Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)=O.[OH-].[Na+]>CCCCCC.C1COCC1>[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:18]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OCC1CCN(C(=O)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(CSc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
4.27 g (0.1068 mol) of sodium hydride (60% dispersion in oil) were washed twice with hexane, suspended in 160 ml of THF and treated with 10.3 ml (0.1068 mol) of thiophenol. The mixture was stirred for 15 min. and then a solution of 5.95 g (0.02 mol) of 1-benzoylpiperidin-4-yl-methyl methanesulfonate in 20 ml of THF was added. The mixture was boiled at reflux for 18 hrs. The reaction mixture was treated with 250 ml of 2N aqueous NaOH and extracted with ether. The organic phase was washed with 2N aqueous NaOH and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:3) as the eluent. 5.8 g (93%) of 1-benzoyl-4thio-phenoxymethylpiperidine were obtained as yellow crystals; m.p. 76°-79°.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:7][C:5]1[CH:4]=[CH:3][C:2]([CH2:8][C:16](=[O:18])[CH3:17])=[N:1][CH:6]=1
Reactant: Cc1ccc(C)nc1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(C)cn1
Temperature: 0 °C

Procedure:
To a stirred solution of 2,5-lutidine (2.68 g) in tetrahydrofuran (16 ml) was added a solution of n-butyllithium in n-hexane (1.66M, 16.6 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (2.56 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(5-methylpyridin-2-yl)propan-2-one (2.60 g).
Reaction SMILES: [CH:1]1([CH:4]2[S:9][CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[CH:23][C:24]([C:28]#[N:29])=[N:25]2)=[CH:20][CH:19]=1>CC#N.CCOC(C)=O>[CH:1]1([CH:4]2[CH2:5][N:6]([CH2:17][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([C:30]5[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=5)=[CH:23][C:24]([C:28]#[N:29])=[N:25]4)=[CH:20][CH:19]=3)[CH2:7][CH2:8][S:9]2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cc(C#N)nc3cc(CBr)ccc23)cn1
Reactant: C1CSC(C2CC2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1cc(-c2cc(C#N)nc3cc(CN4CCSC(C5CC5)C4)ccc23)cn1
Temperature: 60 °C
Yield: 45.2 %

Procedure:
To a solution of crude 2-cyclopropylthiomorpholine (4-14, 100 mg, 0.698 mmol) in CH3CN (3 ml) was added K2CO3 (289 mg, 2.094 mmol) then 7-(bromomethyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (251 mg, 0.768 mmol) all at once as solid. The resulting mixture was heated to 60° C. overnight. The mixture was cooled to rt, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. The crude product was subjected to silica gel chromatography (25 g, 0-100% EtOAc/hexanes, 10 minute gradient) to afford 7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (4-15, 123 mg, 45%) as a light orange foam. 1H NMR (399 MHz, CDCl3): δ 8.19 (d, J=8.7 Hz, 1 μl); 8.09 (s, 1 μl); 7.85 (s, 1 μl); 7.77 (s, 1H); 7.71 (d, J=8.8 Hz, 1H); 7.61 (s, 1H); 4.07 (s, 3H); 3.85-3.70 (m, 2 μl); 3.16 (dd, J=11.6, 2.7 Hz, 1H); 3.01 (d, J=11.6 Hz, 1H); 2.83 (ddd, J=13.4, 10.6, 2.7 Hz, 1H); 2.61-2.53 (m, 1H); 2.45-2.34 (m, 2H); 2.20-2.13 (m, 1H); 0.88-0.80 (m, 1H); 0.61-0.44 (m, 2H); 0.36-0.27 (m, 1H); 0.23-0.16 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].[CH3:27][O:28][C:29](=[O:62])[NH:30][CH:31]([C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[NH:43][C:44]([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)=[CH:45][N:46]=1)=[O:36])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:50]5[CH:51]=[CH:52][C:47]([C:44]6[NH:43][C:42]([CH:38]7[CH2:39][CH2:40][CH2:41][N:37]7[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:62])[CH:32]([CH3:34])[CH3:33])=[N:46][CH:45]=6)=[CH:48][CH:49]=5)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCC6CN(C(=O)OC)CC(=O)N65)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (77 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), potassium carbonate (42.8 mg, 0.31 mmol), 1,2-dimethoxyethane (4 mL) and water (1 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 6-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (16.8 mg, 0.024 mmol, 15%). C38H44BrN8O6 calculated 708.3 observed [M+1]+ 709.4; rt=1.39 min. 1H (DMSO-d6): δ=8.10 (s, 2H), 7.89 (m, 7H), 7.33 (d, J=9 Hz, 1H), 5.03 (t, J=7.8 Hz, 1H), 5.12 (m, 1H), 4.30 (m, 1H), 4.23 (m, 1H), 4.11 (t, J=8.1 Hz, 1H), 3.99 (m, 2H), 3.83 (m, 1H), 3.67 (s, 3H), 3.54 (m, 3H), 2.90 (m, 1H), 2.41 (m, 1H), 2.18 (m, 2H), 2.01 (m, 4H), 1.67 (m, 1H), 0.82 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:7]2=[N:8]S[N:10]=[C:6]2[C:5]([Br:11])=[CH:4][CH:3]=1.N1SN=C2C=CC=CC=12>[Zn].C(O)(=O)C.O>[Br:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:10])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [Zn]
Agent: c1ccc2nsnc2c1
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)ccc(Br)c1N
Temperature: 70 °C
Yield: 70 %

Procedure:
4,7-dibromobenzo[1,2,5]thiadiazole (6.0 g, 20.3 mmol), prepared according to WO 00/55927 PCT/GB00/00911 by bromination of benzo[1,2,5]thiadiazole, was placed in a 200-mL flask under a nitrogen atmosphere. Zinc dust (13.2 g, 203 mmol) and a mixture of acetic acid/water (35 mL/35 mL) were added. The flask was loosely capped with an inverted 1-neck flask. The reaction mixture was heated to 70° C. for 1 hr at which time reaction was complete as determined by TLC. The mixture was then cooled to room temperature and filtered. The solid was extracted with diethylether (3×100 mL). The extract was washed with saturated aqueous sodium bicarbonate and dried over MgSO4. The solution was filtered and evaporated to dryness using a rotary evaporator. The solid was purified by chromatography on a silica gel column, using dichloromethane as eluent. The appropriate fractions were combined and the solvent was removed under reducing pressure. A light yellow product was obtained. Yield: 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:5][C:6]2[N:12]=[CH:11][C@@H:10]3[CH2:13][CH2:14][CH2:15][N:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1.[C:35]([O-:38])([O-])=O.[Ca+2]>C(#N)C.O.Cl[Hg]Cl>[CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[C:23]3[CH:24]=[CH:25][C:26]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:7]=4)=[CH:27][C:28]=3[C:29]3[C:34]2=[CH:33][CH:32]=[C:31]([C:24]2[CH:23]=[CH:28][C:27]([O:38][CH3:35])=[CH:26][CH:25]=2)[CH:30]=3)=[CH:5][C:6]2[N:12]=[CH:11][C@@H:10]3[CH2:13][CH2:14][CH2:15][N:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OCCCn1c3ccccc3c3ccccc31)N=C[C@@H]1CCCN1C2=O
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc3c(c2)c2cc(-c4ccc(OC)cc4)ccc2n3CCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2C=N3)cc1
Yield: 58 %

Procedure:
This compound was prepared according to the method described for the compound 6a employing 9d (764.89 mg, 1.0 mmol) and HgCl2 (582 mg, 2.26 mmol), CaCO3 (230 mg, 2.46 mmol) in acetonitrile-water (4:1) to obtain the pure product 10d (373 mg, 58% yield).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[NH:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: CS(=O)(=O)c1nc(Oc2ccccn2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Clc1ccc(-c2c(Oc3ccccn3)nc(C3CCCN3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 109 (45 mg, 0.09 mmol) was reacted with excess pyrrolidine (0.5 mL) in THF at a sealed tube 60° C. for overnight by general procedure Example 103 to afford the title compound: HPLC/MS: m/e=497 (M++1); Rt4.21 min. 1H-NMR 400 MHz (CDCl3): δ 1.85-1.95 (s 4H), 3.20-3.60 (m, 4H), 7.00-7.19 (m, 8H), 7.31 (d, J=2 Hz, 1H), 7.75-7.80 (m, 1H), 8.38 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14]N)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].N([O-])=[O:17].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][OH:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)c1nccc2c(CN)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1nccc2c(CO)cccc12
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
1-iso-Propyl-5-aminomethylisoquinoline (8.7 g) was dissolved in 20 ml of acetic acid and 20 ml of water, and with ice cooling, 9 g of sodium nitrite was added. The mixture was stirred for 30 minutes. Then, 30 ml of a 10 N aqueous solution of sodium hydroxide was added, and the mixture was heated for 1 hour. The product was extracted with ethyl acetate, washed in water, and dried, followed by distilling off the solvent. Recrystallization of the residue from methylene chloride/n-hexane afforded 7.1 g of 1-isopropyl-5-hydroxymethylisoquinoline as colorless needles having a melting point of 119.9° to 120.9° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[C:30]([F:33])([F:32])[F:31]>O1CCCC1.CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=2[C:30]([F:31])([F:33])[F:32])[C:10]1=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CN2CC[C@H](NC(=O)OC(C)(C)C)C2=O)c(C(F)(F)F)c1

Procedure:
669 mg of (S)-3-(t-butoxycarbonylamino)pyrrolidin-2-one (J. Med. Chem., 1999, 42, 3557-3571) was dissolved in 30 ml of tetrahydrofuran/N,N-dimethylformamide (9:1) and the mixture was stirred under ice cooling. 60% sodium hydride was added thereto and the mixture was stirred for 20 minutes. A solution (3 ml) of ethyl 4-(bromomethyl)-3-trifluoromethylbenzoate (Reference Example 2 (step 2)) in tetrahydrofuran was added dropwise, followed by stirring at room temperature for 6 hours after removing an ice bath. The reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 867 mg of the objective compound as pale yellow crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.S(OC)(O[CH3:15])(=O)=O.[OH-].[Na+]>>[CH3:15][S:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][Cl:1])=[CH:5][CH:6]=1
Reactant: Sc1ccc(CCCl)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(CCCl)cc1
Reaction time: 1 h

Procedure:
The starting material is prepared as follows: (a) 64.3 g of 4-chloroethylthiophenol are placed in a vessel with 13.3 g of dimethyl sulfate; with external cooling (IT<10°), 41 ml of NaOH (25%) are then slowly added dropwise. After approximately one hour, the external cooling is removed and the mixture is heated carefully and kept at 125° for 30 minutes. The cooled solution is extracted with ether and distilled, yielding 4-methylmercaptophenylethyl chloride; b.p. 94°-95°/0.1 mbar.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:16]=1.O[CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][CH:25]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccc(-n2nc(OC)cc2-c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(OC)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Diethyl azodicarboxylate (0.17 ml) was added dropwise to a suspension of 3-methoxy-1-(4-methoxyphenyl)-5-(4-hydroxyphenyl)-1H-pyrazole (215.6 mg), tert-butyl N-(2-hydroxyethyl)carbamate (352 mg), and triphenylphosphine (286 mg) in THF (3 ml). The mixture was stirred at ambient temperature for 7 hours. Triphenylphosphine (19.1 mg) and diethyl azodicarboxylate (11.5 μl) were added and the mixture stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give tert-butyl (2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[N:8]=[N:9][S:10][CH:11]=1)[C:4]([OH:6])=[O:5].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[C:16](=[O:23])[C:15]1=[O:24])[CH3:13]>>[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([NH:2][CH:3]([C:7]2[N:8]=[N:9][S:10][CH:11]=2)[C:4]([OH:6])=[O:5])=[O:21])[C:16](=[O:23])[C:15]1=[O:24])[CH3:13]
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Reactant: NC(C(=O)O)c1csnn1
Agent: Cl
Product: CCN1CCN(C(=O)NC(C(=O)O)c2csnn2)C(=O)C1=O
Yield: 81.3 %

Procedure:
The title compound (1.24 g) was prepared from 2-amino-2-(1,2,3-thiadiazol-4-yl)acetic acid hydrochloride [Example 3(a)] (912 mg) and 4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl chloride (953 mg) by the method of Example 1(a).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]1([N:7]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 5-bromomethyl-1,2,3-trimethoxy-benzene (1.35 g, 5.16 mmol), and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide 1.03 g (65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:20][OH:21].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:21][NH:20][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(CCO)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(CCO)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15c (125 mg, 0.461 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (320 mg, 4.61 mmol) and a freshly prepared solution of sodium methoxide in methanol (159 mg, 6.91 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16c.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:57]1[CH2:62][CH2:61][CH:60]([CH2:63][NH2:64])[CH2:59][CH2:58]1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]([NH:64][CH2:63][CH:60]3[CH2:61][CH2:62][O:57][CH2:58][CH2:59]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(-c2nc(C(Cc3ccccc3)C(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 17.4 %

Procedure:
A solution of the compound (11 mg, 0.02 mmol) obtained in step 2, HATU (76 mg, 0.20 mmol), DEIA (5.13 μL, 0.03 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (3.04 μL, 0.03 mmol) in DMF (2 mL) was stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed to with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give the title compound (1.9 mg, 3.48 μmol, 14.2%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(F)cc2Cl)C1
Reaction time: 16 h

Procedure:
A stirred solution of 2.9 g (0.011 mole) of 3-(2-chloro-4-fluorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4 mL (0.05 mole) of 40% aqueous monomethylamine and stirred for 16 hr. The reaction mixture was diluted with 200 mL of water. The solid which precipitated was collected by filtration (2.7 g). The crude product was recrystallized from benzene/ligroin yielding 2.4 g (84.3%) of fine white crystals, mp 139°-141° C.
Reaction SMILES: C(#N)C=C.CCCCC=C.[CH:11]1[C:24]2[NH:23][C:22]3C(=CC=[CH:20][CH:21]=3)S[C:15]=2[CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:26]>>[CH3:15][CH:24]([NH:23][C:22](=[O:26])[CH:21]=[CH2:20])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: O=S(=O)(O)O
Solvent: C=CCCCC
Solvent: C=CC#N
Product: C=CC(=O)NC(C)CCCC

Procedure:
Following a procedure analogous to that of Examples 1 and 2 from 530 pbw of acrylonitrile, 841.6 pbw hexene-1, 1.0 pbw phenothiazine and 1300 pbw 83% sulfuric acid, there is obtained 1010 pbw of the title product.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.[BH4-].[Na+]>CO.C(OCC)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(C=O)c(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1cc(CO)c(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromine (15 mL, 0.3 mol) was added slowly to a solution of 2-fluoro-5-methoxy-benzaldehyde (23.1 g, 0.15 mol) in chloroform (500 mL) and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes to give 4-bromo-2-fluoro-methoxy-benzaldehyde (20.7 g, 60%). To a solution of 4-bromo-2-fluoro-5-methoxy-benzaldeyde (4.0 g, 17.3 mmol) in MeOH at 0° C. was added NaBH4 (0.65 g, 17.3 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taked up in ethyl ether washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product. (3.9 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3 H), 4.74 (d, J=6.02 Hz, 2 H), 6.82 (q, J=6.1 Hz, 1 H), 7.29 (d, J=10.58 Hz, 1 H).