Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](O)([CH3:9])C)=[CH:4][CH:3]=1.[C:11]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]([OH:38])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:30]([O:38][C@@H:9]([CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(O)c1ccc(Cl)s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: C[C@H](Cc1ccc(Cl)s1)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1(S)2-(5-chloro-2-thienyl-1-hydroxy-1-methylethane (5.7 g) in tetrahydrofuran (100 mL) is added triphenylphosphine (5.34 g) and benzoic acid (2.49 g). Diethyl azodicarboxylate (3.22 mL) is added dropwise and the mixture stirred at room temperature for about 18 hours. The solvent is removed in vacuo. The residue is purified by flash chromatography, eluting with 30% hexanes in methylene chloride, to give (R)-3-(5-chloro-2-thienyl)-2-propyl benzoate. The ester (3.91 g) is dissolved in dioxane (50 mL) and 20% aqueous sodium hydroxide (15 mL) is added. The mixture is heated at 55° C. for 3 hours and concentrated in vacuo. The residue is taken up in ethyl acetate (200 mL) and the organic layer washed with brine, dried over magnesium sulfate, filtered, concentrated in vacuo to give the desired product.
Reaction SMILES: N1C=CC=CC=1.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:37][C:18]3[C:19](=[O:36])[N:20]([C:23]4[CH:24]=[N:25][C:26]([O:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl.O>[C:38]([N:33]1[CH2:34][CH2:35][CH:30]([O:29][C:26]2[N:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][C:17]4[CH:16]=[C:15]([C:12]5[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=5)[S:37][C:18]=4[C:19]3=[O:36])=[CH:28][CH:27]=2)[CH2:31][CH2:32]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(OC2CCNCC2)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(Oc2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)CC1
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
Add pyridine (0.50 mL, 6.18 mmol) to a mixture of 2-(4-chloro-phenyl)-6-[6-(piperidin-4-yloxy)-pyridin-3-yl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride (0.741 g, 1.56 mmol) in dichloromethane at room temperature. After stirring for 5 min, add acetyl chloride (0.16 mL, 2.33 mmol) to the mixture and stir overnight at room temperature. Dilute the mixture with water, extract into dichloromethane (3×50 mL), then dry over sodium sulfate, filter, and concentrate. Purify the residue using silica gel flash column chromatography (1-3% methanol/dichloromethane) and concentrate on high vacuum to yield the titled compound (0.678 g, 90%). MS/ES m/z (37Cl) 483 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:20]3([OH:23])[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2cc3cc(Cl)ccc3s2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A solution of 0.300 gm (1.78 mMol) 5-chlorobenzothiophene in 20 mL tetrahydrofuran was cooled to -78° C. To the cooled solution was then added 1.27 mL (1.78 mMol) n-butyllithium (1.2M in tetrahydrofuran) and the reaction mixture stirred for 1 hour after the addition was complete. To this solution was added 0.218 mL (1.78 mMol) 1-methyl-4-piperidone and the reaction mixture was allowed to warm to 0° C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned by the addition of hexane/diethyl ether. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to provide 0.34 gm of a tan solid. This residue was subjected to silica gel chromatography, eluting with chloroform containing 5% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.34 gm (68%) of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CCNC1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCCC1
Temperature: 0 °C

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 100 ml pyrrolidine. A cooling bath was applied as necessary during the addition. After the addition was complete, the reaction was heated on a steam bath for three hours, cooled, poured into ice water and made acidic with concentrated HCl until precipitation of product was complete. Recrystallization from ethanol gave 19.4 grams 5-nitro-2-(1-pyrrolidinyl)benzoic acid. m.p. = 224°-266° C dec. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-(1-pyrrolidinyl)benzoic acid. m.p. = 205°-208° C dec.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]([CH3:8])=O.[SH2]=N.[C:11]1([NH:17][C:18](C2C=CC=CC=2C(O)=O)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:6]1([NH:17][C:18]([NH:3][CH2:2][CH2:1][NH:4][C:18](=[O:19])[NH:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH:8]=[CH:16][CH:11]=[CH:12][CH:5]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: NCCN
Reactant: CC(C)=O
Agent: N=[SH2]
Solvent: O
Product: O=C(NCCNC(=O)Nc1ccccc1)Nc1ccccc1

Procedure:
A mixture of 0.40 g ethylenediamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 15 ml acetone, under stirring. The reaction mixture was stirred for 45 minutes, diluted with 50 ml water, cooled, the precipitated solid product was filtered, washed with water and dried. 0.62 g N,N'-bis(phenylcarbamoyl)-ethylenediamine was obtained, melting above 240° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)/[C:17](=[CH:18]/[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C1CCNC1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C\N2CCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of wortmannin (30.0 mg, 70.0 μmol) in CH2Cl2 (200 μL) was added pyrrolidine (7.0 μL, 84 μmol) in CH2Cl2. The reaction mixture was stirred at room temperature for 1 h. The solvent and excess thiol were removed in vacuo and the product was purified by chromatography on SiO2 (hexanes/ethyl acetate 9:1, then 1:1) to give PX-867 (30.0 mg, 60.6 μmol, 86%) as an orange oil. The product was analyzed by several experimental methods and shown to be of the correct structure and of high purify as: [α]D −390 (c 0.0073, CH2Cl2, 23° C.); IR (KBr) 3337, 1740, 1684, 1617, 1570, 1261, 1221, 1099, 1018 cm−1; 1H NMR δ 8.29 (s, 1H), 6.72 (s, 1H), 6.07 (dd, 1H, J=6.9,4.8 Hz), 4.47 (dd, 1H, J=7.0, 1.9 Hz), 3.80-3.70 (m, 2H), 3.25 (s, 3H), 3.25-3.14 (m, 2H), 3.02-2.90 (m, 2H), 2.69 (br s, 1H), 2.58 (dd, 1H), J=19.1, 8.4 Hz), 2.39 (dd, 1H, J=14.6. 7.8 Hz), 2.32-2.08 (m, 2H), 2.06 (s, 3H), 1.99-1.95 (m, 5H), 1.84 (dd, 1H, J=14.5, 4.2 Hz), 1.56 (s, 3H), 0.86 (s, 3H); 13C NMR δ 217.5, 178.9, 169.9, 164.9, 153.9, 151.3, 137.6, 137.1, 129.2, 89.4, 82.1, 73.3, 67.7, 59.3, 55.2, 49.2 (2 C), 42.6, 42.4, 37.8, 36.3, 25.6 (2 C), 24.5, 22.4, 21.0, 16.3; MS (EI) m/z (rel. intensity) 499 (M+, 1), 439 (2), 365 (7), 167 (35), 149 (100); HRMS (EI) calculated for C27H33NO8 499.2206; found 499.2191.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Na+:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+:31]
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (2 g) was dissolved in ethanol (15 ml) at reflux. 2M Sodium hydroxide (3.4 ml) was added and the solution heated under reflux for 30 minutes. No residual starting material by HPLC. The solution was filtered and the filter washed with a mixture of hot ethanol (5 ml) and water (5 ml). The combined filtrate and wash were re-heated to reflux, and water (15 ml) added dropwise over ˜5 minutes and the clear solution allowed to cool slowly to room temperature. The product crystallised rapidly at ˜35° C. The resulting thick suspension was cooled to 20-25° C. and stirred for 1 hour. The product was isolated and washed with 1:3 ethanol:water (20 ml) and then dried overnight at 50° C. in vacuo to give the title compound (1.94 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=1)C1C=CC=CC=1.O.C(O)C1C=CC=CC=1>C(OCC)C>[CH2:24]([O:23][C:18]1[CH:17]=[C:16]([CH2:15][OH:14])[CH:21]=[CH:20][C:19]=1[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: OCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(CO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of lithium aluminum hydride in diethyl ether (50 mL) was added dropwise a solution of 3-Benzyloxy-4-methyl-benzoic acid benzyl ester (7.5 g) in diethyl ether (11 mL) under argon atmosphere at 0° C., and this mixture was stirred at room temperature for 6 hours. To this reaction mixture was added dropwise water (3.2 mL), and then Celite was added to this mixture and filtered. This filtrate was concentrated to give title compounds as a mixture of benzyl alcohol (7.0 g).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:31]1([C:34]([NH:36][C:37]2[N:54]=[C:40]3[CH:41]=[CH:42][CH:43]=[C:44]([C:45]4[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=4)[N:39]3[N:38]=2)=[O:35])[CH2:33][CH2:32]1.Cl.[CH3:56][C:57]1([CH3:61])[CH2:60][NH:59][CH2:58]1>C(Cl)Cl.O>[CH3:56][C:57]1([CH3:61])[CH2:60][N:59]([C:49]([C:48]2[CH:47]=[CH:46][C:45]([C:44]3[N:39]4[N:38]=[C:37]([NH:36][C:34]([CH:31]5[CH2:33][CH2:32]5)=[O:35])[N:54]=[C:40]4[CH:41]=[CH:42][CH:43]=3)=[CH:53][CH:52]=2)=[O:50])[CH2:58]1
Reactant: O=C(O)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reactant: CC1(C)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)c2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
EDCI (3.59 g, 0.019 mol), HOBt (2.53 g, 0.019 mol) and DIPEA (4.48 mL) were added to a solution of 4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (4 g, 0.012 mol) in DCM (150 mL) at room temperature. The resulting mixture was stirred for 10 min at room temperature. Dimethylazetidine hydrochloride salt (1.64 g, 0.013 mol) was added to the solution and the reaction is stirred for 16 hrs. Water was added to the reaction mixture. The organic layer was separated and washed with 2 N NaOH solution, 2N HCl solution and water. The organic phase was dried over MgSO4, filtered and evaporated under vacuum. Purification by flash chromatography (eluant: 1:1 petrol/EtOAc to neat EtOAc) afforded cyclopropanecarboxylic acid{5-[4-(3,3-dimethyl-azetidine-1-carbonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH2:16]([Mg][Cl:20])[CH2:17][CH3:18]>C1COCC1>[ClH:20].[ClH:20].[CH2:16]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)[CH2:17][CH3:18]
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCc1cncc(OC[C@@H]2CCCN2C)c1
Product: Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a 1.08 g (4 mmol) sample of 5bromo-3-((1-methyl-2-(S)-pyrrolidinyl)-methoxy)pyridine, prepared as in Example 56a above, dissolved in 30 mL of dry THF and cooled to 0° C. was added 6.0 mL of n-propylmagnesium chloride and 13.0 mg of Ni(dppp)Cl, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched by addition of satd NH4Cl, and the mixture was extracted with chloroform. The solvent was dried over MgSO4 and removed under vacuum, and the residue was purified of a column of silica gel, eluting with 100: 1.25:0.025 chloroform:methanol:ammonium hydroxide. The product was converted into the title compound by treatment with HCl in ether according to Example 14c. MS (DCI/NH3) m/e: 235 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.28 (s, 1H), 8.23 (s, 1H), 7.78 (m, 1H), 4.58 (dd, J=11.4, 3.7 Hz, 1H), 4.42 (dd, J=11.1, 5.9 Hz, 1H), 3.95 (m, 1H), 3.77 (m, 1H), 3.31-3.25 (m, 1H), 3.05 (s, 3H), 2.74 (t, J=7.3 Hz, 2H), 2.48-2.36 (m, 1H), 2.25-2.06 (m, 3H), 1.68 (m, 2H), 0.91 (t, J=7.4 Hz, 3H). Anal. Calc. for C14H22N2O·1.9 HCl·0.3 ether. C, 56.03; H, 8.22; N, 8.60; Found C, 56.35; H, 8.48; N, 8.73. [α]25D =-3.05° (methanol).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:5]1[CH:6]=[CH:7][C:8]([C:16](O)=[O:17])=[N:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.Cl.[NH2:27][C:28]([CH2:35][CH3:36])([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[C:28]([NH:27][C:16]([C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:3][C:2]([F:1])([F:25])[F:24])[CH2:19][C:20]([F:22])([F:21])[F:23])=[C:10]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[N:9]=1)=[O:17])([CH2:35][CH3:36])[CH2:33][CH3:34]
Reactant: O=C(O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)OC
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 162 b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=500.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[CH:11](N(C(C)C)CC)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][CH:4]=1)[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(CBr)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Br)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
Stir 1-bromomethyl-4-hydroxymethyl benzene (20.75 g)in CH2Cl2 (300 ml) with diisopropylethylamine (14.01 g) at 18° C., and add a solution of t-butyl dimethylsilyl chloride (16.34 g) in CH2Cl2 (100 ml). Stir for one half hour at room temperature, then reflux for 19 hours under a N2 atmosphere. Monitor reaction progress by TLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:31])([F:42])[F:43])[CH:35]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.5 g, 0.0012 mol) in DMF (10 mL), was added 3-(trifluoromethoxy)benzyl bromide (0.47 g, 0.0018 mol) and powdered potassium carbonate (1.16 g, 0.0084 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 Hexanes/EtOAc) to give the desired product as oil 0.61 g in 88% yield. 1H NMR (CDCl3) δ 7.20 (s, 1H), 7.19 (m, 11H), 7.04 (s, 1H), 7.01 (t, 2H), 6.88 (d, 1H), 6.69 (m 2H), 4.20 (t, 1H), 3.70 (s, 3H), 3.63 (s, 2H), 3.59 (s, 2H), 3.13 (d, 2H), 2.67 (t, 2H), 1.84 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.5, 149.6, 144.8, 136.7, 131.0, 130.9, 130.0, 129.8, 129.7, 129.6, 128.4, 127.8, 122.8, 122.7, 122.5, 120.6, 116.9, 114.5, 66.8, 61.3, 60.1, 53.4, 51.9, 51.2, 42.7, 28.2.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1C=[N:23][CH:22]=[CH:21][C:18]=1C#N.[CH2:25]([N:27](CC)CC)[CH3:26]>C1(C)C=CC=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:18]=[C:21]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)[CH:26]=[CH:25][N:27]=1
Reactant: N#Cc1ccncc1-c1cccs1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccnc(-c3cccs3)c2)sc2ccccc12
Yield: 48.7 %

Procedure:
Methyl thiosalicylate (0.38 g, 2.2 mmol) and (2-thienyl)isonicotinonitrile (0.26 g, 1.4 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.39 ml, 2.8 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs. The reaction mixture was subjected to a silica gel (30 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.22 g, 30%) as white crystals.
Reaction SMILES: [C:1]([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][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].C(Cl)(Cl)[Cl:31].C(=O)([O-])[O-].[Na+].[Na+].[C:40](Cl)([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>O>[C:40]([N:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])[C:21]1[CH:22]=[CH:23][C:24]([C:25]([Cl:31])=[O:27])=[CH:28][CH:29]=1)([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41]
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid in 200 ml. warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to an oil. The oil is disolved in 300 ml. toluene, treated with 15 ml. of thionyl chloride, and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time to yield a viscous, orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=[O:34].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:34])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O)c1ccccn1
Reaction time: 48 h
Yield: 81.9 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (150 mg, 0.432 mmol), picolinic acid (64 mg, 0.518 mmol) and HOBT (73 mg, 0.540 mmol) in DMF (4 mL) was added N-methylmorpholine (62 μL, 0.562 mmol) followed by EDCI HCl (108 mg, 0.562 mmol). After 2 days, the DMF was removed under reduced pressure. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated to give a brown oil. Purification by chromatography (3-5% MeOH/CH2Cl2) afforded the title compound as a tan foam (160 mg, 0.354 mmol, 82%). The structure was confirmed by NMR and mass spectrometry. MS m/z 453 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1.[H-].[Na+].[CH3:24]I>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][N:14]([CH3:24])[C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1
Reactant: O=C1Cc2cc(OCc3cccc(F)c3)ccc2C=CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C=Cc2ccc(OCc3cccc(F)c3)cc2CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
In a dried flask under an inert atmosphere, 70 mg (0.25 mmol) of 8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one were dissolved in 5 ml of tetrahydrofurane, and the solution cooled to 0° C. Thereupon, 14 mg (0.3 mmol) of sodium hydride (50% in oil) were added and stirring continued at 0° C. for 15 min. Finally, 17 μl (0.3 mmol) of methyliodide were added. The reaction mixture was left to warm to RT and stirring continued for 90 min. For completion of the reaction, the mixture was heated to 40° C. during 2 h. For the working-up, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in 10 ml of ethylacetate, the solution extracted with 4 ml of water, then dried over sodium sulfate and evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 2:1-mixture of heptane and ethylacetate as the eluent. There were obtained 51 mg (69% of theory) of 8-(3-fluoro-benzyloxy)-3-methyl-1,3-dihydro-benzo[d]azepin-2-one as a yellowish solid; MS: m/e=297 (M)+.