Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O=[C:18]([CH3:31])[CH2:19][C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C.C(OCC)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:31])[C:19]([C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)O[C@H](C)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOCC
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone (1.16 g, 5.0 mmol) in ethanol (20 ml) was added (R)-1-phenylethyl 3-oxobutanoate (1.3 g, 6.5 mmol) followed by ytterbium triflate (294 mg, 0.5 mmol). The mixture was stirred at room temperature for 12 hours, then the ethanol was removed under reduced pressure, and the residual viscous oil dissolved in ethyl acetate. The organic phase was poured into a separatory funnel and washed with 1M aqueous hydrochloric acid, water, then brine. The organic phase was seoarated, and the solvent was removed under reduced pressure to provide a viscous oil. This was dissolved in a small amount of diethyl ether, and the solution allowed to stand at room temperature overnight. The white precipitate formed was filtered, washed with cold diethyl ether, and dried under reduced pressure, to provide (R)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate (1.33 g, 67%) as a white powder. Rf=0.26 using 80:20 hexanes:ethyl acetate eluent on glass backed silica gel plates. 1H NMR (CDCl3, 400 MHz) δ 8.98 (d, 1H, J=8.9 Hz); 7.96 (d, 1H, J=7.4 Hz); 7.72 (d, 1H, J=1.95 Hz); 7.6-7.1 (m, 10H); 5.88 (q, 1H, J=6.6 Hz); 3.05 (s, 3H); 1.3 (d, 3H, J=6.6 Hz). LC MS (CI) shows M+H 402.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[CH2:53][C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (5.38 g) in anhydrous acetonitrile (70 ml), N,N'-carbonyldiimidazole (2.04 g) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (2.0 ml) and a solution of the compound (11.00 g), which had been obtained in (2), in anhydrous acetonitrile (35 ml) were added and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated by evaporation under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography (ethyl acetate-methanol) through a silica gel column, whereby the title target compound (10.09 g) was obtained as an amorphous substance.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:16]1([CH2:22][N:23]2[CH2:28][CH:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(N(CC)CC)C>[C:16]1([CH2:22][N:23]2[CH2:24][CH:25]=[C:26]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:7]([C:2]4[C:1]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:8])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
[1,1′-Biphenyl]-2-carbonyl chloride (0.05 mole) was added dropwise to a stirring mixture of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.045 mole) in THF (300 ml) and triethylamine (25 ml). The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was'separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 18.5 g of N-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 11, melting point 142° C.).
Reaction SMILES: C(C1CCCN([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[NH:23][C:19]=3[CH:18]=2)=[O:16])C1)C1C=CC=CC=1.N1C2C=CC=CC=2NC1=O.[Cl:37]CC(Cl)=O>>[Cl:37][CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=C(CN1CCCC(Cc2ccccc2)C1)c1ccc2[nH]c(=O)[nH]c2c1
Agent: O=c1[nH]c2ccccc2[nH]1
Product: O=C(CCl)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
from 5-(2-(3-benzylpiperidino)-1-oxoethyl)-2,3-dihydrobenzimidazol-2-one ("K"; obtainable by reaction of 2,3-dihydrobenzimidazol-2-one with chloroacetyl chloride to give 5-chloroacetyl-2,3-dihydrobenzimidazol-2-one ("L"), then reaction with 3-benzylpiperidine):
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1ncccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-aminonicotinic acid (5.3 g, 38 mmol) and 4-chloroaniline (4.9 g, 38 mmol) and DIEA (9 ml, 48 mmol) at 0° C. in CH2Cl2 was added EDC (9.5 g, 48 mmol) and HOBt (5.1 g, 38 mmol), the reaction was warmed to RT and stirred overnight. The solvent was evaporated under reduced pressure and quenched with 2N NaOH solution (60 ml) and stirred for 20 min. The precipitate was filtered to give the titled compound. MS (ES+): 248 (M+H)+; (ES−): 246 (M−H)−.
Reaction SMILES: N1C=C[C:3](B(O)O)=N1.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1.BrC1C=C2C(=CC=1)CN(C(N[C:41]1[CH:46]=[CH:45][C:44]([C:47](=O)[NH:48][CH2:49][CH2:50][CH3:51])=[CH:43][CH:42]=1)=O)C2>>[CH2:47]([N:48]([CH3:3])[CH2:49]/[CH:50]=[CH:51]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1)[C:44]1[CH:43]=[CH:42][CH:41]=[CH:46][CH:45]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: O=C(Nc1ccc(Br)cc1)N1Cc2ccccc2C1
Reactant: OB(O)c1cc[nH]n1
Product: CN(C/C=C/c1ccc(NC(=O)N2Cc3ccccc3C2)cc1)Cc1ccccc1

Procedure:
The title compound was prepared as described in Example 280, substituting (E)-N-benzyl-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-amine for 1H-pyrazol-3-ylboronic acid and N-(4-bromophenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.12 (s, 1H), 7.52 (m, 2H), 7.37-7.18 (m, 11H), 6.48 (d, J=15.8 Hz, 1H), 6.18 (dt, J=15.8, 6.5 Hz, 1H), 4.77 (s, 4H), 3.53 (s, 2H), 3.15 (dd, J=6.5, 1.4 Hz, 2H), 2.18 (s, 3H); MS (ESI(+)) m/e 398 (M+H)+.
Reaction SMILES: COC1C=C(OC)[CH:47]=[CH:46][C:4]=1[CH2:5][NH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.C(N(CC)CC)C.ClCCCC(Cl)=[O:64].[OH-].[Na+]>ClCCl>[NH2:17][C:12]1[C:11]2[C:10]3[C:9](=[N:34][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:32]=2)[CH2:8][CH:7]([N:6]2[CH2:47][CH2:46][CH2:4][C:5]2=[O:64])[C:16]=3[CH2:15][S:14][N:13]=1
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(N4CCCC4=O)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (47 mg), triethylamine (36 μl), dichloromethane (1 ml) and 4-chlorobutyryl chloride (14 μl) was stirred at room temperature for 12 hours. A 0.1 N sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dehydrated dichloromethane (1.5 ml). 1,3-Dimethoxybenzene (16 μl) and trifluoroacetic acid (1.5 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a 0.1 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dimethylformamide (1 ml) and potassium tert-butoxide (15 mg) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was separated with water and chloroform. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (13 mg, 46%) as a solid.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Cl)(Cl)[Cl:25]>ClCCl>[Cl:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: ClP(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Cl)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.89 g) and phosphorous trichloride (0.57 g) in dichloromethane (50 ml) were stirred at 0° C. for 2 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to dryness. The crude product was purified by column chromatography on silica eluted with a mixture of petroleum ether/ethyl acetate to give 4-[chloro-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 298, 0.79 g) as a yellow oil: NMR: (CDCl3) 1.1 (4H, m) 1.9(1H, m) 6.9(1H, s) 7.9(1H, m) 8.0(1H, s) 8.25(2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13].Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:13]
Reactant: BrCCOCCBr
Reactant: Nc1cc(Br)c(N)c(C(F)(F)F)c1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 180 °C
Yield: 63 %

Procedure:
2-Bromo-6-trifluoromethyl-benzene-1,4-diamine (2.21 g), bis-(2-bromoethyl)ether (1.30 mL) and N,N-diisopropyl-ethylamine (4.64 mL) were mixed in N,N-dimethylformamide (19 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (100 mL) was added and the crude mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 1.78 g (63%) of the title compound as a yellow solid. LC-MS (m/z) 326 (MH+); tR=2.54, (UV, ELSD) 83%, 75%. 1H NMR (500 MHz, DMSO-d6): 2.99 (m, 4H), 3.70 (m, 4H), 5.00 (s, 2H), 7.00 (d, 1H), 7.38 (d, 1H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[CH:18][N:17]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (412 mg, 0.574 mmol) was suspended in trifluoroacetic acid (Aldrich redistilled 99+%, 6.0 mL, 78 mmol) and the flask was fitted with a reflux condenser and put in a preheated oil bath (75° C.) and the reaction was stirred overnight. Then, the reaction was cooled to room temperature and concentrated and diluted with saturated sodium bicarbonate and then with 5N NaOH to raise the pH to about 8-9. The suspension was filtered, and the solid was washed with water. The filtrate was discarded, and the solid was collected with DCM and MeOH, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH. The solid was not >95% pure by HPLC, so the filtrate and solid were combined, concentrated, and purified on a silica gel column (30:1 to 20:1 DCM/MeOH). The fractions with product were collected, concentrated, treated with MeOH, and filtered. The yellow solid was washed with MeOH, collected, and dried under high vacuum at room temperature overnight to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (126.1 mg, 46% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.64 (s, 1H), 8.65 (d, J=2.15 Hz, 1H), 8.36 (d, J=2.35 Hz, 1H), 8.17 (d, J=1.56 Hz, 1H), 8.11 (dd, J=8.90 Hz, 2.25 Hz, 1H), 7.88 (d, J=8.22 Hz, 2H), 7.42 (d, J=7.82 Hz, 2H), 6.78 (d, J=8.80 Hz, 1H), 5.36 (br s, 2H), 4.04 (s, 2H), 3.95 (s, 3H), 3.04 (s, 3H), 2.56 (s, 3H). m/z (ESI, +ve ion) 478 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:12]=1)[CH2:4][OH:5].O.C(=O)([O-])O.[K+].Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(OCC)(=O)C>[CH2:35]([O:34][C:32]([NH:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:11][CH:12]=1)[CH2:4][OH:5])=[O:33])[CH:36]=[CH2:37]
Reactant: C[C@](N)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N[C@@](C)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a suspension of (2R)-2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butan-1-ol (0.5305 g, 1.66 mmol) obtained in Example 20 in a mixed solvent of ethyl acetate (16 ml) and water (16 ml) were added potassium hydrogencarbonate (0.1995 g, 1.99 mmol) first and then allyl chloroformate (0.21 ml, 1.98 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, the reaction mixture was diluted with ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the title compound (0.6202 g, yield: 93%).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC(=O)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Reaction time: 4 h

Procedure:
To 12 g of 3-benzoylpropionic acid and 9.3 g of potassium carbonate in 100 ml of dimethylformamide (DMF), under nitrogen, is added m-phenoxybenzyl bromide (17.1 g). The reaction is stirred about 4 hr and then water added followed by extraction with ether. The combined extracts are washed with water, saturated sodium chloride, dried over calcium sulfate and rotoevaporated to give m-phenoxybenzyl 3-benzoylpropionate which can be further purified by prep. TLC eluting with 15% ethyl acetate/hexane.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 41.1 %

Procedure:
2,5-dihydroxyacetophenone (5.00 g, 0.0329 mol), benzyl bromide (3.72 ml, 0.031 mol), potassium carbonate (4.31 g, 0.031 mol) and acetone (150 ml) were added to a 500 ml round bottom flask. The reaction mixture was heated overnight at reflux and then was cooled to ambient temperature. When cool, deionized water (150 ml) was added to the reaction mixture and the reaction mixture was extracted three times with 100 ml portions of diethyl ether. The combined ether layers were dried with sodium sulfate and concentrated in vacuo yielding a dark solid. This dark solid was recrystallized from 50:50 (ethanol:water) yielding 3.09 g of 2-hydroxy-5-benzyloxyacetophenone as yellow needles.
Reaction SMILES: [CH2:1]([N:8](C(O)CCC1C=CC([N+]([O-])=O)=CC=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[NH4+:35].[CH2:36]([OH:38])[CH3:37]>[Fe]>[NH2:35][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][C@H:37]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:36][OH:38])=[CH:3][CH:4]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(CCC(O)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of (2S)-2-[(N-benzyl-N-((2S)-2-hydroxy-3-phenoxypropyl]amino]-3-(4-nitrophenyl)-1-propanol (1.12 g) in ethanol (11 ml)—water (2.2 ml) were added powdered iron (573 mg) and ammonium chloride (55 mg). The mixture was gently heated to reflux for 1 hour and allowed to cool to room temperature. After the insoluble material was filtered off, the filtrate was concentrated and partitioned between chloroform and water. The organic layer was separated, washed successively with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (990 mg) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:7](=[O:19])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]1[CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]1[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=1)=[O:28].B(Br)(Br)Br.CO>ClCCl>[O:1]=[C:2]1[C:8](=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:7](=[O:19])[N:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]1[CH2:26][C:27]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)[CH:38]([CH3:40])[CH3:39])=[O:28]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=Cc3n[nH]c4ccccc34)C2=O)C(C)C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(C(=O)CN1C=CN(c2ccccc2)C(=O)C(=Cc2n[nH]c3ccccc23)C1=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To the solution of 2-[2,4-dioxo-3-(1H-indazol-3-ylmethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (Example 1) (1 g, 1.86 mM) in 50 ml of dichloromethane was cooled to 0° C. and 10 fold excess of BBr3 was added. The reaction mixture was stirred for 3 hrs at room temp., cooled to 0° C. and methanol was added dropwise. Organic solvents were evaporated under reduced pressure and residue was purified using column chromatography on silica gel using mixture of Hexane-Ethyl Acetate (1:3) as an eluent providing 700 mg of pure racemic product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2O)[CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+].CCOCC>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25][C:16]=1[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1
Reactant: COc1ccccc1N1CCN(CC2CCc3ccccc3C2O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CC2=Cc3ccccc3CC2)CC1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
6.0 g of 1,2,3,4-tetrahydro-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1-naphthalenol (prepared as described in Example 1) is suspended in 24 ml of 20% sulfuric acid/acetic acid and the mixture is heated on a steam bath for 15 minutes. The reaction mixture is then cooled room temperature, diluted with water (200 ml) and then made alkaline to pH 8 using sodium bicarbonate solution. The alkaline suspension is extracted with two 250 ml portions of methylene chloride and the organic phase is back-washed with water (250 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The syrup obtained solidifies upon addition of a minimal amount of ether to yield 5.6 g of the title compound, melting point 84°-85° C.