Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([OH:38])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:54][C:55](=[O:58])[CH2:56]Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:56][C:55]([O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:58])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3c2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 12 ml of DMF, 645 mg of cesium carbonate and 447 mg of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 710 mg.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:58][N:57]([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:56]1.C(N(CC)CC)C>CN(C)C=O>[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:56][N:57]([CH:59]2[CH2:64][CH2:63][N:62]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:61][CH2:60]2)[CH2:58]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)C1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (116 mg) and triethylamine (0.168 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (57.5 mg, 91%).
Reaction SMILES: [CH:1]([Li])([CH2:3]C)[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:17]([CH:27]([CH3:29])[CH3:28])[C:16](=[O:30])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(Br)C=C>C1COCC1>[CH2:3]([C@@H:15]1[CH2:14][C@H:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[C@:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)([CH3:19])[N:17]([CH:27]([CH3:28])[CH3:29])[C:16]1=[O:30])[CH:1]=[CH2:2]
Reactant: [Li]C(C)CC
Reactant: CC(C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@@]1(C)c1ccc(Cl)cc1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@](C)(c2ccc(Cl)cc2)N(C(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
sec-Butyllithium (0.8N in cyclohexane, 0.274 mL, 0.219 mmol) was added over a period of one minute to a degassed (Argon bubbled through solution for 10 minutes at RT) solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one (Example 418, Step H, 75 mg, 0.199 mmol) in THF (6 mL) cooled by an acetone-dry ice bath. The cold bath was removed and the reaction equilibrated to room temperature over fifteen minutes. The reaction was stirred at room temperature for 30 minutes. Allyl bromide (1M in THF, 0.219 mL, 0.219 mmol) was added over one minute at room temperature. After two hours the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was diluted with ethyl acetate and separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were then dried with anhydrous magnesium sulfate and concentrated to afford a faintly orange glass. The diastereomeric products were isolated by chromatography on silica gel (12 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 20 to 80% ethyl acetate gradient in hexane to afford 25 mg of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one as the product eluting first on silica gel TLC plate (Rf=0.52 in 3:1 hexane:ethyl acetate eluent) and 25 mg of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one as the product eluting second on silica gel TLC plate (Rf=0.28 in 3:1 hexane:ethyl acetate eluent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.CC1C=CC=C(C)[N+]=1[O-:25].C(OO)(=O)C>C(OCCCC)(=O)C.C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:25])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Agent: CC(=O)OO
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 98.3 %

Procedure:
To a stirred solution of 3.32 g (15.5 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde (98.8% pure by GC) in n-butyl acetate (15.5 mL) cooled in a wet-ice bath (ca. 2° C.) was added 1.91 g (15.5 mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution was then added slowly dropwise 1.77 g (23.2 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 30 min). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 2 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The reaction solution was transferred into a separatory funnel, was diluted with n-butyl acetate (70 mL), and was washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 15 mL). The butyl acetate layer was further washed with water (50 mL), and the combined water washes were back-extracted with n-butyl acetate (30 mL). The combined butyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 65 mL each). The combined NaOH solutions of sodium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (50 mL) and the white solid thus obtained was dried in a vacuum oven 60 hours at 55° C. (25 mm Hg), giving 3.51 g (98.4%) of naproxen.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])#[N:2].[K+].Cl[CH2:14][C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1)=[O:6])#[N:2]
Reactant: Cc1nc(CCl)cs1
Reactant: N#Cc1ncccc1C(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(COC(=O)c2cccnc2C#N)cs1
Yield: 40.9 %

Procedure:
A mixture of potassium 2-cyanonicotinate (4.1 g; 0.022 mole), 4-chloromethyl-2-methylthiazole (2.95 g; 0.02 mole) and 18-crown-6-ether (0.13 g; 0.0005 mole) in acetonitrile (50 cc) is brought to reflux for 8 hours. The solvent is then evaporated off and the residue taken up in water and extracted with dichloromethane. After drying, evaporation of the dichloromethane and purification by chromatography on a silica column, Compound 1(2.12 g; 41%; m.p. 93° C.) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9](OC)=[O:10])=[C:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:5]=[CH:4][N:3]=1.Cl.O>>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:10])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1NCc1ccc(OC)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Add a solution of methyl 2-(4-chloro-6-(4-methoxybenzylamino)pyrimidin-5-yl)acetate (16.21 g, 1.00 equiv; 50.38 mmol) to HCl (4M in dioxane) (126 mL; 10 equiv; 503.79 mmol) and water (4.54 mL; 5 equiv; 251.89 mmol) and stir at 100° C. for 2 h. Remove dioxane in vacuo and extract with EA. Wash the organic layer with saturated NaHCO3, water, then brine. Dry over MgSO4, filter and concentrate in vacuo. Purify the residue by ISCO 330 g using EA:hex 20 to 70% as eluent to obtain the title compound (11.15 g; 38.49 mmol; 76.39%) as a yellow solid. 1H NMR (300 MHz, DMSO): 8.65 (s, 1H), 7.29-7.26 (m, 2H), 6.89-6.85 (m, 2H), 4.79 (s, 2H), 3.80 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:10][C:11]1[CH:37]=[CH:36][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC3C=CC=CC=3)=[O:26])=[CH:20][C:19]=2[Cl:35])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:42]([O:41][C:39]([NH:38][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:37]=[CH:36][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=2[Cl:35])=[O:16])=[CH:13][CH:12]=1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)OCc3ccccc3)cc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
To a solution of 4-[2-(benzyloxy)-2-oxoethyl]-2-chlorophenyl 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (1.98 g) in tetrahydrofuran (27.1 mL) was added 10% palladium-carbon (196 mg), followed by stirring at room temperature for 1 hour at normal pressure under a hydrogen atmosphere. The reaction suspension was filtered through Celite, and then the filtrate was concentrated under reduced pressure to obtain [4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-3-chlorophenyl]acetic acid (1.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C@@H:11]([CH3:21])[C@H:12]([OH:20])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:5]=[C:4]([Cl:22])[C:3]=1[NH:23][CH2:24][C:25](OCC)=[O:26].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[Cl:22][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][NH:10][C@@H:11]([CH3:21])[C@H:12]([OH:20])[C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:23][CH2:24][C:25]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:26]
Reactant: COCCN
Reactant: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Product: COCCNC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenyl]aminoacetate (44.3 mg) was dissolved in 2-methoxyethylamine (886 μl), and the solution was stirred for 48 hours at 80° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloromethane/methanol=10/1) gave 2-[[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenyl]amino]-N-(2-methoxyethyl)-acetamide (27.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1-n1ccc(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccn(-c2cc(Cl)ccc2C(C)O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanone (400 mg, 1.70 mmol) from Step 1 was dissolved in MeOH (10 mL) and cooled to 0° C. NaBH4 (129 mg, 3.41 mmol) was added portionwise, then the reaction was warmed to RT, stirred for 30 min, then quenched with acetone. The MeOH was removed in vacuo then the residue was partitioned between water and EtOAc and extracted several times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH2Cl2/MeOH/NH4OH) provided the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[O:2].[CH3:12][S:13]([NH2:16])(=[O:15])=[O:14].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.ClCCl>[CH3:12][S:13]([NH:16][C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:1]=[O:2])=[O:7])(=[O:15])=[O:14]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
A mixture of 10.18 g of 3-formylbenzoic acid, 6.99 g of methanesulfonamide, 200 ml of dichloromethane, 8.95 g of dimethylaminopyridine, 15.22 g of dicyclohexylcarbodiimide and 100 ml of tetrahydrofuran was stirred at room temperature. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, a 1 N aqueous sodium hydroxide solution was added, and the layers were separated. To the aqueous layer was added 2 N hydrochloric acid to adjust to pH 1, this was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated to obtain 4.01 g of 3-[(methanesulfonyl)aminocarbonyl]benzaldehyde [Compound No. (j)] as a white solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].CN(C1C=CC=CN=1)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([NH:14][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:12]#[CH:13]
Reactant: C#CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CCNS(=O)(=O)c1ccccc1
Reaction time: 15 h

Procedure:
Benzene sulfonyl chloride (1.16 mL, 9.1 mmol) was added to stirred solution of propargylamine (0.62 mL, 9.1 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (5 mL) at room temperature. The resulting solution was aged at ambient temperature for approximately 15 h. The reaction mixture was diluted with ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound (i-2), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([O:24]CC)=O)[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH3:39]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([NH2:39])=[O:24])[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:37][CH:38]=1
Reactant: N
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Solvent: CO
Product: NC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A suspension of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (40 mg, 0.07 mmol) in 7N NH3 in MeOH (1 ml) was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 40:1) to yield the title compound as a white solid (25 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1[CH:25]=[CH:26][C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.[C:36]([C:38]1[CH:47]=[CH:46][C:41]([C:42]([NH:44][NH2:45])=O)=[CH:40][CH:39]=1)#[N:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl.C(N(CC)CC)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1[CH:25]=[CH:26][C:27]1[O:28][C:42]([C:41]2[CH:46]=[CH:47][C:38]([C:36]#[N:37])=[CH:39][CH:40]=2)=[N:44][N:45]=1
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: O=C(O)C=Cc1nnc(-c2ccc(OCC(F)(F)F)cn2)n1-c1ccccc1Cl
Agent: BrC(Br)(Br)Br
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2nnc(C=Cc3nnc(-c4ccc(OCC(F)(F)F)cn4)n3-c3ccccc3Cl)o2)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a 100 mL flask with 3-{4-(2-Chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-acrylic acid 8 (0.18 g, 0.368 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.20 g, 1.55 mmol) and a drop of DMF. The reaction was kept at ambient temperature for 3 h. The solvent was removed and the residue was further dried under high vacuum and cooled to −20° C. Dichloromethane (10 mL) was added, followed by 4-Cyano-benzoic acid hydrazide (0.18 g, 1.1 mmol) and triethylamine (0.5 mL). The reaction mixture was kept at this temperature for 0.5 h and then ambient temperature for 1 h. The solvent was removed and the crude 4-Cyano-benzoic acid N′-(3-{4-(2-chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-acryloyl)-hydrazide was used for the next step. 4-Cyano-benzoic acid N′-(3-{4-(2-chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-acryloyl)-hydrazide was dissolved in dichloromethane (10 mL) and triphenylphosphine (0.19 g, 0.736 mmol), carbon tetrabromide (0.24 g, 0.736 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 4-[5-(2-{4-(2-Chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-4H-[1,2,4]triazol-3-yl}-vinyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile as a yellow solid. Yield: 0.07 g, 30%.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][CH2:21][C:22]([NH:24][C@H:25]([C:27]([O:29][CH3:30])=[O:28])[CH3:26])=[O:23].Cl>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:27]([O:29][CH3:30])=[O:28])[CH3:26])=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](C)NC(=O)CN
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 74.1 %

Procedure:
Boc-Phe-OH (26.5 g, 100 mmol) was coupled to H-Gly-Ala-OCH3.HCl (19.6 g, 100 mmol) using a mixed anhydride procedure. After crystallization from ethyl acetate:hexane, 30.2 g of Boc-Phe-Gly-Ala-OCH3 (m.p. 126.4°-127.8°) were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:10][CH2:11]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[N+:23]=[N-:24]
Reactant: CS(=O)(=O)OCCC(c1ccc(C#N)cc1)n1ccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(CCN=[N+]=[N-])n2ccnc2)cc1
Reaction time: 4 h

Procedure:
The methanesulfonic acid 3-(4-cyano-phenyl)-3-imidazol-1-yl-propyl ester (600 mg, 2 mmol) was suspended in degassed DMF under argon and sodium azide (650 mg, 10 mmol) was added and the reaction was stirred for 4 hours. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 1:2 ethyl acatate: hexanes. The desired fractions were concentrated in vacuo to give the desired product.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].[CH3:11][C:12]1[O:16][C:15]([C:17]([C:19](=[C:22](SC)[S:23][CH3:24])[C:20]#[N:21])=O)=[CH:14][CH:13]=1>CN(C=O)C>[NH2:7][C:6]1[N:8]=[C:17]([C:15]2[O:16][C:12]([CH3:11])=[CH:13][CH:14]=2)[C:19]([C:20]#[N:21])=[C:22]([S:23][CH3:24])[N:5]=1
Reactant: CSC(SC)=C(C#N)C(=O)c1ccc(C)o1
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
2.22 g (12.3 mmol) guanidine carbonate was added portionwise to a stirred suspension of 0.41 g (10.3 mmol, 60% dispersion in mineral oil) sodium hydride in 20 ml DMF under argon at room temperature and stirring continued at 40° C. for 1 hour. A solution of 2.60 g (10.3 mmol) 2-(5-methyl-furan-2-carbonyl)-3,3-bis-methylsulfanyl-acrylonitrile in 10 ml DMF was then added dropwise and the reaction mixture heated at 100° C. for 1 hour. The reaction mixture was then poured onto 700 ml ice-water, and the precipitate collected by filtration, washed with water then hexane, and dried in vacuo to afford 2.38 g (94%) 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid. EI-MS m/e (%): 246 (M+, 64), 245 ([M—H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([NH:14][CH2:15][CH2:16][NH2:17])(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([NH:14][CH2:15][CH2:16][NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)NCCN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNC(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A solution of 1.3 ml (0.01 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform is added dropwise at 0° to a solution of 1.02 g (0.01 mol) of acetylethylenediamine [J. Amer. Chem. Soc. 61, 822 (1939)] and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform. After 15 minutes, the resulting crystals are filtered off, washed with chloroform and dried. There are obtained 1.9 g of N-(2-acetylaminoethyl)-4-chlorobenzamide, m.p. 222°-224°.