Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[CH3:19])=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[CH3:19])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(-c2cccnc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ncccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (2 g; 8.73 mmol; 1 eq.), 2-methoxypyridin-3-ylboronic acid (1.47 g; 9.60 mmol; 1.10 eq.), K2CO3 (6.03 g; 43.65 mmol; 5 eq.), Pd(PPh3)4 (1.01 g; 0.87 mmol; 0.10 eq.) were taken up in toluene (10 mL) and water (10 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 and refluxed for 24 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (100 mL). The filtrate was concentrated to afford a yellow oil which was taken in EtOAc (100 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution, water and brine, dried over MgSO4 and concentrated affording methyl 4-(2-methoxypyridin-3-yl)-3-methyl benzoate as a yellow oil (2.4 g, HPLC (Method A) Rt 4.02 min). A solution of methyl 4-(2-methoxypyridin-3-yl)-3-methylbenzoate (2.50 g; 9.72 mmol; 1 eq.) in EtOH (75 mL) at RT was treated with sodium hydroxide (5.83 mL; 5 M; 29.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid, which was taken up in water (50 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated (volume divided by 3) and the suspension was filtered affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.96 (br s, 1H), 8.28-8.26 (dd, J=5.07 Hz, 1.86 Hz, 1H), 7.89 (m, 1H), 7.84-7.82 (dd, J=7.94 Hz, 1.52 Hz, 1H), 7.64-7.62 (dd, J=7.26 Hz, 1.86 Hz, 1H), 7.31-7.29 (d, J=7.94 Hz, 1H), 7.16-7.12 (m, 1H), 3.90 (s, 3H), 2.15 (s, 3H). LC/MS (Method A): 241.9 (M−H)−. HPLC (Method A) Rt 3.19 min (Purity: 99.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][CH2:23][O:24][CH3:25]>O1CCCC1.CCOCC>[CH3:25][O:24][CH2:23][CH2:22][C:4]1([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:6][CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3]1
Reactant: COCCBr
Reactant: COC(=O)C1CCCC(C)(C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCC1(C(=O)OC)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 146B (0.60 g) in tetrahydrofuran (5 mL) was added to lithium diisopropylamide (2.0 M, 2.10 mL) at −78° C. After stirring for 30 minutes, 1-bromo-2-methoxyethane (0.64 g) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ether (75 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 1-20% ethyl acetate in hexanes provided the title compound.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[C:11](/[CH2:35][CH3:36])=[C:12](\[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=1)/[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.Cl>O.CCO>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[C:11](/[CH2:35][CH3:36])=[C:12](\[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=1)/[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Cl)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of LiOH (0.23 g, 9.6 mmol) in water (3.2 mL) was added to a solution of (E)-ethyl 3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (2.37 g, 4.8 mmol; Compound 196) in EtOH (20 mL) at room temperature. The resulting mixture was stirred overnight. Upon completion, 1N aqueous HCl was added until the pH was 3. The mixture was diluted with water and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified on a preparative reversed-phased HPLC column using 80-95% acetonitrile in water in the presence of 0.1% TFA to give the title compound (1.3 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.36 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.57-7.53 (m, 2H), 7.44-7.35 (m, 5H), 7.19 (dd, 1H), 6.97 (d, 2H), 6.39 (d, 1H), 2.39 (q, 2H), 0.90 (t, 3H); LCMS: 463 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:29]4[N:28]=[CH:27][N:26](COCC[Si](C)(C)C)[C:25]=4[CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:29]4[N:28]=[CH:27][NH:26][C:25]=4[CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(S(=O)(=O)c3ccc4cc(-c5ccc(F)cc5)ccc4c3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1cccc2[nH]cnc12
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a stirring solution of 4-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (260 mg, 0.49 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (0.60 mL of 1 M solution in THF; 0.6 mmol), and the resulting mixture was heated at reflux for 5 hours. The mixture was allowed to cool to room temperature, then was diluted with water (100 mL) and washed with ethyl acetate (2×50 mL), The combined organic layers were washed with water, then with saturated sodium chloride solution, were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting first with 1:1 ethyl acetate:isohexane, then with 100% ethyl acetate. The resulting material was purified further by flash chromatography on silica gel, eluting with 50% to 70% ethyl acetate in isohexane, and the resulting material was triturated using a 1:1 mixture of diethyl ether and isohexane, to afford the product as a white amorphous solid (85 mg, 43%). 1H NMR (500 MHz, d6-DMSO): δ 12.96 (1H, s), 8.89 (1H, s), 8.38 (1H, s), 8.30 (1H, s), 8.26 (1H, d, J=8.6 Hz), 8.14-8.08 (2H, m), 8.00 (1H, d, J=8.6 Hz), 7.95 (2H, t, J=6.8 Hz), 7.88 (2H, dd, J=5.4, 8.7 Hz), 7.45 (1H, t, J=7.9 Hz), 7.36 (2H, t, J=8.8 Hz); m/z (ES+) 403 [MH+].
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29]C(=O)C)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH2:29])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(=O)(=O)Nc2ccccc2NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(=O)(=O)Nc2ccccc2N)cc1
Temperature: 25 °C

Procedure:
The mixture of 2 g of 4-(4-acetamidophenylamino)-3-benzylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid and 20 ml of 2 N aqueous sodium hydroxide is refluxed for 6 hours under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5 and the precipitate formed filtered off. It is washed with water, taken up in 50 ml of 505 hot aqueous ethanol, the precipitate formed after cooling is filtered off and again recrystallized from 25 ml of 50% aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-benzylamino-5-(2-aminophenylsulfamoyl)-benzoic acid of the formula ##SPC11##
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1.[F:42][C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:49]=[C:50]([NH2:54])[CH:51]=[CH:52][CH:53]=2)=[CH:45][CH:44]=1>C(OCC)(=O)C.CN(C)C=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:54][C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([O:47][C:46]3[CH:55]=[CH:56][C:43]([F:42])=[CH:44][CH:45]=3)[CH:49]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1cccc(Oc2ccc(F)cc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a mixture of N-Boc piperidine-4-carboxylic acid (9.2 g, 0.04 mol) and DCC (dicyclohexylcarbodiimide) (8.2 g, 0.04 mol) in ethyl acetate (150 mL) was added HOAt (1-hydroxy-7-azabenzotriazole) (5.5 g, 0.04 mol) in DMF (dimethylformamide) (40 mL). The mixture was stirred at room temperature for 10 minutes and then 3-(4-fluoro-phenoxy)-phenylamine (8.7 g, 0.043 mol) in ethyl acetate (50 mL) was added. The reaction mixture was allowed to stir overnight at room temperature and then was concentrated to remove most of the ethyl acetate. The precipitated solid was removed by filtration through Celite. The filtrate was diluted with ethyl acetate and washed with 1 N HCl, saturated NaHCO3 and brine (3×60 mL). The organic phase was dried with MgSO4 and concentrated. The residue was purified on silica eluting with 20% ethyl acetate/hexanes to afford 4-[3-(4-fluoro-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (14.2 g, 86%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>CC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:26](=[O:27])[CH2:25][Cl:24])[CH:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(Nc1ccc(Br)cc1)c1c(Cl)ccc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(c1c(Cl)ccc(Cl)c1Cl)N(C(=O)CCl)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3 parts of ethyl α-[(4-bromophenyl)amino]-2,3,6-trichlorobenzeneacetate and 4.5 parts of 2-chloroacetyl chloride is stirred for 4 hours at 80° C. The mixture is taken up twice in methylbenzene and the latter is evaporated each time. The oily residue solidifies on triturating in petroleumether. The latter is decanted and the residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding a first fraction of 1.7 parts of ethyl α-[(4-bromophenyl) (2-chloroacetyl)-amino]-2,3,6-trichlorobenzeneacetate; mp. 140.8° C. The mother liquor is concentrated and a second fraction of 1.2 parts of ethyl α-[(4-bromophenyl) (2-chloroacetyl)amino]-2,3,6-trichlorobenzeneacetate is filtered off.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[C@@H:11]([OH:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.OS(O)(=O)=O>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[C:11](=[O:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(C)(C)[C@@H](O)C[C@H]1c1cc(F)cc(F)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)C(C)(C)C(=O)C[C@H]1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (470 mg, 1.377 mmol, described in Intermediate 21) in acetone (24 mL) at 0° C. was added a solution of chromium (VI) trioxide (174 mg, 1.740 mmol) in H2O (0.5 mL) and H2SO4 (0.147 mL, 2.75 mmol), in three portions over 5 min and the mixture was stirred at 0° C. for 30 min. Most of the acetone was removed by concentration in vacuo, and the residue was basified with saturated aqueous NaHCO3 (75 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (40 mL) and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 92:8, to give the title compound. MS: m/z=340 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:13]1[C:14](=[O:27])[NH:15][C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:13]2[C:14](=[O:27])[NH:15][C:16]3[C:21]([N:22]=2)=[CH:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)NCCC2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of 7-fluoro-1,2,3,4-tetrahydroquinoline (1 g, 6.61 mmol) in NMP (30 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (900 mg, 3.77 mmol) and then stirred for 2 h at 150° C. The resulting solution was diluted with water ((900 ml). The solids were collected by filtration to afford methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a brown solid (900 mg, 39%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18]I)[O:15][C:14]1=[O:20])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].C(OCC)(=O)C>CC(C)=O.O>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][N:21]=[N+:22]=[N-:23])[O:15][C:14]1=[O:20])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CI)OC1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CN=[N+]=[N-])OC1=O

Procedure:
A mixture of (±)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(iodomethyl)oxazolidin-2-one (XXXVIII, EXAMPLE 69, 0.531 g) and sodium azide (0.618 g) are stirred in acetone/water (2/1, 30 ml) at reflux under a nitrogen overnight. After this time the mixture is poured into ethyl acetate and the layers are separated. The aqueous layer is then extracted with ethyl acetate (2×). All organic layers are combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. A small amount of the crude product (oil) is purified on a silica preparative plate (20 cm×20 cm, 1000μ). The plate is eluted in methanol/ethyl acetate (10/90, 5×) to give the title compound as an oil; NMR (CDCl3, 300 MHz) 7.70, 7.53, 7.30, 4.80, 4.15, 3.89, 3.70, 3.60, 2.61 and 3.40 δ; CMR (CDCl3, 75.47 MHz) 13.62, 14.78, 38.62, 48.42, 53.05, 70.60, 109.29, 114.99, 132.1, 132.72, 142.3, 152.8 and 154.9 δ; MS (m/e) 300, 272, 227, 212, 200, 186, 172, 160, 159, 145, 131, 117, 104, 90 and 77; exact mass calcd for C14H16N6O2 =300.1335, found: 300.1333.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)([OH:18])[C:14]([F:16])([F:17])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:15]#[N:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CCN(Cc2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
16.8 q (0.08 mole) (3RS)-1-benzyl-3-chloromethyl pyrrolidine and 5.88 g (0.12 mole) of sodium cyanide was dissolved in 250 ml dimethyl sulfoxide. The mixture was stirred at 60° C. for two days and at room temperature for one week. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 14.7 g (92%) of the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1.O>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCc1cccc(Cl)c1
Yield: 99.7 %

Procedure:
Lithium aluminium hydride (19 g,) was suspended in dry ether (300 ml) and 3-chlorophenylacetic acid (58 g,) in dry ether (600 ml) was added dropwise to the stirred suspension over 1 hr. The mixture was then heated at reflux for 2 hr. when tlc indicated completion of reaction. Excess lithum aluminium hydride was carefully decomposed with water (500 ml). The ether layer was separated off and 2M hydrochloric acid was used to break up the gelatinous aqueous layer which was then extracted with ether (2×400 ml). The combined ether layers were washed with water (300 ml), dried (sodium sulphate) and evaporated in vacuo to give 2-(3-chlorophenyl)ethanol as a pale yellow oil (53.1 g) characterised by its nmr spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:6]([O:20][CH2:21][CH3:22])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-])=O.C(O)(=O)C>C1COCC1.[Zn]>[NH2:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:6]([O:20][CH2:21][CH3:22])=[CH:5][C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])=[CH:3][C:2]=1[Br:1]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cc(F)ccc2[N+](=O)[O-])c(OCC)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cc(F)ccc2N)c(OCC)c1
Temperature: 50 °C

Procedure:
To a solution of the product of step b (3.8 g) in THF (110 ml) were added acetic acid (3.6 ml) and zinc dust (8.2 g). The suspension was heated for 1 h at 50° C. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and washed with sat. NalCO3 and brine. The organic layer was separated, dried (Na2SO4) and concentrated. The remaining solid was stirred with a small amount of ethyl acetate to give the title compound as a pale yellow solid after filtration.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([C:13]2([CH2:27][O:28]CC3C=CC=CC=3)[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[ClH:1].[OH:28][CH2:27][C:13]1([N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: CCC(=O)N(c1ccccc1)C1(COCc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(CO)CCN(CCc2ccccc2)CC1

Procedure:
A mixture of 5.9 parts of N-phenyl-N-[1-(2-phenylethyl)-4-(phenylmethoxymethyl)-4-piperidinyl]propanamide hydrochloride and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed on the filter with methanol. The filtrate is evaporated. The oily residue solidifies on scratching. The solid product is crystallized from 20 parts of 2-propanone at room temperature. It is filtered off and recrystallized from 2-propanol at 0° C, yielding N-[4-(hydroxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride; mp. 218.4° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:28][CH:26]1[CH2:27][N:24]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:25]1
Reactant: OC1CNC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CC(O)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol) and azetidin-3-ol (22 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 15-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (17 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 4.21 (br. s., 2 H) 4.52-4.89 (m, 3 H) 6.22 (d, J=2.27 Hz, 1 H) 6.74 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 7.91-8.10 (m, 3 H) 10.79 (s, 1 H). ESI-MS: m/z 368.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.C1(=[O:15])CCCCC1.OOS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.C1COCC1>[Cl:1][C:2]1[N+:7]([O-:15])=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Cl)[n+]1[O-]
Reaction time: 24 h

Procedure:
To a solution of 6-chloro-2-methylpyridine (49.04 g; 384 mmol) in 500 mL pH 8 buffer and 300 mL THF was added cyclohexanone (3.77 g; 38.4 mmol) and Oxone® (potassium peroxymonosulfate) (236.3 g; 384 mmol). After stirring for three days an additional portion of Oxone® (236.3 g; 384 mmol) was added and the reaction was stirred for 24 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated. The 6-chloro-2-methylpyridine-N-oxide was used with no further purification.