Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[C:30]([CH3:37])[N:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:32][CH:31]=[C:30]([CH3:37])[N:29]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1nc(C)ccc1B(O)O
Solvent: CN(C)C=O
Product: COc1nc(C)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxy-6-methylpyridine-3-boronic acid (CAS RN 1000802-75-4) and using DMF as reaction solvent. Off-white solid (42%). MS (ESI): m/z=469.8 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[CH:23]=[CH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:35][C@@:29]1([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:12][CH:9]4[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]4)[CH:20]=3)[CH:25]=2)[CH2:33][O:32][C:31](=[O:34])[NH:30]1
Reactant: CCCCCC1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
In a 40 mL vial, 4-Pentyl-cyclohexanol (1144.4 mg, 0.0067202 mol) was diluted with tetrahydrofuran (30.0 mL, 0.370 mol, Acros) and subsequently (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (1.4924 g, 0.0061350 mol) and triphenylphosphine (2105.5 mg, 0.0080275 mol) were added and the mixture was stirred. Diethyl Azodicarboxylate in toluene (2.6 mL, 0.0086326 mol, Aldrich) was added, and the mixture was then stirred at room temperature for 38 h. The reaction mixture was evaporated to dryness and chromatographed 0-100% EtOAc/Hexanes (adsorbed onto silica gel). Isolated was 0.6142 g (18%) in approx 70% purity, the remainder being reduced DEAD reagent.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[I-:6].O[CH2:8][CH2:9][N:10]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[ClH:3].[I-:6].[Cl:5][CH2:8][CH2:9][N:10]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(CCO)CCC[N+](C)(C)C
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCN(CCCl)CCC[N+](C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A total of 28 ml of thionyl chloride was added dropwise, with stirring, to 27.35 g of 3-[(2-hydroxyethyl)ethylamino]-N,N,N-trimethyl-1-propanaminium iodide hydrochloride in 200 ml of toluene at 50° C. Upon completion of the addition the mixture was stirred at 50° for 15 minutes, and then heated at 80° C. for 3 hours. The reaction mixture was steam distilled to remove toluene. Organic chloride analysis on the resulting aqueous solution showed the corresponding alkyl chloride was obtained in 88% yield.
Reaction SMILES: C([Li])CCC.CN(CCN(C)C)C.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[C:20]([C:23]1[S:27][C:26]([CH3:28])=[N:25][C:24]=1[CH3:29])(=[O:22])[CH3:21]>C(OCC)C>[CH3:28][C:26]1[S:27][C:23]([C:20]([C:16]2[N:15]([CH3:14])[CH:19]=[CH:18][CH:17]=2)([OH:22])[CH3:21])=[C:24]([CH3:29])[N:25]=1
Reactant: Cn1cccc1
Reactant: CC(=O)c1sc(C)nc1C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1nc(C)c(C(C)(O)c2cccn2C)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 20 ml) in dry diethyl ether was cooled to -70° C. under dry nitrogen and TMEDA (5.8 g) was added. After 5 minutes, 1-methylpyrrole (5.4 g) in diethyl ether was added dropwise. After a further 15 minutes, 5-acetyl-2,4-dimethylthiazole (4.5 ml) was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature and was then worked up in the usual fashion.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[C:1]([CH:3]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CC#N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)C(C)c1ccccc1

Procedure:
In another example, methyl cyanoacetate can be reacted with acetophenone in the presence of ammonium acetate and acetic acid in refluxing toluene solvent followed by hydrogenation with 5% Pd on C catalyst to yield methyl 2-cyano-3-phenylbutyrate. The latter compound can then be reacted with methyl bromacetate in the presence of potassium carbonate to provide the α-methylbenzyl substituted dimethyl cyanoethane-1,2-dicarboxylate starting 1,2-diester (See Example 8, below): ##STR10## The latter material can then be subjected to the aforesaid 1,2-ester transposition to provide the isomeric terminal diester (See Example 1, below.)
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]3[C@H:26]([NH:27][C:28](=[O:64])/[C:29](=[N:43]\[O:44][C:45]4([C:48]([O:50][CH:51]([C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[O:49])[CH2:47][CH2:46]4)/[C:30]4[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:33][CH:34]=4)[C:25](=[O:65])[NH:24]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]1[C@H:26]([NH:27][C:28](=[O:64])/[C:29](=[N:43]\[O:44][C:45]2([C:48]([O:50][CH:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:49])[CH2:46][CH2:47]2)/[C:30]2[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[S:33][CH:34]=2)[C:25](=[O:65])[NH:24]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.167 mmol) in DCM (1.7 mL) was added piperidine (16.50 μl, 0.167 mmol). After 2 h, the reaction mixture was concentrated in vacuo and lyophilized in CH3CN/water mixture to afford the title compound (assumed quantitative). LCMS: Rt=0.93 min, m/z=678.5 (M+1), Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:3]=1.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:19])([C:15]([F:17])([F:18])[F:16])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Ethyl 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren-2-yloxy]butyrate (92.2 g) was dissolved in ethanol (100 ml), 4N aqueous sodium hydroxide (100 ml) was added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water (200 ml) was added, and the mixture was washed twice with toluene (100 ml). The obtained aqueous layer was neutralized with concentrated hydrochloric acid (40 ml), and extracted twice with ethyl acetate (300 ml). The obtained ethyl acetate extract was washed successively with water (100 ml, twice), and saturated brine (100 ml), anhydrous magnesium sulfate and activated carbon (4.2 g) were added, and the mixture was stirred at room temperature for 10 min. The insoluble material was filtered off, and the solvent in the filtrate was evaporated. To the obtained residue was added chloroform (80 ml), and the mixture was heated to 50° C. Hexane (400 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 min, and at room temperature for 2 hr. The precipitated solid was collected by filtration, washed with a mixed solvent of hexane and chloroform (hexane:chloroform=9:1, 50 ml), and dried under reduced pressure at 80° C. for 2 hr to give the title compound (72.5 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[F:9][C:10]([F:20])([F:19])[CH2:11][CH2:12][C:13](N(OC)C)=[O:14].[Cl-].[NH4+]>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:13](=[O:14])[CH2:12][CH2:11][C:10]([F:20])([F:19])[F:9]
Reactant: BrCCC1OCCO1
Reactant: CON(C)C(=O)CCC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCC1OCCO1)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
4,4,4-Trifluorobutyric acid chloride (6.4 g from above) in CH2Cl2 (80 ml) was treated with O,N-dimethylhydroxylamine hydrochloride (60.0 mmol, 5.85 g). The mixture was cooled to 0° C., then treated with pyridine (160.0 mmol, 12.9 ml), then allowed to warm to room temperature overnight. The mixture was diluted with CH2Cl2 (200 ml), then washed with brine(2×50 ml). Solvent was removed from the volatile product by simple distillation at atmospheric pressure to provide 20 g of 4,4,4-trifluoro-N-methoxy-N-methyl butyramide, which may be used without further purification. 1H NMR (CDCl3) δ 3.70 (3H, s), 3.19 (3H, s), 2.78-2.65 (2H, m), 2.57-2.40 (2H, m). Mg (92.0 mmol, 2.2 g) in THF (80 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-[1,3]dioxolane (80 mmol, 9.4 ml), while keeping the internal temperature below 35° C. with the aid of an ice bath. After the addition was complete, the mixture was stirred for 2 h at room temperature, then cooled to −78° C. Crude 4,4,4-trifluoro-N-methoxy-N-methyl butyramide (20 g, prepared above) in THF (40 ml) was cooled to −78° C., then the freshly prepared Grignard reagent was transferred via cannula into the amide solution at −78° C. The resulting mixture was allowed to warm to room temperature, held at room temperature overnight, then poured into saturated aqueous ammonium chloride (200 ml). The mixture was extracted with ethyl acetate (3×75 ml). The combined organics were washed with brine (2×75 ml) and concentrated under reduced pressure to provide crude 1-[1,3]dioxolan-2-yl-6,6,6-trifluoro-hexan-3-one (18 g) 1H NMR (CDCl3) δ 4.91 (1H, t, J=4.1), 3.97-3.82 (4H, m), 2.70 (2H, t, J=7.3), 2.57 (2H, t, J=7.2), 2.49-2.34 (2H, m), 2.01 (2H, dt, J=7.3, 4.1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].S(Cl)([Cl:21])(=O)=O.O.CCOC(C)=O>C(OCC)C>[Cl:21][CH:11]([C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of ethyl 3-(2-nitrophenyl)-3-oxopropanoate (2.0 g, 8.4 mmol) in diethyl ether (50 mL), was added sulfuryl chloride (1.37 g, 10 mmol) at 0° C., and the mixture was stirred for 3 h at rt. To the reaction mixture were added water (200 mL) and EtOAc (100 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g, 75%) as colorless oil.
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]=2[N:4]=1.Cl.[NH2:33][C:34]1[CH:35]=[C:36]([NH:42][C:43](=[O:48])[CH2:44][N:45]([CH3:47])[CH3:46])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].[CH3:49][NH2:50]>C1COCC1.FC(F)(F)CO>[CH3:46][N:45]([CH3:47])[CH2:44][C:43]([NH:42][C:36]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([NH:33][C:3]2[N:16]=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH:50][CH3:49])=[O:17])[C:6]3[CH:19]=[CH:20][N:21]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)(=[O:24])=[O:23])[C:5]=3[N:4]=2)[CH:35]=1)=[O:48]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: COc1ccc(NC(=O)CN(C)C)cc1N
Reactant: CN
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc(NC(=O)CN(C)C)ccc2OC)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
A slurry of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (400 mg, 0.835 mmol) and N1-[3-amino-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide hydrogen chloride (217 mg, 0.835 mmol) in THF (15 mL) in 2,2,2-trifluoroethanol was stirred at rt. After 3 days LCMS indicated incomplete reaction, therefore more N1-[3-amino-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide hydrogen chloride (115 mg, 0.24 mmol) was added and the reaction mixture was heated at 80° C. for 4 h. After allowing to cool to rt the reaction mixture was treated with a MeNH2 solution (2M in THF, 20 mL). The reaction mixture was stirred at it for 20 h, then concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-({2-{[5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide as a yellow solid (487 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 6H), 2.31 (s, 3H), 2.68 (d, J=4.58 Hz, 3H), 3.04 (s, 2H), 3.83 (s, 3H), 6.67 (d, J=4.03 Hz, 1H), 6.96-7.09 (m, 2H), 7.34 (d, J=8.42 Hz, 2H), 7.37-7.45 (m, 2H), 7.53 (dd, J=8.79, 2.56 Hz, 1H), 7.83 (d, J=8.24 Hz, 1H), 7.88-8.00 (m, 3H), 8.39 (br s, 1H), 8.44-8.54 (m, 1H), 9.50 (s, 1H), 10.09 (s, 1H); ESIMS (M+H)+=661.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH3:27]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26][CH3:27])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CCCNCCOC
Product: CCCN(CCOC)Cc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of Example 15 and (2-methoxy-ethyl)-propyl-amine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][CH:13]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH3:26])[CH2:12][CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.[N+](C)([O-])=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N+:1]([O-:4])=[O:2])=[C:10]2[C:15]=1[CH2:14][CH:13]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH3:26])[CH2:12][CH2:11]2
Reactant: CCCc1ccccc1C(=O)NC1CCc2cccc(Cl)c2C1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CCCc1ccccc1C(=O)NC1CCc2c([N+](=O)[O-])ccc(Cl)c2C1

Procedure:
Fuming nitric acid (100 ml), 33% in concentrated sulphuric acid was added dropwise to a solution of 72 g (0.22 mol) 8-chloro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene in 300 ml nitromethane at 0° C. The mixture was allowed to reach ambient temperature and was stirred over night. After pouring on ice water/diethyl ether the mixture was basified (sodium carbonate solution) and the phases separated. The organic phase was dried (magnesium sulphate), filtered and evaporated to a residue of 65.5 g of an isomeric mixture. Elution of the mixture on a silica column (isooctane/diethyl ether, 1:1) gave 19 g of 8-chloro-5-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene and 12 g of the desired isomer; 8-chloro-7-nitro-2-(n-propylbenzoyl)-amino-1,2,3,4-tetrahydronaphthalene. MS m/e 372 (M+, 3), 374 (M+ +2, isotope, 1), 105 (100), 164 (72), 77 (35), 134 (16), 165 (9).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3]CCCCCCCCCCC.[CH2:16]1[O:18][CH2:17]1.C(C1[O:23][CH2:22]1)Cl.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:22]([O:23][CH2:3][CH:2]1[O:15][CH2:1]1)[CH:17]1[O:18][CH2:16]1
Reactant: CCCCCCCCCCCCCCO
Reactant: C1CO1
Reactant: ClCC1CO1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: C(OCC1CO1)C1CO1

Procedure:
One mole of tetradecanol ethoxylated with 2 moles of ethylene oxide per mole of tetradecanol and one mole of epichlorohydrin were reacted in the presence of tin tetrachloride at a temperature of 60 to 70° C. and a glycidyl ether was obtained. A solution of 30% sodium hydroxide in water was added at 80° C. After 30 minutes under vigorous stirring at 80° C., the resulting glycidyl ether was separated from the water phase. It had the structure
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]=[C:12]([C:16]([O:18]C)=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)O)C1

Procedure:
A solution of potassium hydroxide (44 g, 0.79 mol) in water (450 ml) was added to a solution of methyl 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (34.9 g, 145 mmol) in methanol (450 ml). The mixture was refluxed for 3h and evaporated to dryness in vacuo. The residue acidified to pH 2.5 with hydrochloric acid (4M) and extracted with methylene chloride. The organic layer was dried over magnesium sulphate and evaporated to dryness in vacuo to give 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid. (Yield: 28.4g, 86%)
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:37])[F:38])=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C(F)(F)F)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2ccccc2C(F)(F)F)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-(2-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.40 min; [M+H]+=544.1.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[C:15]([CH3:37])([CH3:36])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[C:15]([CH3:37])([CH3:36])[CH2:14]2
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)NS(=O)(=O)C3CC3)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a suspension of 60% sodium hydride (294 mg, 7.4 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (908 mg, 7.5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (300 mg, 0.75 mmol) and 1,1′-carbonyldiimidazole (244 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (113 mg, 30%) as a white solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 505.05, observed: 504.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:20]#[N:21])[CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: N#Cc1cccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 3-cyanobenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-cyanobenzamide as a white crystalline solid, m.p. 200.0-201.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.68 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.10-7.97 (m, 3H), 7.69-7.60 (m, 2H), 7.42 (dt, J=7.5, 1.2 Hz, 1H), 7.20 (dt, J=7.5, 1.5 Hz, 1H), 6.62 (s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.32 (m, 2H), 1.91 (quintet, J=7.5 Hz, 2H), 1.59 (quintet, J=7.5 Hz, 2H); IR (KBr) 3455, 3295, 3072, 2941, 2231, 1638, 1581, 1527, 1479, 1396, 1312, 1251, 1205 cm−1; MS (EI) m/e 384.1699 (384.1699 calcd for C22H20N6O).