Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24]S(C)(=O)=O)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]([F:46])([F:45])[CH2:43]O.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:43][C:42]([F:46])([F:45])[F:41])=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOS(C)(=O)=O)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3cccnc3c2)C1

Procedure:
In analogy to the procedure described in example 23(e), the (3R,4R)-4-[4-(3-methanesulfonyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 23(d)] was reacted with 2,2,2-trifluoro-ethanol and sodium hydride suspension in tetrahydrofuran to yield the (3R,4R)-3-(quinolin-7-ylmethoxy)-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil; MS: 575 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:14]1[CH2:15][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]([C:1]([O:9][CH3:10])=[O:8])[CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C\C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2ccccc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.02 %

Procedure:
To a solution of dimethyl maleate (4.00 g) in CH2Cl2 (100 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq) followed by a solution of TFA in CH2Cl2 (0.1 eq, 1 M) dropwise at 0° C. under N2. The reaction mixture was heated to room temperature and stirred for 6 h, washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 3:1 (v/v) PE/EA) to yield the title compound (6.62 g, 86.02%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 278 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.70-2.75 (m, 2H), 3.12-3.17 (m, 1H), 3.30-3.33 (m, 2H), 3.66 (s, 6H), 7.24-7.31 (m, 5H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:32]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1cnc2ccccc2n1
Yield: 48.8 %

Procedure:
To a solution of 4.30 g (17.8 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 8.68 ml (62.3 mmol) of triethylamine in 200 ml of methylene chloride, 3.43 g (17.8 mmol) of 2-quinoxaloyl chloride was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) and recrystallization (solvent: ethyl acetate-ether) to give 2.82 g of the desired compound (48.9% yield, white crystals).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Product: COc1ccc(Cl)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2-chloro-5-methoxyaniline (27 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (20 mg, 55%). 1H NMR (CDCl3): 8.87–8.82 (m, 1H), 8.72–8.64 (m, 3H), 8.08 (d, J=2.7 Hz, 1H), 7.92 (s, 1H), 7.90–7.86 (m, 2H), 7.45–7.38 (m, 3H), 7.33 (d, J=8.7 Hz, 1H), 6.67 (dd, J=3.0, 9.0 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:23]>C(COC)OC.CCOCC>[Br:23][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(OC)c(CBr)c1)OC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.2 g of ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate was dissolved in 15 ml dimethoxyethane. 1.2 ml phosphorus tribromide was added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with ether and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, to give 2.6 g of ethyl 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate from fractions eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[C:3]1=[CH:4][C:5]1[N:9]=[C:8]([SH:10])[NH:7][C:6]=1[CH:11]=2.[OH-].[Na+].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>O>[CH3:1][C:2]1([CH3:18])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[C:3]1=[CH:4][C:5]1[N:9]=[C:8]([S:10][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[NH:7][C:6]=1[CH:11]=2
Reactant: ClCc1ccccn1
Reactant: CC1(C)CCC(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc3[nH]c(SCc4ccccn4)nc3cc21
Yield: 57.6 %

Procedure:
9.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1H-naphth(2,3-d)imidazole-2-thiol were suspended in 60 ml of alcohol in a 250 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and reflux condenser. A solution of 3.24 g of sodium hydroxide in 20 ml of water was added dropwise thereto while stirring well and the mixture was stirred at room temperature for an additional 30 minutes. After adding 6.0 g of 2-chloromethyl-pyridine hydrochloride, the mixture was boiled at reflux overnight and subsequently evaporated. The residue was taken up in 1 l of ethyl acetate, washed neutral three times with 250 ml of water, dried over sodium sulfate and, after evaporation in vacuo, recystallized from acetonitrile. There were obtained 7.0 g (57.3% of theory) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-[(2-pyridylmethyl)thio]-1H-naphth(2,3-d)-imidazole of melting point 199°-200° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6].CCN(C(C)C)C(C)C.[CH:28]1[CH:33]=[C:32]([CH2:34][O:35][C:36](Cl)=[O:37])[C:31]([Cl:39])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:36]([O:35][CH2:34][C:32]3[CH:33]=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:39])=[O:37])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6]
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: COC(=O)c1ccc(Cn2cc(N)cn2)o1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-amino-pyrazol-1-ylmethyl)-furan-2-carboxylic acid methyl ester (2.90 g, 13.10 mmol) in CH2Cl2 (58.0 mL) was treated with DIPEA (3.37 mL, 19.66 mmol) followed by 2-chlorobenzylchloroformate (2.69 mL, 17.04 mmol). The reaction mixture was stirred at rt for 4 h before being quenched with water (100 mL), extracted with CH2Cl2 (3×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a solid. TLC: rf (50:50 hept-EA)=0.22. LC-MS-conditions 02: tR=0.94 min; [M+H]+=390.37. 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 5.29 (s, 2H), 5.31 (s, 2H), 6.39 (d, J=2.5 Hz, 1H), 6.75 (s, 1H), 7.12 (d, J=3.0 Hz, 1H), 7.23-7.31 (m, 2H), 7.38-7.42 (m, 1H), 7.43-7.46 (m, 2H), 7.75 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: C1COCCOCCOCCOCCOCCN1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and (1-adamantyl) acetyl chloride.
Reaction SMILES: C([C:5]1[C:6]([O:14][CH3:15])=[C:7]([NH2:13])[CH:8]=[C:9]([I:12])[C:10]=1[Cl:11])(C)(C)C.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:10]1[C:9]([I:12])=[CH:8][C:7]([NH:13][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COC(=O)C(C)Br
Reactant: COc1c(N)cc(I)c(Cl)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Nc1cc(I)c(Cl)cc1OC
Temperature: 100 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
A mixture of tert-butyl 4-chloro-5-iodo-2-methoxybenzenamine (2 g, 7.07 mmol), methyl 2-bromopropanoate (1.17 g, 7.07 mmol), K2CO3 (1.94 g, 14.14 mmol) and KI (0.235 g, 1.414 mmol) in DMF (25 mL) was stirred at 100° C. for 16 h. The mixture was allowed to cool to RT, quenched with aqueous NaHCO3 solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:20) to afford the desired product (1.12 g, 43% yield) as a yellow solid. ESI-MS m/z: 370.1[M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(Br)nc1
Yield: 97.5 %

Procedure:
To 6-bromo-pyridine-3-carboxaldehyde (300 mg, 1.61 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (647 mg, 1.94 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-bromo-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 97%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].ClC(OCC(C)C)=O.[CH2:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])[CH3:28].Cl>C1COCC1.C(N(CC)CC)C>[CH2:27]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])[C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:28]
Reactant: CCNCCCCCC(C)O
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CCCCCC(C)O)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: -8 °C
Reaction time: 1.5 h
Yield: 48.5 %

Procedure:
A stirred solution of 4-((methanesulfonyl)amino)-γ-oxobenzenebutanoic acid (as described in EP 164 865) (0.49 g, 1.8 mmol) in THF (15 ml), under nitrogen, was treated with triethylamine (0.28 ml), cooled to -8° C. and treated during 5 minutes with isobutyl chloroformate (0.26 ml, 2.04 mmol). This mixture was kept at -5° to -8° C. for 90 minutes and then treated during 30 minutes with a solution of the product from Step III (0.31 g, 1.95 mmol) and triethyl amine (0.28 ml) in THF (10 ml). The mixture was kept at -8° C. for 2 hours and then poured into 1N HCl (19.2 ml). The product was extracted with EtOAc; the extract was washed successively with water, aqueous NaHCO3, water and brine; dried (MgSO4) and concentrated. The residue was crystallized frown EtOAc-hexane to give 0.36 g (48.6%) of N-ethyl-N-(6-hydroxyheptyl)-γ-oxo-4-((methanesulfonyl)amino)benzenebutanamide, mp 78°-80° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[O:32][CH:31]([CH3:33])[CH2:30][NH:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:29]1[CH2:28][CH:27]([CH3:26])[O:32][CH:31]([CH3:33])[CH2:30]1)=[O:13])[CH2:8]2
Reactant: CC1CNCC(C)O1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CC1CN(c2c(C(=O)NC3C4CC5CC(C4)CC3C5)cnn2-c2ccccc2)CC(C)O1

Procedure:
5-(2,6-Dimethyl-morpholin-4-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2,6-dimethylmorpholine. Mass spectrum (ES) MH+=435.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.Cl.[CH3:21][NH:22][O:23][CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]([O:23][CH3:24])[CH3:21])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccnc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.5 %

Procedure:
A solution of 2-chloronicotinic acid (20.0 g, 127 mmol) in N,N-dimethylformamide (600 mL, 0.21M) was treated with N,N-diisopropylethylamine (66 mL, 379 mmol), N,O-dimethylhydroxylamine hydrochloride (13.63 g, 140 mmol), and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (84.25 g, 190 mmol). The reaction was stirred at 25° C. over 3 d. The resulting reaction was concentrated in vacuo, taken up in ethyl acetate (400 mL) and washed with a saturated aqueous ammonium chloride solution (2×250 mL), a saturated aqueous sodium bicarbonate solution (2×250 mL), and a saturated aqueous sodium chloride solution (250 mL). The organics were dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix IntelliFlash 280 column chromatography, 400 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 2-chloro-N-methoxy-N-methyl-nicotinamide (23.58 g, 93%) as a light yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[CH3:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:21][C:22]1[CH:23]=[N:24][N:25]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:26]=1
Reactant: Cc1cn[nH]c1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnn(-c2cnccc2-c2nc3cc(C(F)(F)F)ccc3o2)c1
Temperature: 60 °C
Yield: 73.2 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of 4-methylpyrazole, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60° C. for 1.5 hours. To the mixture, 0.05 g of 4-methylpyrazole was added and further stirred while heating at 60° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(4-methylpyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 61”).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=O)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[Si:18]([O:17][CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1
Yield: 86.3 %

Procedure:
To a solution of D2 (12.7 g, 0.036 mol) and cyclohexene (excess, 20 ml) in ethanol (100 ml) was added 10% palladium on charcoal catalyst. Reaction was heated at reflux overnight and cooled. Catalyst was filtered and the filtrate concentrated to leave an oil (6.69 g) which was used in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccc(Cl)cc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.38 g, 1.1 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 15 min. Solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(2,4-dichloro-phenyl)-piperidin-4-ol as a white solid (0.23 g, 85%). The material was used as is without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: O=C(N[C@@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Product: O=C(N[C@@H]1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(R)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and 2-(4-fluorophenyl)ethyl p-toluenesulfonate were reacted under the same conditions as in Example 1 to give (R)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](I)[CH3:15].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:14][CH3:15])[C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)propanoic acid (0.7 g, 3.7 mmol) and ethyl iodide (2.6 ml, 32.2 mmol) in THF (10 ml) was added sodium hydride (60% w/w dispersion in mineral oil, 576 mg, 14.4 mmol). The reaction was sealed and stirred at 60° C. overnight, then partitioned between EtOAc and H2O. The aqueous layer was acidified to pH 4 with citric acid solution and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to provide (S)-2-(tert-butoxycarbonyl(ethyl)amino)propanoic acid (700 mg, 87%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]([O:20][NH:21][CH3:22])([CH3:19])[CH3:18].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:21]([CH3:22])[O:20][CH:17]([CH3:19])[CH3:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNOC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(N(C)OC(C)C)n1
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.65 g, 16.61 mmol), O-isopropyl-N-methyl-hydroxylamine hydrochloride (LXIII, 2.09 g, 16.61 mmol) and NaOH (0.66 g, 16.61 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100° C. for 16 h. The volatiles were then removed under reduced pressure. Saturated NaHCO3 solution (50 mL) was added to the residue and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV, 1.93 g, 95%). ESI-MS (m/z): 283 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([F:27])([F:26])[C:15]([N:17]([F:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([F:27])([F:26])[C:15]([N:17]([F:25])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(N(F)Cc1ccccc1)C(F)(F)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(C(F)(F)C(=O)N(F)Cc1ccccc1)CCC2
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)trifluoroacetamide (2.55 g, 6.75 mmol) in THF/MeOH (100 ml, 1:1) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 2-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)trifluoroacetamide which was homogeneous by TLC and used immediately in the next step.