Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:20][O:21][C:22](=[O:27])[C@@H:23]([CH3:26])[NH:24][CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:25][N:24]([C@H:23]([CH3:26])[C:22]([O:21][CH3:20])=[O:27])[C:3](=[O:5])[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH3:1]
Reactant: CN[C@H](C)C(=O)OC
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)N(C)C(=O)C(C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
To a solution of (R/S)-α-methyl-4-benzyloxyphenylacetic acid 45b (300 mg, 1.17 mmol) and N-methyl-D-alanine methyl ester (200 mg, 1.3 mmol) in DMF (5 mL) cooled in an ice bath was added BOP (531 mg, 1.2 mmol) followed by DIEA (0.7 mL, 4 mmol). The mixture was stirred at room temperature for 5 hours. EtOAc was added and the solution washed with NaHCO3, brine, citric acid and brine, dried (MgSO4), and concentrated. Purification on a silica gel column (40% EtOAc/hexane) gave the amide product (398 mg, 99%) as a solid. MS (CI—NH3): (M+H)+=356.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:21][NH2:22]>CCO>[N+:17]([C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:22][N:21]=[C:4]2[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:19])=[O:18]
Reactant: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(Nc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
2-Fluoro-5-nitro-N-phenyl benzamide (100 mg, 0.38 mmol) was suspended in EtOH (10 mL) and the mixture heated to 50° C. To the resulting solution was added hydrazine monohydrate (0.1 mL, 1.9 mmol). The mixture was heated at reflux for 30 minutes, at which time LC-MS showed complete conversion to the aryl hydrazine (ES+m/e=273). The mixture was allowed to cool to room temperature, concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase was dried over sodium sulfate and concentrated to a yellow foam. The residue was dissolved in phosphorous oxychloride (5 mL) and the mixture heated at 90° C. for 30 minutes, then allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated to afford the title compound as a red solid (80 mg, 83%); 1H NMR (400 MHz, DMSO) 6.88 (1H, t), 7.31 (2H, t), 7.51 (1H, d), 7.74 (2H, t), 8.17 (1H, dd), 9.24 (1H, s), 9.42 (1H, s), 12.74 (1H, s); MS (ES+) m/e=255.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2(OC)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)[CH3:2].[ClH:34]>O1CCCC1>[CH2:1]([N:3]([CH2:32][CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([Cl:34])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C2(OC)c3ccccc3N(c3ccccc3)c3ccccc32)cc1
Reactant: Cl
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C2(Cl)c3ccccc3N(c3ccccc3)c3ccccc32)cc1
Yield: 95.8 %

Procedure:
9(p-Diethylaminophenyl)-9-methoxy-10-phenylacridan (12.0 g, 0.0276 mole) is slurried in 150 ml of tetrahydrofuran while anhydrous hydrogen chloride is bubbled in with cooling. The hydrogen chloride is bubbled in until the slurry reaches a pH of 1.0 and a bright yellow color is obtained. The product is collected on a Buchner funnel, washed twice with 10 ml portions of tetrahydrofuran and dried at 50° C. to give 11.6 g (95.8% yield) of 9(p-diethylaminophenyl)-9-chloro-10-phenylacridan.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(OC(=O)C)(=[O:19])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Temperature: 80 °C
Yield: 73 %

Procedure:
4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol) was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution was concentrated to a volume of 15 mL, and the solid was filtered off, rinsed with CH2Cl2 and dried under vacuum to provide the title compound (1.29 g, 73%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (ddd, J=8.7, 8.7, 2.9 Hz, 1H), 7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4, 2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](CC(C)C)[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=CC=1)CCC.C[N:34](C=O)C.S(Cl)(Cl)=O>C1COCC1>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:32][C:19]=2[CH:20]=[C:21]([C:29]([NH2:34])=[O:30])[CH2:22][CH2:23]1
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)C1=Cc2ccccc2NCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (16 ml) was added dropwise to a solution of N-methyl-N-[(1-propylimidazol-2-yl)methyl]-1,4-benzodiamine (0.38 g) and triethylamine (2.04 ml) in THF (7.6 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[methyl[(1-propylimidazol-2-yl)methyl]]amino]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 264) (0.92 g).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Cl)[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC1C2C(=CC=CC=2)N(CCCC)C1=O)(=O)C1C=CC=CC=1.C(OCC1C2C(=CC=CC=2)N(C(=O)C2C=CC=CC=2)C=1)(=O)C1C=CC=CC=1>>[C:1]([O:9][C:10]1([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][CH2:21][CH2:22][CH3:34])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: CCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Agent: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Product: CCCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2ccccc21

Procedure:
This compound was made in an analogous method as 3-((1H-indol-3-yl)methyl)-5-chloro-2-oxo-1-propylindolin-3-yl benzoate) using 1-butyl-2-oxoindolin-3-yl benzoate and (1-benzoyl-1H-indol-3-yl)methyl benzoate. 1H-NMR δ 8.03 (d, 2H), 7.97 (bs, NH), 7.54 (t, 1H), 7.48 (d, 1H), 7.42 (m, 2H), 7.28 (d, 1H), 7.24 (dd, 1H), 7.15 (m, 2H), 7.05 (dd, 1H), 6.94 (dd, 1H), 6.70 (m, 2H), 3.75 (d, 1H), 3.68 (m, 1H), 3.52 (d, 1H), 3.41 (m, 1H), 1.28-1.09 (m, 4H), 0.81 (t, 3H).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[CH2:13][O:12][C@H:11]1[N:34]1[CH:41]=[C:40]([CH2:42][CH2:43][N:44]2[C:48](=[O:49])[C:47]3=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]3[C:45]2=[O:54])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.C[O-].[Na+].O>CO>[C:45]1(=[O:54])[N:44]([CH2:43][CH2:42][C:40]2[C:38](=[O:39])[NH:37][C:35](=[O:36])[N:34]([C@@H:11]3[O:12][CH2:13][C@@H:14]([OH:25])[C@@H:15]([OH:16])[C@H:10]3[OH:9])[CH:41]=2)[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]12
Reactant: O=C(O[C@@H]1[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1cn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 93.4 %

Procedure:
15 g (20 mmol) of 34 were dissolved in 500 ml of MeOH in a 1 l round-bottomed flask, treated with 324 mg (6 mmol) of NaOMe and stirred at room-temp. overnight with exclusion of water (TLC checking, AcOEt/n-heptane 1:1). Amberlite IR-120 was added to the resulting suspension until the pH was <7. The solid was dissolved in the presence of heat, filtered off hot from the ion exchanger and washed with MeOH. After removing the solvent, the residue was co-evaporated twice using 150 ml of water each time. This yielded 9 g of crude product, which was heated under reflux in 90 ml of MeOH for 10 min. After cooling to room temp., the mixture was treated with 60 ml of Et2O and stored overnight at 4° C. Filtration, washing with Et2O and drying in an oil pump vacuum yielded 7.8 g (93%) of 35.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[CH:16]=CC(C=C)=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[NH+]1([O-])CC[O:24]CC1.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>C1COCC1.O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[N:12]=[CH:13][C:29]([CH:28]([OH:24])[CH2:32][OH:31])=[CH:30][CH:16]=2)=[CH:4][CH:3]=1
Reactant: [O-][NH+]1CCOCC1
Reactant: C=Cc1ccc(NCC(C)(C)c2ccc(F)cc2)nc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CC(C)(CNc1ccc(C(O)CO)cn1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 86 %

Procedure:
N-(2-(4-fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine (158 mg, 0.6 mmol, 1.0 equiv) was added to a foil-covered 20 dram vial and then dissolved in a 50% THF/water mixture (6 mL). Osmium tetraoxide (15 mg, 0.06 mmol, 0.1 equiv) and morpholine N-oxide (103 mg, 0.9 mmol, 1.5 equiv) were added, and the reaction was stirred for 1 h. Additional THF (3 mL) was added, and the reaction was stirred for 3 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to give 129 mg (86%) of 1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol (m/z [M+H]=305).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N(C)C(=O)C2C=C(C=O)C=CC=2OCC2C=CC=CC=2)C=CC=CC=1>>[CH2:28]([N:27]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([CH:18]=[O:19])=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Agent: CN(C(=O)c1cc(C=O)ccc1OCc1ccccc1)c1ccccc1
Product: O=Cc1ccc(C(=O)N(Cc2ccccc2)Cc2ccccc2)c(OCc2ccccc2)c1

Procedure:
N,N-dibenzyl-2-benzyloxy-4-formylbenzamide was prepared from 2-benzyloxy-4-formylbenzoic acid (146 mg, 1 eq) and dibenzylamine (0.22 mL, 2 eq) using the same procedure as for N-phenyl-N-methyl-2-benzyloxy-5-formylbenzamide. The product was obtained as a brown oil (236 g, 95%). 1H NMR (CDCl3) δ9.96 (s, 1H, O═C—H), 5.24 (m, 3H, OCH2Ph and NCH2Ph), 4.33 (d, 1H, NCH2Ph), 4.11 (m, 2H, NCH2Ph).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:41])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:34][CH2:35][C:36]([O:38]CC)=[O:37])=[C:23]([CH:33]=2)[C:24]([O:26]CC(OCC)=O)=[O:25])=[O:17])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[CH2:1]([NH:8][C:9](=[O:41])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[C:23]([CH:33]=2)[C:24]([OH:26])=[O:25])=[O:17])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)c1cc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)ccc1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1C(=O)O
Yield: 95.3 %

Procedure:
378 mg of ethoxycarbonylmethyl 5-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-ethoxycarbonylmethoxy-benzoate, 6.5 ml of ethanol and 1.29 ml of 2N sodium hydroxide solution are stirred for 5 hrs. at RT. After the addition of 3 ml of acetic acid and 2 ml of water the mixture is warmed until a homogeneous solution is obtained. After cooling the precipitate is filtered off under suction, washed with acetic acid-water 1:1 and dried. There are obtained 290 mg of 5-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-carboxymethoxy-benzoic acid, m.p. 219° C., MS: 471 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].C1C=CC2N=CNC(=O)C=2C=1.[Cl:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][CH2:30][N:7]1[C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8]1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cnc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(CCCCl)c(=O)c2cc1OC

Procedure:
3-(3-chloropropyl)-6,7-dimethoxy-4(3H)-quinazolinone was prepared starting from 6,7-dimethoxy-4-(3H)quinazolinone (1.61 g, 8 mmol). The quinazolinone was combined with 1-chloro-3-iodopropane (1.9 mL, 8 mmol), an excess of potassium carbonate (10 g) and stirred in 30 mL DMF overnight. The salts were filtered off and the reaction mixture dilluted with water. The solid that formed was collected via vacuum filtration, washed with water and dried, 0.70 g (31%); brown solid; m.p. 143° C., MS: 282.8 (M+H)+
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:32]([C:40]1[C:41]([C:53]([F:56])([F:55])[F:54])=[C:42]2[C:46]3=[C:47]([CH2:49][NH:50][CH2:51][CH2:52][N:45]3[CH:44]=[CH:43]2)[CH:48]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.[C:58]([NH:65][CH2:66][C:67](O)=[O:68])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>C1COCC1>[O:68]=[C:67]([CH:51]1[NH:50][CH2:49][C:47]2=[C:46]3[C:42](=[C:41]([C:53]([F:56])([F:55])[F:54])[C:40]([CH2:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:48]2)[CH:43]=[CH:44][N:45]3[CH2:52]1)[CH2:66][NH:65][C:58](=[O:59])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h

Procedure:
HATU (172 mg, 0.45 mmol) and triethylamine (1.97 mmol) was added to a mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 150 mg, 0.39 mmol) and N-Boc-glycine hydrochloride (72 mg, 0.41 mmol) in THF (7 mL). After stirring overnight, the resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed sequentially with NaHCO3 (sat'd., aq) and brine, then dried and concentrated. The resulting residue was purified by reverse-phase chromatography to yield tert-butyl (2-oxo-2-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethyl)carbamate (200 mg, MS m/z 502 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([N:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[CH2:26][C@H:15]34)=[O:13])=[CH:10][C:4]=2[N:3]=1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Nc1nc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1nc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc2[nH]1
Yield: 71 %

Procedure:
The title compound is prepared from 2-amino-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 71% of theory; LC (method 4): tR=1.64 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH2:22].[CH:23]([NH:26][CH2:27][CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:25])[CH3:24].CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][C:6](=[O:7])[N:26]([CH2:27][CH2:28][CH:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)NCCC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.8 %

Procedure:
To a solution of CDI (0.146 g, 0.900 mmol) and DMAP (small catalytic amount) in DCM (1.3 mL) at room temperature was added benzo[d]thiazol-2-amine 3 (0.101 g, 0.672 mmol). The reaction mixture was stirred at room temperature for 1 d and N-isopropyl-3,3-diphenylpropan-1-amine 2 (0.213 g, 0.841 mmol) and DMF (0.5 mL) were added. The reaction mixture was stirred at room temperature for 3 d. Direct purification by flash column chromatography on silica gel (eluted with 50% to 100% DCM in hexanes) gave 3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-isopropylurea 4 (0.190 g) as a white solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:45])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:42][CH3:43])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[C:25]([CH3:41])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:44])[CH:13]=1)C.Cl>CO.O>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([CH2:7][C:6]([OH:45])=[O:5])[CH:9]=[N:10][CH:11]=2)=[C:15]([CH3:44])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:37])([F:38])[F:39])[C:32]([F:34])([F:35])[F:33])=[C:25]([CH3:41])[CH:24]=1)[CH2:42][CH3:43])[CH3:22]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A 6 N sodium hydroxide aqueous solution (0.009 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 75-(1); 5.0 mg, 0.0084 mmol) in methanol (0.3 mL) and water (0.030 mL), and the mixture was stirred for two hours. 2 N hydrochloric acid aqueous solution and water were added to the reaction mixture, followed by extraction with diethyl ether and ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (dichloromethane/methanol=5/1) to give the title compound (3.0 mg, 60%).
Reaction SMILES: [C:1]([C:9]([O:12][C:13]1[CH:19]=[CH:18][C:16](N)=[CH:15][CH:14]=1)([CH3:11])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20].N([O-])=O.[Na+].[OH2:25]>CC(C)=O.C(O)(=O)C=C>[Cl:20][CH:2]([CH2:3][C:16]1[CH:18]=[CH:19][C:13]([O:12][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([CH3:11])[CH3:10])=[CH:14][CH:15]=1)[C:1]([OH:8])=[O:25]
Reactant: Cl
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)c1ccccc1
Reactant: O
Agent: C=CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(CC(Cl)C(=O)O)cc1)C(=O)c1ccccc1

Procedure:
In 30 ml of acetone is dissolved 2.6 g of 4-(2-benzoyl-2-propyloxy)aniline and, under cooling with ice and stirring, 3.5 ml of hydrochloric acid, a solution of 0.8 g sodium nitrite in 3 ml water, 7 ml of acrylic acid and 0.7 g of finely divided cuprous chloride are added in the order mentioned. The mixture is stirred at 35° C for 1 hour and at room temperature for 1 hour, after which it is extracted with benzene. The extract is washed three times with water, and then the solvent is distilled off. The residue is dissolved in 10% of aqueous sodium bicarbonate, the solution is washed with benzene and then acidified with hydrochloric acid. The resultant oily substance is extracted with ether and the ether is distilled off to give 2 g of 2-chloro-3-[4-(2-benzoyl-2-propyloxy)phenyl]-propionic acid as a yellow oily substance.
Reaction SMILES: C[C:2]1(C)[O:6][C@H:5]([CH2:7][NH:8]C(=O)OCC2C=CC=CC=2)[C:4](=[O:19])[O:3]1.[ClH:21].[H][H]>CO.CCOCC.[Pd]>[ClH:21].[NH2:8][CH2:7][C@@H:5]([OH:6])[C:4]([O:3][CH3:2])=[O:19]
Reactant: CC1(C)OC(=O)[C@@H](CNC(=O)OCc2ccccc2)O1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](O)CN

Procedure:
Benzyl [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]methylcarbamate (7.76 g) prepared by the method described in Step B above was dissolve in methanol (70 mL) with 0.62 g 10% Pd/C. A 1 M HCl in ether solution was added (25 mL). This mixture was hydrogenated using a hydrogen balloon for 22 hours. The reaction mixture was purged with nitrogen, filtered though a pad of Celite, and evaporated under vacuum to give the title compound as a yellowish solid. 1H NMR (CD3OD, 500 MHz) δ 4.45 (dd, J=4 and 8 Hz, 1H), 3.82 (s, 3H), 3.31 (dd, 1H), 3.15 (dd, J=8 and 13 Hz, 1H).