Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:9][C:10]([C:12]1[C:25]2[C:16](=[N:17][C:18]3[C:23]([N:24]=2)=[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]2=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1)=[O:11])[CH2:5][N:6]([CH3:8])[CH3:7].[BH4-].[Li+]>O1CCCC1.C(O)(C)C>[CH3:7][N:6]([CH3:8])[CH2:5][CH:4]([NH:9][C:10]([C:12]1[C:25]2[C:16](=[N:17][C:18]3[C:23]([N:24]=2)=[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]2=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1)=[O:11])[CH2:3][OH:2]
Reactant: COC(=O)C(CN(C)C)NC(=O)c1cccc2nc3ccc4c(OC)cccc4c3nc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cccc2c1ccc1nc3cccc(C(=O)NC(CO)CN(C)C)c3nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-dimethylamino-2-[(4-methoxy-benzo[a]phenazine-11-carbonyl)-amino]-propionic acid methyl ester (335 mg) and lithium borohydride (72 mg) in tetrahydrofuran (10 mL) and isopropanol (10 mL) was stirred at room temperature for 18 hours. Another 5 equivalents of lithium borohydride were added and the mixture stirred for another 18 hours. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate, dried (MgSO4) and the solvent removed in vacuo to yield a brown gum. Purification using flash chromatography and trituration with ether yielded the desired title compound as an orange powder.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][CH3:34])=[CH:22][C:21]3=[O:35])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH2:33][CH3:34])=[CH:22][C:21]2=[O:35])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]1
Reactant: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H](O)CO)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 83, 95 mg, 0.19 mmol) in tetrahydrofuran (20 mL) was treated with 2N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was diluted with ethyl acetate, washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated to afford (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in dichloromethane (20 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The mixture was filtered to give (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (51 mg, 61%) as a light yellow solid: HR-ES-MS m/z calculated for C24H32N4O6 [M+H]+ 473.2395, observed 473.2395; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H) 0.91 (d, J=6.4 Hz, 3H) 1.24 (t, J=6.9 Hz, 3H) 1.40 (br. s., 1H) 1.46-1.62 (m, 1H) 1.64-1.80 (m, 1H) 3.17-3.40 (m, 2H) 3.69-3.79 (m, 1H) 3.79-3.90 (m, 1H) 3.98-4.11 (m, 4H) 4.49 (d, J=18.4 Hz, 1H) 4.72 (s, 1H) 4.86 (dd, J=11.0, 4.7 Hz, 1H) 6.38 (d, J=2.1 Hz, 1H) 6.97 (t, J=7.1 Hz, 1H) 7.13-7.20 (m, 1H) 7.21-7.33 (m, 2H) 7.51 (d, J=2.1 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[CH3:36][Mg]I>>[OH:17][C:8]([CH3:36])([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1
Reactant: C[Mg]I
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(=O)CCc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(C)(O)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 36, Step 1, using 1-{4′-[3-methyl-4-(2-oxo-4-phenyl-butyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and methylmagnesium iodide.
Reaction SMILES: CN([P+](O[N:12]1N=[N:19][C:14]2C=CC=C[C:13]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:28]([C:31]1[CH:36]=[N:35][N:34]2[CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=[C:33]2[C:32]=1[NH:46][C@@H:47]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:48](O)=[O:49])(=[O:30])[NH2:29].NCC#N.C(N(CC)CC)C>CN(C=O)C>[C:13]([CH2:14][NH:19][C:48](=[O:49])[C@@H:47]([NH:46][C:32]1[C:33]2[N:34]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)[N:35]=[CH:36][C:31]=1[C:28]([NH2:29])=[O:30])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)#[N:12]
Reactant: NC(=O)c1cnn2cc(-c3ccccc3)cc2c1N[C@H](C(=O)O)c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
BOP reagent (17.2 mg, 0.039 mmol) was added in one portion to a solution of (S)-2-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2-phenylacetic acid (Example 122, 10 mg, 0.026 mmol), 2-aminoacetonitrile (1.82 mg, 0.032 mmol) and triethylamine (0.011 ml, 0.078 mmol) in DMF (0.01 ml). The reaction was allowed to stir at rt for 1 hour before being purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aq sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded the title compound (7 mg, 60% yield). HPLC (condition B): retention time=1.57 min. LCMS (condition B): MH+ m/z 425.2. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (1H, s), 8.07 (1 H, d, J=1.66 Hz), 7.86 (1 H, s), 7.75 (4 H, dd, J=7.63, 2.08 Hz), 7.60 (2H, t, J=7.49 Hz), 7.49-7.57 (3 H, m), 7.41 (1 H, t, J=7.35 Hz), 7.31 (1 H, d, J=1.66 Hz), 6.11 (1 H, s), 4.22-4.44 (1 H, m), 3.17 (2 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[Cl:10].[N:11]([O-])=O.[Na+]>CC(O)=O.O>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:11]=[CH:9]2
Reactant: O=N[O-]
Reactant: Cc1c(N)ccc(Br)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1c(Br)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) in CH3CO2H (450 mL) was added NaNO2 (5.4 g, 78.3 mmol) in H2O (15 mL) at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was triturated with petroleum ether affording the title compound (4.5 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][OH:22])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH:21]=[O:22])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1c2cccc(CCO)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1c2cccc(CC=O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Reaction time: 0.67 h
Yield: 81.2 %

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one (1.08 g, 2.13 mmol) in CH2Cl2 (21 mL). Add NaHCO3 (1.08 g, 12.9 mmol) and 3,3,3-triacetoxy-3-iodophthalide (1.09 g, 2.56 mmol) at room temperature. Stir 40 min. Add saturated NaHCO3 solution and saturated Na2S2O3 solution, extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give the title compound as a white foam (0.87 g, 1.73 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.C(O)(=O)C.[NH:35]1[CH2:38][CH:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.C(N(CC)CC)C>CN(C=O)C>[C:22]1([C:16]2[O:15][N:14]=[C:13]([C:12]3[O:11][N:10]=[C:9]4[C:28]5[C:5]([CH2:6][CH2:7][C:8]=34)=[CH:4][C:3]([CH2:2][N:35]3[CH2:36][CH:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38]3)=[CH:30][CH:29]=5)[C:17]=2[C:18]([F:20])([F:21])[F:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a cloudy solution of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6C, 550 mg, 1.157 mmol) and tert-butyl azetidine-3-carboxylate acetic acid (377 mg, 1.736 mmol) in anhydrous DMF (12 mL) was added triethylamine (0.645 mL, 4.63 mmol) dropwise at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hr before being concentrated. The solid residue was partitioned between dichloromethane (2 mL) and saturated aqueous sodium bicarbonate solution (6 mL). The aqueous layer was extracted with dichloromethane (2×2 mL). The combined dichloromethane solutions were dried over sodium sulfate, concentrated and purified by silica gel chromatography (20 to 75% ethyl acetate in heptane) to afford tert-butyl 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (520 mg, 0.943 mmol, 81% yield) as a solid. To the solid was added TFA (3 mL) and the mixture stirred at room temperature for 70 min before being concentrated. Dichloromethane (15 mL) was added and the mixture concentrated again. The residue was mixed with water (4 ml) and neutralized to pH=5 with an aqueous sodium acetate solution. The resulting solid was filtered and washed with water (3×1 mL). To the solid was added methanol (1 mL) and water (0.5 mL), the contents were sonicated, and filtered. To the solid was added acetonitrile (0.5 mL) and water (6 mL). Lyophilization gave 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (420 mg, 0.805 mmol, 69.6% yield) as a white solid. The compound had an HPLC retention time=3.25 min. (condition C). LC/MS M+1=496.2. 1H NMR (400 MHz, MeOD+CDCl3) δ ppm 8.06 (1H, d, J=7.9 Hz), 7.77 (2H, d, J=7.3 Hz), 7.59-7.71 (3H, m), 7.51 (1H, s), 7.48 (1H, d, J=7.7 Hz), 4.42 (2H, s), 4.25-4.34 (4H, m), 3.55-3.65 (1H, m), 3.14 (4H, s).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]1=[C:28]([C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)=[O:40])[C:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O)=[O:30].C1(P(=O)(C2C=CC=CC=2)[CH2:55][C:56]([F:59])([F:58])[F:57])C=CC=CC=1>C1COCC1>[NH:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:19][C:20]1=[C:28]([C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33](/[CH:34]=[CH:55]\[C:56]([F:59])([F:58])[F:57])[CH:32]=1)=[O:30])[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)=[O:40]
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(C(C(=O)c1cccc(/C=C\C(F)(F)F)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
A 25 ml portion of THF solution containing 7.8 g of tetrabutylammonium fluoride and 24 g of Molecular Sieve 4A was stirred at room temperature for 12 hours in an atmosphere of argon. After cooling to 0° C., 20 ml of THF solution containing 300 mg of 3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzaldehyde and 1.7 g of diphenyl(2,2,2-trifluoroethyl)phosphine oxide was added dropwise thereto. This was stirred at room temperature for 5 hours. The reaction mixture was filtered, the filtrate was washed with water, dried with anhydrous sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography to obtain 201 mg (57%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-{3-[(1Z)-3,3,3-trifluoroprop-1-en-1-yl]phenyl}propane-1,3-dione as a yellow powder from an ethyl acetate-hexane (1:3) eluate. FA: 463
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1C=CC2N=NN(OS(C3C=CC(Cl)=CC=3)(=O)=O)C=2[CH:45]=1.C(O)C.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([O:21][CH2:26][CH3:45])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)O)C(N)=O
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a solution of t-butyloxycarbonyl-L-valyl-D-isoglutamine (1.73 g, 5 mmol) in DMF (5 ml) was added TEA (0.84 ml) and 6-chloro-1-p-chlorobenzenesulfonyloxybenzotriazole (2.06 g, 6 mmol) under cooling. After being stirred at room temperature for 4 hours, the mixture was cooled with ice again and ethanol (3 ml) and TEA (0.7 ml) were added. The mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 ml) was added to the reaction mixture and the organic layer was then washed with a 5% aqueous sodium bicarbonate solution, 1 N hydrochloric acid and water successively. The mixture was then dried over anhydrous sodium sulfate and evaporated. The crystalline residue was recrystallized from ethyl acetate/petroleum ether to obtain ethyl t-butyloxycarbonyl-L-valyl-D-isoglutaminate (820 mg). m.p. 128°-129° C. [α]D23 +8.4° (C 0.5, DMF). Rf2 =0.72, Rf3 =0.28.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH3:5][N:6]1[C:15]2[NH:14][C:13]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]=3[N:11]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[O:32])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[CH2:10][C:9]=2[CH:8]=[N:7]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:5][N:6]1[C:15]2[NH:14][C:13]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]=3[N:11]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:1][CH2:2][CH3:3])[CH2:35][CH2:34]4)=[O:32])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[CH2:10][C:9]=2[CH:8]=[N:7]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CCC(=O)N2CCNCC2)c(C)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCN1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(C)ccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of propionaldehyde (0.29 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=515.5
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15](=[O:26])[CH2:16][NH:17][C:18]2[C:23](Cl)=[CH:22][N:21]=[N:20][C:19]=2[Cl:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15](=[O:26])[CH2:16][NH:17][C:18]2[C:23]([O:29][CH3:28])=[CH:22][N:21]=[N:20][C:19]=2[Cl:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CN(C(=O)CNc1c(Cl)cnnc1Cl)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1cnnc(Cl)c1NCC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Yield: 30.9 %

Procedure:
A solution of Compound 139 (10 mg) and sodium methoxide (1.3 mg) in methanol (1 mL) was stirred overnight under reflux. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.,; NH-DM1020) column chromatography (ethyl acetate: hexane=1:9 to 1:1) to give 3.0 mg (30% yield) of the desired product as a white amorphous.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]([C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])([OH:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C#CC(=O)OCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
n-Butyl lithium (2.28 ml, 1.6M solution in hexanes, 3.64 mmol) was added slowly to a cooled (-78° C.) solution of ethyl propiolate (0.370 ml, 3.64 mmol) in tetrahydrofuran (10 ml). the soluton was stirred for 10 min. at -78° C. after addition was complete then (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1, 1,0 g, 3.64 mmol) in tetrahydrofuran (10 ml) was added, the temperature being maintained below -75° C. The mixture was stirred for a further 10 min, then warmed to -60° C. when glacial acetic acid (1 ml) was added. The mixture was warmed to room temperature and poured into saturated aqueous sodium hydrogen carbonate (20 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a gum (801 mg, 59%), 1H NMR (250 MHz, CDCl3) δ7.50 (2H, m), 7.35 (3H, m), 5.49 (1H, s), 4.25 (2H, q, J 7.12 Hz), 4.15 (1H, m), 3.02 (1H, m), 2.23 (2H, m), 2.00 (2H, m), 1.78 (1H, m), 1.37 (9H, s), and 1.29 (3H, t, J 7.12 Hz), m/z (ES+) 374 (M+1).
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:21][CH3:22])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30]>C(N(CC)CC)C>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:11](=[O:12])[C:10]1[CH:14]=[C:15]([O:21][CH3:22])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([F:7])[CH:9]=1
Reactant: CC1CCCCC1N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 5 ml of ethyl acetate and 0.30 g of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride were added 0.15 g of 2-methylcyclohexylamine and 0.40 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 2 hours. Then, the reaction product was subjected to silica gel column chromatography to obtain 0.34 g of N-(2-methylcyclohexyl)-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 48 of the present invention) represented by the formula:
Reaction SMILES: C([O:8][C:9](=[O:21])[C@H:10]([CH2:19][Br:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1>O1CCCC1.[Pd]>[C:12]([NH:11][C@H:10]([C:9]([OH:21])=[O:8])[CH2:19][Br:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CBr)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CBr)C(=O)O
Reaction time: 8 h
Yield: 103.3 %

Procedure:
The N-Boc-β-bromoalanine benzyl ester (22.0 g, 61.41 mmoles) was dissolved in tetrahydrofuran (160-180 mL) and treated with 10% Pd—C (10-15% w/w). The suspension was stirred under hydrogen atmosphere overnight. The mixture was filtered and the solvents removed to afford ˜17.0 g of the Boc-β-bromoalanine free acid.