Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:18]C(=O)OC(C)(C)C)[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5].[ClH:26].CCOCC>CO>[ClH:26].[NH2:18][C@@H:3]([CH2:2][OH:1])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)[C@H](CO)NC(=O)OC(C)(C)C)[C@@H]1CCCc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN(C(=O)[C@@H](N)CO)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl [(1S)-1-(hydroxymethyl)-2-[methyl[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-2-oxoethyl]carbamate (1.11 g, 3.19 mmol) (i.e. the product of Example 17, Step A) in methanol (15 mL) was added a 2 M solution of hydrogen chloride in ether (15 mL, 30 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in methanol and concentrated in vacuo again. The residue was dried in high vacuum to give 750 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCCCCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 2 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 1.4 g of potassium carbonate, 4 ml of ethyl 6-bromohexanoate, and 50 ml of methylisobutylketone, a reaction similar to that conducted in Example 171 was carried out. As a result, 2.89 g of N-(trans-4-methylcyclohexyl)-4-[5-(ethyoxycarbonyl)pentyloxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:19][C@H:20]([C:22]([OH:24])=[O:23])[CH3:21]>>[CH2:10]([O:23][C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(F)cc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccc(F)cc1
Yield: 73 %

Procedure:
Working as in Example 60, but starting with 2-acetylthiomethyl-3-(4-fluorophenyl)butanoic acid and benzyl esters of alanine, the title compound is obtained in a yield of 73% as an oil having the characteristics: Rf =0.23 [cyclohexane/ethyl acetate (7:3 by volume)].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.2 %

Procedure:
The product from Step B (52 mmol) was treated with tetrabutylammonium tribromide (25.5 g, 52.9 mmol) in methanol/methylene chloride (1/3, 240 ml) under nitrogen. After stirring 3 days at room temperature, the solvents were removed in vacuo, and the residue dissolved in diethyl ether (200 ml), washed with water (4×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (120 g) eluting with hexanes/ethyl acetate (30/1) afforded the desired □-bromoacetophenone (6.23 g) as a crystalline solid: 1H NMR (300 MHz, CDCl3) δ 7.70–7.81 (m, 2H), 7.55 (t, J=7.7 Hz, 1H), 4.39 (s, 2H); CI MS m/z=251 [C8H5BrClFO+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2ncccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2c1CCCN2
Temperature: 90 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
To a mixture of quinoline-5-carboxylic acid (4 g) in acetic acid (40 ml) was added borane-pyridine complex (8.59 g) at ambient temperature. After stirred for 18 hours, to the reaction mixture was added 1N hydrochloric acid and heated at 90° C. for 1 hour. The mixture was neutralized with aqueous sodium bicarbonate solution and ethyl acetate was added thereto. The precipitate was filtered off. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography eluted with chloroform-methanol and crystallized from diisopropyl ether to give 1,2,3,4-tetrahydroquinoline-5-carboxylic acid (1.12 g) as pale brown crystals.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.N([O-])=O.[Na+].[OH-].[Na+].[ClH:20]>O>[Cl:20][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2
Reactant: Cl
Reactant: Cc1ccc2c(N)c(Cl)ccc2n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(Cl)c(Cl)ccc2n1

Procedure:
5-Amino-6-chloroquinaldine (4 g) was dissolved in 40 ml of concentrated hydrochloric acid and the resulting solution was cooled with ice. Then, a solution of 2.1 g of sodium nitrite dissolved in 5 ml of water was added thereto dropwise while ice-cooling. After continuing the reaction at the same temperature as above, the reaction mixture was added to a solution of 7 g of cuprous chloride dissolved in 15 ml of concentrated hydrochloric acid and the resulting mixture was allowed to react on a water bath at a temperature of 50° C. for 1 hour, during which time vigorous formation of nitrogen gas was observed. Subsequently, the reaction mixture was cooled, rendered alkaline with 30% sodium hydroxide, and filtered and extracted using 300 ml of chloroform and Celite (diatomaceous earth). After drying over anhydrous sodium sulfate the chloroform fraction was concentrated and recrystallized from a mixture of isopropanol and water to give 3.5 g of 5,6-dichloroquinaldine as white needles having a melting point of 84° to 85° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: Nc1cccc(C(=O)O)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(F)cc12
Yield: 45 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-fluoro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 14) (26 mg, 0.10 mmol) and 3-aminobenzoic acid (26 mg, 0.19 mmol). The title compound was obtained in 45% yield (16.5 mg). MS (ESI+) calcd mass for C16H12FNO4S2 365.019178, found 365.018988.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:38]([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C@@H:39]([OH:49])[CH:40]([OH:48])[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C.C(N(CC)CC)C>[NH2:1][CH:41]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:40]([OH:48])[CH:39]([OH:49])[CH2:38][CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chlorofrom/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucy}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.1 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)-ethoxy)methyl)piperidine-1-carboxylate (10.7 g, 25 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (150 mL). The reaction mixture was stirred at room temperature for 1 h. TLC showed the reaction was completed. A solution of saturated sodium bicarbonate was added drop wise to adjust pH 8-9. The resulting mixture was extracted with CH2Cl2 (3×200 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (11.2 g, 100%), which was used for next step directly without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([NH:23][C:24]([C:26]2[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=2[CH3:31])=[O:25])=[C:16]([CH3:34])[CH:15]=1)([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].[C:35](OC(=O)C)(=[O:37])[CH3:36].Cl>O1CCCC1>[C:35]([N:23]([C:17]1[CH:18]=[C:19]([CH2:20][CH2:21][CH3:22])[C:14]([C:5]([O:4][CH3:3])([C:6]([F:9])([F:8])[F:7])[C:10]([F:13])([F:11])[F:12])=[CH:15][C:16]=1[CH3:34])[C:24]([C:26]1[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=1[CH3:31])=[O:25])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(NC(=O)c2c(C)nn(C)c2C)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(N(C(C)=O)C(=O)c2c(C)nn(C)c2C)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Sodium hydride (32 mg, 60%, 0.8 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-methyl-5-n-propylphenyl}-1,3,5-trimethylpyrazole-4-carboxamide (250 mg, 0.53 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of acetic anhydride (80 mg, 0.78 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (139 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a white solid as a mixture of diastereoisomers (4.56 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(Cl)c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)c(Cl)c2)sc2cc(O)ccc12
Yield: 59.2 %

Procedure:
By the method described in Example 2, the product of Example 4 (0.61 g, 1.14 mmol), ethanethiol (0.42 mL, 5.77 mmol), and aluminum chloride (1.07 g, 8.03 mmol) were stirred in anhydrous CH2Cl2 (20 mL). After chromatography (silica gel, 5-10% MeOH in CH2Cl2) the remnant crystallized from MeOH/CH2Cl2 to give 343 mg (59%) of the title product as a yellow solid; 1H NMR d 1.33 (m, 2H), 1.44 (m, 4H), 2.37 (m, 4H), 2.48 (s, 1H), 2.60 (t, J=5.7 Hz, 2H), 4.06 (t, J=5.7 Hz, 2H), 6.83-6.93 (m, 4H), 7.12 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.25 (m, 2H), 7.33 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 9.82 (br s, 1H); 13C NMR (DMSO-d6) d 23.8, 25.4, 54.2, 57.0, 65.9, 107.1, 114.5, 115.3, 116.9, 119.9, 123.5, 124.8, 128.2, 129.4, 129.5, 130.6, 131.7, 132.0, 138.5, 139.3, 153.5, 155.6, 162.9, 192.3; HRMS (FAB) m/e calc'd. for C28H27ClNO4S (MH+): 508.1349, found: 508.1344.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[C:5]1([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][NH:15]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cccc3c2CCN3)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
1.0 g of sodium cyanoborohydride is gradually added to a solution of 1.5 g of 4-phenylindole in 20 ml of trifluoroacetic acid under argon, cooled to a temperature of about −5° C. The reaction mixture is stirred at a temperature of about 0° C. for 2 hours, and is then poured into 50 g of ice and alkalinized with 30 ml of a concentrated sodium hydroxide solution. After the addition of 100 ml of ethyl acetate, the mixture is stirred at ambient temperature and treated with 10 ml of concentrated sodium hydroxide, and then separated by settling out. The organic phase is dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is treated again with a mixture of 50 ml of water, 50 ml of ethyl acetate and 10 ml of a concentrated sodium hydroxide solution and stirred at ambient temperature for 15 minutes, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×50 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is triturated from 20 ml of diisopropyl ether and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 50 g column of 20-45 μm silica, elution being carried out with pure dichloromethane. 0.74 g of 4-phenyl-2,3-dihydro-1H-indole is thus obtained in the form of a cream-colored solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][P:23]([CH:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:27]([CH3:29])[CH3:28])([OH:25])=[O:24])[C:17]([O:19]CC)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][P:23]([CH:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:27]([CH3:29])[CH3:28])([OH:25])=[O:24])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)CP(=O)(O)C(NC(=O)CCc1ccccc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)CC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
The crude ethyl 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate (222 mg) obtained in the above step (f) was dissolved in a mixed solvent of ethanol:water (10:7) (3.4 ml). The mixture was added with 1 N aqueous sodium hydroxide (0.6 ml) and stirred at room temperature for 3 hours, at 50° C. for 2 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with hydrochloric acid and the organic substances were extracted with ethyl acetate, and then the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was concentrated to obtain crude 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (181 mg, 86%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)=O>C(N(CC)CC)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
3.60 g (0.025 mol) of Meldrum's acid and 3.8 g (0.025 mol) of p-nitrobenzaldehyde were weighed in to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example l. The reaction mixture was heated to 105° C. during 1 hour and reacted at the same temperature for 1 hour. The product was isolated according to Example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.0 g, 2.94 mmol), 3-[(methyloxy)-carbonyl]benzoic acid (0.58 g, 3.24 mmol), HBTU (1.34 g, 3.53 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (30 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and the solution extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using CombiFlash chromatography, eluting with 80% ethyl acetate in hexane. The product fractions were combined and concentrated to give methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoate as an oil (1.40 g, 99%). LC-MS m/z 467 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[S:19][C:20]2[C:26]([CH:27]=O)=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.O>O1CCCC1>[CH3:17][C:18]1[S:19][C:20]2[C:26](/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1nc2cccc(C=O)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nc(C)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
Under nitrogen atmosphere, to a suspension of 60% sodium hydride (1.26 g, 31.5 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (7.06 g, 31.5 mmol) in tetrahydrofuran (50 mL) at 0° C. and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl-1,3-benzothiazole-7-carbaldehyde (4.60 g, 26.0 mmol) in tetrahydrofuran (100 mL), and the mixture was warmed to room temperature over 2 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.50 g, yield 98%).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=O>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]1[O:10][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCc1nc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
A solution of benzamidoxime (0.77 g, 5.68 mmol) and triethylamine (0.95 mL, 0.82 mmol) in toluene (10 mL) was treated with 0.45 mL (5.65 mmol) of chloroacetyl chloride at room temperature for 30 min., refluxed for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with water, and extracted with ethyl acetate. The organic extracts were then washed with water and dried with MgSO4. Concentration in vacuo gave an oil which was chromatographed on silica gel using ethyl acetate, hexanes (1.9), giving 0.24 of the title compound as a light yellow oil which solidified on standing. 1H NMR (250 MHz, CDCl3) δ 8.1 (m, 2H), 7.5 (m, 3H), 4.8 (s, 2H).