Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([CH3:29])=[CH:23][C:22]=3[N+:30]([O-:32])=[O:31])[N:12]=[N:11]2)=[CH:7][CH:6]=1.Cl>O1CCCC1.CCOCC.O>[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([CH3:29])=[CH:23][C:22]=3[N+:30]([O-:32])=[O:31])[N:12]=[N:11]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1c(C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(C)cc3[N+](=O)[O-])c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1N aqueous sodium hydroxide solution (1.1 ml) was added to a solution of ethyl 1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl )-1,2,3-triazole-5-carboxylate (b-1) (243 mg, 0.535 mmole) obtained in the preceding step (b) in tetrahydrofuran (6 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ether, and water was added. The aqueous layer was acidified with hydrochloric acid, it was extracted with ethyl acetate, and washed with water and a saturated aqueous saline. After the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2, 3-triazole-5-carboxylic acid (c-1': LP) as a pale yellow crystalline powder (204 mg, 89%). Next, 1-(4-methoxybenzyl)-4-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylic acid (c-1': LP) (200 mg, 0.469 mmole) thus obtained was dissolved in a mixed solvent of ethanol (12 ml) and ethyl acetate (12 ml), 10% palladium on carbon (25 mg) was added, and the mixture was stirred under the hydrogen atmosphere at room temperature for 6.5 hours. After the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and precipitates were collected by filtration to give 4-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylic acid (c-1 LP) as a red crystalline powder (178 mg, 96%).
Reaction SMILES: [O:1]1[C:19]([CH3:22])([CH2:20][CH3:21])[CH:2]1[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.[H][H]>[Pt]=O.C(OCC)(=O)C>[O:1]1[C:19]([CH3:22])([CH2:20][CH3:21])[CH:2]1[CH2:3][CH2:4][CH:5]([CH3:18])[CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCC2
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCC1(C)OC1CCC(C)CCOc1ccc2c(c1)OCC2

Procedure:
1.0 g. of 6-[(6,7-epoxy-3,7-dimethyl-2-nonenyl)-oxy]-2,3-dihydrobenzofuran is dissolved in 25 ml. of ethyl acetate and hydrogenated in the presence of 50 mg. of platinum oxide until the theoretical amount of hydrogen has been taken up. The catalyst is then removed by filtration and the filtrate evaporated. By chromatography on silica gel using hexane/diethyl ether (19:1 parts by volume) there is obtained pure 6-[(6,7-epoxy-3,7-dimethylnonyl)-oxy]-2,3-dihydrobenzofuran; nD20 = 1.5118.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:20])[F:19].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:40](=[O:55])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:42]=1>>[CH3:54][S:51]([C:43]1[CH:42]=[C:41]([CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=1)[C:40]([N:4]([CH2:3][C:2]([F:1])([F:22])[F:23])[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:19])([F:20])[F:21])=[O:55])(=[O:53])=[O:52]
Reactant: FC(F)(F)CNc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)(F)F)c2cnccc2-c2ccccc2OC(F)(F)F)cc(C(F)(F)F)c1
Yield: 20 %

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2,2,2-trifluoro-ethyl)-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-amine (37) and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) after a reaction time of 12 hours at 25° C. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to give the desired compound as an off-white solid (12 mg, 20%). MS (ESI): m/z=587.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C.CCOCC>C1COCC1.CO>[CH3:14][O:5][C:4](=[O:6])[C:3]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-6-nitrobenzoic acid (10.3 g, 56 mmol) was dissolved in THF/MeOH (100 mL/40 mL) and the mixture was cooled to 0° C. 2M Trimethylsilyldiazomethane in ether (33.4 mL, 67 mmol) was then added dropwise. The reaction was allowed to stir overnight while gradually warming to room temperature. The reaction mixture was then reduced en vacuo to afford 11.1 grams of 2-fluoro-6-nitrobenzoic acid methyl ester as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J=7.32), 7.61 (m, 1H), 7.50 (m, 1H), 4.00 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=O)C.O[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-].[Na+]>[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][N:17]2[C:16]=1[CH:21]=[CH:20][CH:19]=[CH:18]2
Reactant: C=C(C(=O)OC)C(O)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2ccccn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetic anhydride (80 mL) and 193a (6.68 g, 34.6 mmol). The reaction mixture was heated at reflux under nitrogen for 4 h. After this time the reaction was cooled to room temperature, poured onto the mixture of ice (100 g) and aqueous saturated sodium bicarbonate (200 mL), and stirred for 1 h. The resulting solution was neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride (3×200 mL). The combined organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 petroleum ether/ethyl acetate (10:1) to afford 193b as a white solid (2.1 g, 35%). MS-ESI: (M+H)+ 176.2. 1H NMR (500 MHz, CDCl3) δ 7.86-7.84 (m, 1H), 7.79 (d, J=1.0 Hz, 1H), 7.36-7.34 (m, 1H), 6.82 (s, 1H), 6.70-6.66 (m, 1H), 6.55-6.51 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])(C1C=CC(C)=CC=1)(=O)=O.[NH2:54][C:55]1[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=[C:59]([CH2:61][OH:62])[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:62][CH2:61][C:59]1[CH:60]=[C:55]([NH:54][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH:56]=[C:57]([CH2:63][OH:64])[CH:58]=1
Reactant: Nc1cc(CO)cc(CO)c1
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred mixture of methyl 1-(tosyloxy)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265b) (700 mg, 0.890 mmol) and (5-amino-1,3-phenylene)dimethanol (26) (150 mg, 0.978 mmol) in anhydrous DMF (2.0 ml) was added potassium carbonate (184 mg, 1.334 mmol). The reaction was stirred at 80° C. overnight. The mixture was cooled to room temperature, quenched with water and extracted with 10% Methanol/Methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluted with 5→15% MeOH/CH2Cl2) to give methyl 1-(3,5-bis(hydroxymethyl)phenylamino)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265c) (285 mg, 42%). 1H NMR (400 Hz, CDCl3): δ 6.62 (s, 1H), 6.51 (s, 2H), 4.52 (s, 4H), 3.72 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.61 (m, 48H), 2.94 (s, 2H), 2.63 (s, 1H), 2.57 (t, J=6.4 Hz, 2H); MS (m/z). found 790.4 (M+Na)+.
Reaction SMILES: N[C:2](N)=[S:3].C(Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([C:16]1[CH:20]=[C:19]([Cl:21])[S:18][C:17]=1Cl)(=[O:15])[CH3:14].[OH-].[Na+]>O.C1COCC1>[C:13]([C:16]1[CH:20]=[C:19]([Cl:21])[S:18][C:17]=1[S:3][CH2:2][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:15])[CH3:14]
Reactant: BrCc1ccccc1
Reactant: NC(N)=S
Reactant: CC(=O)c1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)sc1SCc1ccccc1
Temperature: 50 °C
Yield: 88 %

Procedure:
A mixture consisting of thiourea (858.4 g, 11.28 mol), benzyl bromide (1,930 g, 11.28 mol), THF (9000 ml), and water (3000 ml) was heated at reflux temperature for 2 hr followed by cooling to 50° C. To this solution was added 3-acetyl-2,5-dichlorothiophene (2000 g, 10.25 mol) and an aqueous solution of sodium hydroxide (2,200 g of 50% NaOH diluted to 3000 ml); this mixture was heated at reflux temperature for 4 hr, cooled to room temperature, and the two layers separated. The organic layer was diluted with ethyl acetate (6000 ml) and washed with water (3×2000 ml) and saturated aqueous sodium chloride, dried (MgSO4), and the solvent evaporated to give a residue which was triturated with hexane. This solid was collected by filtration and dried to give the desired product (2,550 g, 88%): mp 86°-88° C.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:45](O)(=[O:48])[CH2:46][OH:47]>C(Cl)Cl>[OH:48][CH2:45][C:46]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)=[O:47]
Reactant: O=C(O)CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)CO)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (300 mg, 0.72 mmol), in DCM (5 mL), were added EDC (180 mg, 0.94 mmol), HOBt (127 mg, 0.94 mmol) and NMM (0.32 mL, 2.89 mmol) and glycolic acid (60.4 mg, 0.79 mmol), at 0° C. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.35:9.65 MeOH:CHCl3) to provide the title compound (160 mg, 59%) as off white solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:17]([O: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][CH3:35])=[O:18]>C(Cl)(Cl)Cl>[CH3:8][CH:5]1[CH2:6][CH2:7][N:2]([NH:1][C:17](=[O:18])[O: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][CH3:35])[CH2:3][CH2:4]1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: CC1CCN(N)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)NN1CCC(C)CC1
Temperature: 25 °C

Procedure:
6.3 Grams of N-amino-4-methylpiperadine, 6.0 g of triethylamine and 120 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the solution was slowly added dropwise 15.2 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 16.8 g of the desired product. m.p. 92° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCO
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCCO)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2-aminoethanol, the title compound was obtained in 75% purity by HPLC. MS(ESI+): m/z=396.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[O:10]C.[C:12](=[O:14])=O.CC(C)=[O:17].B(Cl)(Cl)Cl>ClCCl>[OH:17][C:9]1[C:12]([OH:14])=[C:8]([CH3:3])[CH:7]=[CH:6][C:5]=1[CH:4]=[O:10]
Reactant: O=C=O
Reactant: CC(C)=O
Reactant: COc1cccc(C)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C=O)c(O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2-dimethoxy-3-methyl-benzene (13.8 g, 76.66 mmol) cooled to −30° C. (dry ice/acetone) in dichloromethane (200 mL) was added boron trichloride (230 mL, 230 mmol) dropwise and the mixture was left to stir overnight at room temperature. The solution was cooled to 0° C. and ice/water was added carefully, and then extracted with excess of dichloromethane. The organic layer was washed with water, dried (Na2SO4) and the solvent was evaporated. Purification by silica gel column chromatography (10-20% EtOAc/hexane) gave the title compound as a crystalline solid: yield 9.2 g (80%). 1H NMR (400 MHz, CDCl3) δ (ppm): 11.11 (s, 1H), 9.82 (s, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.67 (s, 1H), 2.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:10]=1)[C:5](O)=[O:6].[CH3:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:6])[N:34]([CH3:35])[CH3:33])[CH:3]=1)[CH2:11][O:12][CH2:13][C:14]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(=O)O)c2)(c2ccccc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Br)cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1.5 h

Procedure:
A stirred solution of 3-bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methyl)benzoic acid (160 mg, 0.32 mmol) in dimethylformamide (5 mL) was cooled to 0° C. and sequentially treated with methylene chloride (2 mL), dimethylamine (1 N in tetrahydrofuran, 0.32 mL, 0.32 mmol), N,N-diisopropylethylamine (90 μL, 0.64 mmol), and PyBop® (0.21 g, 0.38 mmol). The solution was stirred for 1.5 h and concentrated. The product was purified by column chromatography (30% ethyl acetate/hexanes) to give 120 mg (70%). 1H-NMR (CDCl3, 500 MHz) δ 7.38-7.40 (m, 1H), 7.33-7.35 (m, 4H), 7.22-7.24 (m, 2H), 7.03 (s, 1H), 4.32 (s, 2H), 3.74-3.77 (m, 2H), 3.38 (s, 2H), 3.08 (s, 3H), 2.99-3.05 (m, 2H), 2.90 (s, 3H), 2.16-2.19 (m, 2H), 1.83-1.89 (m, 2H), 1.43 (s, 9H). Mass spec.: 533.24 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:28]([CH3:27])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CN(Cc1ccccc1)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-methyl-1-phenylmethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methylterephthalamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13](Cl)[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3
Reactant: CN1CCNCC1
Reactant: Clc1nc2ccc(Br)c3c2n1CCC3
Product: CN1CCN(c2nc3ccc(Br)c4c3n2CCC4)CC1
Yield: 57 %

Procedure:
A solution of 7-bromo-2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in N-methylpiperazine (20 ml) was stirred under reflux, under nitrogen, for two hrs. The reaction mixture was quenched with dilute sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel; 7:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate-ether to give 2.1 g (57%) of product, mp 132°-133° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[O:38][C:37](=[O:39])[CH2:36][C:35](=[O:40])[CH2:34]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[O:38][C:37](=[O:39])[CH:36]([CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[C:35](=[O:40])[CH2:34]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cn1ccnc1C=O
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 1-methyl-1H-imidazole-2-carbaldehyde was substituted in place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in that example.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][C:3](=O)[CH2:2]2.O=P(Cl)(Cl)[Cl:10].CN([CH:16]=[O:17])C>C(Cl)Cl>[Cl:10][C:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C:2]=1[CH:16]=[O:17]
Reactant: O=C1CC2CC2C1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: O=CC1=C(Cl)C[C@@H]2C[C@H]12

Procedure:
Bicyclo[3.1.0]hexan-3-one (192 mg, 2.0 mmol) was reacted with POCl3, (0.33 mL, 3.6 mmol) and dry DMF (0.31 mL, 4.0 mmol) in dry CH2Cl2 (0.3 mL) according to General Procedure 1.1.A. The material was purified by passing through a pad of silica gel eluting with Et2O to afford the title compound. The material was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 100 °C

Procedure:
To (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.42 g) in toluene (14 ml) warmed to 40° C. was added phosphorous tribromide (0.16 ml) and the mixture was then heated to 100° C. After heating for 6 hours the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.40 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1.O>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:1]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(Cl)cc2cccnc12
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: O
Product: Clc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 135 °C
Reaction time: 120 h
Yield: 29.4 %

Procedure:
8-amino-6-chloroquinoline (Step 1, 0.49 g) and bis(chloroethyl)amine hydrochloride (0.49 g) were dissolved in chlorobenzene (13 mL) and heated with vigorous stirring at 135° C. for 5 days. The reaction was cooled to room temperature, diluted with water and extracted with Et2O. The aqueous phase was made basic by addition of solid Na2CO3 and then extracted with Et2O. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give the desired compound (0.20 g) as a yellow semi-solid; MS (ES) m/z (relative intensity) 248 (M+H)+ (100).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:8](I)[CH3:9]>C(O)C>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: CCI
Reactant: C1CNCCNC1
Solvent: CCO
Product: CCN1CCCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Homopiperazine (100 g) is dissolved in ethanol (500 ml), and thereto is added dropwise gradually ethyl iodide (19.8 ml). The mixture is stirred at room temperature overnight, and the insoluble materials are removed by filtration. The filtrate is evaporated to remove the solvent. Purification is performed by distillation to give 1-ethylhomopiperazine (50 g) as colorless oil.