Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN1CCOCC1.Cl[CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].C(Cl)Cl.CCOC(C)=O>O1CCOCC1>[O:25]=[C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=[C:15]1[C:13]([NH:12][C:4]1[CH:3]=[C:2]([NH:1][S:36]([CH:35]=[CH2:34])(=[O:38])=[O:37])[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=1)=[O:14]
Reactant: Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of N-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide (429) (500 mg 1.4 mmol) in 1,4-dioxane (4 mL) was added NMM (0.4 mL, 3.6 mmol). β-Chloroethylsulfonyl chloride (0.16 mL, 1.51 mmol) was added under an argon atmosphere. The mixture was stirred at room temperature for 6½ h, after which TLC (CH2Cl2-EtOAc, 8:2) showed a new spot with a very similar Rf to the starting material. Another 0.5 eq. of NMM was added, and the mixture was stirred at room temperature overnight. LCMS analysis of the crude mixture showed >85% conversion to the desired product. The mixture was concentrated, treated with 1M HCl (5 mL), and extracted with EtOAc (3×10 mL) and CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide as an orange foam (0.495 g, 79%), which was used in the next step without further purification. 1H-NMR (d6-Acetone, 300 MHz) δ 8.92 (s, 1H), 8.41-8.38 (m, 1H), 7.94 (m, 2H), 7.78 (br s, 2H), 7.53-7.47 (m, 1H), 7.30 (s, 1H), 6.87-6.79 (dd, J=9.9 Hz, 1H), 6.28 (d, J=16.5 Hz, 1H), 6.09 (d, J=9.9 Hz, 1H); ESI-MS 436.4 m/z (MH−)
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([Cl:13])[C:6]=2[Cl:14])[CH2:11][CH:3]1[CH2:1][CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC)C2
Temperature: 60 °C

Procedure:
A mixture of 2-ethyl-5-hydroxy-6,7-dichloro-1-indanone (9.8 g., 0.04 mole), dimethylformamide (30 ml.), potassium carbonate (12.5 g., 0.09 mole) and ethyl bromoacetate (15 g., 0.09 mole) is stirred and heated on a water bath at 60° C. for one hour. The reaction mixture is poured into ice water (200 ml.) and extracted with two 50 ml. portions of ether. The ether extract is washed with water, dried over magnesium sulfate and the ether distilled at reduced pressure. The ethyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetate thus obtained melts at 116°-118° C. after recrystallization from ethyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C([Li])CCC.F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].Cl>O1CCCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=2)=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)c1cn(C)nc1N
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C)nc1Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 3-amino-1-methylpyrazole-4-carboxylate (Helv. Chim. Acta (1959) 42 349)(17 g) in dry tetrahydrofuran (250 ml) was stirred under nitrogen at -10° C. n-Butyl lithium (75 ml of 1.84 molar solution in hexane) was added at -10° to -15° C. The mixture was stirred at -15° C. for 10 minutes and a solution of 2,5-difluoronitrobenzene (16 g) in dry tetrahydrofuran (50 ml) was added at -15° to -10° C. The solution was warmed to room temperature and stirred for 1 hour. The ink-blue solution was poured into 500 ml of a 1:1 mixture of hydrochloric acid (2M) and ice-brine, extracted with chloroform (3×250 ml), washed with water (2×250 ml), dried with magnesium sulphate and evaporated to dryness. The brick-red residue was crystallised from ethanol (800 ml) to give the title compound having a m.p. of 162° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=408.05.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH:11][C@H:12]([B:20]([O:22]C23CC(C2(C)C)CCC3(O)C)[OH:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C1(B(O)O)C=CC=CC=1.C1(B(O)O)C=CC=CC=1.C12(O)CC(C1(C)C)CCC2(O)C>CC#N.CCCCCC>[C:1]1([CH2:7][S:8]([NH:11][C@H:12]([B:20]([OH:22])[OH:21])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(O)CCC2CC1(OB(O)[C@H](Cc1ccccc1)NS(=O)(=O)Cc1ccccc1)C2(C)C
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: CC#N
Solvent: CCCCCC
Product: O=S(=O)(Cc1ccccc1)N[C@@H](Cc1ccccc1)B(O)O
Yield: 92.2 %

Procedure:
To a solution of 15a (245 mg, 0.54 mmol) in CH3CN (3 mL), HCl (1M aqueous solution, 350 μL, 0.35 mmol), phenylboronic acid (62 mg, 0.51 mmol) and n-hexane (3 mL) were sequentially added and the resulting biphasic solution was vigorously stirred. After 30 min the n-hexane layer, containing the pinanediol phenylboronate, was removed and fresh n-hexane (3 mL) was added. This last procedure was repeated several times until a TLC analysis revealed no remaining pinanediol boronate. The acetonitrile phase was then concentrated affording 16 as a yellowish solid (159 mg, 92% yield). Mp 107° C. (dec). [α]D+78.0 (c 1.0, MeOH). 1H-NMR (400 MHz, MeOD): δ 2.83 (2H, d, J 7.1, CHCH2), 3.05 (1H, t, J 7.1, BCH), 4.20 (2H, s, CH2SO2), 7.16-7.44 (10H, m, HArom). 13C-NMR (100 MHz, MeOD): δ 38.8, 39.3 (CB), 58.6, 126.1, 127.2, 128.0, 128.2, 129.0, 130.1, 130.6, 133.3. EI-MS and elemental analysis were not obtainable, but exposure of 16 to an equimolar amount of (+)-pinanediol in anhydrous THF afforded compound 15a in quantitative yield and satisfactory elemental analysis; Anal. Calcd. for C25H32BNO4S: C, 66.23; H, 7.11; N, 3.09; S, 7.07. Found: C, 66.14; H, 6.91; N, 3.32; S, 6.89.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.O>CN(C=O)C>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: N#CCCN1CCC(N)CC1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1C(=O)C(NC2CCN(CCC#N)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 88.7 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.283 g, 2.800 mmol) and 3-(4-aminopiperidin-1-yl)propanenitrile (0.161 g, 1.050 mmol) in DMF (3 mL) was heated in a microwave reactor at 120° C. for 10 mins. Water was added and the mixture was extracted with EtOAc. The organic phase was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a mixture of heptane and EtOAc (20:80) to 100% EtOAc, then a mixture of MeOH and EtOAc (1:99) as eluant, to give the title compound (0.25 g, 89%); 1H NMR (500 MHz, CDCl3): δ 7.54-7.51 (m, 2H), 7.49-7.44 (m, 3H), 5.20 (br d 1H), 4.46-4.38 (m, 1H), 3.01-2.91 (br m, 1H), 2.70-2.65 (br m, 2H), 2.55 (t, 2H), 2.41 (t 2H), 1.74-1.63 (m 4H), 1.60 (d 6H) 1.44-1.35 (m 2H); 13C NMR (125 MHz, CDCl3): δ 158.7, 134.5, 131.8, 130.1, 128.9, 125.3, 118.8, 106.8, 53.3, 51.5, 50.0, 47.8, 32.4, 20.4, 16.4: Mass Spectrum: M−H+ 403.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][OH:22])=[O:15].C(N(CC)CC)C.C([Mg]Br)C.[Cl-].[NH4+]>O1CCCC1.C(O)C>[Cl:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH:21]([CH2:1][CH3:2])[OH:22])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(c1ccccc1Cl)N1CCCC1CO
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(O)[C@@H]1CCCN1C(=O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Tetrahydrofuran (24 ml) was cooled to −60° C. with stirring and oxalyl chloride (1.15 ml, 13.2 mmol) was added. Dimethylsulfoxide (0.98 ml, 13.8 mmol) was then added dropwise. The mixture was stirred for 20 minutes, then a solution of 1-(2-chlorobenzoyl)-2-pyrrolidinemethanol (3.0 g, 12.5 mmol) in tetrahydrofuran (24 ml) was added dropwise over 15 minutes. After a further 15 minutes, the mixture was treated with triethylamine (7.0 ml, 50.1 mmol). The mixture was warmed briefly to 0° C. before re-cooling to −78° C. Ethylmagnesium bromide (3.0 M in diethyl ether; 16.7 ml, 50.1 mmol) was added dropwise to the vigorously stirred reaction mixture. The reaction was warmed to −40° C. for 1 h, re-cooled to −78° C. and then cautiously treated with ethanol (5 ml) followed by saturated ammonium chloride solution. The mixture was allowed to warm to room temperature, and then extracted with ethyl acetate (ca. 150 ml). The organic layer was dried (Na2SO4) and concentrated to afford crude (2S,αRS)-1-(2-chlorobenzoyl)-α-ethyl-2-pyrrolidinemethanol as a mixture of diastereoisomers. The crude product was dissolved in dimethylformamide (100 ml) under nitrogen. Sodium hydride (60% dispersion in mineral oil; 1.0 g, 25.0 mmol) was added, portionwise. The reaction was stirred at room temperature for 30 minutes and then heated to 120° C. for 5 h, after which the temperature was reduced to 80° C. for a further 16 h. The reaction was allowed to cool to room temperature and then quenched with methanol (10 ml) and stirred for 10 minutes. The solvents were removed under reduced pressure. The residue was taken up in water (50 ml) and extracted with dichloromethane (2×50 ml) to afford the product as a crude mixture of diastereoisomers (ratio approx. 30:70). Flash chromatography on silica (eluting with 0% to 80% ethyl acetate in heptane) afforded the title compound (80 mg) as a colourless oil; 1H NMR (400 MHz; CDCl3) δ 4.24 (1H, dt, J 10.5, 2.3 Hz, 11-H); EIMS: m/z=232 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[Na].[CH:14]([OH:17])([CH3:16])[CH3:15]>>[Cl:12][CH2:11][C:4]1[CH:3]=[C:2]([O:17][CH:14]([CH3:16])[CH3:15])[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1cc(CCl)nc(C(C)C)n1

Procedure:
6-Chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61) is reacted with isopropanol and sodium analogously to the process described in Example 62 in order to produce 4-chloromethyl-2-isopropyl-6-isopropoxy-pyrimidine which is required as the starting material in Example 22. This product is obtained in the form of an oil, 1H-NMR (CDCl3): 1.30 (d, 2×CH3), 1.37 (d, 2×CH3), 3.10 (m, CH), 4.50 (s, CH), 5.40 (m, CH), 6.65 (s, CH).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Cl[C:12]1[C:21]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:23])=[C:20]([CH3:33])[C:19]2[C:14](=[CH:15][C:16]([C:34]([F:37])([F:36])[F:35])=[CH:17][CH:18]=2)[N:13]=1.CCCCCC>CN(C=O)C.O>[F:32][C:28]1[CH:27]=[C:26]([CH2:25][NH:24][C:22]([C:21]2[C:12]([S:10][CH2:7][CH2:8][CH3:9])=[N:13][C:14]3[C:19]([C:20]=2[CH3:33])=[CH:18][CH:17]=[C:16]([C:34]([F:37])([F:36])[F:35])[CH:15]=3)=[O:23])[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(C(=O)NCc2cccc(F)c2)c(Cl)nc2cc(C(F)(F)F)ccc12
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 40 °C
Yield: 66 %

Procedure:
209 mg (1.5 mmol) K2CO3 and 137 μl (1.5 mmol) propanethiol were added to a solution of 200 mg (0.5 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxamide (VVV17) in DMF (4 ml) and the mixture was heated in a closed vessel for 72 h at 40° C. After cooling to RT the mixture was diluted with water and extracted with EE. The organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 3:1) of the residue yielded 146 mg (0.33 mmol, 67%) N-[(3-fluorophenyl)-methyl]-4-methyl-2-(propylsulfanyl)-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 437.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]([N:12]([C:25](=[O:28])[CH2:26][CH3:27])[C:13]1[C:18]([I:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[S:21](O)(=[O:23])=[O:22])[CH2:10][CH3:11].P(Cl)(Cl)(Cl)(Cl)[Cl:30].CCOCC>ClCCl>[O:8]=[C:9]([N:12]([C:25](=[O:28])[CH2:26][CH3:27])[C:13]1[C:18]([I:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[S:21]([Cl:30])(=[O:23])=[O:22])[CH2:10][CH3:11]
Reactant: CCC(=O)N(C(=O)CC)c1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)N(C(=O)CC)c1c(I)cc(Br)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 32.5 g (55 mmol) of the N,N-diethylethanamine salt of 2-[bis(1-oxopropyl)amino]-5-bromo-3-iodobenzenesulphonic acid in dichloromethane are added portionwise, at 0° C. under nitrogen, 16.8 g (82.4 mmol) of phosphorus pentachloride. The mixture is allowed to warm to room temperature and is heated for 4 hours at the reflux temperature. 200 ml of ether are poured in, the mixture is filtered and the filtrate is concentrated. The residue is purified by chromatography on a column of florisil™ eluting with an ether/hexane mixture (2/8). The product is recrystallized from an ether/pentane mixture. 12 g of product are obtained in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][C@@H:14]([OH:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:18]>O1CCOCC1.O>[OH:16][C@@H:14]([CH3:15])[CH2:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:1]=[O:18])[CH:11]=[CH:10]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2cccc(OC[C@H](C)O)c2n1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](O)COc1cccc2ccc(C=O)nc12
Yield: 57 %

Procedure:
To a solution of (S)-1-(2-methylquinolin-8-yloxy)propan-2-ol (0.15 g, 0.69 mmol) in dioxane (10 mL) and water (0.1 mL) was added selenium dioxide (0.092 g, 0.83 mmol) and the resultant mixture heated at reflux for 2.5 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (20-40% ethyl acetate/hexanes) providing the title compound (0.091 g, 57%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C@H:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C@H:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (180 mg) in ethanol (30 ml) was added sodium borohydride (10.0 mg) at room temperature and stirred for 2 hours. To the reaction solution was further added sodium borohydride (10.0 mg), and the mixture was stirred for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 82) (141.4 mg) as yellow amorphous.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:28][CH:29]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2cnccc2CCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(CCc2cnccc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
tert-Butyl 4-[2-(4-(phenethyl)pyrid-3-yl)ethyl]benzoate (0.36 g, 0.95 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (0.5 ml). The reaction was stirred at ambient temperature for 5 hours, then partitioned between ethyl acetate and buffer (pH 6). The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to give the title product (0.168 g) as a salt with THF.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:38](#[N:41])[CH:39]=[CH2:40]>>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:40][CH2:39][C:38]#[N:41])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C=CC#N
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCN(CCC#N)CCCCCCCCCCCCCCCCCC

Procedure:
3-(Dioctadecylamino)propionitrile is prepared by refluxing a mixture of dioctadecylamine (200 g.) and acrylonitrile (1903.8 ml.) for eighteen hours. The mixture is then concentrated to a waxy semi-solid which is slurried in acetone, filtered, and air dried overnight.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[CH2:24]([O:26][C:27]([CH:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][CH2:30]1)=[O:28])[CH3:25].BrCC#N>C1COCC1.O>[CH2:24]([O:26][C:27]([C:29]1([CH2:2][C:1]#[N:4])[CH2:38][CH2:37][C:32]2([O:33][CH2:34][CH2:35][O:36]2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)NC(C)C
Agent: N#CCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a stirred solution of diisopropylamine (10.09 ml, 69.76 mmol) in THF (150 ml) was added nBuLi (1.9 M solution in hexane, 26.09 ml, 51.1 mmol) drop wise at −40° C. followed by HMPA (31.0 ml, 178.0 mmol) under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at −40° C. It was then cooled further to −78° C., and a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (10 g, 46.5 mmol) in THF (20 ml) was added keeping the temperature below −70° C. throughout the addition. After stirring for 25 min at −78° C., bromoacetonitrile (3.8 ml, 55.8 mmol) was added slowly, and the reaction mixture was then allowed to warm to 25° C. The mixture was poured into cold water (100 ml) and the aqueous layer was extracted with EtOAc (5×70 ml). The combined organic layer was washed successively with saturated aqueous solution of NH4Cl (3×50 ml), H2O (2×50 ml) and then with brine (1×40 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude compound obtained was purified by column chromatography over silica gel (22-25% EtOAc/hexane) to give the title compound (6 g) as a pale yellow liquid. MS (m/e): 254.2 [MH+].
Reaction SMILES: [C:1]([N:10]([CH2:12][C:13]([NH2:15])=[S:14])[CH3:11])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].N1C=CC=CC=1.[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>C(O)C>[Cl:22][CH2:23][C:24]1[N:15]=[C:13]([CH2:12][N:10]([C:1]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:2])[CH3:11])[S:14][CH:25]=1
Reactant: O=C(CCl)CCl
Reactant: CN(CC(N)=S)C(=O)Oc1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: CN(Cc1nc(CCl)cs1)C(=O)Oc1ccccc1
Yield: 77.1 %

Procedure:
To a cooled solution of (N-carbophenoxy-N-methylamino)thioacetamide (1.0 g; 4.46 mmoles) and dry pyridine (0.36 ml, 4.46 mmoles) in 6 ml of absolute ethanol was added a solution of 1,3-dichloropropanone (0.57 g; 4.49 mmoles) in 3 ml of absolute ethanol. The mixture was heated at reflux temperature for 1.5 hours, then evaporated under reduced pressure and the oil residue partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether phase was washed with water, saturated aqueous sodium chloride solution and dried. Filtration and evaporation yielded 1.02 g of the title compound as a viscous oil; TLC [silica/CH2Cl2 :CH3CN (85:15)] gave Rf=0.82. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 7.16 (m, 6H); 4.77 (broad s, 2H); 4.60 (s, 2H); 3.07 (broad s, 3H).