Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([CH:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]2([Cl:20])Cl)[N:4]=1)#[N:2].[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1.[Cl-:26].[NH4+]>C1COCC1>[C:1]([C:3]1[C:7]([C:21]2([OH:25])[CH2:24][CH2:23][CH2:22]2)=[CH:6][N:5]([C:9]2[C:10]([Cl:20])=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:14]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: [Cl-]
Reactant: O=C1CCC1
Reactant: N#Cc1nn(C2C=CC(C(F)(F)F)=CC2(Cl)Cl)cc1I
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1(O)CCC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-Cyano-1-(2,2-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (500 mg, 1.16 mmol, WO9707102) was dissolved in THF (10 ml) in a dry, nitrogen-flushed flask and cooled to -78° C. n-Butyllithium 0.46 ml, 2.5M in hexanes) was added dropwise over a period of 30 min, keeping the internal temperature at ca. -72° C. The reaction mixture was stirred at -78° C. for 20 min. then cyclobutanone (0.10 ml, 1.28 mmol), dissolved in THF (4 ml), was added dropwise and the mixture was stirred for 1 hr at -78° C. before warming to -20° C. After 2 hr, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into aqueous ammonium chloride (20 ml) and extracted with diethyl ether (2×20 ml). The combined organics were washed (brine), dried (Na2SO4), filtered and the solvents removed in vacuo to leave a yellow oil. This was purified by silica chromatography (eluting with a solvent gradient of DCM to 3% methanol/DCM) to yield 256 mg as a clear gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH3:14])[CH:9]=[N:8]1.C=O.[ClH:18].[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1.Cl.[CH2:30](O)C>C(O)C>[ClH:18].[CH3:12][C:11]1[N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[N:8]=[CH:9][C:10]=1[C:13](=[O:15])[CH2:14][CH2:30][N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Reactant: CCO
Reactant: c1ccc2c(c1)CCNC2
Agent: C=O
Agent: Cl
Product: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1

Procedure:
1.01 g of 1-(2-pyrimidinyl)-4-acetyl-5-methylpyrazole was dissolved in 100 ml of ethanol. After adding 450 mg of paraformaldehyde and 848 mg of 1,2,3,4-tetrahydroisoquinoline hydrochloride, the mixture was heated under reflux overnight. Next, 200 mg of paraformaldehyde was further added to the reaction mixture which was then concentrated by heating under reflux overnight. To the obtained residue was added chloroform. Then it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography and developed with a solvent mixture (chloroform/methanol, 30:1). A fraction containing the terget compound was concentrated. To the residue thus obtained was added a 1N hydrochloric acid/ethanol solution. After concentration, ethanol was added to the residue. After recrystallization, 550 mg of the title compound was obtained.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[CH2:16]1)=O)(C)(C)C>[OH-].[Na+]>[Cl:27][C:22]1[CH:21]=[C:20]([CH:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Clc1cc(Cl)cc(C2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Synthesized according to General Procedure 4. A solution of HCl in 1,4-dioxane (4M, 32.5 mL, 0.130 mol) was added to tert-butyl-3-(3,5-dichlorophenyl)pyrrolidine-1-carboxylate (18.3 g, 0.058 mol) and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was slowly poured into aqueous 2 M NaOH solution (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were then dried over Na2SO4 and concentrated under reduced pressure to provide crude 3-(3,5-dichlorophenyl)pyrrolidine (12.48 g, 0.058 mol, 100% yield)) as a brown oil. The crude material was dissolved in MeOH (39 mL) and treated with oxalic acid (5.2 g, 0.058 mol) in one portion. The resulting solution was allowed to stand at RT for 30 minutes, the precipitated solid was filtered off, washed with diethyl ether (2×50 mL) and then dried under vacuum to constant weight to provide 3-(3,5-dichlorophenyl)pyrrolidine oxalate as an off-white solid (12.4 g, 0.041 mol, 70% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.52 (t, J=1.8 Hz, 1H), 7.47 (d, J=1.7 Hz, 2H), 3.62 (dd, J=8.2, 11.0 Hz, 1H), 3.53-3.30 (m, 2H), 3.25-3.08 (m, 2H), 2.40-2.33 (m, 1H) and 2.00-1.90 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=216.3; tR=1.00 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(C(F)(F)F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(3-trifluoromethyl-phenyl)thiazole-4-carboxylic acid.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH:69][C:70](=[O:75])[C:71]([F:74])([F:73])[F:72])[CH2:68][CH2:67][CH2:66]2)=[CH:61][C:60]=1[O:76][CH3:77]>>[F:72][C:71]([F:73])([F:74])[C:70]([NH:69][C:65]1([C:62]2[CH:63]=[CH:64][C:59]([NH:58][C:2]3[N:7]=[CH:6][C:5]4=[CH:8][CH:9]=[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:22])[N:4]4[N:3]=3)=[C:60]([O:76][CH3:77])[CH:61]=2)[CH2:66][CH2:67][CH2:68]1)=[O:75]
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Reactant: COc1cc(C2(NC(=O)C(F)(F)F)CCC2)ccc1N
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C2(NC(=O)C(F)(F)F)CCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Into a 8-dram vial, N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (176 mg, 0.552 mmol), N,N-Dimethylformamide (2.00 mL, 25.8 mmol), N,N-Diisopropylethylamine (0.211 mL, 1.21 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.236 g, 0.662 mmol) were added. The reaction was stirred at room temperature for 30 minutes. N-[1-(4-Amino-3-methoxy-phenyl)-cyclobutyl]-2,2,2-trifluoro-acetamide (0.350 g, 1.21 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2,2,2-Trifluoro-N-[1-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-cyclobutyl]-acetamide as a yellow solid (180 mg, 55%). LCMS (E/I+) 589.23 (M+H). NMR 1H (DMSO-d6)-9.98 (s, 1H), 8.96 (s, 1H), 7.93-8.00 (m, 1H), 7.90 (d, 1H, J=8.35 Hz), 7.77 (s, 1H), 7.60-7.68 (m, 1H), 7.48-7.56 (m, 2H), 7.04 (s, 1H), 7.02 (d, 1H, J=4.74 Hz), 6.95 (d, 1H, J=4.74 Hz), 6.87 (d, 1H, J=8.51 Hz), 3.84 (s, 3H), 3.03 (s, 3H), 2.09 (s, 3H), 2.54 (t, 4H, J=7.44 Hz), 1.70-2.00 (m, 2H).
Reaction SMILES: Br.[C:2]([S:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[NH:4])[NH2:3].[C:16]([O-])(=O)[CH3:17].[NH4+].C([N:23]=[C:24]=[O:25])C.O>CN(C=O)C>[CH2:16]([N:13]([CH2:10][CH3:11])[C:24]([NH2:23])=[O:25])[CH3:17].[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:5][C:2](=[NH:3])[NH2:4])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CCN=C=O
Reactant: CC(=O)[O-]
Agent: Br
Agent: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-nitrobenzyl carbamimidothioate hydrobromide (2.5 g, 8.55 mmol) in DMF (10 mL) was added aqueous buffer solution of ammonium acetate (pH ˜7, 4.0 mL) followed by addition of ethyl isocyanate (10 mL. 85.57 mmol) at rt and the mixture stirred at rt for 48 h. After completion of reaction (by TLC), water (10 mL) was added and a white precipitate formed. The reaction mixture was filtered and solid was washed with water to obtain the desired product as white solid (1.40 g, 41%). MS: 354.18 [M+H]+
Reaction SMILES: CO[C:3](=[O:37])[CH:4]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12]C1C=CC=CC=1)=[O:10].O.[NH2:39][NH2:40]>CN(C)C=O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH:4]([C:3]([NH:39][NH2:40])=[O:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:30])[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:10])[C:20]1[CH:29]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: COC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 967.8 %

Procedure:
A mixed solution of 1.0 g (194 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine methyl ester and 0.64 g (0.2 mmole) of 80% hydrazine hydrate in 10 ml of dimethylformamide was stirred for 2 hours at room temperature and then left standing overnight at room temperature. Dimethylformamide was removed by evaporation under reduced pressure. Water was added to the residue, and the mixture was stirred to form a powdery precipitate, which was collected by filtration, washed with a mixture of diethyl ether and hexane and dried to yield 1.0 g (100%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine hydrazide melting at 163°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][CH:19]1[CH2:23][CH2:22][CH:21]([CH3:24])[NH:20]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][N:20]1[CH:21]([CH3:24])[CH2:22][CH2:23][CH:19]1[CH3:18]
Reactant: Fc1cc(Br)c(CCl)cc1F
Reactant: CC1CCC(C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1CCC(C)N1Cc1cc(F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 152 μl of 2,5-dimethylpyrrolidine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: [CH:1](/[S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])=[CH:2]\[C:3]#[CH:4].[NH2:20][OH:21]>C1COCC1>[OH:21][NH:20][CH:2]([C:3]#[CH:4])[CH2:1][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: NO
Reactant: C#C/C=C/S(=O)(=O)N1CCN(c2ccccn2)CC1
Solvent: C1CCOC1
Product: C#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)NO
Temperature: 60 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a solution of 1-[(1E)-1-buten-3-ynylsulfonyl]-4-(2-pyridinyl)piperazine (30 mg; 0.11 mmol; 1.00 eq.) in THF (3 mL) was added an aq. solution of hydroxylamine (50%, 0.10 mL; 1.62 mmol; 15.0 eq.) and the resulting reaction mixture was stirred at 60° C. for 4 h. Evaporation of the solvents (rotavap gave an oil). Purification on silicagel (50/50 up to 70/30 AcOEt-c-Hex) a colorless oil (15 mg, 44% yield). LC/MS, M+ (ESI): 311.1, M−(ESI): 311.1, M− (ESI): 309.0.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]#[N:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:2][CH2:3][C:4]#[N:5])=[CH:9][CH:8]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: N#CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCSc1ccc(Cl)cc1

Procedure:
10 ml of β-chloropropionitrile (0.13 mol) are added, whilst stirring at 70°-80° C, to a solution of 17.4 g (0.12 mol) of p-chlorothiophenol and 4.8 g of sodium hydroxide pellets in 50 ml of water. The mixture is kept at 80° C for half an hour. After cooling, it is extracted with ether and the extract is washed with water and dried. 22.5 g of 3-(p-chlorophenylthio)-propionitrile. Melting point = 53-54° C.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+].Cl>CO.ClCCl.C(OCC)C>[ClH:1].[CH3:17][O:16][C:14](=[O:15])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH3:28])=[CH:22][CH:21]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-phenylmorpholine hydrochloride (6.05 g), 1-(4-carbomethoxymethoxyphenyl)propan-2-one (6.63 g) and sodium cyanoborohydride (1.61 g) in methanol (100 ml) was stirred at room temperature for 22 hours. The solvent was removed under reduced pressure and aqueous sodium bicarbonate solution added to the residue and extracted with dichloromethane (×2). The extracts were washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness to give an oil. Chromatography on silica gel in 0→7% methanol in dichloromethane gave an oil which was dissolved in diethyl ether and treated with an ethereal solution of hydrogen chloride. Evaporation to dryness and trituration of the residue with ethyl acetate gave a solid. Recrystallisation of this solid gave the title compound, m.p. 187°-190° C. (methanol-ethyl acetate), of analytical purity.
Reaction SMILES: [Cl:1][C:2](=[N:7][OH:8])[C:3]([Cl:6])=[N:4][OH:5].[C:9](Cl)(=[O:11])[CH3:10].C(N(CC)CC)C>ClC(Cl)C>[C:9]([OH:11])(=[O:5])[CH3:10].[C:9]([OH:11])(=[O:5])[CH3:10].[Cl:1][C:2](=[N:7][OH:8])[C:3]([Cl:6])=[N:4][OH:5]
Reactant: CC(=O)Cl
Agent: ON=C(Cl)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)O

Procedure:
The mixture of 2.0 g (0.0127 mol) of dichloroglyoxime (Compound No.6), 20 ml of dichloroethane and 2.4 g (0.0306 mol) of acetyl chloride was stirred in an ice bath. To the mixture, triethylamine (3.1 g, 0.0307 mol) was added dropwise, followed by stirring for 30 minutes. The reaction mixture was washed twice with 15 ml of water. The dichloroethane solution was concentrated under reduced pressure, to obtain white crystals of dichloroglyoxime diacetate (Compound No.2, yield: 30%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])[CH2:37][OH:38])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44](C)[CH2:45]O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]5[CH2:39][CH2:45][CH2:44][C@H:37]5[OH:38])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: C[C@@H](N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H]5CCC[C@H]5O)c4)cc23)CC1
Yield: 21.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (1R,2R)-2-aminocyclopentanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 9.6 mg of the title compound (21.8%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1CC#N.[OH-:13].[K+].[CH2:15]([OH:18])[CH2:16]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:16][C:15]([OH:18])=[O:13]
Reactant: OCCO
Reactant: COc1cccc(Cl)c1CC#N
Reactant: [OH-]
Agent: [K+]
Product: COc1cccc(Cl)c1CC(=O)O

Procedure:
325 g of 2-chloro-6-methoxyphenylacetonitrile are reacted with 171 g of potassium hydroxide in 690 ml of ethylene glycol. 331 g of solid are obtained (m.p. 164-165° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](OC)=[O:27])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Lithium aluminium hydride (0.026 g, 0.7 mmol) was suspended in dry THF (1 mL) under a nitrogen atmosphere and cooled in an ice bath. A solution of 4-(2-methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 0.7 mmol) in dry THF (2 mL) was added drop wise and the reaction mixture stirred for 1 hour. The reaction mixture was diluted with diethyl ether (5 mL) and quenched with hydrochloric acid (1 N, 5 mL). The organic solution was separated and washed with saturated aqueous sodium hydrogen carbonate (5 mL) and brine (5 mL), dried over magnesium sulphate, filtered and the solvent removed under vacuum to give the title compound as a colourless gum (0.13 g). LCMS m/z 292.0 [M+H]+. R.T.=4.57 min (Analytical Method 4).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]=2[CH:20]=1)[CH3:3].[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.[OH-].[Na+].[Cl:51]CCl>>[ClH:51].[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:18][CH2:19]3)[C:9]=2[CH:20]=1)[CH3:1]
Reactant: ClCCl
Reactant: O=C1CCOCC1
Reactant: CC(C)Oc1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of 6-[(1-methylethyl)oxy]-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D50, 229 mg, 0.89 mmol) in dichloromethane (10 ml) was treated with tetrahydro-4H-pyran-4-one (623 mg, 6.23 mmol), sodium triacetoxyborohydride (1.3 g, 6.23 mmol) and triethylamine (270 mg, 3.67 mmol) and stirred at room temperature for 2 hrs. The mixture was diluted with dichloromethane, then aqueous NaOH solution (pH12) was added and the organic layer separated. The NaOH solution was extracted with dichloromethane (×2) and the combined dichloromethane extracts was washed with aqu, NaOH solution, dried (MgSO4) and concentrated under vacuum to leave a pale orange oil, which was purified by chromatography on silica gel eluting with 0-50% of 10% methanol/dichloromethane: dichloromethane to afford the title compound as a pale orange solid (101 mg, 33%). M++H=360.2 which was converted to its HCl salt.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(OC(=O)c1ccccc1)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 92 %

Procedure:
2.5 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate were refluxed with 1.2 min. of benzoyl chloride in 60 ml of methylene chloride in the presence of 1.3 ml of triethylamine for 1(1/2) hours. The product was diluted with methylene chloride washed with water, 1M HCl and brine and dried over MgSO4. The product was purified by silica gel chromatography (total yield 92%) and was identified as a mixture of two stereoisomers of the above ethyl benzoyloxypentanoate.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:30][CH2:31][C:32]2[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=2)=[CH:4][C:5]2[N:6]([CH:29]=1)[C:7](=[O:28])[C:8](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13](C=O)[CH2:12]1)[N:10]=2.C[O-:41].[Na+].O>CO>[F:1][C:2]1[C:3]([CH2:30][CH2:31][C:32]2[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=2)=[CH:4][C:5]2[N:6]([CH:29]=1)[C:7](=[O:28])[C:8](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:41])[CH2:12]1)[N:10]=2
Reactant: CC(C)c1csc(CCc2cc3nc(N4CCCC(C=O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)c1csc(CCc2cc3nc(N4CCCC(O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 65.4 %

Procedure:
The tert-butyl (E)-3-{7-fluoro-2-(3-formylpiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (147 mg, 0.258 mmol) obtained in (L) was dissolved in methanol (3ml), added with sodium methoxide (33.6 mg, 0.618 mmol), and then stirred at room temperature for 9 hours. The reaction mixture was added with distilled water and extracted with chloroform (twice). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by preparative TLC (chloroform:methanol=100:5) to obtain the title compound (91.6 mg, 65%).