Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[N:20]1([CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:27]([CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: c1cc(NCCN2CCCC2)ccn1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N(CCN2CCCC2)c2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-[2-(pyrrolidin-1-yl)ethylamino]pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)-pteridine 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([NH:7][C:8]2[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[N+:21]([O-])=O)=[CH:5][CH:4]=1.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:21][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])[C:8]=1[NH:7][C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12]([OH:14])=[O:13]
Reactant: COc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: COc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
By substituting 4-(p-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 214°C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH2:16][CH2:17][O:18][CH:19]=[CH2:20]>>[CH:19]([O:18][CH2:17][CH2:16][NH:15][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)=[CH2:20]
Reactant: C=COCCN
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Product: C=COCCNC(C)Cc1cccc(C(F)(F)F)c1
Yield: 32 %

Procedure:
N-(2-vinyloxyethyl)-α-methyl-β-(3-trifluoromethylphenyl)-ethyl amine was prepared from 3-trifluoromethylphenylacetone and 2-aminoethylvinylether according to the method of Example 1. The product was obtained in 32% yield as a colorless oil, b.p. 81°-83°/0.5 mm; ND25 1.4650.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])[N:4]=1.[CH3:17][S:18]([NH2:21])(=[O:20])=[O:19].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([CH3:16])[C:13]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[O:14])[N:4]=1
Reactant: COc1cc(OC)nc(OC(C)C(=O)O)n1
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OC(C)C(=O)NS(C)(=O)=O)n1
Yield: 58.6 %

Procedure:
To a solution of 1,1-carbonyldiimidazole (1.70 g, 0.0105 mol) in dry tetrahydrofuran (130 ml), 2-(4,6-dimethoxypyrimidin-2-yl)oxypropionic acid (2.28 g, 0.01 mol), prepared as described in Example 1(b) above, in tetrahydrofuran (30 ml) was added dropwise at room temperature (~ 20° C.). The solution was refluxed for 1/2 hour and allowed to cool. Methanesulphonamide (0.95 g, 0.01 mol) Was added in one solid portion and the mixture stirred for 15 minutes before 1,8-diazabicyclo[5.4.0]undec-7-ene (1.52 g, 0.01 mol) in tetrahydrofuran (30 ml) was added dropwise at room temperature (18 20° C.). After a short duration the tetrahydrofuran was removed and the residue acidified with 1M hydrochloric acid solution. The product was extracted with chloroform, backwashed with water and dried. The solvent was removed and the product purified on silica gel eluting with 3% by volume methanol/chloroform to yield the title compound as a solid (1.79 g).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@@H:7]1[C@@H:11]([CH2:12][Si:13]([CH3:21])([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:22][OH:23])=[CH:9][CH2:8]1)([CH3:4])[CH3:3].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30].[Mg+2]>CO.C(OCC)(=O)C>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][C@H:7]1[CH2:8][C@@H:9]2[C@@:10]([CH2:22][OH:23])([O:30]2)[C@@H:11]1[CH2:12][Si:13]([CH3:21])([CH3:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC=C(CO)[C@@H]1C[Si](C)(C)c1ccccc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H]2O[C@@]2(CO)[C@@H]1C[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a cooled (0° C.), stirred solution of 44 (14 g, 37.23 mmol) in MeOH (50 mL) was added magnesium monoperoxyphthalate (MPPA, 80% pure, 27.62 g, 44.68 mmol) in six portions over a period of 1 hour, keeping the temperature <0° C. The reaction mixture was stirred at the same temperature for 4 hours to complete the reaction. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated sodium bisulfite (200 mL), sodium hydroxide (0.5 N, 2×150 mL), brine (150 mL) and dried over magnesium sulfate. The organic layer was concentrated in vacuo to dryness to give the crude title compound (13.5 g, 92%)
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25][SH:26]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:26][CH2:25][C:19]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: Fc1cccc(Cl)c1CS
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3c(F)cccc3Cl)c21
Yield: 70.1 %

Procedure:
The title compound (cis/trans=18:82) was prepared as pale brown crystals in 70.1% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=(22/78) and 2-chloro-6-fluorophenylmethanethiol.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:37]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=2[Cl:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>C(O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:3][CH:4]=3
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(-n2c3ccc(Br)cc3c3cc(Br)ccc32)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-n2c3ccc(Br)cc3c3cc(-c4ccccc4)ccc32)cc1
Yield: 51.7 %

Procedure:
3,6-Dibromo-N-(4-methylphenyl)carbazole (6.23 g) and phenylboronic acid (2.01 g) were added to a solvent mixture of toluene (60 mL) and ethanol (15 mL), followed by bubbling with nitrogen. Then, tetrakistriphenylphosphine palladium (290 mg) and 21.2% aqueous sodium carbonate solution (15.0 g) were added to the mixture, and the resultant mixture was refluxed under nitrogen flow for 5 hours. The mixture was diluted with toluene. The toluene layer was washed with water and dried and the toluene was evaporated. The residue was treated through silica gel column chromatography (eluent: toluene/hexane=1/4 (by mass)), to thereby obtain 3.20 g of 3-bromo-6-phenyl-N-(4-methylphenyl)carbazole as colorless powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][N:26]([CH3:32])[C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH3:25][N:26]([CH3:32])[C@@H:27]1[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:28]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(CCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)C1

Procedure:
The product from Example 1C and 3-(R)-(dimethylamino)pyrrolidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 360 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[CH:22]=[C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=1>CN(C=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1cnc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Br)ncc2[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])CC1
Temperature: 150 °C
Yield: 42 %

Procedure:
Palladium (II) acetate (32 mg, 0.14 mmol) was added to (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (268 mg, 0.4 mmol) in DMF/toluene (1/1) and the resulting mixture was degassed under a stream of nitrogen gas for 10 minutes. 2-Amino-5-cyanopyrazine (172 mg, 1.43 mmol), sodium tert-butoxide (207 mg, 2.15 mmol) and tert-butyl 4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (595 mg, 1.43 mmol) were added and the mixture was degassed for a further 5 minutes before being heated at 150° C. for 30 minutes using microwave irradiation. The mixture was concentrated in vacuo and partially purified by silica chromatography, eluting with 40% ethyl acetate-hexane, to give 273 mg of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate at a purity of 75% which was used without further purification.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][OH:18].[H-].[Na+]>O1CCCC1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: COc1ccc(CO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1=C(C)C(OCc2ccc(OC)c(OC)c2)CC1=O
Reaction time: 0.5 h

Procedure:
2-Allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part) was dropwise added to a mixture of 3,4-dimethoxybenzyl alcohol (4 parts), tetrahydrofuran (4 parts) and sodium hydride (1/40 part) in the same flask as used in Example 1 at a temperature of 10° to 20° C. for 30 minutes. Then, the reaction mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the mixture was treated in the same manner as in Example 25 to obtain 2-allyl-3-methyl-4-(3,4-dimethoxybenzyloxy)-2-cyclopentenone. Yield, 96%. nD20 1.5514.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Product: COC(=O)c1ccc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Temperature: 130 °C

Procedure:
A mixture of methyl 4-fluoro-3-nitrobenzoate (1.00 g, 5.02 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.00 g, 5.02 mmol) were heated to 130° C. for 3 h (reaction completion monitored by TLC). The mixture was cooled to room temperature, the resulting solid was collected and washed with n-hexanes to afford (R)-tert-butyl 3-((4-(methoxycarbonyl)-2-nitrophenyl)amino)piperidine-1-carboxylate (I-21a) as a red solid. 1H-NMR (400 MHz, CDCl3): ∂ 8.89 (s, 1H), 8.40 (d, J=7.2 Hz, 1H), 8.06 (dd, J=2 and 6.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 4.75 (d, J=13.6 Hz, 2H), 3.97-3.90 (m, 4H), 3.69-3.63 (m, 2H), 3.24-3.01 (m, 2H), 2.10-2.06 (m, 1H), 1.84-1.73 (m, 2H), 1.46 (s, 9H); MS calculated for C18H24N3O6 (M−H−) 378.17. found 378.4.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 500 mg, 1.76 mmol) in toluene (10 mL) was added with stirring the [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium DCM complex (144 mg, 0.176 mmol), B-(3-chlorophenyl)-boronic acid (552 mg, 3.53 mmol) and sodium carbonate (467 mg, 4.41 mmol) in water (3 mL). The resulting mixture was stirred at 80° C. for 23 h, cooled, poured onto ice/water, acidified with hydrochloric acid (15 mL, 1 N) and partitioned between water and ethyl acetate. The organic portion was washed with brine, combined, dried over Na2SO4, filtered and concentrated. The crude product precipitated as brown solid from the concentrated solution and was used without further purification in the next step. MS (ESI, m/z): 268.1 (M).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][O:24][CH3:25]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][O:24][CH3:25])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COCCBr
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(CCOC)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
This compound was prepared following the procedure described in example 1, part D, starting with 5.5 g (0.02 mol) of 4-(1H-indol-3-yl)-piperidine-carboxylic acid ethyl ester and 2.3 ml (0.0233 mol) of 1-bromo-2-methoxyethane. The reaction mixture was stirred at room temperature for 24 h and after standard work-up, 6.5 g (98% of yield) of 4-[1-(2-methoxyethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Li+].[OH-].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1.O>[Br:11][C:9]1[CH:10]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(Br)cc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc(Br)cc1-c1ccccc1
Temperature: 70 °C

Procedure:
A solution of 2,4-dibromo-benzoic acid, (2.3 g, 18.8 mmol), phenyl boronic acid (5 g, 17.9 mmol), Pd2(dba)3 (818 mg, 8.9 mmol) and LiOH (1.65 g, 39.3 mmol) in a 1:1 mixture of NMP/water (100 mL) was heated to 70° C. for 2 d. After this time, the reaction mixture was cooled to RT, and the reaction mixture was adjusted to pH=4-5 with 3 N HCl. The mixture was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 10:1 to 1:1) to afford 5-bromo-[1,1′-biphenyl]-2-carboxylic acid as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15](O)=[O:16])[CH2:10]1.Cl.N[C@H]1CC[C@H](C(O)=O)CC1>>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]1
Reactant: N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: Cl
Agent: N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCC[C@H](CO)C1

Procedure:
((1S,3R)-3-Aminocyclohexyl)methanol was synthesized as a white powder (157 mg, 59%) using a procedure analogous to that described in Step 1 of Example 179, substituting (1S,3R)-3-aminocyclohexanecarboxylic acid trifluoroacetate from the previous step for trans-4-aminocyclohexanecarboxylic acid hydrochloride used in Example 179.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COC(=O)C=CC=CCBr
Reactant: COc1ccc(S)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.50 g, 7.3 mmol) and 4-methoxythiophenol (0.93 mL, 7.3 mmol) in tetrahydrofuran (40 mL) was added dropwise triethylamine (1.1 mL, 8.0 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for one hour, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (50 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography ((9:1 to 8:2 40-60° C. petroleum ether:diethyl ether) to give the title compound as a colourless oil (1.6 g, 86%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:23][S:24]([O:15][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[N:10][S:11][C:12]=1[C:16]([F:22])([F:21])[C:17]([F:18])([F:19])[F:20])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methanol (108 mg, 0.32 mmol, 1.00 equiv), dichloromethane (10 mL). The solution was cooled to 0 degree C. MsCl (73 mg, 0.64 mmol, 2.00 equiv) and triethylamine (0.097 g, 0.96 mmol, 3.00 equiv) were added dropwise. The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 5 mL of water. Organic phase was separated and the aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.150 g (crude) of [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a white solid. And it could been used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C15H14F5NO3S2, 416.4 (M+H). found 416.4.
Reaction SMILES: Cl.O1CCOCC1.[N:8]([CH2:11][CH:12]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])(C)C)=[O:27])[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[N+:9]=[N-:10].C(=O)([O-])[O-].[K+].[K+].C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC[CH2:42][Si:43](C)([CH3:45])[CH3:44]>>[N:8]([CH2:11][CH:12]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH2:32][Si:43]([CH3:45])([CH3:44])[CH3:42])=[O:27])[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[N+:9]=[N-:10]
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CN=[N+]=[N-])c2ccc(Br)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOC(=O)N1CCC(C(CN=[N+]=[N-])c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Preparation 1-B: A solution of hydrogen chloride in 1,4-dioxane (4 M, 60 mL, 240 mmol) was added to tert-butyl 4-[2-azido-1-(4-bromophenyl)ethyl]piperidinecarboxylate 13 (2.5 g, 6.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure. The residue containing 4-[2-azido-1-(4-bromophenyl)ethyl]piperidine hydrochloride 14 was dissolved in a 50% v/v aqueous tetrahydrofuran solution (68 mL). Potassium carbonate (2.12 g, 15.3 mmol) and 2-(trimethylsilyl)ethyl p-nitrophenyl carbonate (1.74 g, 61.4 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. Organic solvent was evaporated under reduced pressure. Ethyl acetate was added. The organic layer was washed with aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography eluted with ethyl acetate-hexanes (1:5 v/v) to afford 2-(trimethylsilyl)ethyl 4-[2-azido-1-(4-bromophenyl)ethyl]piperidinecarboxylate 15 (2.1 g, 4.6 mmol). MS (LCMS-Electrospray) 454.1 MH+.