Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-:17].[Na+].OOS([O-])=O.[K+].S(=O)(O)[O-].[Na+].Cl>C(#N)C.CC(C)=O.O.ClCCl.C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:17])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=S([O-])O
Agent: O=S([O-])OO
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4-(4-chlorophenyl)benzaldehyde (0.84 g, 3.9 mmol) in 30 mL acetonitrile-acetone (2: 1) is added 15 mL water and solid sodium bicarbonate (3.5 g, 41.7 mmol). After 5 min. a 25 mL solution of oxidation reagent (Oxone: 4.8 g, 7.8 mmol in 25 mL water containing 4×10−4 M EDTA) is added dropwise over 15 min. then stirred for an additional 3.5 h. The reaction mixture is then treated with 18 mL aq. sodium bisulfite (9.5 g), stirred 2 h, then acidified with 10 mL 6 M HCl. The mixture is transferred to a separatory funnel and diluted with 300 mL dichloromethane and 400 mL water. The water layer is washed with dichloromethane (3×120 mL), organic layers combined, then washed with 500 mL water. The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The desired acid is crystallized from acetone-water (5:2), filtered, washed with water, and evaporated under reduced pressure from toluene affording 0.6 g product. Remaining product could be isolated by chromatography but the amount obtained is satisfactory. TLC: Rf=0.3 (chloroform-methanol; 10:1).
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 2-amino-3,6,7-trichloroquinoxaline (1.54 g, 6.20 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (2.01 g, 9.30 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.21 g of the titled compound (yield, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:15].C(=O)(O)[O-].[Na+].[C:21]([O:25][C:26](=O)[O:27]C(C)(C)C)([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:25][C:26](=[O:27])[N:7]([CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[C:3]([CH3:15])[CH:4]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc(CNCCC(C)C)ccc1Br
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1Br
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(4-bromo-3-methyl-benzyl)-(3-methyl-butyl)-amine (I-2b: 13.7 g) was dissolved in 100 mL of ethyl acetate and treated with 200 mL of a saturated aqueous sodium bicarbonate solution and di-tert-butyl-carbonate (14.3 g, 65.5 mmol). The reaction mixture was stirred at 50° C. for 2 hours before cooling to room temperature and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (I-2c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=N)[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C([OH:24])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=[O:24])[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=N)NN1
Agent: Cl
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
26.9 g of 3-(4'-fluoro-4-biphenylyl)-3-methyl-5-imino-pyrazolidine [obtainable from 3-(4'-fluoro-4-biphenylyl)-2-butenoic acid nitrile and hydrazine] are boiled for 10 minutes with 150 ml of 20% strength aqueous hydrochloric acid and 150 ml of ethanol, and the solution is concentrated, neutralized and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:3]1.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[CH:27][C:26](O)=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO.C(N(CC)CC)C>C(#N)C>[CH2:33]([O:32][C:30]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)[CH:27]=2)[NH:22][C:21]=1[CH3:20])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C)C2)cc1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1[nH]c2ccc(OCC3CCCN(C)C3)cc2c1C(=O)OCc1ccccc1
Reaction time: 96 h
Yield: 24 %

Procedure:
Toluene-4-sulfonic acid 1-methyl-piperidin-3-ylmethyl ester (0.753 g, 2.66 mmol, 1.0 eq) was dissolved in dry acetonitrile (30 mL), and treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (0.759 g, 2.70 mmol, 1 eq) and potassium carbonate (0.690 g, 5 mmol, 2.0 eq.). The reaction was heated to reflux and followed by TLC (ethyl acetate/methanol/triethylamine 87/10/3). After 96 hours, the reaction was loaded directly on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3) to afford a white solid: 0.237 g (24% yield). This was converted to the corresponding hydrochloride salt: LC/MS (ESI+) 393 (M+1), Anal. (C24H28N2O3.HCl.0.6H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH:19]([CH3:21])[CH3:20])=[C:4]([C:15](O)=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[Br:1][C:2]1[C:3]([O:18][CH:19]([CH3:21])[CH3:20])=[C:4]([C:15]([NH:34][C:35]2[NH:39][N:38]=[N:37][N:36]=2)=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(Br)c(Br)n(Cc2ccccc2)c1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)Oc1c(Br)c(Br)n(Cc2ccccc2)c1C(=O)Nc1nnn[nH]1
Yield: 49.6 %

Procedure:
Prepared by the method described in Example 115 from 4,5-dibromo-3-(1-methylethoxy)-1-(phenylmethyl)-1H-pyrrole-2-carboxylic acid (2.1 g, 0.005 moles), 1,1'-carbonyldiimidazole (0.9 g, 0.0055 moles), and 5-aminotetrazole (0.43 g, 0.005 moles). Recrystallization from acetonitrile gave the product (1.2 g); mp 199°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[Br:12][CH:13]([CH3:24])[C:14](OCC)(OCC)OCC>>[Br:12][CH:13]([C:24]1[O:6][C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)=[N:7][N:8]=1)[CH3:14]
Reactant: CCOC(OCC)(OCC)C(C)Br
Reactant: NNC(=O)c1cccc(Cl)c1
Product: CC(Br)c1nnc(-c2cccc(Cl)c2)o1
Yield: 32 %

Procedure:
3-Chloro-benzoic acid hydrazide (170 mg, 1 mmol) and 2-bromo-1,1,1-triethoxypropane (1 ml) were heated in a sealed vial at 120° C. for 10 min. The reaction mixture was place directly onto a flash column (silica gel) and purified using 0-50% dichloromethane in hexanes. The product was re-purified by flash column chromatography using a mixture of ethyl acetate:hexanes:dichloromethane (1:19:20) to afford 2-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (93 mg, 32%, colorless oil). 1H NMR (CDCl3) d (ppm): 8.09 (t, 1H), 7.99 (t, 1H), 7.55 (m, 3H), 5.30 (m, 1H), 2.21 (q, 3H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Cl)(=[O:3])[CH3:2].[CH:25](=[O:37])[C:26]1[CH:36]=[C:33]([O:34][CH3:35])[C:31]([OH:32])=[C:28]([O:29][CH3:30])[CH:27]=1>CC(C)=O.[OH-].[K+].O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:32][C:31]1[C:33]([O:34][CH3:35])=[CH:36][C:26]([CH:25]=[O:37])=[CH:27][C:28]=1[O:29][CH3:30])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Reaction time: 18 h

Procedure:
A solution of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride (18.3 g, 50 mmol) in acetone (100 ml) was added to a solution of syringaldehyde (9.1 g, 50 mmol) in 1M potassium hydroxide solution (100 ml). The mixture was then stirred for 18 h and then diluted with water. The precipitated crystalline solid (10.8 g, 42%) was then filtered off, washed well with water and recrystallised from acetone-water water to give the title compound, m.p. 222°-225°, [α]D +3° (c 0.9, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:14]([F:17])([F:15])[F:16])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[C:13]=1[N+:23]([O-:25])=[O:24]
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 11.0g. (0.04 mole) of 6-chloro-1-ethyl-2-methyl-5-trifluoromethylbenzimidazole dissolved in 110 ml. of concentrated sulfuric acid was added 11 ml. of 90% fuming nitric acid while cooling with an ice bath. The addition required 3 hours and the resulting red-brown solution was stirred for 6 hours at 0°C. and then at room temperature for 2.5 days. After pouring onto ice, the product was precipitated by the addition of 350 ml. of concentrated ammonium hydroxide. The crude solid was isolated and dissolved in 300 ml. of chloroform. The chloroform solution was washed with water, dried over Na2SO4, filtered, and the filtrate evaporated. Crystallization of the residual solid from hexane --CCl4 (3:1) gave 9.0g. (70%) of reddish solid, m.p. 114°-116°C., whose nuclear magnetic resonance pattern confirmed it to be the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14]CC)=[O:13])[NH:7]2)#[N:2].O[Li].O>C(O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2)#[N:2]
Reactant: CCOC(=O)c1cc2c(C#N)cccc2[nH]1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2[nH]c(C(=O)O)cc12
Yield: 87.1 %

Procedure:
To a solution of ethyl 4-cyano-1H-indole-2-carboxylate (I-3a: 330 mg, 1.542 mmol) in ethanol (10 mL) was added LiOH.H2O (129 mg, 3.08 mmol) and the mixture was refluxed for 16 h. The solvent was evaporated under reduced pressure and the residue diluted with water (10 mL). The aqueous layer was acidified with 10% aq. HCl solution to pH 6.0 and the precipitated solid was filtered. The residue was washed with water and dried under vacuum to afford 250 mg (87%) of 4-cyano-1H-indole-2-carboxylic acid (I-3b) as an off-white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:26])[N:10]([C:17]1([CH3:25])[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16]>C1COCC1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:26])[N:10]([C:17]1([CH3:25])[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: C1CCOC1
Product: CC1(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 84.6 %

Procedure:
Chloroacetyl chloride (0.9 g, 7.8 mmol) was added to a stirred suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (1.5 g, 5.2 mmol) in THF (20 mL). The mixture was refluxed for 30 minutes. The mixture was cooled to room temperature and filtered to give 2-chloro-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide (1.6 g, 84%): 1H NMR (DSO-d6) δ 1.89 (s, 3H, CH3), 2.03-2.08 (m, 1H), 2.50-2.70 (m, 3H), 4.53 (s, 2H, CH2), 7.60 (d, J=7.3 Hz, 1H, Ar), 7.84 (t, J=7.7 Hz, 1H, Ar), 8.51 (d, J=8.4 Hz, 1H, Ar), 10.26 (s, 1H, NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.98, 28.53, 29.04, 43.14, 58.89, 116.95, 118.54, 125.27, 131.30, 135.39, 136.16, 165.69, 167.31, 168.74, 171.98, 172.16.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[N:15])[CH2:9][CH2:8][N:7]([CH2:16][C:17]#[N:18])[CH2:6][CH2:5]1)#[N:2].B.C1COCC1.[OH-].[Na+]>C1COCC1.Cl.O>[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:4]([CH2:3][CH2:1][NH2:2])[CH2:5][CH2:6][N:7]([CH2:16][CH2:17][NH2:18])[CH2:8][CH2:9]1
Reactant: N#CCN1CCN(CC#N)CCN(CC#N)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCN(CCN)CCN(CCN)CC1
Yield: 85 %

Procedure:
1,4,7-tris(cyanomethyl)-1,4,7-triazacyclononane (0.320 g, 1.23 mmol) and BH3.THF 1 M solution in THF (40 cm3) were refluxed under nitrogen for 48 h. After cooling, excess borane was destroyed by adding water (5 cm3), then the solution was dried under vacuum. The white solid obtained was dissolved in 50 cm3 of HCl 7M and heated under reflux for 40 h. After cooling, the solution was dried in vacuum to yield a white solid. The solid was dissolved in the minimum amount of water and the solution obtained was passed through a Dowex 1×8-200 column (10 g) activated with a solution 1M of sodium hydroxide. The solvent was removed under reduced pressure to yield a colourless oil. (0.270 g, 1.045 mmol) Yield: 85%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:25]#[N:26])([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Yield: 66.3 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(2,4-dichloro-phenyl)-acrylonitrile (2.2 g, 6.7 mmol) prepared in Example 56a, AgF (2 g, 16 mmol), and triethylamine (5 g, 50 mmol) in dichloromethane (200 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:19]([CH3:37])([C:21]2[N:25]([CH3:26])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[N:23][N:22]=2)[CH3:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11]O)=[O:8].COCCN(CCOC)S(F)(F)F.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:19]([CH3:20])([C:21]2[N:25]([CH3:26])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[N:23][N:22]=2)[CH3:37])=[C:6]([C:7]2[O:8][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=2)[CH:17]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cc(Cl)ccc1OC(C)(C)c1nnc(-c2ccccc2C(F)(F)F)n1C
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(-c2cc(Cl)ccc2OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
Methyl N-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoyl]-L-serinate (1.41 g) was mixed with dichloromethane (45 ml), followed by cooling to −78° C. under a nitrogen atmosphere. 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethanamine (0.580 ml) was added thereto, followed by stirring for 2 hours, and bromo(trichloro)methane (0.920 ml) and DBU (1.40 ml) were sequentially added thereto at 0° C., followed by stirring for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether to obtain, as a white solid, methyl 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylate (1.05 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[C:35]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 541.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:32][CH:33]([CH2:47][CH2:48][CH2:49][CH3:50])[CH:34]([C:36]1[O:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:39][N:40]=1)[OH:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[OH:35][CH:34]([C:36]1[O:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:39][N:40]=1)[CH:33]([NH:32][C:11]([CH:10]([NH:9][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])[CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:16])=[O:12])[CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CCCCC(N)C(O)c1nnc(-c2ccccc2)o1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCC(NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1)C(O)c1nnc(-c2ccccc2)o1
Reaction time: 14 h
Yield: 69.5 %

Procedure:
To a stirred mixture of 2-[(morpholine-4-carbonyl)-amino]-3-phenylmethane-sulfonyl-propionic acid (135 mg, 0.37 mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-hexanol TFA salt (135 mg, 0.36 mmol), prepared as in Reference 1, and HOBt (66 mg, 0.43 mmol) in MeCl2 (5 ml), was added EDC (103.6 mg, 0.54 mmol) and N-methylmorpholine (0.4 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated. The residue was subjected to silica gel column chromatography to yield morpholine-4-carboxylic acid (1-{1-[hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-pentylcarbamoyl}-2-phenylmethane-sulfonyl-ethyl)-amide (150 mg); MS: 598.6 (M−1), 600.6 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[OH:5]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(C(O)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a THF (50 ml) solution of 2-bromo-5-methoxybenzaldehyde (10 g) was added dropwise a THF (30 ml) solution of the Grignard reagent prepared from 5-Bromo-1,3-benzodioxole (11.2 g) and Mg (1.6 g). The mixture was stirred for 1 hour at room temperature and ammonium chloride solution was added therein, then extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated. The residue was purified with silica gel column (Hex/EA=3/1) to give (2-bromo-5-methoxyphenyl) (1,3-benzodioxol-5-yl)methanol as an oily substance (15 g). (2-bromo-5-methoxyphenyl)(1,3-benzodioxol-5-yl)methanol was dissolved in ether (300 ml) and n-BuLi(1.6M/Hex: 64 ml) was added dropwise at -78° C. The reaction mixture was stirred for 5 minutes at -78° C., then stirred for 1 hour at 0° C. To the mixture was added DMF (30 ml) and stirred for 1 hour at room temperature. To the reaction mixture was added water and extracted with ether. The extract was washed with water and dried with magnesium sulfate then concentrated under reduced pressure. The obtained residue was dissolved in toluene (250 ml) and maleimide (6 g) and p-toluenesulfonic acid monohydrate (1.0 g) were added thereto. The reaction mixture was refluxed for 20 hours and the separated solid was filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue was added concentrated hydrochloric acid and heated under reflux for 1 hour. The mixture was cooled to room temperature and the resultant yellow-brown solid was collected by suction and washed with water, then recrystalized with THF to give the entitled compound (5.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[N:10]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH:26][C:5]3[C:4](=[O:7])[C:3](=[O:8])[C:2]=3[NH2:1])[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1c(N)c(=O)c1=O
Reactant: NCCCOc1cc(CN2CCCC2)ccn1
Product: Nc1c(NCCCOc2cc(CN3CCCC3)ccn2)c(=O)c1=O

Procedure:
By the methods of Example 1, 1-amino-2-methoxycyclobut-1-ene-3,4-dione and 3-[4-(pyrrolidinomethyl)pyrid-2-yloxy]prop-1-ylamine are reacted to form the title product.