Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:18]=[C:17]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1.[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34]Br)(=[O:29])[CH3:28].[H-].[Na+]>>[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][O:16][CH2:15][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:20][C:19]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:18][C:17]=2[Cl:26])[O:14][N:13]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCCOCBr
Reactant: OCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOCOCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl}-3-isoxazolylmethoxymethoxyethyl acetate [XXIV; n=5, R1 and R2 =Cl] was prepared from 4.0 g of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 116) and 2.0 g of 2-acetoxyethoxymethyl bromide [CH3COCH2CH2OCH2Br] in the presence of sodium hydride according to the procedure of Example 117, and was obtained in the form of a colorless oil (2.4 g).
Reaction SMILES: [F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(C)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Fc1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reactant: OCCN1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: OCCN1CCN(C2Cc3ccccc3Sc3cc(F)c(Cl)cc32)CC1

Procedure:
A mixture of 7-fluoro-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine (the preparation of which is described in Example 19) (4.5 g), 1-(2-hydroxyethyl)piperazine (4.1 g) and chloroform (5 ml) was refluxed for 7.5 hours. The reaction mixture was then diluted with chloroform (50 ml) and the solution washed with water. The chloroform was evaporated the residue dissolved in benzene (200 ml) and the solution shaken with 3 N-HCl (60 ml). The separated hydrochloride was filtered, suspended in the aqueous layer of the filtrate and the suspension made basic with ammonium hydroxide. The liberated base was taken up in chloroform and isolated as usual; m.p. 150°-152° C. (acetone), yield 4.8 g (81%).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4].[H][H]>C(O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: C=C(CCCCCCC)C(=O)O
Solvent: CCO
Product: CCCCCCCC(C)C(=O)O
Yield: 98.9 %

Procedure:
In a 200 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 3.0 g (17.6 mmoles) of 2-methylenenonanoic acid and 50 ml of ethanol. Then, 6.9 mg (0.007 mmole) of [Ru((-)-T-BINAP)](ClO4)2 prepared according to the same manner as in Referential Example 6 except using (-)-T-BINAP in place of (+)-T-BINAP was added to the mixture to perform hydrogenation for 15 hours at a hydrogen pressure of 30 kg/cm2 and at a reaction temperature of 20° C. Thereafter, the solvent was distilled off to provide 3.0 g of 2-methylnonanoic acid. The theoretical yield (hereafter simply referred to as "yield") was 100%.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH3:4])[C:4]1[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC=O
Reactant: Cc1cc(N)n[nH]1
Product: CCCCN(CCCC)c1cc(C)[nH]n1
Yield: 106.1 %

Procedure:
Following a procedure analogous to that for the synthesis Example 106, 5-methyl-1H-pyrazol-3-amine (Aldrich, 486 mg, 5.00 mmol) and butyraldehyde (541 mg, 7.50 mmol) were converted to the title compound (555 mg, 53%). 1H NMR (CDCl3) δ 5.34 (s, 1H), 3.17 (t, J=7.3 Hz, 4H), 2.21 (s, 3H), 1.55 (td, J=15.1, 7.5 Hz, 4H), 1.34 (qd, J=15.0, 7.3 Hz, 4H), 0.94 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 210.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:27]=[N:28][C:29]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][CH:31]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc(-c5ccccc5)nn4)cc3CC[C@@H]12
Yield: 48.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 3-chloro-6-phenyl-pyridazine (88 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 77 mg (49%) of the title compound as an amorphous solid. mp 199°-200°. FDMS: m/e=415. α[D]589 =+67.26 (c=0.63, chloroform).
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:14]([NH2:16])=[O:15])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:33])[CH:30](O)[OH:31].C(O)(=O)CCCC(O)=O.Cl.Cl.Cl.N(CCCCCCC=CC(NC(O)C(N)=O)=O)C(N)=N>O>[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:33])[CH:30]([NH:16][C:14](=[O:15])[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:31]
Reactant: N=C(N)NCCCCCCC=CC(N)=O
Reactant: NCCCNCCCCNC(=O)C(O)O
Agent: Cl
Agent: N=C(N)NCCCCCCC=CC(=O)NC(O)C(N)=O
Agent: O=C(O)CCCC(=O)O
Solvent: O
Product: N=C(N)NCCCCCCC=CC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C
Yield: 38.9 %

Procedure:
A mixture of 206.2 mg (0.84 mmole) of 9-guanidino-2-nonenamide hydrochloride, 291.0 mg (1.00 mmole) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, 109.6 mg (0.84 mmole) of glutaric acid and 0.2 ml of water was heated at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was purified in a manner similar to that in Example 1 using CM-Sephadex® C-25 (Na-type) and Sephadex®LH-20 to obtain 135.0 mg (31.1% yield) of a white powder of N-[4-(3-aminopropyl)aminobutyl]-2-(9guanidino-2-nonenamido-2-hydroxyethanamide trihydrochloride.
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18](=[O:25])[C:19](CO)([CH3:22])[CH2:20][OH:21]>C(Cl)Cl.N1C(C)=CC=CC=1C>[CH3:16][O:17][C:18](=[O:25])[C:19]([CH3:22])([O:1][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:20][O:21][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:1]
Reactant: COC(=O)C(C)(CO)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)(COS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F

Procedure:
Add Tf2O (80 mL) dropwise to a cold (−78° C.) solution of 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid methyl ester (32.5 g) in CH2Cl2 (400 mL) and 2,6-lutidine (80 mL). The reaction is allowed to reach room temperature and stir until only product spot detected by TLC analysis (ca. 2 h). Dilute with CH2Cl2 (400 mL) and wash with HCl (3% aqueous solution). Dry the organic layer over MgSO4, filter and concentrate. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate 5%, to give 2-methyl-2,3-bis-trifluoromethanesulfonyloxy-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CC(CC)=O.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (63.7 mmol) 2-fluoro-4-nitrophenol, 17.6 g (127 mmol) potassium carbonate and 13.24 g (70.0 mmol) 3-fluorobenzyl bromide in 200 ml ethyl methyl ketone is hold overnight at 80° C. The reaction mixture is diluted with water and extracted with ethyl acetate. Crystallisation from diethyl ether/n-hexane gives 12.68 g (75%) of a slightly yellow solid. MS: m/e=265.1 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([C@@:22]1([CH2:36][CH:37]([F:39])[F:38])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1)=[O:21].C(N(CC)CC)C>CS(C)=O>[F:39][CH:37]([F:38])[CH2:36][C@:22]1([C:20]([N:14]2[CH2:15][C@@H:16]3[CH2:19][C@H:13]2[CH2:18][N:17]3[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)=[O:21])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3)C1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)n2)C1
Temperature: 120 °C

Procedure:
Prepared as described in example 24 using 2-chloro-6-(trifluoromethyl)pyridine in place of 4-chloro-6-(trifluoromethyl)pyrimidine and modifying step 9 as follows. To a solution of HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (183 mg, 0.43 mmol) in DMSO (2 ml) was added triethylamine (0.2 ml, 1.43 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (179 mg, 1.05 mmol). The reaction was heated to 120° C. for 14.5 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[6-(trifluoromethyl)pyridin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a brown foam (58 mg 28%). LC/MS (M+H)=533.2551 exp, 533.2546 obs; 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.51 (1H), 6.91-6.89 (1H), 6.51-6.38 (1H), 5.94-5.54 (1H), 5.11-4.70 (2H), 4.06-4.01 (1H), 3.93-3.87 (1H), 3.70-3.53 (2H), 3.51-3.31 (6H), 3.27-3.20 (3H), 2.78-2.61 (1H), 2.53-2.36 (1H), 2.20-1.80 (7H), 1.68-1.38 (5H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]3[CH2:49][CH2:48][N:47]4[CH2:51][CH2:52][CH2:53][C@H:46]4[CH2:45]3)=[O:17])[CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Reactant: C1C[C@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1)N1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 3.05 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.27 g, 3.35 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (S)-octahydropyrrolo[1,2-α]pyrazine (0.55 g, 4.33 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and then diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2=[C:19]3[C:14](=[N:15][C:16](S(C)(=O)=O)=[N:17]2)[N:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:12][CH2:11][C:10]3=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CS(C)=O.CCN(C(C)C)C(C)C>[CH2:1]([N:8]1[C:18]2=[C:19]3[C:14](=[N:15][C:16]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:17]2)[N:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:12][CH2:11][C:10]3=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN2CCc3nn(Cc4ccccc4)c4nc(S(C)(=O)=O)nc2c34)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(CN2CCc3nn(Cc4ccccc4)c4nc(N5CCOCC5)nc2c34)cc1
Temperature: 100 °C

Procedure:
The mixture of 1-benzyl-5-(4-methoxybenzyl)-7-(methylsulfonyl)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene (0.1 mmol) and morpholine (0.2 mmol) in anhydrous DMSO (1 mL) and DIPEA (0.06 mL) was heated at 100° C. for 64 h in 2-dram vials. The solvent was then removed on Genevac. The residue was re-brought up to DMSO (1.2 mL) and was purified by HPLC using reverse phase column chromatography with a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% trifluoroacetic acid , to yield the 4-(1-benzyl-5-(4-methoxybenzyl)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylen-7-yl)morpholine compound 131 White solid, 50% yiled, M.p. 118-120° C.; 1H NMR (CDCl3, 400 MHz) δ 7.33-7.23 (m, 7H), 6.86 (d, J=8.4 Hz, 2H), 5.33 (brs, 2H), 4.71 (s, 2H), 3.92 (m, 4H), 3.79 (m, 7H), 3.48 (m, 2H), 2.98 (t, J=6.4 Hz, 2H). LC-Mass (m/e): 457.56 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:28][CH3:29])[C:11]1[C:12]([O:23][CH3:24])=[CH:13][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 103 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester and 17.3 g. of sodium hydride (50% dispersion in oil) in 1 liter of absolute dimethylformamide was stirred at room temperature for 4 hours and subsequently treated with 56.2 g. of ethyl iodide with stirring and ice-cooling. After stirring at room temperature for 30 minutes, the dimethylformamide was removed at 60° C. under vacuum. Then, 1 liter of water was added to the residue and the mixture was extracted with two 1.5 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 700 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained N-ethyl-2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester having a melting point of 85°-86° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cu](C#N)[C:32]#[N:33].N.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:32]#[N:33])[CH:29]=1
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Temperature: 80 °C
Yield: 51 %

Procedure:
To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) in N,N-dimethyl formamide (25 ml) under N2 was added copper cyanide. The resultant suspension was refluxed for 1 hour. The reaction was monitored by TLC and checked for the completion. Heating was discontinued and the reaction mixture was cooled down to 80° C. Ice water (15 ml), 25% aqueous ammonia (15 ml), and ethyl acetate (50 ml) were added to quench the reaction. The mixture was filtered to remove the solids. From the filtrate organic layer was separated. The organic layer was washed with water, saturated brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude material dried at 60° C. under high vacuum then purified by column with ethyl acetate as eluent to provide the product (3 g, 51%) as an off white solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 70/30, 30 min elution) tR 23.70 min, 99.4% purity; 1H NMR (400 MHz, CDCl3) δ8.10 (t, J=2.9 Hz, 1H), 8.06 (t, J=2.7 Hz, 1H), 8.04 (m, 1H), 7.85 (t, J=2.5 Hz, 1H), 7.83 (m, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.37 (s, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.41 (s, 1H), 5.94 (s, 2H), 2.88 (m, 1H), 2.24 (s, 3H), 0.86 (dd, J=6.9, 6.1 Hz, 2H) 0.61 (m, 2H) ppm; 13C NMR (400 MHz, CDCl3) δ186.6, 167.2, 151.5, 141.3, 140.7, 140.3, 135.1, 134.5, 134.0, 132.2, 131.8, 129.5, 128.7, 126.2, 118.1, 113.0, 103.7, 30.9, 23.2, 17.7, 6.8 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32][CH3:33])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][N:18]([C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:35]=2[Cl:34])[C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Yield: 87.4 %

Procedure:
4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (133 mg, 0.28 mmol) was dissolved in 1,2-dichloroethane (2.8 mL) and was treated with 2,4-dichlorobenzoyl chloride (60 μL, 0.43 mmol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 4-{[(2,4-Dichloro-benzoyl)-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (0.156 g, 85% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=[O:42].[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:41]([C:37]2[S:36][CH:40]=[CH:39][N:38]=2)[OH:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1nccs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3nccs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1,3-thiazole-2-carbaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:28](O)C>>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([S:17][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:25])=[CH:5][CH:6]=2)[CH2:11][CH:12]([CH3:28])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCO
Reactant: CCCCCCC(Sc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(C)CC(Sc1ccc(Br)cc1)c1ccc(C(=O)O)cc1

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-heptyl)-benzoic acid methyl ester (1760 mg, 7.04 mmol) in toluene (70 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2664 mg, 10.56 mmol) at 0° C., followed by the additions of tributylphosphine (2.63 mL, 8.38 mmol) and 4-bromo-benzenethiol (1597 mg, 8.45 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-heptyl]-benzoic acid methyl ester. 1700 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoic acid (1700 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2[N+](=O)[O-])C1
Temperature: 120 °C
Yield: 77.2 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (1.41 g, 10.0 mmol), (R)-3-aminopiperidine-1-carboxylic acid tertbutyl ester (2 g, 10.0 mmol) and potassium carbonate (152 mg, 11.0 mmol) in DMF (18 mL) was heated to 120° C. under microwave irradiation for 30 min. The reaction mixture was partitioned between EtOAc (150 mL) and water. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10% EtOAc in DCM) affording (R)-3-(2-Nitrophenylamino)piperidine-1-carboxylic acid tertbutyl ester as an orange oil (2.48 g, 77%). LCMS: RT 3.95 min [M+H-tBu]+ 266.2.