Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:22]([O-])=O)[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:22])[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Suspended 236 mg of 6-chloro-7-(4-methyl-piperazin-1-yl)-8-nitro-9H-β-carboline in 100 ml of methanol and added 10% Pd/C (48 mg) under argon. The flask was flushed with hydrogen (3×) and the reaction mixture was stirred under a hydrogen atmosphere at RT overnight. The reaction mixture was filtered and Pd/C was removed using a pad of celite. The reaction mixture was evaporated to remove solvent and purified by flash chromatography to give 119 mg (55% yield) of the desired 6-chloro-7-(4-methyl-piperazin-1-yl)-8-amino-9H-β-carboline. 1H-NMR (300 MHz, methanol-d4): δ 2.39 (s, 3H), 2.46 (m, 2H), 2.87 (m, 4H), 3.83 (m, 2H), 7.50 (s, 1H), 7.97 (d, 1H), 8.24 (d, 1H), 8.78 (s, 1H). Retention Time (LC, method: ammonium acetate polar): 1.32 min. MS (M+H+): 316.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:7]=1[C:8](OCC)=[O:9])[CH:3]([CH3:5])[CH3:4]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:13]=[C:7]2[C:8](=[O:9])[NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]2=[N:16][CH:15]=1
Reactant: CCOC(=O)c1cc(Cl)cnc1[C@@H](N)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1NC(=O)c2cc(Cl)cnc21

Procedure:
A solution of ethyl(S)-2-(1-amino-2-methylpropyl)-5-chloronicotinate (282 mg, 1.10 mmol) was heated in toluene (5 mL) at 100° C. for 15 h. The solvent was removed in vacuo to yield crude (S)-3-chloro-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, which was carried forward without further purification. LCMS: tR=0.73 min in in 1 min chromatography, MS (ESI) m/z 211.2 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.70 (d, J=2.8 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 6.75 (broad s, 1H), 4.55 (dd, J=1.2 Hz, 3.6 Hz, 1H), 2.49-2.41 (m, 1H), 1.23 (d, J=7.2 Hz, 3H), 0.74 (d, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CN(C=O)C>[CH2:3]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
403 mg (10.1 mmol) of sodium hydride (60% oily) was added to 1.102 g (10.2 mmol) of benzyl alcohol in 15 ml of DMF, and they were stirred for 30 minutes. 2.51 g (9.99 mmol) of ethyl 8-bromooctanoate was dissolved in 5 ml of DMF, and the obtained solution was added dropwise to the reaction mixture in ice bath. After stirring at room temperature for 1.5 hours, 2 N hydrochloric acid was added to the mixture. DMF was evaporated under reduced pressure. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1/) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13][C:12]1=[O:21]>CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:15](=[O:16])[C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13][C:12]2=[O:21])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1NC2(CCCC2)C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Solvent: CO
Product: Nc1ccc(N2C(=O)NC3(CCCC3)C2=O)c(Cl)c1
Reaction time: 1 h

Procedure:
3-(2-chloro-4-nitrophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (268 mg; 0.87 mmol) was stirred in MeOH (15 mL) and catalytic Rainey-Ni (30 mg) was added. The reaction flask evacuated and purged with Ar. The flask was then evacuated and purged with hydrogen (1 atm) via balloon. After vigorous stirring for 1 h, the mixture was filtered through Celite, washed with MeOH and CH2Cl2 and the filtrate was concentrated yielding 3-(4-amino-2-chlorophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione that was taken to the next step without purification, 1.2.13.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:12]([C:22]([OH:24])=O)[CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:32][C@@H:33]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.CN1CCOCC1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[NH:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:12]([C:22]([NH:32][C@@H:33]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:24])[CH2:13][S:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
HOBt (1.90 g) was added to a DMF solution (50 ml) of Boc-Cys(Bzl)-OH (4.34 g) and D-Phg-OEt hydrochloride (3.00 g), to which were added N-methylmorpholine (1.65 ml) and WSC (4.00 g) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes and was further stirred at room temperature for 80 minutes, to which water was added, and extracted with AcOEt. The organic phase was washed with saturated saline, dried with magnesium sulfate anhydride, and then filtered and concentrated. The residue was purified by silica gel chromatography (h-hexane/AcOEt=4/1→2/1) to obtain Boc-Cys(Bzl)-D-Phg-OEt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](I)[CH3:37]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:36][CH3:37])[CH:24]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(OC)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in example 83 using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) and ethyl iodide (0.13 mL) as starting materials, 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained. By the reaction and treatment of this compound (0.40 g) in the same manner as in Example 133, N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.30 g) was obtained. melting point: 211-213° C.
Reaction SMILES: C1C=CC=CC=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>O>[CH2:26]([O:25][C:23]([C:13]12[CH2:12][CH2:11][CH2:10][CH:15]([C:16]3[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:22])=[O:24])[CH3:27]
Reactant: CCOC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C12CCCC(C1=O)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of benzene (400 ml.) and sodium hydride (5.3 g. of a 57% suspension in nujol), which is free of nujol, is added dropwise, under dry nitrogen, -(3-bromopropyl)-1-ethoxycarbonyl-2-indanone (39.3 g.) in 100 ml. of benzene. The mixture is stirred at room temperature for 18 hours. Water is added and the organic layer is separated, washed with aqueous sodium chloride, dried, concentrated and distilled to give after a small forecut, 20.5 g. of the title product with b.p. 130°-145° at 0.5 mm.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)[CH3:3].[CH3:30][I:31]>CN(C=O)C>[I-:31].[CH3:3][N+:2]([CH3:30])([CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])=[CH:9][CH:10]=1
Reactant: CI
Reactant: CN(C)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccccc4)ccc3CC2)cc1
Solvent: CN(C)C=O
Product: C[N+](C)(C)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccccc4)ccc3CC2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In DMF (2 ml) was dissolved N-[4-(dimethylaminomethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (80 mg), and to the mixture was added methyl iodide (39 μl). The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. The residue was recrystallized from methanolethyl acetate to give trimethyl[4-(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]ammonium iodide (Compound 10) (92 mg) as colorless crystals.
Reaction SMILES: [CH2:1](O)/[CH:2]=[CH:3]/[CH3:4].C(O[C:9]([O:14]CC)([O:11][CH2:12][CH3:13])[CH3:10])C.C(O)(=O)C>>[CH3:4][CH:3]([CH:2]=[CH2:1])[CH2:10][C:9]([O:11][CH2:12][CH3:13])=[O:14]
Reactant: C/C=C/CO
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: C=CC(C)CC(=O)OCC
Temperature: 125 °C
Yield: 71 %

Procedure:
To a solution of (E)-but-2-en-1-ol (50 g, 693 mmol) in 1,1,1-triethoxyethane (890 mL 4854 mmol) was added acetic acid (5 g, 83 mmol) at room temperature. The reaction was heated to 125° C. for 4 h. The by-product ethanol was distilled by normal distillation to get crude compound ethyl 3-methylpent-4-enoate (70 g, 71.0%) as color less oil. This was taken to next step without further purification; 1H NMR (DMSO-d6) δ ppm 5.82-5.73 (m, 1H), 5.03-4.92 (m, 2H), 4.08-4.02 (m, 2H), 2.50 (m, 1H), 2.31-2.26 (m, 2H), 1.17 (t, J=8 Hz, 3H), 1.00 (d, J=8 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5]C)(=O)C.[CH:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=1.[CH3:15][NH:16][CH3:17]>O>[OH:14][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:5](=[O:4])[N:16]([CH3:17])[CH3:15])=[CH:7][CH:8]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(C)=O
Reactant: CNC
Solvent: O
Product: CN(C)C(=O)Nc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
In a 2 liter-flask were placed 100 g of diphosgene (trichloromethyl chloroformate), 1 liter of ethyl acetate and 109 g of p-aminophenol were added portionwise with stirring and cooling with ice-water. After completion of the addition, the mixture was warmed and refluxed for one hour. After cooling, 180 g of 50% aqueous dimethylamine solution were added dropwise while cooling with water and, after completion of the addition, stirring at room temperature was continued for 20 minutes. The resulting crystalline mass was filtered with suction, washed with water and thereafter dried to give 148 g of the end product as white crystal (yield: 82.1%). After recrystallization from a mixed solvent of acetone and methanol, the product showed of a melting point of 205°-6° C. The compound thus obtained was used in the following Preparation Examples 1 and 2.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:18]([O:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(COc2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 25.1 %

Procedure:
To a RB flask equipped with overhead stirrer, condenser and N2 inlet line with bubbler was added 1-hydroxypyrene (Cambridge Chemical, Inc., 5.0 g, 23 mmol), benzyl bromide (Aldrich, 15.64 g, 92 mmol, 10.94 mL), K2CO3 (Mallinckrodt, 12.72 g, 92 mmol) and acetone (100 mL). The mixture was refluxed overnight, cooled and then poured into H2O (250 mL) and extracted with EtOAc (3×100 mL). The EtOAc layers were combined and washed successively with 1N NaOH (100 mL), H2O (100 mL) and saturated NaCl solution (2×100 mL). The solution was then dried (K2CO3) and the solvent removed by rotary evaporation to give the crude product. This material was purified by passing it through a plug of SiO2 using PhCH3 as the eluting solvent. The solvent was then removed from the appropriate fractions by rotary evaporation and the solid recrystallized from CH2Cl2 /hexane to give 1.78 g (25.9% yield) of 1-benzyloxypyrene, mp 105°-106°, (C,H).
Reaction SMILES: [SH:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21].CC(C)=O>O>[C:7]1([C:4]2[N:3]=[C:2]([S:1][CH2:21][C:20]#[CH:19])[O:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: Sc1nc(-c2ccccc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCSc1nc(-c2ccccc2)no1
Yield: 74 %

Procedure:
A mixture of 5-mercapto-3-phenyl-1,2,4-oxadiazole (100 parts), potassium carbonate (39 parts), propargyl bromide (66 parts) and dry acetone (500 parts) was heated at reflux for one hour. The solution was cooled, poured into water and extracted with chloroform. The extract was washed and dried and the solvent evaporated off to give 3-phenyl-5-propargylthio-1,2,4-oxadiazole (90 parts, 74% yield), melting point 39.40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[N+:37]([C:40]1[CH:41]=[C:42]([N:46]=[C:47]=[O:48])[CH:43]=[CH:44][CH:45]=1)([O-:39])=[O:38].C(O)(C)C>ClCCl>[CH3:33][C:29]1([CH3:32])[O:28][C:27]2[CH:34]=[CH:35][C:24]([C@H:22]3[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][C:4]4[CH:3]=[C:2]([NH:1][C:47]([NH:46][C:42]5[CH:43]=[CH:44][CH:45]=[C:40]([N+:37]([O-:39])=[O:38])[CH:41]=5)=[O:48])[CH:7]=[CH:6][CH:5]=4)[CH2:23]3)=[CH:25][C:26]=2[CH2:31][O:30]1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc([N+](=O)[O-])c5)c4)C(=O)O3)ccc2O1
Reaction time: 4 h
Yield: 85 %

Procedure:
A solution of (5R)-3-{6-[2-{(3-aminophenyl)methoxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.00 g) in anhydrous dichloromethane (15 ml) was treated under nitrogen at 20° with 3-nitrophenyl isocyanate (0.43 g) and the mixture stirred for 4 h. Isopropanol (20 ml) was added and the mixture stirred for 17 h before the solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with dichloromethane-EtOH-ammonia (325:8:1) followed by solvent evaporation in vacuo gave the title compound (1.13 g). LCMS RT=3.85 min, ES+ve 663 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:35][CH2:36][C:37]1[N:41]([C:42]2[S:43][C:44]([CH2:56][CH3:57])=[CH:45][C:46]=2[C:47](=[O:55])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[Cl:54])[C:40]([CH3:58])=[N:39][N:38]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[Cl:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[C:47]([C:46]1[CH:45]=[C:44]([CH2:56][CH3:57])[S:43][C:42]=1[N:41]1[C:40]([CH3:58])=[N:39][N:38]=[C:37]1[CH2:36][NH:35][C:10](=[O:12])/[CH:9]=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:55]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)/C=C/c1ccccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2O)s1
Yield: 17.8 %

Procedure:
Reaction was carried out in the same manner as in Example 186 using trans-3-(2-hydroxyphenyl)propenoic acid (1.64 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g), triethylamine (5.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g), and the obtained product was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as an eluent to give 0.90 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-hydroxyphenyl)propenamide. NMR (270 MHz, CDCl3):1.17(3H,t,J=7.6 Hz), 2.21(3H,s), 2.78(2H,q, J=7.6 Hz), 4.33(1H,dd,J=4.3 Hz,15.5 Hz), 4.51(1H,dd,J=6.3 Hz,15.5 Hz), 6.60(1H,d,J=16.8 Hz), 6.75-6.90(3H), 7.18(1H,m), 7.35-7.65(6H), 8.52(1H,m), 10.01(1H,s)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26]P(=O)(OCC)OCC.[CH2:35]([C:38]1([CH:53]=O)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[CH2:42][CH2:41][C:40]2[CH:49]=[CH:50][CH:51]=[CH:52][C:39]1=2)[CH:36]=[CH2:37].[NH4+].[Cl-]>C1COCC1>[CH2:35]([C:38]1([CH:53]=[CH:26][O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[C:39]2[CH:52]=[CH:51][CH:50]=[CH:49][C:40]=2[CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]1=2)[CH:36]=[CH2:37]
Reactant: C=CCC1(C=O)c2ccccc2CCc2ccccc21
Reactant: CCOP(=O)(COC1CCCCO1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C=COC2CCCCO2)c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Dissolved diisopropylamine (9.2 g, 0.0910 mol) in 200 mL of dry THF. Cooled to 0° C. under a nitrogen atmosphere. Added 2.5M n-butyl lithium in hexane (35.2 mL, 0.0880 mol) via syringe. Stirred at 0° C. for 10 mins then cooled to -78° C. Added diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate in 45 mL of dry THF via addition funnel. Stirred at -78° C. for 1 hour. Added 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde in 100 mL of dry THF via addition funnel. Warmed to room temperature then refluxed for 16 hours. Cooled to room temperature, and added 500 mL of saturated NH4Cl. Separated layers, and extracted aqueous solution with ether. Washed combined organic extracts with saturated NaHCO3, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% ether-hexane then 5% ether-hexane. Combined appropriate fractions and evaporated to give 12.7 g (46% yield) of 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl-(2-tetrahydropyranyloxy-ethene).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([CH3:12])([OH:11])[CH3:10]>C(O)C>[CH3:8][C:9]([OH:11])([CH3:12])[CH2:10][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CC(C)(O)CCl
Solvent: CCO
Product: CC(C)(O)CN1CCNCC1
Temperature: 110 °C
Reaction time: 6 h
Yield: 59.8 %

Procedure:
piperazine (6.88 g, 80.0 mmol) was dissolved in ethanol (40 mL), and 1-chloro-2-methyl-2-propanol (2.18 g, 20.0 mmol) was added thereto, and then, the mixture was stirred at 110° C. for 6 hours. After the mixture was left to cool to room temperature, the solvent was evaporated. Then, ethyl acetate was added to the residue, and the precipitated solid was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10) to give 2-methyl-1-(piperazin-1-yl)propan-2-ol (1.89 g, 11.96 mmol, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[CH3:21][N:22](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:22][CH3:21])=[O:14])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1Sc1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Sc2cc(Cl)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (ii) (0.23 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g), 1-hydroxybenzotriazole (0.15 g), N,N-diisopropylethylamine (0.3 g) and methylamine (2M in THF, 0.78 ml) in DMF (10 ml) was stirred at RT overnight. Water was added and the mixture extracted with ethylacetate, the organics were dried and evaporated under reduced pressure, yield 0.24 g.
Reaction SMILES: N[C:2]1[C:12]([Br:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].FC(F)(F)C(O)=O.N(OCCC(C)C)=O.[PH2](O)=O>C(O)C>[Br:13][C:12]1[CH:2]=[C:3]([CH:9]=[C:10]([CH3:14])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(C)cc(Br)c1N
Agent: CC(C)CCON=O
Agent: O=[PH2]O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C)cc(Br)c1
Yield: 87.3 %

Procedure:
Ethanol (20 mL) was added to ethyl 2-amino-3-bromo-5-methylbenzoate obtained in Example (259d) (715 mg, 2.8 mmol). While the mixture was stirred, trifluoroacetic acid (0.82 mL, 11.1 mmol), isopentyl nitrite (649 mg, 5.5 mmol) and hypophosphorous acid (7.3 g, 55.4 mmol) were added under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was diluted and extracted with ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0/10, 2/8) to obtain 594 mg of the title compound as a light yellow oily substance (88%).
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[NH:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)=[O:32])[N:26]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.I[CH3:53].[H-].[Na+]>C1COCC1>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[N:39]([CH:40]4[CH2:43][CH2:42][CH2:41]4)[CH3:53])=[O:32])[N:26]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(N[C@@H](CCCCO)C(=O)N1CCN(C(=O)OC2CCC2)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)[C@@H]1CCCN1C(=O)COc1cc(C(=O)N[C@@H](CCCCO)C(=O)N2CCN(C(=O)OC3CCC3)CC2)nn1-c1ccccc1)C1CCC1
Reaction time: 2 h

Procedure:
To a solution of 65 mg 4-{(S)-2-[(5-{2-[(S)-2-(Cyclobutylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-6-hydroxy-hexanoyl}-piperazine-1-carboxylic acid cyclobutyl ester in 5 ml THF were added at −20° C. 6 l iodomethane and 5 mg sodium hydride (95%). After 2 h and 12 h equivalent amounts of iodomethane and sodium hydride were added before the reaction mixture was quenched with 0.1 M HCl and extracted with dichloromethane. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound as a mixture with its trifluoroacetyl ester. Repeated lyophilization from MeCN/water yielded the pure title compound. Yield: 17 mg MS (ES+): m/e=722.