stirred at room temperature for 4 hours. To the reaction solution, toluene (5 ml) was added and the precipitated solid was collected by filtration to obtain the title compound (12.7 mg).
Reaction SMILES: C(OC([N:8]([O:30]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:26][C:24]1[C:23]([Cl:27])=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][OH:30])=[CH:16][CH:15]=3)[C:18]([CH2:28][CH3:29])=[N:19][C:20]=2[CH:25]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCNO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole (step 1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 mL) in ethyl acetate (20 mL) was stirred at room temperature for 1 day. The reaction mixture was poured into water (100 mL), neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 162 mg (quant.) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 10.35 (2H, br.s), 7.89 (1H, s), 7.46–7.50 (2H, m), 7.29 (2H, d, J=6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J=6.9 Hz), 3.12 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=6.9 Hz), 1.34 (3H, m).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:13](Cl)(=O)CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH2:5][CH3:13]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CC
Yield: 92.9 %

Procedure:
Under the same conditions as in Example 1, 130 g (1.0 mol) of ethyl acetoacetate in a mixture of 1.2 l of methylene chloride and 300 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 106.5 g (1.15 mol) of propionyl chloride. The subsequent reaction time after the ammonia had been metered in was 4 hours at a pH of 9.3. This gave 134 g (GC purity 72.0%) of ethyl propionylacetate (yield 67.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[OH-].[K+].[CH3:17]I.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:17])[N:11]=1
Reactant: COc1ccccc1Nc1cc[nH]n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Nc1ccn(C)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The pyrazole from Example 5 (b) (4.0 g) was added to a mixture of crushed potassium hydroxide pellets (4.7 g) in dry dimethylsulphoxide, which had previously been stirred for 5 minutes under nitrogen at room temperature. After stirring for 0.75 hours, methyl iodide (3.1 g) was added to the red solution and stirring was maintained for a further 0.75 hours. The reaction mix was poured into water, extracted with ethyl acetate, the organic layer washed, dried, evaporated and chromatographed to give a light brown oil.
Reaction SMILES: [F:1][C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([CH3:11])[CH2:3][C:4]([CH3:13])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5]1
Reactant: CCOC(=O)C1CC(C)(F)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CC(C)(F)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
To a solution of Intermediate 288A (0.13 g, 0.812 mmol) in THF (2 mL) was added LDA (1.623 mL, 1.623 mmol, 1 M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.203 mL, 3.25 mmol) was then added at −78° C. and the mixture was allowed to slowly warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 307A as a yellow liquid (85 mg, 60%). The crude product was reacted under saponification conditions without further purification 1H NMR (400 MHz, DMSO-d6) δ ppm 4.08 (q, J=7.0 Hz, 2H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz, 3H), 1.36 (s, 3H) 1.22-1.11 (m, 3H).
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.[CH2:22]([Sn:26]([Li:35])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C1COCC1>[CH2:22]([Sn:26]([Li:35])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH3:25].[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Brc1ncccn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li][Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Temperature: 25 °C

Procedure:
(Example of the general procedure Tin-03, below) Tri-n-butylstannyl lithium was prepared at 0° C. in dry THF (20 mL) from tri-butyltin hydride (2.2 mL) and LDA (lithium diisopropylamide, 2M, 4.09 mL). The tri-n-butylstannyl lithium solution was then cooled to −78° C. and to it was added 2-bromopyrimidine (1 g). The reaction mixture was then allowed to warm up to room temperature over 8 hours. The reaction was then quenched with aqueous ammonium chloride solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-(tri-n-butylstannyl)-pyrimidine (190 mg).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][OH:32]>CC(C)=O>[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:31]([OH:3])=[O:32]
Reactant: CC1=C(C)C(=O)C(C(CCCC#CCO)c2ccccc2)=C(C)C1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC1=C(C)C(=O)C(C(CCCC#CC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Jones' reagent (2.25 ml) was added dropwise to a solution of 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-2-heptyne-1-ol (1.01 g, 3.0 mmole) in acetone (15 ml) at room temperature over the 15-minutes period. The mixture was stirred at room temperature for another 30 minutes and the acetone was distilled off under reduced pressure. Isopropyl ether and water were added to the residue, and extraction was effected. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was recrystallized from isopropyl ether to give 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-2-heptynoic acid (0.71 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][CH3:28])[CH2:15][CH2:14]1
Reactant: CCCI
Reactant: COc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2OC)CC1

Procedure:
Preparation according to Example 1: 4-[2-methoxy-3-(trifluoro-methyl)phenyl]piperidine (0.38 g, 1.47 mmol), acetonitrile (40 ml), potassium carbonate (0.4 g, 3.7 mmol) and 1-iodopropane (0.115 ml, 1.47 mmol). Yield: 0.33 g (74%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 235.5° C. MS m/z (relative intensity, 70 eV) 301 (M+, 7), 273 (22), 272 (bp), 229 (6), 159 (13).