Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC(F)(F)CC[N:6]1[CH2:15][CH2:14][C:13]2[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7]1.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:21]1[CH2:22][CH2:23][O:24][C:19]2[CH:18]=[C:17]([NH:16][C:12]3[C:13]4[CH2:14][CH2:15][N:6]([C:31]5[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=5)[CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:26]=[CH:25][C:20]1=2
Reactant: Cc1cccc(B(O)O)c1
Reactant: FC(F)(F)CCN1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine from Example 7 (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4A moleculer seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20](N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:45]1([C:51]2[N:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)=[CH:53][N:52]=2)[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:48]1[CH2:49][CH2:50][N:45]([C:51]2[N:52]=[CH:53][C:54]([C:57]3[CH:58]=[CH:59][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:61][CH:62]=3)=[CH:55][N:56]=2)[CH2:46][CH2:47]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 86 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-(4-trifluoromethylphenyl)-pyrimidine, dihydrochloride (0.250 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.360 g), to yield the title compound as an off-white solid (0.480 g, 86%).
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N:18]1([C:24](=[Se:26])[NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)(C)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[N:25]=[C:24]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[Se:26][C:2]=2[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)C(=O)Cc1ccc(Cl)cc1
Reactant: NC(=[Se])N1CCOCC1
Solvent: CC(C)O
Product: CCOC(=O)c1[se]c(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
In a round bottomed flask were placed ethyl 2-chloro-4-(4-chlorophenyl)-3-oxobutanoate (84.4 mg, 0.3069 mmol), isopropyl alcohol (5 mL), and morpholine-4-carboselenoamide (80.0 mg, 0.414 mmol). The resulting mixture was brought to reflux under an atmosphere of nitrogen (all solids dissolved to give a clear pale pink solution). After ˜1 hour reflux, TLC analysis indicated that all starting materials had been consumed with the production of one major product. The reaction was allowed to cool to room temperature and stir overnight. The solvent was removed on the rotovap then the residue was dissolved in minimal dichloromethane and purified by column chromatography on silica gel (gradient 100% hexane to 35% ethyl acetate) to afford 35 mg (28% yield) product as a white solid. LC/MS (FA) ES+ 413/415/417. NMR (400 MHz, DMSO) δ 7.37-7.23 (m, 4H), 4.25-4.14 (m, 4H), 3.72-3.62 (t, J=4.9 Hz, 4H), 3.50-3.41 (t, J=4.8 Hz, 4H), 1.27-1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4].B1([O-])O[O:22]1.O.O.O.O.[Na+]>CC(O)=O>[Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:22])=[CH:13][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4]
Reactant: [O-]B1OO1
Reactant: CSc1ccc(C(=O)c2cc(C(=O)CCl)cn2C)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(S(C)=O)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A mixture of 2.5 g (0.008 mole) of 2-chloro-1-[1-methyl-5-(4-(methylthio)benzoyl]-1H-pyrrol-3-yl]-ethanone, 1.2 g of sodium perborate tetrahydrate and 50 mL of HOAc was stirred for 3 h. The solvent was evaporated in vacuo and the residue partitioned between CH2Cl2 and NaHCO3. The organics were separated off and washed again with NaHCO3, water, brine and dried (Na2SO4). The solvent was evaporated in vacuo. The residue was passed through a Biotage flash 40 L column (silica gel 9:1 CH2Cl2: MeOH) to give 2.2 g (85%) of 2-chloro-1-[1-methyl-5-(4-(methylsulfinyl)benzoyl]-1H-pyrrol-3-yl]-ethanone. CIMS m/z=324 (MH+). HNMR (CDCl3) δ8.0 (d, 2H); 7.75 (d, 2H); 7.6 (s, 1H); 7.15 (s, 1H); 4.4 (s, 2H); 4.1 (2, 3H); 2.8 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=1.[Br-:17].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:17][CH2:11][C:10](=[O:12])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])([CH3:13])[CH3:14]
Reactant: [Br-]
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(=O)CBr
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of the above ketone (1.34 g, 6 mmol) in methylene chloride (35 mL) and MeOH (5 mL), benzyltrimethylammonium tribromide (2.57 g, 6.6 mmol) was added at ambient temperature. After 30 minutes, TLC (hexanes-EtOAc (9:1)) showed complete disappearance of the starting material. The reaction mixture was diluted with methylene chloride (50 mL), washed with two 50 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 1-bromo-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (80%) which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>O>[CH3:1][C:2]1[N:7]2[C:8]([CH2:11][S:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ncc(CSc3ccc([N+](=O)[O-])cc3)n12
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cccc2ncc(CSc3ccc(N)cc3)n12
Yield: 103.1 %

Procedure:
A mixture of 5-methyl-3-[(4-nitrophenylthio) methyl]imidazo[1,2-a]pyridine (1.80 g), reduced iron (1.68 g) and calcium chloride (0.33 g) in 15% water-containing ethanol (54 ml) was heated to reflux for 24 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give 4-[[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]thio]aniline (1.67 g) as yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[NH2:13][NH2:14]>>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:13][NH2:14])=[O:2]
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: NN
Product: Cc1ccc(C(=O)NN)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8): 1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])C(C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:42]([C:44]([F:47])([F:46])[F:45])=[CH:10][C:9]2[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][N:36]=[N:35]4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M124) (0.44 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (170 mg, 49%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](Cl)=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)=[O:25])[N:10]=[CH:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cnc(N)c1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cnc(NC(=O)c2ccc3c(c2)OCO3)c1
Yield: 16.5 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-amine (example 10-40a) (110 mg, 0.57 mmol), benzo[d][1,3]dioxole-5-carbonyl chloride (105 mg, 0.57 mmol), and triethylamine (90 μL, 0.69 mmol) in dichloromethane was stirred for 16 hours. The reaction was diluted with dichloromethane (30 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated by rotary evaporation. The crude product was purified by reverse phase HPLC (Solvent system:acetonitrile/water, 10% to 100% gradient, 25 minute run) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-yl)benzo[d][1,3]dioxole-5-carboxamide as a white crystalline solid (32 mg, 15% yield). MS M+H calculated 341.3. found 341.3. 1H NMR (400 MHz, DMSO-d6): δ 2.08 (s, 3H), 2.41 (s, 3H), 5.02 (s, 2H), 6.07 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.54 (m, 3H), 10.6 (s, 1H). The compound had an IC50 on hT2R8 bitter receptor of 12.1 μM.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:26])[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC#N>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](N)C(=O)Nc1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)c1ccccc1)C(=O)Nc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a stirring solution of (7S)-7-amino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester (8.0 g, 21.6 mmol) in dry MeCN (100 mL) and to this solution was added benzoyl chloride (2.78 mL, 23.8 mmol) and triethylamine (6.1 mL, 43.2 mmol). The solution was stirred at 0° C. for 1 h, then at RT for 2 h. The solvent was removed, and residue was dissolved in 400 mL EtOAc, and stirred with 100 mL 0.5 M NaHCO3 for 1 h. The aqueous layer was removed, and the organic layer was washed with 100 mL 0.5 M NaHCO3, then with 50 mL water. The solution was dried over anhydrous Na2SO4. The product (8.1 g) was obtained after column purification (EtOAc as eluent) in 78.8% yield as a thick oil. 1H NMR (CDCl3) δ 9.40 (1H, s), 8.80 (1H, d), 8.22 (1H, d), 8.0–7.0 (10H, m), 5.0 (1H, m), 2.2–1.2 (19H, m). MS (ESI): (MH+) 476.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH:21]1[CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][CH:21]1[CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(Cl)cc(C)c1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(C)c1OC1CCC1
Temperature: 37 °C
Reaction time: 288 h
Yield: 67.6 %

Procedure:
A 100 mL round bottom flask is charged with 5-chloro-2-hydroxy-3-methyl-benzoic acid methyl ester (0.92 g, 4.59 mmol). Dry N,N-dimethylformamide (DMF, 15 mL) and a stirring bar are added. Stirring is initiated. After dissolution, K2SO4 (1.90 g, 13.76 mmol) and bromocyclobutane (0.65 mL, 6.88 mmol) are added. After 12 days, tlc analysis (silica, 25% EtOAc/heptanes) indicated a slight consumption of starting material and the appearance of a UV positive spot with a slightly higher Rf value. The reaction is fitted with a heating mantle and warmed to 37° C. After 3 more days, tlc analysis (silica, 25% EtOAc/heptanes) indicates a slight consumption of starting material and complete conversion to a UV positive spot with a slightly higher Rf value. The reaction mixture is filtered through a pad of Celite. The filtrate is diluted with EtOAc and (100 mL) and transferred to a separatory funnel. The EtOAc solution is washed with saturated NaHCO3 (2×25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated by pumping to constant weight to give 0.79 g of semi-solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:45]2[CH:49]=[N:48][N:47]=[N:46]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C:22](=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])[CH:13]2[C:29]([NH:31][C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38]C(C)(C)C)=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:11])[CH:7]=1.COCCN.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:45]2[CH:49]=[N:48][N:47]=[N:46]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[C:22](=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])[CH:13]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:43][CH:44]=2)=[O:30])=[O:11])[CH:7]=1
Reactant: COCCNC(=O)c1cccc2c1CCN(C(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C2C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COCCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)c1cccc2c1CCN(C(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C2C(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 24 h

Procedure:
(E)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(2-methoxyethylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: To 3A (46 mg, 0.073 mmol), 2-methoxyethanamine (5.49 mg, 0.073 mmol), BOP (32.3 mg, 0.073 mmol) in DMF (1 mL) was added DIEA (12.77 μL, 0.073 mmol). After 24 h, the reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4). MS (ESI) m/z: 686.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([O:13][CH2:24][O:25][CH3:26])([CH3:11])[CH3:12]
Reactant: COCCl
Reactant: Cc1cc(F)c(C(C)(C)O)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(C)(C)c1c(F)cc(C)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of 2-(2-bromo-6-fluoro-4-methylphenyl)propan-2-ol (12 g, 48.56 mmol) in DCM (120 mL) and diisopropylethylamine (6.9 g, 53.42 mmol) in DCM (120 mL) was added dropwise chloromethylmethylether (4.3 g, 53.42 mmol) at 0° C. under argon and the mixture was then stirred at rt for 15 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give 1-bromo-3-fluoro-2-(2-(methoxymethoxy)propan-2-yl)-5-methylbenzene (10 g, 70.73% yield) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 6.71-6.75 (m, 1H), 4.54 (s, 2H), 3.33 (s, 3H), 2.20 (s, 3H), 1.72 (d, J=5.2 Hz, 6H) ppm.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH:22]([NH:24][OH:25])[CH3:23].C(N(CC)CC)C.Cl>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH:22]([N:24]([OH:25])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: CC(Cc1ccc(Cl)cc1Cl)NO
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cc1ccc(Cl)cc1Cl)N(O)C(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (2.10 g; 11.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxylamine (2.0 g; 9.10 mmol), prepared as described in example P17, triethylamine (3.10 ml; 22 mmol) in dichloromethane (15 ml) at 0° C. The reaction mixture was stirred over night at ambient temperature. The reaction mixture was poured onto 1M HCl (50 ml), extracted with dichloromethane (3×20 ml) and then dried over Na2SO4. After removal of the solvent the residue (5.08 g) was purified by flash chromatography over silica gel (eluant: c-hexane/ethyl acetate 7:3). 1.51 g (43.8% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxy-amide (compound 1.028) was obtained in form of a white solid (m.p. 162-167° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH2:7]([N:10]=[C:11]=[S:12])[CH2:8][CH3:9].NC1N(C(NCCC)=S)N=CN=1>CN(C)C=O>[NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:11]([NH:10][CH2:7][CH2:8][CH3:9])=[S:12])[N:3]=1
Reactant: CCCN=C=S
Reactant: Nc1nc[nH]n1
Agent: CCCNC(=S)n1ncnc1N
Solvent: CN(C)C=O
Product: CCCNC(=S)n1cnc(N)n1
Yield: 35 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (4.00 g), dimethylformamide (30 ml) and n-propyl isothiocyanate (5.7 ml) were used as reagents. After the reaction, the reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3.07g of a 1:1 mixture of 5-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole and 3-amino-1-[n-propylamino(thiocarbonyl)]-1H-1,2,4-triazole as a white solid (yield 35%). The solid was applied to high performance liquid chromatography (acetonitrile-water) and recrystallization from hexane-ethyl acetate to give colorless transparent thin film crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.[Cl:23][C:24]1[C:33](Cl)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>C1(C)C=CC=CC=1.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>[Cl:23][C:24]1[C:33]([C:4]2[CH:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([CH3:1])[N:3]=2)=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nc3ccccc3nc2Cl)nc(C)n1
Temperature: 120 °C
Yield: 70.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (1.6 g, 3.73 mmol), 2,3-dichloroquinoxaline (1.484 g, 7.45 mmol, Aldrich) and tetrakis(triphenylphosphine)palladium (0.431 g, 0.373 mmol, Strem Chemicals) in toluene (5 mL). Argon was bubbled through for 2 min. The reaction mixture was stirred and heated at 120° C. for 36 h. The mixture was cooled to room temperature, filtered through Celite® (diatomaceous earth) washing with 10% methanol-DCM, and the filtrate was concentrated. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0-100% DCM-hexane to give 2-chloro-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxaline (0.8 g, 2.64 mmol, 70.9% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.23 (dd, J=8.02, 1.56 Hz, 1H); 8.13-8.19 (m, 1H); 7.96-8.05 (m, 2H); 7.73 (s, 1H); 2.67 (s, 3H); 2.61 (s, 3H). m/z (ESI, +ve ion) 303 (M+H)+.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13](O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]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)C(C)C)(C)C.[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]([NH2:66])[CH3:65])([O-:57])=[O:56]>CN(C=O)C>[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]([NH:66][C:13]1[C:12]2[N:11]=[CH:10][N:9]([C:18]=2[N:17]=[CH:16][N:15]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1)[CH3:65])([O-:57])=[O:56]
Reactant: CC(N)c1ccccc1[N+](=O)[O-]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a suspension of 2′-deoxyinosine (100 mg, 0.4 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 210 mg, 0.48 mmol) in anhydrous DMF (1 mL), N,N-diisopropylethylamine (100 μL, 0.6 mmol) was added followed by the addition of a solution of 1-(2-nitrophenyl)ethylamine (250 mg, 1.51 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 64 hours. Silica gel 60 (1 g, 60-200 mesh) was added, and the mixture was evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography to yield N6-[1-(2-nitrophenyl)ethyl]-2′-deoxyadenosine dA.19 (67 mg, 42%, 1:1 mixture of diastereomers) as a white foam.