Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1>CN(C=O)C>[OH:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:8]([C:5]2[C:4](=[O:11])[N:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])=[CH:48][CH:49]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.70 g, 7.35 mmol), HOAT (1.2 g, 8.82 mmol), and EDCI (1.68 g, 8.82 mmol) in DMF (40 mL) was added Et3N (2.6 mL, 18.38 mmol) drop wise. The solution was stirred at rt for 20 minutes, then a solution of 4-aminophenol (994 mg, 9.11 mmol) in DMF (6 mL) was added drop wise to the reaction system. The reaction was heated at 70° C. for 5 hours, then concentrated to 2 mL in vacuo, and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (2.02 g, 85%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([SH:24])[CH3:23].Cl>CN(C)C(=O)C>[CH:22]([S:24][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:23])[CH3:21]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(C)S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) in 6 ml N,N-dimethylacetamide were added 15.2 mol cesium carbonate and 10.1 mmol 2-propanethiol and the mixture was stirred at 90° C. for 3 h. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow liquid which was used in the next step without further purification (yield 99%). EI-MS (m/e): 274.1 (M+, 35%), 232.1 ([M−C3H6]+, 30%, 214.1 (M−C3H6−H2O)+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)=[O:35])[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:35])=[CH:41][CH:40]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (33% yield). LCMS: 542.20 (M+1)+; HPLC: 98.72% (@ 254 nm), (Rt; 5.034); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.96 (bs, 1H), 8.39 (s, 1H), 8.32 (d, 2H, J=8 Hz), 8.20 (s, 1H), 7.56 (d, 2H, J=7.6 Hz), 5.90 (s, 1H), 5.35-5.32 (m, 1H), 4.42 (d, 2H, J=4 Hz), 3.64 (bs, 2H), 3.38 (m, 2H), 2.37 (bs, 2H), 2.28 (bs, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28](Cl)=[O:29]>ClCCl.CN(C)C=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:28]([C:24]2[S:25][CH:26]=[CH:27][C:23]=2[Cl:22])=[O:29])[CH:11]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)c1sccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4-chlorobenzoate (200 mg, 1.1 mmol) and diisopropylethylamine (285 μL, 1.6 mmol) were dissolved in a solution of dichloromethane (4 mL) and dimethylformamide (2 mL). 3-Chlorothiophene-2-carbonyl chloride (235 mg, 1.3 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was re-dissolved in 25 mL of ethyl acetate. The reaction mixture was washed one time each with 10 mL portions of water, 0.1 M NaOH, and saturated aqueous NaCl. The organic layer was dried with MgSO4 and 90 mg of solid was precipitated by the addition of hexanes. The material was used without further purification. MS (EI) for C13H9Cl2NO3S: 330 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:7][C:6]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)c1cc(-c2cccc(C(F)(F)F)c2)nc2c(I)cnn12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.4 %

Procedure:
A mixture of 3-iodo-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (8.23 g, 18.7 mmol), trimethylsilylacetylene (4.67 mL, 33.7 mmol) and triethylamine (5.22 mL, 37.5 mmol) in N,N-dimethylformamide (20 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (132 mg, 1 mol %), PPh3 (49 mg, 1 mol %) and CuI (11 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (8.68 g) as a light brown solid, which was dissolved in THF (42 mL) and MeOH (98 mL), while stirring at 0° C. potassium carbonate (293 mg, 2 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (150 mL) and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4) and evaporated. The crude product was further purified by silica gel column chromatography (heptane/EtOAc 4:1) followed by trituration with heptane to give 7-difluoromethyl-3-ethynyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (4.34 g, 61%) as an orange solid. MS (EI) 337.1 [(M)+]; mp 149° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=O)[NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:35][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NCC(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)s1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
The mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbarnoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.44 mmol) and Lawesson's reagent (1.23 g, 3.0 mmol) in THF (16 ml) was heated at 80° C. for 4 hours. The solvent was removed under reduced pressure and the mixture was diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 2-[5-(4-Bromo-phenyl)-thiazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (655 mg). m/z: 410.7 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([C:45](Cl)=[O:46])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>O1CCCC1>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([C:45]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:46])=[CH:43][CH:44]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(C(C)(C)C)cc3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 25 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. 4-Tert-butylphenylcarbonyl chloride (0.15 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 min. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (31 mg, yield 25%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][C@@:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@:8]([CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:22][CH:21]=1
Reactant: CC(=O)NNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc(C[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(Br)cc3)C(=O)O2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of N′-acetyl-2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetohydrazide (100 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added pyridine (37 mg, 0.46 mmol). The reaction mixture was cooled to −10° C. and triflic anhydride (125 mg, 0.44 mmol) was added. The reaction mixture was stirred at −10° C. for 1 h and at 0° C. for 1 h. The mixture was warmed to rt and quenched by addition of satd aq NaHCO3. The aqueous layer was washed with CH2Cl2 and the combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (56 mg, 58%). 1H NMR (400 MHz, CDCl3): δ=1.51 (d, 3H), 2.32-2.41 (m, 2H), 2.48 (s, 3H), 2.73 (m, 2H), 3.16 (m, 2H), 5.49 (m, 1H), 6.78 (d, 2H), 7.24 (m, 2H), 7.32 (m, 2H), 7.41 (m, 3H).
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](CC)[C:33](=O)[C:34](F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O.N[C@H](C(O)=O)CCCCN>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:34][CH2:33][NH:32][CH:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1)[CH3:31]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 188 mg of keyhole limpet hemocyanin (KLH) in 5.5 ml of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution were added 6 mL of dimethylsulfoxide dropwise, and the reaction temperature was maintained below room temperature. Then a solution of 54 mg (0.10 mmol) of 2L in 1.2 mL of DMF was added to the protein solution dropwise. The mixture was allowed to stir at room temperature 18 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each for at least 6 hours each). The protein concentration was determined to be 2.1 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 34 mL of the conjugate was obtained. The extent of available lysine modification was determined to be 60% by the TNBS method (Habeeb AFSA, Anal. Biochem. 14:328-34, 1988).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[BH4-].[Na+].O>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[OH:16]
Reactant: COC(=O)C1(CCCCl)Oc2ccccc2OCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(CCCCl)Oc2ccccc2OCC1O
Yield: 69.5 %

Procedure:
To a mixture of 2.5 g of methyl 2-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate obtained in Reference Example 4 in 20 ml of methanol, sodium borohydride is added in small portions with stirring and under ice-cooling. After completion of the reaction, the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1→1:1). From the first fraction eluted, 1.75 g of methyl 2-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate (A isomer) is obtained as a colorless oil. Mass spectrum m/e: 300, 302 (M+). IR νmaxneat cm-1 : 3500(OH), 1755, 1735. NMR (CDCl3) δ: 3.21 (4H, multiplet), 3.3 (2H, triplet, ClCH2 --), 3.70 (3H, singlet, OCH3), 4.2 (3H, multiplet).
Reaction SMILES: Cl.C1(C[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)C=CC=CC=1.C(O)C.[H][H]>CO.[Pd]>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:29]=[CH:28][C:27]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)([OH:16])[CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:32][CH:31]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 10.0 grams (0.019 mole) of N-phenylmethyl-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine hydrochloride (prepared as in Steps A and B of Example 12) and 3.0 grams of 5% palladium (catalyst) on charcoal in about 200 mL of 1:1 methanol:ethanol was shaken in a Parr hydrogenator for five to six hours at about 85° C., until the theoretical amount of hydrogen gas was taken up. The mixture was cooled to ambient temperature where it stood for about 18 hours. The mixture was filtered and concentrated under reduced pressure to a residue, which was stirred with ethyl acetate and an aqueous solution saturated with sodium bicarbonate until the residue dissolved. The organic layer was separated and passed through phase-separation paper to remove aqueous material. The organic layer was concentrated under reduced pressure, yielding about 7.0 grams of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[C@H:6]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:9]([F:12])([F:11])[F:10])#[N:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:45]2N=CC=C[C:44]=2N=N1.Cl.C1(N)CC1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)C.C(N(CC)CC)C>[C:1]([C:3]1([NH:4][C:5](=[O:33])[C@H:6]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:7][C@@H:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:9]([F:10])([F:12])[F:11])[CH2:45][CH2:44]1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NCC#N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reaction time: 48 h

Procedure:
To a mixture of N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucine from Example 8 (0.83 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.78 g), cyclopropylamine hydrochloride (0.466 g) in DMF (18 mL) at 0° C. was added triethylamine (0.9 mL). The mixture was kept at room temperature for 48 hours and then poured into dilute aqueous ammonium chloride and diethyl ether. The ether layer was separated and the aqueous further extracted with diethylether. The combined ether extracts were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo. The residue was purified in SiO2 using ethyl acetate and hexanes (1:1) as eluant, followed by a swish in diethyl ether to yield the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1sccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccsc1C(=O)O
Reaction time: 1 h

Procedure:
48.5 g (0.31 mmoles) of 3-hydroxy-2-thiophene carboxylic acid methyl ester (IV: R3 =H) are dissolved in 400 ml of acetone, 84.7 g (0.61 moles) of potassium carbonate, 77.3 g (0.61 moles) of dimethylsulfate are added, and the mixture is refluxed with stirring for 1 hour. The salt mass is aspirated, washed several times with acetone and the combined filtrate is concentrated in vacuo. 750 ml of aqueous 2N sodium hydroxide are added and boiled. The reaction solution is cooled, washed with ether and acidified with concentrated HCl. The precipitating colorless crystals are aspirated and recrystallized from ethanol. Yield: 43.1 g (89%), m.p. 184°-185° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cn1
Yield: 61.6 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (0.5 g) and 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.7 g) in pyridine (3 ml) was heated under reflux for 3.5 hours and evaporated to dryness. The residue was purified by elution from a column of silica gel with ethyl acetate:ethanol:28% w/w aqueous ammonia (by volume 10:15:2) and recrystallisation from acetonitrile to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.58 g) m.p. 128°-129.5°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([C:6]1[CH:11]=C[CH:9]=[CH:8][N:7]=1)[OH:5].C(C1C=NC=C[N:16]=1)(=O)C>>[CH3:1][NH:2][CH2:3][C@H:4]([C:6]1[CH:11]=[N:16][CH:9]=[CH:8][N:7]=1)[OH:5]
Reactant: CC(=O)c1cnccn1
Reactant: CNC[C@@H](O)c1ccccn1
Product: CNC[C@@H](O)c1cnccn1

Procedure:
As described for the preparation of (1R)-2-(methylamino)-1-pyridin-2-ylethanol, 2-acetylpyrazine is converted to the title compound, isolated as a light orange liquid that solidified on standing.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.CN(C)C=O.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>C(Cl)Cl.C(Cl)(Cl)Cl.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:35](=[O:38])[CH2:36][CH3:37])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: CCC(=O)Cl
Reactant: Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 4.5 h

Procedure:
To a mixture of 4-[4-(3-indolyl)piperidinomethyl]-2-aminothiazole (1.5 g), triethylamine (2.68 ml) and N,N-dimethylformamide (15 ml) was added dropwise a solution of propionyl chloride (0.63 ml) in methylene chloride (1.2 ml) over a period of 10 minutes under ice-cooling and the mixture was stirred for 4.5 hours. The reaction mixture was dissolved in a mixture of chloroform and methanol (100 ml, 10:1 V/V) and the solution was washed with water (50 ml×3) and brine (50 ml) successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel and the column was eluted with a mixture of chloroform and methanol (30:1 to 15:1 V/V). The fractions containing the desired compound were combined and concentrated to give a residue, which was recrystallized from ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-propionylaminothiazole (0.72 g).