Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([O:7][C:8]([F:25])([F:24])[C:9]([F:23])([F:22])[O:10][C:11]([F:21])([F:20])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([F:6])([F:5])[F:4].[CH2:26]([O:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[N:38][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([O:33][C:34]1[CH:39]=[N:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:23])([F:22])[C:8]([F:25])([F:24])[O:7][CH:2]([F:1])[C:3]([F:6])([F:5])[F:4])([F:21])[F:20])=[CH:44][CH:45]=2)=[N:36][CH:35]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: FC(OC(F)(F)C(F)(F)OC(F)(F)COCCCCCBr)C(F)(F)F
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 5-(2-(2-(tetrafluoroethoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-1-bromopentane (7.2 g, 15.0 mmol), 5 -heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 11.0 mmol), potassium carbonate (1.6 g, 12.7 mmol), and acetonitrile (50 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 4.95 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[N:39]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:35]=3[CH:36]=[CH:37][CH:38]=[N:39]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CC(C)O
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 70 °C
Yield: 51 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (79.8 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→100% acetone in hexanes) affording the desired product (118.2 mg) as a white solid. ESMS: MH+ 580.4 (base).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[OH-].[NH4+:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([S:15](=[O:17])(=[O:16])[NH2:20])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)cc1Br)C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.1 %

Procedure:
16.2 g (1 mol equiv.) 3-Bromo-4-(2,2,2-trifluoro-acetylamino)-benzenesulfonyl chloride was dissolved in 150 mL acetonitrile and cooled to 0° C. Dropwise, 20.8 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. during which a white precipitate was formed. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 14.3 g (94%) N-(2-bromo-4-sulfamoyl-phenyl)-2,2,2-trifluoro-acetamide. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.88 (dd, J=8.2, 1.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 11.55 (s, 1H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].BrBr.[NH2:11][C:12]([NH2:14])=[S:13].[OH-].[NH4+]>C(O)(=O)C.O>[NH2:11][C:12]1[S:13][C:4]([N+:5]([O-:7])=[O:6])=[CH:3][N:14]=1
Reactant: NC(N)=S
Reactant: CN(C)C=C[N+](=O)[O-]
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc([N+](=O)[O-])s1
Temperature: 17 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a stirred mixture of 3.5 g of N,N-dimethyl-2-nitroetheneamine in 25 ml of acetic acid cooled to 17° C. was added 4.8 g bromine at such a rate the reaction temperature did not exceed 25° C. During bromination an orange solid was formed. After stirring the resulting slurry for 10 minutes, 3.0 g thiourea was added and the reaction mixture exothermed to 32° C. A yellow solid formed. The mixture was stirred for 1 hour and then was diluted with 25 ml of water. This mixture and an approximately equal volume of 29% ammonium hydroxide were added simultaneously to 25 ml of acetic acid at such rates that the pH remained between 4 and 5 and the temperature did not exceed 30° C. After all of the reaction mixture had been added the pH was adjusted to 7 with 29% ammonium hydroxide. The product was then filtered off, washed with water and dried to give 2.7 g (62% yield, 92.9% assay) of 2-amino-5-nitrothiazole.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:29]=[CH:28][C:19]4[CH2:20][CH2:21][CH:22]([C:24]([O:26][CH3:27])=[O:25])[O:23][C:18]=4[C:17]=3[CH2:30][CH2:31][CH3:32])=[C:9]([CH2:35][CH2:36][CH3:37])[C:8]=2[O:38][CH3:39])=[CH:4][S:3]1.[N+]([CH3:43])([O-])=O.CI>C(OCC)C.O>[CH3:39][O:38][C:8]1[C:9]([CH2:35][CH2:36][CH3:37])=[C:10]([CH:33]=[CH:34][C:7]=1[C:5]1[N:6]=[C:2]([S:1][CH3:43])[S:3][CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]2[CH2:20][CH2:21][CH:22]([C:24]([O:26][CH3:27])=[O:25])[O:23][C:18]=2[C:17]=1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(=S)[nH]3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: CI
Solvent: CCOCC
Product: CCCc1c(OCCCOc2ccc(-c3csc(SC)n3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Yield: 97.6 %

Procedure:
The compound of Example 25 (18 mg, 31.4 μmol) was added to 1.0 ml of nitromethane, and 0.3 ml of methyl iodide was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into ethyl ether/water, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated. The crude product was chromatographed on silica gel using 20:1 to 10:1 hexane/ethyl acetate as eluant to give the product (51 mg, 87.0 μmol, 97.6% yield). High resolution mass spectrum, m/e 585.2223 (calculated for C31H39N6S2, 585.2219).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]=12
Reactant: O=[N+]([O-])c1cnc2c(c1)CCC2
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (C) (340 mg, 2.07 mmol) was dissolved in methanol. Pd/C (40 mg) was added to it. The resulting mixture was stirred at room temperature for 2 h under H2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to afford desired 6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine (D). (250 mg, 90%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCN(C(C)C)C(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:32]([CH:29]4[CH2:28][CH2:27][N:26]([C:23](=[O:25])[CH3:24])[CH2:31][CH2:30]4)=[O:33])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)C2CCN(C(C)=O)CC2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.25 M in dimethyl formamide, 50 μmole) was added 1-acetylpiperidine-4-carboxylic acid (220 μL of 0.25M in DMF), 300 μL of EDCI (0.25M in DMF) and 220 uL of HOBT (0.25M in DMF) and 30 μL DIEA. The solution was allowed to stir for 48 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone 2 (5.2 mg), [M+H]+=456.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: OCCn1cccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCn2cccc2)cccc1[N+](=O)[O-]
Yield: 42.5 %

Procedure:
Prepared as in Example 160d from 2-(1H-pyrrol-1-yl)ethanol and 2,6-dinitrobenzonitrile, in 42.5% yield. MS 258 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32]Br)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:34]([O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH3:35].ClCCl>O>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32][N:39]([CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOCCNCCOCC
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C(CBr)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Solvent: O
Solvent: ClCCl
Product: CCOCCN(CCOCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
A solution of 10 parts of 3β-acetoxy-6-(bromomethyl)cholest-5-ene and 20 parts of bis(ethoxyethyl)amine in 13 parts of dichloromethane is allowed to stand at room temperatures for 24 hours, whereupon 5 volumes of water is introduced and the oil which separates is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation to give 3β-acetoxy-6-[di(2-ethoxyethyl)aminomethyl]cholest-5-ene as the residue. The product, an oil, has the formula ##SPC9##
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:30][CH:29]=1)[C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:12]([C:13](=[O:26])[CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)[C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:39])=[O:2])=[CH:29][CH:30]=1)[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid methyl ester (6.6 g, 12.3 mmol) was dissolved in MeOH (150 mL) and 1M NaOHaq. (25 mL) was added. Stirring was continued for 1 h. A solution of 10% citric acid was added till the pH=6, followed by removal of the MeOH under reduced pressure and the addition of NaCl (solid) to saturate the solution. The product was extracted with EtOAc (2×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give 6.55 g (quant. yield) of 2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid. LC-MS: tR=1.16 min; [M+H]+=524.38.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=432.1, tR (minutes, Method F)=2.48. [α]D20=+32.38 (c=3.27 mg/mL,CHCl3)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Cl:14])[CH:8]=1)C.[OH-].[Na+]>C1COCC1>[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: CCOC(=O)CNc1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCNc1ccc(F)c(Cl)c1
Yield: 90.8 %

Procedure:
ethyl-2-(3-chloro-4-fluoroanilino)acetate (J. Med. Chem. 1965, 405-407) (2 g, 8.6 mmol) in THF (15 ml) ether (10 ml) was treated with Li Al H4 (460 mg, 12.1 mmol) at 40° C. for 4 hours. The mixture was then poured onto ice, treated with NaOH (2N, 10 ml), extracted with ethyl acetate, dried, evaporated to give title compound (1.48 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[CH3:28][O:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:32]
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)COC)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and methoxy acetyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.26-1.36 (m, J=7.38, 7.38, 7.38, 7.38, 7.38 Hz, 2H) 2.23 (t, J=7.33 Hz, 2H) 3.40 (s, 3H) 4.06 (s, 2H) 6.76 (s, 1H) 7.64 (t, J=7.71 Hz, 1H) 7.70 (d, J=8.34 Hz, 2H) 7.87 (t, J=7.71 Hz, 1H) 7.91-7.96 (m, 1H) 7.98 (d, J=8.59 Hz, 2H) 8.15 (d, J=8.34 Hz, 1H) 10.18 (s, 1H); ESI-MS: m/z calc'd for C24H24N4O3S 448.54. found 449.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:18][C:19]([O:21]CC)=[O:20].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Yield: 84.9 %

Procedure:
A mixture of this ester (0.9 g), sodium hydroxide (0.7 g) and water (40 ml) was refluxed for 1 hour. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 0.7 g of 4-chloro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 280°-281° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](S(C)=O)=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)=[N:6][CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:46](=[O:49])[CH:47]=[CH2:48]>CO.C(Cl)(Cl)Cl>[C:46]([NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[NH:38][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)[N:4]=1)(=[O:49])[CH:47]=[CH2:48]
Reactant: CS(=O)c1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Reactant: C=CC(=O)Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccccc1Nc1nc(N[C@@H]2CCC[C@H](C(N)=O)C2)ncc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 3 (1.4 g, 4.43 mmol) in 0.04 M PTSA/1,4-dioxane (12 mL, 0.106 mmol) was added N-(2-aminophenyl)acrylamide (1.72 g, 6.64 mmol), and the reaction mixture was stirred at 70° C. for 1 h. After completion of the reaction (TLC System: 5% methanol/chloroform, (Rf): 0.5), the reaction mixture was concentrated and diluted with water (30 mL), and the precipitate was filtered, washed with saturated sodium bicarbonate solution (15 ml) and dried to afford the desired compound as a white solid. (1.1 g, 59.7%). 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.26 (m, 3H), 1.26-1.32 (m, 2H), 1.67-1.69 (m, 2H), 1.76-1.79 (m, 2H), 2.05 (m, 1H), 5.79 (d, 1H J=11.4 Hz), 6.28-6.32 (d, 1H J=16.9 Hz), 6.46-6.52 (dd, 1H J=10.2 Hz and 17 Hz), 6.64 (br s, 1H), 7.14 (br s, 1H), 7.22-7.27 (m, 2H), 7.43 (d, 1H J=7.4 Hz), 7.74 (d, 1H J=7.8 Hz), 8.01 (s, 1H), 8.86 (br s, 1H), 10.15 (s, 1H). MS m/z: 415.2 (ES+, M+H).
Reaction SMILES: [O:1]=[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.C[Si](Cl)(C)C.C([O-])(O)=O.[Na+].C1C(=O)N([Br:32])C(=O)C1>CN(C=O)C.C1COCC1.CCCCCC.O>[Br:32][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in 30 mL of DMF at RT was added TEA (7.7 mL, 55 mmol) followed by TMSCl (3.5 mL, 27.6 mmol), then the mixture was stirred at 75° C. overnight. The reaction was cooled to RT, cold sat. aq. NaHCO3 (200 mL) was added followed by cold hexane (200 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated to get the crude product directly used in the next step. The residue was dissolved in 15 mL of THF and stirred at 0° C. for 15 min. A solution of NBS (4.47 g, 25 mmol) in 80 mL of THF was added slowly. After addition, the reaction was stirred at RT overnight. Water (200 mL) was added to the reaction followed by 200 mL of hexane. The organic layer was washed with brine, dried over Na2SO4 and concentrated to get crude product which was chromatographed on 60 g of silica gel using PE/EA (20/1 to 8/1) as eluant to afford 5.56 g (78%) of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.85-4.70 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.55 (m, 3H), 2.80-2.68 (m, 1H), 2.54-2.44 (m, 1H), 1.43 (s, 9H). MS (ESI) m/e [M-t-Bu]+ 221.9, 224.0.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:13][Si:14]([C:17]#[C:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:17]([Si:14]([CH3:16])([CH3:15])[CH3:13])[N:3]=[N:2]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C[Si](C)(C)C#CN1CCOCC1
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1nnn(-c2ccc([N+](=O)[O-])cc2)c1N1CCOCC1
Temperature: 60 °C

Procedure:
A mixture of 1-azido-4-nitrobenzene (0.5 g, 3.0 mmol), 4-((trimethylsilyl)ethynyl)morpholine (1.0 g, 9.0 mmol) and toluene (10 mL) was heated in a sealed tube to 60° C. for 24 h. The reaction mixture was concentrated in vacuo to give 4-(1-(4-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazol-5-yl)morpholine which was further reduced following procedure D to afford 4-(5-morpholino-4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)aniline.
Reaction SMILES: Cl[C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[H][H]>[C].[Pd].O>[F:9][C:8]1[CH:2]=[C:3]([CH:5]=[C:6]([F:10])[CH:7]=1)[NH2:4]
Reactant: [H][H]
Reactant: Nc1cc(F)cc(F)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cc(F)cc(F)c1
Temperature: 50 °C
Yield: 92 %

Procedure:
Into a 500 ml SUS autoclave, 45.4 g (purity: 98%, 0.272 mol) of 2-chloro-3,5-difluoroaniline, 1.84 g of 5% palladium-carbon, 30.2 g (0.299 mol) of triethylamine and 45.4 g of water were introduced, and hydrogen gas was sealed in. Then, the mixture was reacted under a hydrogen gas pressure of 15 kg/cm2 at a temperature of 100° C. for 4 hours. Then, the reaction solution was cooled to 50° C. Then, palladium-carbon was filtered off, and 50 g of a 25% sodium hydroxide aqueous solution was added. The mixture was stirred and left to stand still. Then, the oil layer was separated. Then, this oil layer was distilled to recover 28.5 g of triethylamine, and then 32.3 g (purity: 99%, yield: 91.0%) of 3,5-difluoroaniline was obtained.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:14][N:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:16]1=[O:26]>C(O)(C)C>[OH:13][CH:3]([CH2:4][O:5][C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][N:23]1[CH2:22][CH2:21][CH:20]([N:17]2[CH2:18][CH2:19][N:15]([CH3:14])[C:16]2=[O:26])[CH2:25][CH2:24]1
Reactant: OC(CCl)COc1cccnc1Cl
Reactant: CN1CCN(C2CCNCC2)C1=O
Solvent: CC(C)O
Product: CN1CCN(C2CCN(CC(O)COc3cccnc3Cl)CC2)C1=O

Procedure:
A mixture of 7.3 g of 1-chloro-3-(2-chloro-3-pyridyloxy)-2-propanol and 5.0 g of 3-methyl-1-(4-piperidyl)-imidazolidin-2-one is refluxed in 100 ml of isopropanol for 2 hours. Working up analogously to Example 1 yields oily 1-{1-[2-hydroxy-3-(2-chloro-3-pyridyloxy)-propyl]-4-piperidyl}-3-methyl-imidazolidin-2-one.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.CN(C)[CH:37]=[O:38]>C1COCC1>[Si:5]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:17])=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH:37]=[O:38])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:6])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
tert-Butyl(2-fluorophenethoxy)dimethylsilane (example 78, step a) (5.00 g) was added over 5 minutes to a stirred solution of sec-butyllithium (1.4 molar solution in cyclohexane, 14.0 mL) and N1-(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (4.10 mL) in THF (25 mL) cooled to −78° C. After 2 h, N,N-dimethylformamide (10.06 g) was added, the reaction mixture was stirred at −78° C. for 1 h, and then the cooling bath was removed. After a further 0.5 h, the reaction was quenched with water. Ethyl acetate (300 mL) was added and the reaction mixture washed with water (3×150 mL), 2M HCl (2×50 mL), water (2×50 mL), brine then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as an oil. Yield 5.3 g.