Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:27])[C:25]=1[OH:26])[CH:21]=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:27])[C:25]=1[OH:26])[CH:21]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4](=[O:5])[CH2:3][CH:2]([CH3:16])[CH3:1])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: CC(C)CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Product: CC(C)CC(=O)c1ccc2c(c1)C(=Cc1cc(Cl)c(O)c(Cl)c1)C(=O)N2

Procedure:
The title compound was synthesized in an identical manner to example 2 except 5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one was used in place of 5-(2methyl-thiazol4-yl)- 1,3-dihydro-indol-2-one and 3,5-dichloro-4-hydroxy-benzaldehyde was used in place of 3,5-bromo-4-hydroxy-benzaldehyde. 1H NMR (DMSO-d6): δ11.05 (s, 1H); 10.99 (s, 1H1); 8.63 (s, 1H); 8.28 (s, 1H); 7.92 (s, 1H); 7.85 (d, J=8.2, 1H); 7.77 (s, 1H); 6.89 (d, J=8.2, 1H); 2.84 (d, J=6.8, 2H); 2.21-2.08 (m, 1H); 0.92 (d, J=6.8, 6H). ESI-MS: m/z 388 (m−H)−.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][Br:20])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Yield: 59.9 %

Procedure:
A solution of 54.8 g (192 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylbenzenesulfonamide in 420 ml of tetrachloromethane is heated at reflux for 6-8 h under a nitrogen protective-gas atmosphere, following addition of 36 g (202 mmol) of N-bromosuccinimide and 0.5 g of azobisisobutyronitrile (AIBN) with simultaneous irradiation with a daylight lamp. The solution is then filtered and then washed in succession with sodium disulphide solution, sodium hydrogen carbonate solution and water, dried over Na2SO4 and evaporated to dryness i.v. Crystallization of the residue from diisopropyl ether/ethyl acetate yields 41.9 g (57%) of N-tert-butyl-5-bromomethyl-2-methoxycarbonylbenzenesulfonamide of mp. 88-90 °C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:27]([CH2:29]O)[CH:28]=1.O>C(#N)C>[Br:20][CH2:29][C:27]1[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(Cl)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)cc1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (1.19 g) was suspended in acetonitrile (50 ml), bromine (0.24 ml) was added, and the mixture was stirred at room temperature for 30 min. A solution of [5-chloro-2-(methylsulfonyl)phenyl]methanol obtained in Step 2 (1 g) in acetonitrile (10 ml) was added to the reaction mixture. The mixture was stirred at 70° C. for 3 hr, treated with water, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:3) to give 2-(bromomethyl)-4-chloro-1-(methylsulfonyl)benzene (0.46 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 147.3 is prepared in analogy to a published literature procedure (J. Med. Chem. 2006, 49, 3101-3115). 55% of NaH in mineral oil (881 mg, 20.2 mmol) is added to a solution of 6-Chloroindole (3.0 g, 19.8 mmol) in THF (28 mL) at 0° C. After 1 h, TsCl (3.85 g, 20.2 mmol) is added, and the reaction mixture is stirred at RT. After completion, the reaction mixture is quenched by saturated aqueous NaHCO3 and diluted with Et2O. The organic layer is dried over Na2SO4 and evaporated in vacuo to provide crude solid. The crude product is washed with small amount of Et2O to give the title compound as orange crystal; ES-MS: M+=306.1: AtRet=5.60.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[S:26])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)c2ccccn2)cc1
Yield: 53.6 %

Procedure:
N-(4-fluorophenyl)-2-pyridinecarboxamide (11.47 g, 53.0 mmol) and Lawesson's reagent (25.75 g, 63.7 mmol) were refluxed in toluene for 6.5 hours, preadsorbed onto silica gel, and flash chromatographed (500 g of silica gel eluted with 15% ethyl acetate in petroleum ether) affording N-(4-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (6.60 g, 54%) m.p. 82°-85° C.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@:19]23[CH2:27][O:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[C@H:24]2[CH2:23][S:22][C:21]([NH2:32])=[N:20]3)[CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:32][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([C:28]([F:31])([F:29])[F:30])[O:26][CH2:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:2][F:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])[N:20]=1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(CF)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
5-(Fluoromethyl)pyrazine-2-carboxylic acid (32.6 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (70.0 g, 1.0 equiv) were charged to a reactor and EtOAc (630 mL) was added to the mixture to give a suspension. A solution of ®T3P (146 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to 15-20° C. and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30° C. EtOAc (245 mL0 was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (490 mL). The organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL). The organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL). The solution was concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide as a white solid (70.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31](OC)=O)=[CH:24][C:23]=2[O:22]1>>[O:29]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31]3[NH:20][C:18](=[O:19])[C:3]4[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:24][C:23]=2[O:22][CH2:21]1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 18 mg (0.066 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 40.8 g (0.21 mmol) of methyl 3,4-methylenedioxyphenylacetate.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:12])([CH:10]=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:19].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[CH:1]([CH:4]1[CH2:5][CH2:6][C:7]([CH3:12])([C:10]([OH:19])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)C1CCC(C)(C=O)CC1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)C1CCC(C)(C(=O)O)CC1
Yield: 100.4 %

Procedure:
A flask was charged with 10 g of 4-isopropyl-1-methyl cyclohexane carbaldehyde, 200 mL of tert-butanol and 100 mL of 2-methyl-2-butene. While stirring the contents of the flask, a solution prepared by dissolving 13 g of sodium chlorite and 11 g of sodium dihydrogenphosphate in 80 mL of water was added to the flask at 0° C. After stirring the contents of the flask at room temperature for 40 min, a part of tert-butanol in the flask was distilled off, and then a small amount of sulfuric acid was added to the flask. The resulting reaction mixture was extracted with an ether, and the thus obtained extract solution was concentrated and then purified by a silica gel column, thereby obtaining 11 g of 4-isopropyl-1-methyl cyclohexanecarboxylic acid.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[CH3:23][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:25]O>C1(C)C=CC=CC=1>[C:1]([O:22][CH2:23][CH:24]([CH3:25])[CH2:27][CH2:28][CH3:29])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:23][CH:24]([CH3:25])[CH2:27][CH2:28][CH3:29])=[O:19]
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCC(C)CO
Solvent: Cc1ccccc1
Product: CCCC(C)COC(=O)CCCCCCCCCCCCCCCCC(=O)OCC(C)CCC
Temperature: 115 °C
Reaction time: 5 h

Procedure:
Octadecanedioic acid (ODDA, 5.00 g) was added to a 100-mL three-necked round-bottom flask. A Dean-Stark condenser was attached, followed by the addition of toluene to the ODDA and to the trap. 2-Methylpentyl alcohol (5.90 mL) was added to the ODDA mixture. The flask was immediately purged with nitrogen gas and p-toluenesulfonic acid (0.17 g) was added. The reaction mixture was heated to 115° C. and the reaction proceeded for 5 hours. Heat was then removed and the reaction mixture was allowed to cool to 60° C., at which point aqueous NaHCO3 (saturated) was added to achieve a neutral pH. After vigorous stirring, the organic layer was separated and dried over Na2SO4. The dried product was then subjected to a vacuum treatment to remove any residual solvent. A yellow oil was obtained. Analysis by 1H NMR provided the following chemical shifts: (400 MHz, CDCl3) δ 0.90-0.85 (m), 1.10-1.20 (m), 1.21-1.50 (m), 1.55-1.7 (t), 1.77 (o), 2.30 (t), 3.85 (dd), 3.95 (dd). Anaylsis by 13C NMR provided the following chemical shifts: (400 MHz, CDCl3) δ C, 173.947; CH, 32.366; CH2, 69.200, 35.691, 34.438, 29.701, 29.684, 29.641, 29.516, 29.319, 29.220, 25.095, 19.975; CH3, 16.885, 14.258.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.Br[C:16]1[S:17][CH:18]=[C:19]([Br:21])[CH:20]=1>>[Br:21][C:19]1[CH:20]=[C:16]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)[S:17][CH:18]=1
Reactant: Brc1csc(Br)c1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: FC(F)(F)c1ccn2c(-c3cc(Br)cs3)cnc2n1
Yield: 15 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (547 mg, 2.06 mmol) was reacted with 2,4-dibromothiophene over 1 h as described in Example 17. The resulting crude residue was purified by column chromatography on silica, using 40% EtOAc in isohexanes as the eluent, to yield 3-(4-bromothien-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (104 mg, 15%) after recystallisation from dichloromethane/isohexanes: δH (400 MHz, d6-DMSO) 7.57 (1H, d, J 8.3), 7.72 (1H, d, J 1.6), 8.10 (1H, d, J 1.6), 8.34 (1H, s), 9.34 (1H, d, J 7.0); m/z (ES+) 347, 349 (1:1) (M+).
Reaction SMILES: B.CSC.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]([C:31]4(O)[CH2:33][CH2:32]4)=[O:30])[CH2:25][CH2:24]3)=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]([CH:23]3[CH2:28][CH2:27][N:26]([CH:29]([OH:30])[CH:31]4[CH2:33][CH2:32]4)[CH2:25][CH2:24]3)=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1
Reactant: O=C(N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1)C1(O)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OC(C1CC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 16 h
Yield: 23.1 %

Procedure:
Borane-methyl sulfide complex (1.68 mL, 2.0 M solution in THF) was added drop wise to stirred solution of the product of Step 1 (224 mg) in dry THF (5 mL) under nitrogen. After 16 h at room temperature, the solution was cooled, and excess borane was quenched with methanol. The solvent was evaporated to dryness, and the residue was dissolved in THF (5 mL). 2-(Dimethylamino)ethanol (0.67 mL) was added, and the reaction mixture was heated under reflux for 3 h, cooled, and evaporated to dryness. The residue was purified by preparative TLC (CH2Cl2—MeOH, 90:10) to give the title compound (50 mg). NMR (CD3OD): 0.54-0.59 (m, 2H, cyclopropyl),0.75-0.77 (m, 2H, cyclopropyl),1.85, 2.02, 2.32, 2.61 (4 m, 8H, piperidinyl),2.64-2.69 (m, 1H, CH),3.26-3.29 (d, 2H, CH2),6.20 (s, 1H, H-4),7.08-7.11 (m, 2H, H-2 & H-6 of 4-F-phenyl),7.24-7.26 (m, 2H, H-2 & H-6 of pyridinyl),7.33-7.37 (m, 2H, H-3 & H-5 of 4-F-phenyl),8.24-8.26 (m, 2H, H-3 & H-5 of pyridinyl)
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CO>[CH2:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC(C(=O)OC)C(=O)OC
Yield: 78.3 %

Procedure:
350.1 g of 30 percent sodium methylate solution in methanol were diluted with 550 ml of methanol under nitrogen and while stirring. 264.2 g of dimethyl malonate were added dropwise. After warming the suspension to 40° 321.0 g of 1-bromohexane were added dropwise. After stirring at 40° for 1 hour, under reflux for 2 hours, at 65°-69° for 2.5 hours and cooling the suspension to room temperature water was added and the mixture was stirred. The organic phase was separated. The aqueous phase was extracted with methylene chloride, the combined organic extracts were dried and filtered, the filter cake was washed with methylene chloride and the combined filtrates were concentrated. After distillation of the product there were obtained 329.3 g (78.3%) of dimethyl n-hexylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(C)c4)nc23)cc(C)n1
Yield: 45.6 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 46%). MS (ISP) 417.2 [(M+H)+]; mp 254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNc1ccc(Cl)c(C(=O)OC)c1

Procedure:
55.0 g (296 mmol) of methyl 2-chloro-5-aminobenzoate and 49.1 g (356 mmol) of potassium carbonate are suspended in 500 ml of acetonitrile p.a. 22.1 ml (356 mmol) of methyl iodide are added dropwise to the reaction mixture. The suspension is then boiled under reflux for 3 hours. After cooling, the reaction mixture is filtered. The filtrate is diluted with water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is purified by column chromatography. This gives 30.0 g (51%) of methyl 2-chloro-5-(methylamino)benzoate.
Reaction SMILES: [C:1]1(C(=CC=CC=1)O)O.[C:9]([O:12][C:13]1[C:14](=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:15][C:16](=[O:18])[CH3:17])(=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>CC(C)=O>[CH2:9]([O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH2:1]
Reactant: Oc1ccccc1O
Reactant: CC(=O)Oc1ccccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1ccccc1OC(C)=O
Yield: 154.8 %

Procedure:
A mixture of 10.7 g of catechol, 17.3 g of catechol diacetate, 34.5 g of potassium carbonate, 30.3 g of allyl bromide and 200 ml of acetone was refluxed for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography to give 26.5 g (yield 71%) of 2-acetoxyphenyl allyl ether as a pale yellow liquid. Ten grams of this liquid was heated at 220° to 230° C. for 1.5 hours. After cooling, the reaction mixture was purified by column chromatography to give 6.5 g (yield 65%) of 2-acetoxy-6-allylphenol as a pale yellow liquid. Then, 3.0 g of this liquid and 12 ml of an acetic acid solution of 25% hydrobromic acid were reacted at 70° C. for 6 hours. The reaction mixture was poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The concentrate was hydrolyzed with potassium hydroxide and aqueous ethanol, and worked up in a customary manner. The product was then purified by column chromatography to give 0.7 g (yield 31%) of the desired product as a pale yellow liquid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:16][C:15](=[O:17])[NH:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(#N)C>[N:24]1([CH2:12][C@H:13]2[NH:14][C:15](=[O:17])[CH2:16]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CC(=O)N2)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C[C@@H](CN2CCCCC2)N1
Yield: 100 %

Procedure:
A mixture of [(2S)-4-oxoazetidin-2-yl]methyl 4-methylbenzenesulfonate a41 (0.23 g, 0.9 mol, 1 eq), potassium carbonate (0.25 g, 1.8 mmol, 2 eq) and piperidine a14 (0.15 ml, 1.5 mmol, 1.6 eq) is refluxed in acetonitrile (5 ml) for 4 h. The reaction mixture is then concentrated and the residue is taken up in ether, filtered and concentrated to give 0.17 g of (4S)-4-(piperidin-1-ylmethyl)azetidin-2-one a42.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13](C(O)O)[O:12][C:11](=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:30]([O:35][CH3:36])([O:33][CH3:34])OC.C([O-])(O)=O.[Na+]>ClCCl>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:30]([O:33][CH3:34])[O:35][CH3:36])[O:12][C:11](=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxymethyl)-tetrahydropyran-2-one (V′) in 100 mL of dichloromethane, 50 mg of toluenesulfonic acid and 4.5 mL of trimethyl orthoformate are added. After 2 hours of stirring at 25° C., 0.2 g of NaHCO3 is added and dichloromethane is distilled off. The residue is flash chromatographed (MTBE/hexane 1/1) and the solvents are distilled off to get the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1[C:19]([Cl:20])=[C:18]([C:21](Cl)=[O:22])[C:17]([Cl:24])=[N:16]1.CC(C)([O-])C.[K+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:21]([C:18]2[C:17]([Cl:24])=[N:16][N:15]([CH3:14])[C:19]=2[Cl:20])[OH:22])[C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
1.00 g of 4-tert-butylphenylacetonitrile and 1.23 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride were dissolved in 20 ml of THF, and 1.01 g of potassium t-butoxide was added thereto with cooling with ice. After the resulting mixture was stirred overnight at room temperature, water was added thereto, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was dissolved in a mixed solvent of 10 ml of water and 10 ml of dioxane, and 0.38 g of potassium hydroxide was added thereto and heated under reflux for 4 hours. After having been left to be at room temperature, this was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 0.64 g of 2-(4-tert-butylphenyl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile from the fraction eluted with n-hexane:ethyl acetate=2:1.