Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][NH:30][CH2:31][CH2:32][CH3:33]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([N:30]([CH3:29])[CH2:31][CH2:32][CH3:33])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CCCNC
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 25° C., 6.83 g (0.02 mole) 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 4.1 g (0.03 mole) K2CO3, 3.1 mL (0.03 mole) N-methyl-N-propylamine and a catalytic amount of CuF2 were slurried in 50 mL 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 35° C. for 2 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was purified chromatographically using 15% ethyl acetate in hexane as the eluent to give 6.8 g (86%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-2-nitro-N-propylbenzeneamine as an orange oil, nD25 1.5534.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2>C(O)C>[C:1]1([S:7][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCC2OC2C1
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thiophenol (2.14 g, 0.0194 mole) was added to freshly prepared sodium ethoxide (sodium, 0.45 g) in ethanol (30 ml). After several minutes, cyclohexene oxide was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated with a gentle flow of nitrogen gas. The residue was dissolved in diethyl ether (75 ml) and washed with in hydrochloric acid (19 ml). The diethyl ether was washed three times with 50 ml of 5% sodium carbonate, once with 0.5N hydrochloric acid (50 ml) and once with brine (25 ml), dried over anhydrous magnesium sulphate, filtered and concentrated with a rotary evaporator to give the product as an oil. The structure was supported by NMR and infrared spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH3:17])[C:9](=[O:16])[C:10]3[C:15]([C:6]=2[CH:5]=[C:4]([Cl:18])[C:3]=1[O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=[N:12][CH:11]=3.Cl>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:3]1[C:4]([Cl:18])=[CH:5][C:6]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[N:8]([CH3:17])[C:7]=2[C:2]=1[Cl:1]
Reactant: CC(C)C[C@@H](COc1c(Cl)cc2c3ccncc3c(=O)n(C)c2c1Cl)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](N)COc1c(Cl)cc2c3ccncc3c(=O)n(C)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a solution of (S)-tert-butyl (1-((7,9-dichloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.120 g, 0.243 mmol) in anhydrous methanol (5 mL) was added a 4M solution of HCl in 1,4-1,4-dioxane (2 mL, 8 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (10 mM ammonium acetate in water; acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-7,9-dichloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (28 mg, 0.063 mmol, 26% yield) as a yellow solid. LC/MS (ESI) m/e 394.2 [(M+H)+, calcd for C19H22Cl2N3O2 394.1]; LC/MS retention time (method A): tR=1.48 min; HPLC retention time (method A): tR=5.21 min; HPLC retention time (method B): tR=5.73 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.50 (d, J=0.75 Hz, 1H), 8.87 (d, J=5.52 Hz, 1H), 8.58 (s, 1H), 8.32 (d, J=5.27 Hz, 1H), 4.17 (dd, J=9.03, 4.02 Hz, 1H), 4.05 (dd, J=9.03, 7.28 Hz, 1H), 3.93 (s, 3H), 3.37-3.43 (m, 1H), 1.82-1.93 (m, 1H), 1.38-1.57 (m, 2H), 0.99-1.05 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:11][CH2:10][C:9]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:8]1=2)C.[C:25]([OH:30])([C:27]([OH:29])=[O:28])=[O:26].O=C(C(=O)O)O>O>[C:27]([OH:29])(=[O:28])[C:25]([OH:30])=[O:26].[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2([CH2:6][CH2:5][CH2:4][NH:2][CH3:1])[C:8]3[C:9](=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=3)[CH2:10][O:11]2)=[CH:23][CH:22]=1
Reactant: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: O=C(O)C(=O)O
Solvent: O
Product: CNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21

Procedure:
A solution of 1-[3-(N-methyl-ammonium)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-carbonitrile (0.70 g, 2.24 mmol) and formaldehyde (0.5 mL, 6.7 mmol, 37% aqueous solution) in 98% formic acid (5 mL) was refluxed for 4 h. After cooling, 4 M HCI (2 mL) was added and the resulting mixture was evaporated. 1 M NaOH (50 mL) was added to the residue and extracted with Et2O (3×100 mL). The organic extract was washed with brine, dried and evaporated. The oxalate salt was isolated from acetone (0.22 g, 30%). DSC (open chamber), Tonset=157.73, Tpeak=160.80. The NMR-spectra were identical with those obtained from citalopram oxalate prepared in example 2. Anal. (C20H21N2O, C2H2O4, ¼ H2O) calcd. C: 63.06; H: 5.67; N: 6.69. Found C: 63.24; H: 5.65; N: 6.62.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]([OH:9])[CH2:7][CH3:8])C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:18]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]([CH:6]([OH:9])[CH2:7][CH3:8])[C:4]([OH:25])=[O:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C(O)CC)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To 17.7 g (51.9 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester in 245 ml tetrahydrofurane were added 8.80 g (208 mmol) lithium hydroxide monohydrate dissolved in 44 ml water. The mixture was stirred at 60° C. for 2.5 days and the organic solvent was removed by distillation. Water was added followed by extraction with diethylether. The waterphase was adjusted to pH 1. Extraction with ethylacetate yielded 14.8 g (91%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid, MS m/e (%): 314.1 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[F:13][C:2]([F:1])([F:12])[C:3]1[N:4]([CH2:15][C:16](=[O:18])[CH3:17])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)CCl
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cn1c(C(F)(F)F)nc2ccccc21

Procedure:
4 g of 2-trifluoromethylbenzimidazole, 2.8 g of chloroacetone, 3.4 g of potassium carbonate and 0.32 g of potassium iodide are dissolved in 50 ml of acetone and boiled under reflux for 4 h. After cooling, the precipitate is filtered off, washed with acetone and dried in a vacuum. 1-(2-trifluoromethylbenzimidazol-1-yl)-propanone is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]1([CH2:32][CH:33]2[CH:38]([NH2:39])[CH:37]3[CH2:40][CH2:41][N:34]2[CH2:35][CH2:36]3)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:39][CH:38]1[CH:37]2[CH2:36][CH2:35][N:34]([CH2:41][CH2:40]2)[CH:33]1[CH2:32][N:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:9]
Reactant: NC1C2CCN(CC2)C1CN1CCCC1
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)NC2C3CCN(CC3)C2CN2CCCC2)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 62.9 %

Procedure:
a suspension of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (3.13 g, 14.5 mmoles) in anhydrous tetrahydrofuran (20 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (2.44 g, 15 mmoles), stirred for 90 minutes, cooled (0° C.), and treated with 2-(1-pyrrolidinylmethyl)-1-azabicyclo[2.2.2]octane-3-amine (3.14 g, 15.0 mmoles) in anhydrous tetrahydrofuran (10 ml). After 24 hours at room temperature and one hour at 60° C., the solution was concentrated in vacuo and partitioned between methylene chloride (100 ml) and 1.0N aqueous sodium carbonate (50 ml). The organic layer was separated and the aqueous solution was extracted with methylene chloride (40 ml). The combined organic solution was washed with brine (50 ml), dried (Na2SO4), concentrated in vacuo, dissolved in tetrahydrofuran, and filtered. The filtrate was passed through alumina (eluted with 15% methanol/ethyl acetate), and concentrated in vacuo to provide 3.71 g (63%) of a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl-].[Ca+2].[Cl-].C(O)C>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1ccc2ncc(CSc3ccc([N+](=O)[O-])cc3)n2c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc2ncc(CSc3ccc(N)cc3)n2c1
Yield: 88.2 %

Procedure:
A mixture of 6-methyl-3-[[(4-nitrophenyl)thio]methyl]imidazo[1,2-a]pyridine (3.0 g), reduced iron (2.80 g) and calcium chloride (0.56 g) in 15% water-containing ethanol (150 ml) was heated to reflux for 20 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give 4-[[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]thio]aniline (2.38 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.OS(O)(=O)=O.[C:16]([O-])(O)=O.[Na+].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:16])=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)s1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(OC)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a 200 mL round-bottomed flask fitted with a condenser was added 5-(methyloxy)-2-thiophenecarboxylic acid (1.3 g, 8.22 mmol) in Methanol (40 mL). H2SO4 (5 mL, 94 mmol) was added slowly at room temperature and the reaction stirred at 50° C. overnight. The mixture was cooled to 0° C. and sat. NaHCO3 was added to neutral pH followed by 5N NaOH to pH 10. The mixture was partitioned between H2O/CHCl3 and the organic phase was separated and dried over Na2SO4. The solution was adsorbed onto silica and purified via column chromatography (5-50% EtOAc/Hexanes) affording the title compound (827 mg, 4.56 mmol, 56%): LC-MS (ES) m/z=173 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([CH3:22])=[CH:19][C:20]=1[OH:21])#[N:15]>CC(C)=O>[C:14]([C:16]1[S:17][C:18]([CH3:22])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: Cc1cc(O)c(C#N)s1
Reactant: COP(=S)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COP(=S)(OC)Oc1cc(C)sc1C#N
Temperature: 20 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
11.2 g of potassium carbonate and 12.8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 11.2 g of 2-cyano-3-hydroxy-5-methyl-thiophene in 200 ml of acetone and the mixture was stirred for 15 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 18.7 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-methyl-thiophene with a refractive index of nD20 =1.539.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH2:8]([O:15][C:16](=[O:30])[CH2:17][C@H:18]([C:27](O)=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC)=O.Cl.CNC>ClCCl>[CH2:8]([O:15][C:16](=[O:30])[CH2:17][C@@H:18]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27]([N:3]([CH3:4])[CH3:1])=[O:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Triethylamine (2.8 mL, 20.0 mmol) was added at 0° C. to a solution of Boc-D-aspartic acid 4-benzyl ester (5.00 g, 15.0 mmol) in dichloromethane, then ethyl chloroformate (1.91 mL, 20.0 mmol) was added dropwise. The reaction mixture was stirred for 1 h at 0° C., then a solution of dimethylamine hydrochloride (2.65 g, 32.0 mmol) and triethylamine (4.53 mL, 32.0 mmol) in dichloromethane (100 mL) were added dropwise. The reaction mixture was allowed to reach room temperature over 16 h, then washed with brine, and concentrated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced (R)-3-tert-butoxycarbonylamino-N,N-dimethyl-succinamic acid benzyl ester (3.77 g, 70%). Colorless oil, m/e=351.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:23]([O:22][CH:21]([O:25][CH2:26][CH3:27])[CH2:20][N:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[N:9]1)[CH3:24]
Reactant: Fc1ccc(-c2cc[nH]n2)nc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cn1ccc(-c2ccc(F)cn2)n1)OCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-fluoro-2-(1H-pyrazol-3-yl)pyridine obtained in Reference Example 10 (11.7 g, 58.6 mmol) in DMF (195 mL), Cs2CO3 (57.3 g, 0.18 mol) and 2-bromo-1,1-diethoxyethane (11.5 mL, 76.2 mmol) were stirred for 18 hours at 80° C. The reaction mixture was allowed to cool to room temperature, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane/EtOAc=88/12 to 35/65) to obtain the title compound (8.2 g) (colorless oil).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 690.2 (M+H)+.
Reaction SMILES: ClC[CH2:3][O:4][CH2:5][CH3:6].[CH2:7]([OH:11])[CH2:8][CH2:9][OH:10].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:5]([O:4][CH2:3][O:10][CH2:9][CH2:8][CH2:7][OH:11])[CH3:6]
Reactant: CCOCCCl
Reactant: OCCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A solution of chloroethylethyl ether (50 mmol) in dry tetrahydrofuran (10 ml) was added dropwise at 0°-5° C. to a stirred solution of 1,3-propanediol (150 mmol) in dry tetrahydrofuran (100 ml) and N,N-diisopropylethylamine (75 mmol). The mixture was stirred for 2 hours at room temperature, the solvent was evaporated in vacuo and the residue was purified by column chromatography on silica, eluting with dichloromethane:methanol (98:2) to give the title compound as a colourless oil (5.6 g, 83%); νmax (Film) 3420, 2980, 2940, 2880, 1480, 1445, 1390 and 1180 cm-1 ; δH (CDCl3) 1.20 (3H, t, J=6.5 Hz, CH3CH2), 1.8 (2H, m, CH2CH2CH2), 3.2 (1H, s, OH), 3.6 (6H, m, CH2OH, CH2O and CH3CH2), 4.8 (2H, s, OCH 2 O).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C>O>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[C:18]3[S:12][C:13](=[S:14])[NH:15][C:16]3=[O:17])=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C1CSC(=S)N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Twenty grams (133.2 mmol) of piperonal were reacted with 17.74 g (133.2 mmol)of rhodanine in 38.24 g (466.2 mmol) of glacial acetic acid at reflux for about 3 hours. The mixture was then poured into water and stirred overnight. A precipitate formed which was recovered by filtration and then air dried overnight to provide 27.8 g of title product. m.p. 194°-195° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Yield: 15 %

Procedure:
A solution of 2-chloro-5-trifluoromethyl-pyridine (2.45 g, 13.50 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 16.19 mmol, 1.2 equiv; commercially available) in DMAc (12 mL) was heated by microwave irradiation to 155° C. for 6 h. A solution of 1 M NaOH (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) to yield 0.69 g (15%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.31-1.47 (m, 2H), 1.40 (s, 9H), 1.92-1.98 (m, 2H), 2.81-2.92 (m, 2H), 3.72-3.83 (m, 1H), 3.97-4.03 (m, 2H), 4.77 (d, J=8.1 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 8.25 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ27.45, 31.17, 41.64, 47.51, 78.72, 105.86, 114.65 (q, J=32.8 Hz), 123.58 (q, J=268.6 Hz), 133.26, 145.15, 153.76, 158.36. 19F NMR (282 MHz, CDCl3): 1-61.22. MS (ISP): 346.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:16]([F:27])[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[CH:9]=1)=[O:7].[C:28]([NH:35][C@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>O.CC(N(C)C)=O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[C:8]([C:6]([NH:5][O:4][CH2:3][CH2:2][O:1][C:40](=[O:41])[CH:36]([NH:35][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:37]([CH3:39])[CH3:38])=[O:7])=[CH:9][C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]=2[F:27])=[C:20]([Cl:26])[CH:21]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
Dimethylacetamide (30 mL) was added to a mixture of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide (3 g, 6.555 mmol), BOC-L-valine (1.710 g, 7.866 mmol), HOBT·H2O (1.004 g, 6.555 mmol) and, TEA (0.929 g, 9.177 mmol) in a 500 mL RBF with a magnetic stirrer and nitrogen line. After 5 minutes, EDCl (1.759 g, 9.177 mmol) was added to the brown solution in the 500 mL RBF. The mixture was stirred overnight at room temperature. The reaction mixture was added slowly to 210 mL of deionozied water with mechanical stirring. The white slurry was stirred for 1 hour, filtered through a medium fritted funnel. The cake was washed with about 100 mL of water and pulled air through the cake for 10-15 minutes. Tert-butyl methyl ether (70 mL) was added to the cake and stirred with a spatula. The vacuum filtration was continued. The solids were dried under vacuum at 50° C. to give 2 g of the product containing about 80% of the undesired isomer. The t-butyl methyl ether layer was concentrated to a foam (2.18 g) enriched in the desired product comprising a mixture of isomers.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=O)C.[CH3:26][NH2:27]>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:3])[N:27]([CH3:26])[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reactant: CN
Product: COC(=O)C1CN(C)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that it was prepared from the compound of Example 3 and methylamine, and recrystallized with ethylacetate/hexane to obtain a white solid (yield 73%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(C#Cc4ccccc4)cc23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(-c2n[nH]c3ccc(C#Cc4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-phenylethynyl)-1-(tetrahydropyran-2-yl)-1H-indazole in tetrahydrofuran (15 mL) was added 6 N hydrochloride solution (10 mL) and the mixture was stirred at ambient temperature overnight. After tetrahydrofuran was evaporated, the aqueous phase was neutralized with 5% sodium carbonate and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.071 g, 90% yield). 1H NMR (CDCl3) δ 10.19 (br, 1H), 8.20 (s, 1H), 7.94–7.98 (m, 2H), 7.55–7.61 (m, 3H), 7.48 (dd, 1H), 7.34–7.41 (m, 3H), 7.23 (t, 2H); ES-MS (m/z) 313 [M+1]+.