Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C(#N)C>[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)=[CH:20][CH:19]=1
Reactant: BrCc1ccc(I)cc1
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCN(Cc2ccc(I)cc2)CC1

Procedure:
A 3 L flask was charged with 4-piperidinone hydrate (10.4 g, 60.8 mmol), K2CO3 (45 g, 326 mmol), acetonitrile (2000 mL) and NaI (0.49 g, 3.3 mmol). To the mixture while stirring was added 4-iodobenzyl bromide (17.5 g, 58.8 mmol). The mixture was stirred at rt overnight, filtered over a coarse glass frit and the filtrate concentrated to give 25 g crude. Recrystallization from hot EtOAc in hexanes gave 11 g (53%) of a clean crop as orange crystals: LRMS (M+1)=316.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2](=[N:18][O:16][CH3:17])[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (×3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t, 2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([N:17]2[CH2:16][CH:15]3[CH:19]([CH2:20][N:13]([C:9]4[N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:12]=[CH:11][N:10]=4)[CH2:14]3)[CH2:18]2)=[O:35])=[CH:26][CH:27]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: Cc1ccc(-c2ccccc2C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)CC3C2)cc1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 4′-methyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C30H28N4O, 460.58; m/z found 461.3 [M+H]+.
Reaction SMILES: C(COC)OC.[CH2:7]([O:9][C:10](=[O:46])[C:11]([CH3:45])([CH3:44])[CH2:12][C:13]1[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[C:15]2[C:20]([C:21]=1[S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:18]([OH:27])=[CH:17][CH:16]=2)[CH3:8].Br[C:48]1[CH:49]=[CH:50][C:51]([O:54][CH2:55][CH3:56])=[N:52][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C.O>[CH2:7]([O:9][C:10](=[O:46])[C:11]([CH3:45])([CH3:44])[CH2:12][C:13]1[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:48]3[CH:53]=[N:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=3)=[CH:31][CH:30]=2)[C:15]2[C:20]([C:21]=1[S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:18]([OH:27])=[CH:17][CH:16]=2)[CH3:8]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OCC)nc2)cc1
Temperature: 75 °C
Reaction time: 19 h
Yield: 80.2 %

Procedure:
To a stirring mixture of dimethoxyethane (16.5 L) and water (6.6 L) in a 50 L reaction flask under nitrogen was added 3-{3-tert-butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (1652.19 g), 5-bromo-2-ethoxypyridine (650.30 g), and potassium carbonate (605.03 g). The mixture was sparged with nitrogen for 30 minutes to remove dissolved oxygen gas, and then tetrakis(triphenylphosphine)palladium(0) (59.15 g) was added, and the reaction mixture was heated to 65-85° C. over 2 hours and stirred at 65-85° C. under nitrogen for 19 hours. Once no starting material was seen by tlc analysis, the reaction was cooled to 40° C. and water (6.6 L) was added. Ethyl acetate (6.6 L) was added, and the mixture was agitated for 20 minutes and then allowed to separate over 1.5 hours. The aqueous layer was separated, and additional water (6.6 L) was added to the organic layer. The mixture was agitated for 2 minutes and then allowed to separate over 1 hour, with additional ethyl acetate (1.4 L) added to facilitate phase separation. The aqueous layer was separated, and the two aqueous layers were combined. Ethyl acetate (5.0 L) was added to the combined aqueous layer, and the mixture was agitated for 3 minutes and allowed to separate over 2 minutes. The aqueous layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (446.43 g). The mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2″ pad of Celite. The reaction flask was rinsed twice with ethyl acetate (1.25 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material. Methyl tert-butyl ether (8.2 L) was added to the solids, and the mixture was agitated for 1.5 hours and filtered. The flask was rinsed with methyl tert-butyl ether (1 L) three times and then filtered through the filter cake. The isolated solids were dried in a drying oven at 25° C. under vacuum for 3 days to give the desired product (1314 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[N:27]1[C:31]([NH2:32])=[CH:30][C:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[N:28]1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[N:27]1[C:31]([NH:32][C:2]2[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)=[CH:30][C:29]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:28]1
Reactant: Cc1ccc(C)c(-n2nc(-c3ccc(F)cc3)cc2N)c1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1ncc(Nc2cc(-c3ccc(F)cc3)nn2-c2cc(C)ccc2C)c(C(=O)O)n1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
A mixture of 5-chloro-2-(methylthio)pyrimidine-4-carboxylic acid (89 mg, 0.44 mmol), potassium carbonate (66 mg, 0.48 mmol), 1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-amine (123 mg, 0.44 mmol), synthesized in a similar manner as Intermediate G, and copper (II) acetate (1.6 mg, 0.009 mmol) in DMF (1 mL) was heated (150° C.) in a sealed tube for 16 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 24.2 mg (12.3%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 8.95 (s, 1H), 8.90 (s, 1H), 7.85 (dd, 2H), 7.10-7.28 (m, 5H), 7.62 (s, 1H), 2.58 (s, 3H), 2.38 (s, 3H), 2.14 (s, 3H); ES-MS m/z 406.3 (MH+-CO2), HPLC RT (min) 4.07.
Reaction SMILES: C(OC(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)(C)(C)C.[C:20]([O:24][C:25]([NH:27][C@H:28]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@H:40]2COC(C)(C)[O:41]2)=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].ClCC([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=O>>[C:20]([O:24][C:25]([NH:27][C@H:28]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:41])=[CH:36][CH:37]=1)[C:29]([OH:31])=[O:30])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Reactant: O=C(CCl)N1CCOCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC(=O)N2CCOCC2)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) 4-iodoaniline was used in place of 4-bromoaniline in step 2 and (ii) (R)-tert-butoxycarbonylamino [4-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butyloxycarbonylamino-4-methoxyphenylglycine. (R)-tert-Butoxycarbonylamino[4-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-acetic acid was prepared by a method similar to that used for the preparation of (R)-tert-butyloxycarbonylamino-4-methoxyphenylglycine in example 1 except that 2-chloro-1-morpholin-4-yl-ethanone was used in place of iodomethane.
Reaction SMILES: [ClH:1].Cl.Cl.[OH:4][CH2:5][CH2:6][N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[NH:28])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.Cl.[C:34](=[NH:39])(OCC)[CH3:35].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:34]([N:18]1[CH2:17][CH2:16][CH:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([N:7]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[NH:28])[CH2:6][CH2:5][OH:4])=[CH:9][CH:10]=2)[CH2:20][CH2:19]1)(=[NH:39])[CH3:35]
Reactant: N=C(N)c1cccc(/C=C/CN(CCO)c2ccc(OC3CCNCC3)cc2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C(=N)N)c3)CCO)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.6 %

Procedure:
To a solution of 3-[3-[N-(2-hydroxyethyl)-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (295 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (362 mg) and triethylamine (0.41 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 16% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (175 mg, yield 55%) as a pale yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(Br)cc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(-c4ccc(S(C)(=O)=O)cc4F)cc3o2)CC1
Yield: 17 %

Procedure:
Following the General Procedure-1, the titled compound (21 mg) was prepared from Intermediate 10 (100 mg, 0.26 mmol) and Intermediate 3 (102 mg, 0.34 mmol) as an off-white solid. M.P.: 174-178.3° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85-7.75 (m, 3H), 7.73-7.64 (m, 2H), 7.50 (d, J 8.2, 1H), 4.15 (d, J 12.4, 2H), 3.20-3.10 (m, 4H), 3.0 (t, J 12.5, 2H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH:8](O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:26]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:31])[N:25]1[CH:8]([CH2:7][O:6][C:5]1[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC(O)COc1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(COc1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 1.5 g of rac-tert-butyl [3-(4-fluorophenoxy)-2-hydroxypropyl]carbamate (5.26 mmol, 1 equivalent), 0.93 g of phthalimide (6.31 mmol, 1.2 equivalents) and 2.07 g of triphenylphosphine (7.9 mmol, 1.5 equivalents) were initially charged in 22 ml of dry THF. 1.56 ml of diisopropyl azodicarboxylate (7.9 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 1.97 g of the title compound (90% of theory).
Reaction SMILES: [C:1]([CH2:5][CH2:6][Si:7]([Cl:10])(Cl)[Cl:8])([F:4])([F:3])[F:2].[C:11]([CH2:15][CH2:16][SiH](Cl)Cl)([F:14])([F:13])[F:12]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Si:7]([CH2:6][CH2:5][C:1]([F:4])([F:3])[F:2])([CH2:16][CH2:15][C:11]([F:14])([F:13])[F:12])([Cl:10])[Cl:8]
Reactant: FC(F)(F)CC[Si](Cl)(Cl)Cl
Reactant: FC(F)(F)CC[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: FC(F)(F)CC[Si](Cl)(Cl)CCC(F)(F)F
Temperature: 50 °C

Procedure:
2 moles CF3CH2CH2SiCl3, 3.5 moles Me2SiHCl, and 2.6 moles tetra(n-butyl)ammonium chloride were introduced into a flask and heated under reflux for 3 days with stirring. A mixture of chlorosilanes was then recovered by distillation in vacuo. According to analysis by gas chromatography, the main components of the reaction product were CF3CH2CH2SiCl3, CF3CH2CH2SiHCl2, Me2SiHCl, and Me2SiCl2. The CF3CH2CH2SiCl3 and CF3CH2CH2SiHCl2 fraction was isolated by distillation in vacuo. The CF3CH2CH2SiCl3 and CF3CH2CH2SiHCl2 mixture was placed in a flask, 5 g isopropanolic chloroplatinic acid solution (concentration=10%) was added, and, while stirring and heating to 50° C., CF3CH=CH2 gas was then continuously injected through a glass tube inserted into the liquid. Its addition was halted when the peak for CF3CH2CH2SiHCl2 had disappeared in gas chromoatographic analysis. (CF3CH2CH2)2SiCl2 (bp=128° C./20 mmHg) was then isolated by distillation in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C2C=CC=CC=2)=O)=[CH:10][C:9]2[C:4](=[C:5]([OH:21])[CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:1][C:2]1[C:11]([C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])=[CH:10][C:9]2[C:4](=[C:5]([OH:21])[CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(Oc1ccccc1)c1cc2cccc(O)c2cc1O
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cc2cccc(O)c2cc1O
Temperature: 25 °C

Procedure:
The aromatic ester is reacted with an aniline in a solvent and heating to form the anilide product. The reaction temperature can be varied to from about 140° C. to about 280° C. or above. Specifically, phenyl 2,8-dihydroxy-3-naphthoate can be reacted with aniline in methyl N-pyrrolidinone at about 250° C. The ratio of the phenyl ester to the aniline can vary, for example, from about 1:1 equivalent and up to about 20 equivalents. After the reaction is completed, the product mixture is cooled to room temperature, about 25° C., and discharged into an acidic aqueous solution, such as a 5 percent HCl ice cold solution. The precipitated anilide product, 2,8-dihydroxy-3-naphthanilide, is isolated by filtration and washed with water. Purification can be accomplished by first dissolving the crude product in a hot solvent, such as DMF, and then precipitating the product by adding water or methanol, or a mixture of methanol and water. The purified product is then characterized by m.p., IR, mass spectrometry, NMR spectroscopy and elemental analysis.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O)=CC=1.[C:20]([O-])(=[S:22])[CH3:21].[K+].O>CC(C)=O>[C:20]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:16])([F:17])[F:18])(=[S:22])[CH3:21]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=S)OCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.3 %

Procedure:
2-(2,2,2-trifluoroethoxy)ethyl p-toluenesulfonate (14.0 g, 47 mmol) and potassium thioacetate (10.0 g, 88 mmol) were dissolved in acetone (100 ml) and the mixture was stirred at room temperature for 2 days. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography (n-hexane/ethyl acetate=10/1) gave 2-(2,2,2-Trifluoroethoxy)ethyl thioacetate (8.3 g, 87%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)C>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[C:31]([NH2:32])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc3c2cc(C(N)=O)n3Cc2cccc(F)c2)CC1
Agent: Cl
Solvent: CCO
Product: NC(=O)c1cc2c(C3CCNCC3)cccc2n1Cc1cccc(F)c1
Temperature: 100 °C

Procedure:
4-[2-Carbamoyl-1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (76 mg) was dissolved in 4 ml ethanol. To this solution was added 2 M ethanolic hydrochloric acid solution (1 ml.) The reaction mixture was heated at 100° C. for 20 minutes, at which time a crystalline solid formed. The solution was allowed to cool to room temperature and 40 mg of 1-(3-Fluoro-benzyl)-4-piperidin-4-yl-1H-indole-2-carboxylic acid amide hydrochloride salt was collected as a yellow powder. MS: 352 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:13])=[CH:4]1.I[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C>[CH2:24]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:13])=[CH:4]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCI
Reactant: CN1CCCCC1COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)OCC2CCCCN2C)c2ccccc21
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a DMF (5 ml) suspension of 60% sodium hydride (0.10 g, 2.5 mmol) was dropwise added a DMF (7 ml) solution of (1-methyl-2-piperidyl)methyl 1H-indole-3-carboxylate (0.50 g, 1.7 mmol) at room temperature over a period of 10 min. The mixture was stirred for 45 min., onto which was then poured 1-iodopentane (0.38 g, 1.9 mmol) followed by stirring for additional 4 hours. A reaction solution was poured onto ice water followed by extraction with ethyl acetate (50 ml). The extract was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a pale yellow crude product (0.52 g). Purification of the product by column chromatography on silica gel (SiO2 : 20 g, CHCl3 /MeOH=20/1) afforded the title compound (0.33 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:20])([F:19])[F:18])[O:5][CH2:6][CH2:7][O:8]C(=O)C.[OH-].[K+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][OH:8])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)([OH:28])[C:17]([F:19])([F:20])[F:18]
Reactant: CC(=O)OCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cnc(C(O)(C(C)c2ccc(OCCO)cc2Cl)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of acetic acid 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenoxy}-ethyl ester in ethanol was added to a solution of KOH in ethanol. The reaction mixture was stirred for 3 h at r.t., before it was taken up in ethyl acetate, washed with water and brine, and the solvent was evaporated. Flash chromatography provided the title compound. MS (m/e)=391.0 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[N:4]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH2:35].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH:35][C:23]([C@H:20]1[CH2:21][CH2:22][C@@H:17]([NH:16][C:5]2[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:6]=2)[CH2:18][CH2:19]1)=[O:24]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CNc1nc(NC2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)NCc3ccc(Cl)cc3Cl)CC2)nc(N2CCN(C)CC2)n1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A solution of 4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (150 mg, 0.43 mmol), [(2,4-dichlorophenyl)methyl]amine (95 mg, 0.54 mmol) and DMAP (8 mg, 0.06 mmol) in DCM was stirred at room temperature. To this was added EDCl (90.8 mg, 0.47 mmol) and the resulting mixture was allowed to stir overnight. The solution was washed with water. The organic layer was dried and purified by HPLC to afford 78 mg (36% yield) of the product as a white solid. MS (ES+): m/e 507.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1>CO>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
Sodium borohydride (3.8 g, 100.4 mmol) was added in portions to a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (20 g, 100.4 mmol) in methanol (600 mL) at 0° C. After 15 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 3 hours. Sodium hydroxide (1.0 N, 100 mL) was added and the organic solvent was evaporated. The aqueous was extracted with ether four times. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated to give tert-butyl 4-hydroxy-1-piperidinecarboxylate (20.48 g, 100%). 1H NMR (CDCl3) δ 1.48 (s, 9H), 1.63 (m, 2H), 1.87 (m, 2H), 3.03 (m, 2H), 3.83 (m, 3H).