Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH3:14][NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([CH2:17][CH2:16][N:15]([CH3:14])[CH2:3][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:1]([O:11][CH2:12][CH3:13])=[O:10])=[O:19])[CH3:22]
Reactant: C=C(C(=O)OCC)c1ccccc1
Reactant: CCOC(=O)CCNC
Product: CCOC(=O)CCN(C)CC(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
184.47 g of ethyl atropate (of Example 1c) are added dropwise, over a 20 minute period, to 132.16 g of ethyl β-methylaminopropionate (of Example 1a). The mixture is stirred for 18 hours at room temperature under a nitrogen atmosphere. The mixture is combined with 1.8 l. of ether and then the resultant mixture is extracted with two 800 ml portions of 2 N hydrochloric acid. The acid solution is extracted with two 150 ml portions of ether. The aqueous extracts are basified with 50 weight percent aqueous NaOH solution and then extracted with three 900 ml portions of ether. The ether extracts are combined and dried for 18 hours over MgSO4. The combined ether portions are filtered and concentrated in vacuo to yield ethyl N-(2-ethoxycarbonylethyl)-3-methylamino-2-phenylpropionate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([OH:15])[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCC(O)C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(OS(C)(=O)=O)C(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)-4-hydroxycyclohexanecarboxylate (12.0 g, 42 mmol) and triethylamine (12.7 g, 126 mmol) in dichloromethane (150 mL) was added methanesulfonyl chloride (9.5 g, 84 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 3 hours. The solution was washed with water (100 mL×3) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (15 g, crude) as a yellow oil. MS (ES+) C15H27NO7S requires: 365, found: 266 [M+H−100]+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH2:35][CH2:36][CH3:37]>CS(C)=O.C(OCC)(=O)C>[CH2:34]([N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:20][C:19]=2[C:16]2[N:15]=[C:14]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:4]([Cl:3])[CH:5]=3)[O:18][N:17]=2)[C:24]([CH2:28][CH2:29][C:30]([O:32][CH2:5][CH2:4][CH2:9][CH3:8])=[O:31])=[CH:25]1)[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCOC(=O)CCc1cn(CCCC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (65 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodobutane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford butyl 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D123) (61 mg). δH (CDCl3, 400 MHz): 0.73 (3H, t), 0.92 (3H, t), 1.03 (2H, m), 1.34 (2H, m), 1.45 (8H, m), 1.59 (2H, m), 2.71 (2H, t), 3.12 (2H, t), 4.08 (2H, t), 4.16 (2H, t), 4.72 (1H, m), 6.94 (1H, s), 7.07 (1H, d), 7.19 (1H, t), 7.53 (1H, dd), 7.76 (1H, dd), 8.08 (1H, dd), 8.25 (1H, d); MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[O-:15][C:16]#[N:17].[K+].Cl>O>[OH:8][C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:16]([NH2:17])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NC(c1ccccc1)C1(O)CCCC1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC(c1ccccc1)C1(O)CCCC1
Temperature: 80 °C

Procedure:
A 5 mL microwave vial was charged with 1-(amino(phenyl)methyl)cyclopentanol (191.3 mg, 1.0 mmol), potassium cyanate (406 mg, 5.00 mmol), water (1 ml) and hydrochloric acid (6N, 0.5 ml, 3.00 mmol). The vial was capped and heated to 80° C. for 1 h in a microwave. The contents of the vial were cooled to room temperature, the formed precipitate filtered, washed through with water and dried in a vacuum oven (40° C.). The crude 1-((1-hydroxycyclopentyl)(phenyl)methyl)urea was taken forward without further purification. MS: [M+H]+ m/z 235.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([OH:14])[CH2:12][OH:13].N1C=CC=CC=1>>[C:1]([O:13][CH2:12][CH2:11][OH:14])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCO
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCCO
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Capryloyl chloride (0.602 mol; 98 g) was dropwise added during 1.5 hour into a mixture of ethylene glycol (3 mol; 186 g) and pyridine (0.6 mol; 47.4 g). The mixture was further stirred for 2 hours at laboratory temperature, allowed to stand overnight, and threetimes extracted with benzene (100+50+25 ml). The benzene extract was shaken with a 10% aqueous solution of NaHCO3 (2×30 ml) and water and benzene was evaporated in a rotation evaporator. Distillation of the residue gave 4 raw fractions with purity 79.9 to 97.9% at the overall yield of 2-hydroxyethyl caprylate 79.5%. Further procedure was carried out according to example 1.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[CH:12][CH:11]=1)=[O:5])C.[OH-].[Na+]>C1COCC1>[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCNC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Yield: 77 %

Procedure:
Compound 79 (1.0 g, 2.75 mmol) was dissolved in THF (30 mL), and the solution was added with 2 mol/L aqueous sodium hydroxide solution (20 mL), followed by neutralization and filtration to obtain (E)-N-(2-carboxyethyl)-4-[2-(1H-indazol-3-yl)vinyl]benzamide (710 mg, 77%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[CH:14][N:13]=[C:12]3[NH2:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:19][C:17]1[N:16]2[C:11]([C:12]([NH2:18])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:8][CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2cc(CCCN3CCCC3)cc12
Solvent: CN(C)C=O
Product: Nc1ncnn2c(Br)c(CCCN3CCCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of the compound (257 mg, 1.05 mmol) prepared in Example 12 in DMF (8 mL) at −78° C. was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (150 mg, 0.52 mmol) portion wise over a period of 5 minutes. The reaction was stirred for 30 minutes and was allowed to warm to room temperature, and stirred overnight. DMF was removed under vacuum, and the crude solid was extracted with DCM/sodium hydroxide (1N) solution. The organic layer was dried, concentrated, and the crude product was purified by prep HPLC. The pure fractions were concentrated, extracted with saturated sodium bicarbonated/DCM, and the organic layer was dried sodium sulfate, filtered and concentrated to obtain the title compound (135 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[N:7]([C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:32]4[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)nn12
Temperature: 150 °C
Yield: 77.7 %

Procedure:
A mixture of [(S)-1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert butyl ester (83 mg, 0.21 mmol), 2-methoxypyridine-3-boronic acid (43 mg, 0.28 mmol), K2CO3 (87 mg, 0.63 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.4 mg, 0.011 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (69.3 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9H) 2.11-2.29 (m, 2H) 2.84 (s, 3H) 3.40 (dd, J=10.48, 6.95 Hz, 1H) 3.46-3.53 (m, 1H) 3.67-3.74 (m, 2H) 4.08 (s, 3H) 4.94 (br. s., 1H) 6.61 (d, J=9.60 Hz, 1H) 7.03 (dd, J=7.58, 4.80 Hz, 1H) 7.77 (d, J=9.85 Hz, 1H) 8.12-8.18 (m, 2H) 8.86 (dd, J=7.58, 1.77 Hz, 1H). LRMS (ESI) m/z 425.3 [(M+H)]+, calc'd for C22H28N6O3: 424.51.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[C:18](Br)#[C:19][CH3:20]>>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:20][C:19]#[CH:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC#CBr
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Product: C#CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1

Procedure:
An 11.61 g portion of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reacted with propynyl bromide as described in Example 6, giving N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynylacetamide, mp 98°-101° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]2([C:17]([CH3:21])([CH3:20])[CH2:18][F:19])[CH2:16][O:15]2)=[CH:10][CH:9]=1>C(O)CC>[F:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:14]([CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:23][CH:22]=1)([OH:15])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(CF)C1(COc2ccc(F)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(CF)C(O)(COc1ccc(F)cc1)Cn1cncn1
Yield: 28.7 %

Procedure:
15.2 g (0.22 mol) of 1,2,4-triazole were added to 0.46 g (0.02 mol) of sodium in 200 ml of n-propanol. The solution was heated to the boil, and 48.5 g (0.2 mol) of 2-(4-fluorophenoxymethyl)-2-(fluoro-tert.-butyl)-oxirane, dissolved in 50 ml of n-propanol, were added dropwise. The reaction solution was stirred under reflux for a further 48 hours and was concentrated, and 200 ml of ethyl acetate and 100 ml of water were added to the residue. The organic phase was separated off, washed twice with water, dried over sodium sulphate and concentrated. The residue was dissolved in ether, and the solution was gassed with hydrogen chloride. The precipitate formed was filtered off under suction and washed with ether, and ethyl acetate/1N sodium hydroxide solution were added. The crude product obtained was purified over a silica gel column (mobile phase: methylene chloride/ethyl acetate, 2:1), and recrystallised from acetonitrile. 17.9 g (29% of theory) of 4-fluoro-2-(4-fluorophenoxymethyl)-3,3-dimethyl- 1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 97° to 99° C. were obtained.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1.[H][H]>C(O)C.C1COCC1.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(NCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(N)c1

Procedure:
262 mg (purity 66%, 0.55 mmol) of (+/−)-ethyl 2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate were dissolved in 5 ml of ethanol/THF (1:1), 26 mg of palladium on carbon (10%) were added and the mixture was hydrogenated at RT using a hydrogen pressure of 1 bar for 24 h. The reaction mixture was then filtered through celite, the residue was washed with ethanol and the filtrate was concentrated. The crude product obtained in this manner was purified by preparative HPLC. This gave 87 mg (69% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][CH:12]=2)=[C:4]([Cl:21])[CH:3]=1.[C:22]1([NH2:33])[C:27](F)=[C:26](F)[C:25](F)=[C:24]([NH2:31])C=1F.Cl.Cl>CCO>[Cl:20][C:14]1[CH:15]=[C:16]([N:19]=[N:31][C:24]2[CH:25]=[CH:26][CH:27]=[CH:22][N:33]=2)[CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]=[N:31][C:24]3[CH:25]=[CH:26][CH:27]=[CH:22][N:33]=3)=[CH:3][C:4]=2[Cl:21])=[CH:12][CH:11]=1
Reactant: Nc1ccc(-c2ccc(-c3ccc(N)cc3Cl)o2)c(Cl)c1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: Clc1cc(N=Nc2ccccn2)ccc1-c1ccc(-c2ccc(N=Nc3ccccn3)cc2Cl)o1
Yield: 25 %

Procedure:
2,5-Bis[2-chloro-4-(2-pyridylimino)aminophenyl]furan (4j, DB712) was prepared according to the procedure for 4f using diamine 3d and S-(2-naphthylmethyl)2-pyridylthioimidate hydrobromide as starting materials. Free base: orange crystalline solid, mp 189-190° C. (EtOH). Yield: 25%. 1H NMR (DMSO-d6): 6.85 (br s, 4NH), 7.02 (dd, 2H), 7.08 (d, 2H), 7.17 (s, 2H), 7.56 (m, 2H), 7.93-7.98 (m, 4H), 8.29 (d, 2H), 8.64 (m, 2H). Dihydrochloride: yellow/orange solid, mp>180° C. dec. 1H NMR (DMSO-d6): 7.45 (s, 2H), 7.60 (d, 2H), 7.80 (s, 2H), 7.86 (dd, 2H), 8.23 (m, 4H), 8.50 (d, 2H), 8.90 (d, 2H), 9.54 (br s, 2H), 10.23 (br s, 2H), 11.98 (br s, 2H). MS (EI): m/z 530, 528, 526 (M+, 13.2, 69.8, 100), 426, 424, 422 (7.9, 48, 72.4), 322, 320, 318 (2.6, 17.4, 26.6). Anal. Calcd. for C28H20Cl2N6O.2.0HCl.1.5H2O (627.35): C, H, N, Cl.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].ClC(OCC)=O.C(N(CC)CC)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[Cl-].[Na+]>C1COCC1>[CH:22]1([NH:25][C:1](=[O:8])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CCC/C=C\C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC/C=C\C(=O)NC1CC1
Yield: 77 %

Procedure:
3Z-Hexenoic acid 1 eq, ethyl chloroformate 1.1 eq, triethylamine 1.2 eq, cyclopropylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=77%. 0.49 ppm (m, 2H), 0.75 ppm (m, 2H), 0.98 ppm (t, 3H, J=7.48 Hz), 2.05 ppm (d, 2H, J=0.97 Hz, of pentet, J=7.46 Hz), 2.70 ppm (octet, 1H, J=3.59 Hz), 2.98 ppm (d, 2H, J=7.46 Hz), 5.46-5.52 ppm (m, 1H), 5.58-5.66 ppm (m, 1H), 6.19 ppm (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[S:35]1[C:39]([NH2:40])=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:39]4[S:35][N:36]=[CH:37][N:38]=4)(=[O:20])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: Nc1ncns1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE XXXX, 150.33 mg, 0.291 mmol), 1,2,4-thiadiazol-5-amine (35.4 mg, 0.350 mmol), and cesium carbonate (285 mg, 0.874 mmol). acetonitrile (1457 μl) was added, and the mixture was stirred for 1.5 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from MeOH. The residue was taken up in MeOH, sonicated, and filtered on a membrane filter. The collected solid was washed with MeOH (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(5-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100.0 mg, 0.231 mmol, 79% yield) as a cream-colored solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.49 (s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.59 (dd, J=2.7, 8.9 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 3.65 (s, 3H). m/z (ESI) 432.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[C:41]([N+:43]([O-])=O)[CH:40]=[CH:39][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:38])([CH3:37])[O:10][Si:11]([CH3:36])([CH3:35])[O:12][Si:13]([CH3:34])([CH3:33])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=1[Cl:32])([CH3:17])[CH3:16].[H][H]>[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][Si:15]([CH3:16])([CH3:17])[O:14][Si:13]([CH3:34])([CH3:33])[O:12][Si:11]([CH3:36])([CH3:35])[O:10][Si:9]([CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:2]=2[Cl:1])([CH3:37])[CH3:38])=[C:24]([Cl:32])[CH:25]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1Cl)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1Cl)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1Cl
Yield: 91.9 %

Procedure:
0.936 g of the above (2h) (1.38 mmol) and 10 mL of a 10 wt % Pd/C (0.0469 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a brown oily material of 1,7-bis[4-(4-amino-2-chlorophenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3h) (0.860 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3h), and results are shown below.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCc1c(/C=C/C(=O)O)ccc2ccc(OC)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)ccc2ccc(OC)cc12
Yield: 83.1 %

Procedure:
As in Example 113, (E)-3-(1-butyl-7-methoxy-2-naphthalenyl)-2-propenoic acid (1.35 g) was reacted with 4-nitrophenol (0.73 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (0.99 g) to give 1.6 g of (E)-3-(1-butyl-7-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester. Crystallization of a portion from diethyl ether furnished the analytical sample, mp 114°-115° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 70.85; H, 5.56; N, 3.24
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[CH3:2].CCCCCC.C([Li])CCC.[CH3:27][S:28]SC.[OH-].[Na+]>C(OCC)C>[CH2:1]([O:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[C:8]=1[S:28][CH3:27])[CH3:2]
Reactant: CCOCOCc1ccc2c(c1)OCO2
Reactant: CSSC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOCOCc1ccc2c(c1SC)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
1.05 g of 1-[(ethoxymethoxy)methyl]-3,4-methylenedioxybenzene was dissolved in 10 ml of diethyl ether, 2 ml of a 2.52 M n-butyllithium hexane solution was added thereto at 0° C., and the mixture was stirred for 2 hours, and then 471 mg of methyldisulfide was added dropwise at −70° C. After completing the dropwise addition, the mixture was further stirred at room temperature for 12 hours. A 1N aqueous sodium hydroxide was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 561 mg of the title compound as a colorless oil.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:18][C:19]1[CH:20]=[C:21](O)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Reactant: CS(=O)(=O)OC1CCN(c2ccncn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(OC2CCN(c3ccncn3)CC2)c1C
Temperature: 60 °C
Yield: 41.7 %

Procedure:
A 250 mL round bottom flask was charged with 1-(pyrimidin-4-yl)piperidin-4-yl methanesulfonate (713 mg, 2.77 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (0.301 mL, 2.218 mmol), Cs2CO3 (867 mg, 2.66 mmol) and N,N-dimethylformamide (6 mL). The flask was equipped with a reflux condenser and heated at 60° C. for 3 days, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture filtered. LCMS showed some starting chlorophenol remained, so the EtOAc was removed in vacuo and the residue dissolved in N,N-dimethylformamide (6 mL). Cs2CO3 (867 mg, 2.66 mmol) was added and the reaction was heated to 80° C. overnight, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture was filtered. The EtOAc was removed in vacuo and crude residue was purified by reverse phase HPLC (Column: Phenomenex Gemini-NX, 30×100, 5μ, C18. Gradient: 7 min, 30-60% acetonitrile/0.1% formic acid in water). Two additional HPLC purifications using the same column (Gradient: 7 min, 10-90% acetonitrile/0.1% formic acid in water; and Gradient: 7 min, 10-90% acetonitrile/0.1% TFA in water) were performed to provide methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate (335 mg, 0.926 mmol, 41.7% yield) as a yellow viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.34 (dd, J=1.52, 7.58 Hz, 1H), 7.44 (d, J=2.02 Hz, 1H), 7.34 (d, J=2.02 Hz, 1H), 7.27 (d, J=7.58 Hz, 1H), 4.85-4.96 (m, 1H), 4.05 (br. s., 2H), 3.91 (br. s., 2H), 3.83 (s, 3H), 2.30 (s, 3H), 2.01-2.13 (m, 2H), 1.71-1.87 (m, J=3.92, 7.03, 7.03, 13.61Hz, 2H). MS(ES) [M+H]+ 362.1.