Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26](O)=O)[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=3)[N:12]=2)[CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: COc1ccc(C(=N)NO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: COc1ccc(-c2noc(C3CCCN(C(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 80 °C
Yield: 0.1 %

Procedure:
A mixture of N-Hydroxy-4-methoxy-benzamidine (0.20 g, 1.50 mmol), 1-Boc-piperidine-3-carboxylic acid (0.34 g, 1.50 mmol), HOBT (0.23 g, 1.50 mmol) and EDCI.HCl (0.43 g, 2.25 mmol) in dioxane (2.5 ml) was stirred at R.T for 7 H. After this time the mixture was heated at 80° C. overnight with the carousel Radley's. The mixture was concentrated. The organic layer was washed with water, NaOH 1N and water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (DCM/MeOH: 99/1) to afford 0.39 mg (72%) of 3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester as white solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:9](=[O:11])[CH2:8][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cc1ccccc1OCC(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1OCC(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred mixture of 2-(o-tolyloxy)acetic acid (100 mg, 0.60 mmol) in DCM (5 mL) was added DIEA (116 mg, 0.90 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (124 mg, 0.60 mmol) and Bop-Cl (183 mg, 0.72 mmol). The mixture was stirred at 25° C. for 16 hours then quenched by addition of water (20 mL). The resulting mixture was extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the product (79 mg, Yield 37%). 1H NMR (400 MHz, MeOD) δ 7.14-7.01 (m, 6H), 6.95-6.82 (m, 2H), 4.55 (s, 2H), 4.04-4.01 (m, 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 1H), 3.42-3.34 (m, 1H), 2.93-2.84 (m, 2H), 2.83-2.74 (m, 2H), 2.57 (d, J=6.3 Hz, 2H), 2.27 (s, 3H). LCMS (m/z): 355.1 (M+1).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH2:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: OCc1ccccc1
Reactant: CCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)OCc1ccccc1

Procedure:
The activated esters of type (3) react with alcohols, and also with phenols, thiophenols or mercaptans, to form esters. For example, activated propionic acid and benzyl alcohol in tetrahydrofuran, in the presence of triethylamine, give a very good yield of benzyl propionate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:7][CH:6]=1.[I:32]I.Cl>[NH4+].[OH-].CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[C:15]([I:32])[C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:7][CH:6]=1
Reactant: II
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(2-Bromoethoxy)-benzyl)-3-(2,4-dichlorophenyl)-7-hydroxy-chromen-2-one (2.734 g, 5.26 mmol) in NH4OH (22 mL), MeOH (55 mL) and CH2Cl2 (33 mL) was added I2 (1.334 g, 5.26 mmol), and the resulting mixture was stirred at r.t for 30 min. Aqueous 4 M HCl was then added to lower the pH of the aqueous layer to 5. The resultant layers were separated and the aqueous phase was extracted with AcOEt (3×). The combined organic layers were washed with brine (2×), dried (MgSO4) and concentrated in vacuo. The residual beige solid (3.25 g, 96%) was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO) δ 11.43 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.51–7.42 (m, 3H), 7.02 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.5 Hz, 2H), 4.21 (t, J=5.0 Hz, 2H), 4.04 (d, J=15.5 Hz, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.70 (d, J=15.5 Hz, 1H); MS (ESI) m/z 642.7 (M−H)−; HPLC tR 7.27 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>[Pd].C(O)C>[CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A mixture of 4-(4-isopropoxybenzoyl)-nitrobenzene (14.0 g, 49.09 mmol) and 10% palladium on carbon (2.0 g) in a solution of ethanol (250 mL) and concentrated hydrochloric acid (30 mL) was hydrogenated at 50 psi in a Parr apparatus for 16 hours. The catalyst was removed by filtration through a Celite pad, and filtrate was concentrated in vacuo. The residue was diluted with ice cold water, basified with concentrated ammonium hydroxide solution, and extracted into ethyl acetate. The organic extracts were washed with water and brine, and dried (MgSO4). Removal of the solvent gave a thick oil which on crystallization from ethyl acetate/hexanes gave 4-(4-isopropoxybenzyl)-phenylamine (10.4 g, 87%) as a white solid, m.p. 92-93° C.; Analysis for C16H19NO: Calc.: C, 79.63; H, 7.94; N, 5.80; Found: C, 79.51; H, 7.92; N, 5.96. MS m/e (%): 241 (M+, 83).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][C:31](/[CH:35]=[CH:36]/[Sn](CCCC)(CCCC)CCCC)([OH:34])[CH2:30][CH2:29]1>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:6]2[CH:7]=[C:2](/[CH:36]=[CH:35]/[C:31]3([OH:34])[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:11][CH:12]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Reactant: CCCC[Sn](/C=C/C1(O)CCN(C)CC1)(CCCC)CCCC
Product: COc1ccc(/C=C/C2(O)CCN(C)CC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1

Procedure:
The title compound is prepared analogously to example 9 from (5-bromo-2-methoxy-phenyl)-[4-(2,4-difluoro-phenylamino)-phenyl]-methanone and 1-methyl-4-((E)-2-tributylstannanyl-vinyl)-piperidin-4-ol.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[C:20]([SH:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].N1C=CC=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:21][C:20]2[C:19]([F:22])=[C:18]([F:23])[C:17]([F:24])=[C:16]([F:25])[C:15]=2[F:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1c(F)c(F)c(S)c(F)c1F
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)Sc2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (4.96 g) in dry dichloromethane (20 ml) was added dropwise over 15 minutes to a stirred solution of pentafluorothiophenol (5.00 g), pyridine (2.1 ml) and 4-N,N-dimethylaminopyridine (50 mg) in dry dichloromethane (75 ml), the mixture being maintained close to 5° C. by immersion in an ice-bath. The reactants were allowed to reach room temperature overnight and the organic solution was washed successively with aqueous 2M hydrochloric acid, a saturated sodium bicarbonate solution and water. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester (8.79 g).
Reaction SMILES: [OH:1][CH: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.[H-].[Na+].Cl[C:18]1[C:19]2[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>CN(C=O)C.O>[Cl:28][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[C:19]=2[N:27]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g, 1.000 mmol) in DMF (5.00 ml) was added NaH (0.052 g, 55% dispersion in mineral oil, 1.20 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.2 g, 1.000 mmol) was added to the mixture. After stirring for 3 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.236 g, 65%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.91-1.99 (2H, m), 2.10-2.13 (2H, m), 3.21-3.27 (2H, m), 3.83-3.97 (2H, m), 5.55-5.62 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.41 (1H, s).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[C:49]1([S:55](Cl)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([S:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:57])=[O:56])[CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 7 (200 mg, 0.37 mmol) is dissolved in dry CH2Cl2 (4 mL) and the flask sealed under N2. DIEA (96 μL, 0.56 mmol) is added, followed by benzenesulfonyl chloride (46 μL, 0.36 mmol), then the mixture stirred at RT for 2 h. The reaction is subsequently diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL), brine (50 mL) and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to afford an oil which is purified by flash chromatography on silica gel (25% Et2O/CH2Cl2). The title compound is isolated as a colourless glass (216 mg, 86% yield): 1H NMR δ (CDCl3) 7.51-7.86 (m, 5H), 7.03-7.25 (m, 4H), 6.69 (v br s, 1H), 6.04 (br d, J=8.2 Hz, 1H), 5.16-5.25 (m, 1H), 4.29-4.75 (br m, 3H), 3.47-4.21 (br m, 3H), 2.69-2.88 (br m, 5H), 2.38-2.67 (m, 2H), 1.81-2.09 (m, 5H), 1.55 (s, 3H), 1.46 (s, 9H), 1.23-1.31 (br m, 2H), 0.84-0.92 (br m, 3H), 0.76 (d, J=6.7 Hz, 2H); LCMS (APCl+) 685.6 (MH+, 100%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15].[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[CH2:22]([O:21][C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15])[CH3:23]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under argon atmosphere and cooling with an ice-bath, a solution of lithium diisopropylamide in THF (1.7 L, 2.0 M, 3.4 mol) was slowly dropped into a solution of 1,5-dibromopentane (950 g, 4.0 mol) and ethyl isobutyrate (396 g, 3.4 mol) in THF (5 L) while keeping the temperature below +5° C. The reaction mixture was stirred at room temperature for 20 h and quenched by slow addition of saturated ammonium chloride solution (3 L). The resulting solution was divided into three 4-L portions. Each portion was diluted with saturated ammonium chloride solution (5 L) and extracted with ethyl acetate (2×2 L). Each 4-L portion of ethyl acetate was washed with saturated sodium chloride solution (2 L), 1 N hydrochloric acid (2 L), saturated sodium chloride solution (2 L), saturated sodium bicarbonate solution (2 L), and saturated sodium chloride solution (2 L). The three separate ethyl acetate layers were combined into a single 12-L portion, dried over magnesium sulfate, and concentrated in vacuo to give the crude material (1.7 L) which was purified by vacuum distillation. Two fractions were obtained: the first boiling at 88-104° C./0.6 torr (184.2 g), the second at 105-120° C./1.4 torr (409.6 g) for a total yield of 60%. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 2H, J=7.2 Hz), 3.39 (t, 2H, J=6.8 Hz), 1.85 (m, 2H), 1.56-1.35 (m, 4H), 1.24 (t, 3H, J=7.2 Hz), 1.31-1.19 (m, 2H), 1.16 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 177.9, 60.2, 42.1, 40.5, 33.8, 32.6, 28.6, 25.2, 24.2, 14.3. HRMS (EI, pos): Calcd. for C11H22BrO2 (MH+): 265.0803. found: 265.0810.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Br:5][C:6]1[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[S:10][C:9]([S:11]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:13])=[O:12])=[CH:8][CH:7]=1
Reactant: C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
Azetidine (0.258 mL, 3.82 mmol) was added to a solution of 5-bromo-2-thiophenesulfonyl chloride (500 mg, 1.912 mmol) in DCM (4.8 mL) in a 4 dram vial. The reaction was stirred at room temperature for 5 min. The reaction mixture was concentrated under a stream of nitrogen at 50° C. and dried under high vacuum. The residue was taken up in EtOAc (10 mL) and extracted with saturated NaHCO3 (2×2 mL). The organic layer was dried (Na2SO4), concentrated under a stream of nitrogen at 50° C., and dried under high vacuum, giving 501 mg of the title compound.
Reaction SMILES: [Na].C(Cl)C[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([O:37]CCOCCOO)[CH2:21]CCCCCCCCCCCCCCC>C(O)COCCO>[CH2:13]([CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH2:21][CH2:20][OH:37])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCl
Reactant: CCCCCCCCCCCCCCCCCOCCOCCOO
Agent: [Na]
Solvent: OCCOCCO
Product: CCCCCCCCC(CCO)CCCCCC
Temperature: 140 °C
Reaction time: 17 h

Procedure:
To a round bottom flask is added 42.4 (0.4 mol) of diethylene glycol under a nitrogen atmosphere. To this reaction mass is added 2.3 g (0.1 mole) of sodium over 1 hour. The reaction mass is heated to 130° C. whereby all of the sodium has reacted. Then 27.4 g (0.1 mol) of C17H35Cl is added over 1 hour and then kept for 17 hours at these conditions. Reaction temperature is then increased to 140° C. and kept for 17 hours at these conditions for 24 hours. The reaction mass upon cooling consists of 2 layers. GC shows the bottom layer to be mostly diethylene glycol. The reaction mass is filtered and the bottom diethylene glycol layer separated. The top organic layer is diluted with diethyl ether, water washed and dried over anhydrous MgSO4. After filtering, the organic layer is fractionally distilled to give a fraction at from 200°-220° C. and 2.25-2.5 mm containing the desired product, C17H35O(CH2CH2O)2OH, in two isomeric forms, one of which is the desired isomer of this invention, namely C8H17 (C6H13)CHCH2CH2 (OCH2CH2)2OH.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][C:37]#[N:38]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[O:28][CH2:36][C:37]#[N:38]
Reactant: N#CCBr
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.24 mmol), and cesium carbonate (0.12 g, 0.38 mmol) in dioxane (1 mL) was added bromoacetonitrile (0.034 g, 0.28 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.11 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(CC)CC.[Cl:15][C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[C:36]4[CH2:40][CH2:41][NH2:42])[N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[C:36]4[CH2:40][CH2:41][NH:42][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:24])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
Ethyl bromoacetate (167 mg) and Et3N (101 mg) were added to the solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (530 mg) in toluene (3 mL). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by Mass Directed Auto Prep to afford ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycinate (D86) (132 mg) as a yellow solid. MS (ES): C25H27ClN4O4 requires 482; found 483.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]#[CH:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:3]1[NH:22]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C@@H:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]#[CH:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Yield: 99 %

Procedure:
tert-Butyl [(2R,3S)-4-oxo-2-phenyl-5-prop-2-yn-1-yl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67b) (125 mg, 0.318 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (4 mL) and kept at ambient temperature for 90 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford the title compound (92 mg, 99%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.36 (br s, 2H), 2.29 (t, 1H, J=2.3 Hz), 4.10 (m, 1H), 4.56 and 4.61 (dd, 1H, J=2.4 Hz), 4.76 and 4.81 (dd, 1H, J=2.4 Hz), 5.46 (d, 1H, J=7.4 Hz), 7.27 (m, 3H), 7.38 (m, 3H), 7.47 (m, 3H). MS APCI, m/z=293 (M+1). LC/MS: 1.63 min.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:10]([O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:10]([O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:16]1)[CH3:11]
Reactant: O=C1CCC1
Reactant: CCOC(=O)CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of cyclobutanone (0.3 mL, 3.94 mmol) in acetic acid (0.19 mL, 3.28 mmol) was added to a stirred solution of piperidin-4-yl acetic acid ethyl ester (562 mg, 3.28 mmol, obtained in above step) in dichloromethane cooled at 0° C. Solid sodium triacetoxyborohydride (1.39 grams, 7.2 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain (1-Cyclobutyl piperidin-4-yl) acetic acid ethyl ester (652 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:28]([F:31])=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[C:28]([F:31])=[CH:29][CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1c(F)ccc(Cl)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3c(F)ccc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2,6-difluorobenzoic acid: MS (APCI) m/z 440 (M+1).
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([C:3]([OH:5])=[O:4])=O.Cl.[CH3:14][O:15][NH2:16].C(=O)(O)[O-].[Na+]>O>[C:3]([C:1](=[N:16][O:15][CH3:14])[CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)Cn1nnnc1S
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(Cn1nnnc1S)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 1-oxalomethyl-1H-tetrazole-5-thiol (1.09 g) and methoxyamine hydrochloride (0.47 g) in water (15 ml) was adjusted to pH 6.5 with sodium bicarbonate and stirred at room temperature for 2 hours. After washing with ethyl acetate, the aqueous solution was adjusted to pH 1.8 with 10% hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to give 1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazole-5-thiol (1.05 g), mp 84° to 86° C.