Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S)C=CC=CC=1.C1(Br)CCCC1>>[C:1]1([S:7][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)C1CCCC1
Agent: BrC1CCCC1
Agent: Sc1ccccc1
Product: c1ccc(SC2CCCC2)cc1

Procedure:
The cyclopentyl phenyl sulfone used in this synthesis is also a novel compound. It was initially prepared by reacting benzenethiol with cyclopentyl bromide to form cyclopentyl phenyl sulfide which was in turn oxidized to produce the sulfone. Benzenethiol was reacted with cyclopentyl bromide in the presence of potassium carbonate in an acetone solvent at reflux temperature for 4 hours. The acetone was stripped off, water added, and 30-60 petroleum ether used to extract the sulfide. The ether phase was washed twice with 5 percent sodium hydroxide, once with water, and dried with anhydrous magnesium sulfate. The petroleum ether was then distilled off, leaving a residue which was used in the preparation of the sulfone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:18][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(C)c1

Procedure:
A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (2.00 g, 0.0082 mol), 4chlorophenyl isothiocyanate (1.68 g, 0.0099 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.37 g (70%), m.p. 180°-182 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: OCc1cc(Cl)ccc1C(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cc(Cl)ccc1C(F)(F)F
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Dissolve (5-chloro-2-trifluoromethylphenyl)-methanol (347 mg, 1.66 mmol) in dichloromethane (10 mL). Add pyridinium chlorochromate (717 mg, 3.32 mmol) and stir for 2 h. Dilute with diethyl ether and stir for 1 h. Filter and concentrate. Chromatograph on silica gel eluting with 10% ethyl acetate in hexane to give the title compound as a clear oil (285 mg, 82%). 1H NMR (400 MHz, MeOH-d4) 10.33 (s, 1H), 7.90 (s, 1H), 7.69 (d, 1H, J=8.4 Hz), 7.54 (d, 1H, J=8.4 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:2]=1.[CH:31](=O)[CH3:32]>>[CH2:31]([N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:32]
Reactant: Oc1ccc(CCNc2nccc(-c3cccc(NCc4cccnc4)c3)n2)cc1
Reactant: CC=O
Product: CCN(Cc1cccnc1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 25 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 426. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (s, 1H) 8.39 (d, 1H) 8.2 (d, 1H) 7.6 (d, 1H) 7.5 (s, 1H), 7.3 (m, 3H), 7.0 (d, 1H), 6.9 (d 1H), 6.8 (d, 2H), 6.5 (d, 2H), 4.6 (s, 2H), 3.6 (m, 4H), 2.8 (t, 2H), 1.2 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:13]=[C:14]=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:18]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:13][C:14]([NH2:18])=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: N
Reactant: S=C=NC(c1ccccc1)c1ccc(Cl)cc1
Solvent: CCOCC
Product: NC(=S)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-chlorobenzhydryl isothiocyanate [5.2g (0.02M)] in 50 mls of dry ether at 0° C is treated with NH3 (anhyd.) for 1/2 hour while maintaining a temperature of 0° C with stirring. Stirring is continued an additional 1.5 hours at 9° to 10° C. during which time a white solid appears. The crude thiourea is filtered and washed thoroughly with ether; mp 173°-5° C. The filtrate is concentrated in vacuo to yield additional product. The combined crops of N-(4-chlorobenzhydryl) thiourea are used in the next step without further purification.
Reaction SMILES: CO[C:3](=[N:12][N+:13]([O-:15])=[O:14])[NH:4][CH2:5][C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1.[CH3:16][NH2:17]>O>[Cl:11][C:9]1[S:10][C:6]([CH2:5][NH:4][C:3]([NH:17][CH3:16])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CN
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To a suspension of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (1.00 g, 4.00 mmol) in water (10 ml) was added 40% aqueous solution of methylamine (0.77 g, 9.92 mmol) dropwise. The mixture was stirred at room temperature for 14 hours and the resulting crystals were collected by filtration, washed with water (10 ml), and dried. As a result, 0.92 g (92.0% yield) of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)=[O:23])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+]>CO.O>[NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)=[O:23])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To the stirring mixture of methyl 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate (420 mg, 0.972 mmol, 1 eq) in MeOH—H2O (3:1, 20 mL) at room temperature was added potassium hydroxide pellets (272 mg, 5 eq) and the reaction mixture was stirred at 65° C. for total of two hours, at which time the reaction mixture became a clear yellow solution. The solution was concentrated under reduced pressure to remove most part of methanol. The mixture was then cooled in an ice-bath, concentrated hydrochloride was added dropwise, and the pH was adjusted to about 3. After the mixture was stirred for about another 30 minutes, it was filtered through a Buchner funnel, rinsed with water, and 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid was obtained as a yellow solid in quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:14])[CH2:8][CH2:9][NH:10][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=[CH:3]1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][N:10]1[CH2:9][CH2:8][C:7](=[O:14])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:11]1(=[O:13])=[O:12]
Reactant: Cn1ccc2c1C(=O)CCNS2(=O)=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ccc2c1C(=O)CCN(CCCCl)S2(=O)=O
Yield: 94.6 %

Procedure:
A suspension of 214 mg (1 mmol) of Compound 14, 630 mg (4 mmol) of 1-bromo-3-chloropropane and 276 mg (2 mmol) of potassium carbonate in 5 ml of acetone was refluxed for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/hexane=1/2), whereby 275 mg of the title compound were obtained (yield: 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)CC>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(OCc3ccccc3)ccc12
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol) and propionic acid (700 mL) was heated to 125° C. with vigorous stirring. Nitric acid (23.11 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature between 121° C. and 125° C. After the addition, the reaction was stirred at 125° C. for 1 hour then allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed with water, and dried in an oven for 1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinolin-4-ol as a grayish powder. 1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.12 (s, 1H), 8.17 (dd, J=3.3, 6.3 Hz, 1H), 7.51-7.33 (m, 5H), 7.21-7.17 (m, 2H), 5.25 (s, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]4[CH:22]=[N:23][C:24](Cl)=[CH:25][C:20]=4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>O.O1CCOCC1>[C:36]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:41]=[CH:40][C:39]([C:24]2[N:23]=[CH:22][C:21]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:18]([O:17][C@@H:16]4[CH2:15][O:14][C@@H:13]5[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]45)=[N:19][C:20]=3[CH:25]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)ncc2n1COCC[Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Palladium tetrakistriphenylphosphine (42.6 mg, 0.037 mmol) was added to a stirred suspension of 2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine (Intermediate 46, 100.0 mg, 0.184 mmol), 4-biphenylboronic acid (54.8 mg, 0.277 mmol), and potassium phosphate tribasic (117.0 mg, 0.553 mmol) in degassed 20% water in dioxane (1.44 mL). The reaction mixture stirred under N2 at 85° C. After 2 h, more palladium tetrakistriphenylphosphine (42.6 mg, 0.037 mmol) was added. The reaction mixture heated under N2 at 85° C. for another 7 h, then cooled to room temperature and the lower aqueous layer was drawn off and discarded. The remaining reaction mixture was added to EtOAc (50 mL), filtered, and the resulting solids were washed with EtOAc (2×15 mL). The filtrate was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C36H49N3O5Si2 659.32 observed m/e: 660.13 (M+H)+ (Rt 1.58/2.0 min).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([O:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[C:17]3=[C:33]([CH3:37])[N:34]=[C:35]([CH3:36])[N:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1(C)C=CC=CC=1>[CH3:37][C:33]1[N:34]=[C:35]([CH3:36])[N:16]2[C:17]=1[C:18]([O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)=[N:19][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: C1COCCN1
Reactant: COc1cc(Oc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Oc2nc(-c3ccc(N4CCOCC4)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
28 mg (0.29 mmol) of sodium tert-butoxide are introduced into a second Schlenk tube under argon. Subsequently, 100 mg (0.21 mmol) of 2-(4-bromophenyl)-5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]triazine from Exam-ple 16A, 22 mg (0.25 mmol) of morpholine and 2 ml of anhydrous toluene are added. Solution A is likewise added, and the whole is stirred overnight at 100° C. After cooling, the mixture is then filtered off with suction through a glass frit. The filtrate is concentrated to dryness under reduced pressure and purified by flash chromatography (cyclohexane/ethyl acetate 10:1-4:1-3:2-1:1).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[S:57]1[CH:61]=[CH:60][N:59]=[C:58]1[S:62](Cl)(=[O:64])=[O:63]>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([NH:52][S:62]([C:58]3[S:57][CH:61]=[CH:60][N:59]=3)(=[O:64])=[O:63])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 30 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (2.5 g, 7.2 mmol) and thiazole-2-sulfonyl chloride (1.45 g, 7.88 mmol) the title compound of Step A was obtained (1.05 g, 30.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (br. s., 2H), 8.58 (d, J=5.2 Hz, 1H), 8.09 (d, J=3.2 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.49-7.40 (m, 1H), 7.31-7.25 (m, 1H), 6.88 (d, J=5.6 Hz, 1H), 3.35-3.30 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 496 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:34])([F:15])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[C:29]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)C(F)F)cc1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 46.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.975 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.13 g of 2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.847 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH3:11])=[N:9][CH:10]=1)=[N+]=[N-].C(OCC)(=O)C>[Pd]>[CH3:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][N:7]=1
Reactant: Cc1ncc(CN=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncc(CN)cn1
Reaction time: 2 h

Procedure:
A mixture of 5-(azidomethyl)-2-methylpyrimidine (55 mg, 0.00037 mol) in ethyl acetate (20 mL, 0.2 mol), and 10% Pd—C (70 mg) was stirred under H2 (1 atm) for 2 hr. The catalyst was filtered off and filtrate was concentrated in vacuo to afford a white solid. LC/MS m/e 124.3 (M+H+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:29][CH:30]=3)=[O:14])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)cnc3o2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Cyanofuro[2,3-b]pyridine-2-carboxylic acid (108 mg, 0.574 mmol) and t-butyl 4-aminophenoxyacetate (141 mg, 0.632 mmol) were dissolved in N,N-dimethylformamide (10 ml) and 1-hydroxy-1H-benzotriazole (85.3 mg, 0.632 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.632 mmol) were added. The mixture was stirred at room temperature for 14 hours. Water (100 ml) was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Low boiling matters were distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to quantitatively give 232 mg of t-butyl 4-(5-cyanofuro[2,3-b]pyridine-2-carbonylamino)phenoxyacetate as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][S:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2ccsc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)c2c1SCC2
Temperature: 60 °C
Yield: 12.7 %

Procedure:
To a solution of 4-fluoro-7-methoxy-1-benzothiophene (1.55 g, 8.5 mmol, 1 eq) in trifluoroacetic acid (40 ml) was added triethylsilane (3.40 ml, 21.25 mmol, 2.5 eq). The mixture was heated to 60° C. for 48 hours, then cooled to room temperature and the solvent removed in vacuo. The crude product was purified by flash chromatography with a gradient of 40-60% chloroform in heptane to give 1.24 g, 80% recovered starting material and 199 mg, 13% yield of the title compound as a colourless oil: δH (300 MHz, CDCl3) 3.78-6.58 (2H, m, ArH), 3.82 (3H, s, CH3) and 3.44-3.30 (4H, m, SCH2CH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:7]O)([O-:3])=[O:2].S(Cl)([Cl:21])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:7][Cl:21])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CO)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CCl)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
170.5 g of 3-nitro-6-(phenylthio)-benzyl alcohol are suspended in 54.5 ml of pyridine and 170 ml of chloroform and treated dropwise at a temperature below 20° C over a period of 30 minutes with a solution of 78g of thionyl chloride in 55 ml of chloroform. The mixture is stirred for 30 minutes at 30° C and subsequently diluted with water. The organic phase is washed successively with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated. There is obtained crude 3-nitro-6-(phenylthio)-benzyl chloride of melting point 58° - 60° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CC(=O)Nc1cc(F)ccc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 57.9 %

Procedure:
To a solution of 5.01 g of N-(5-fluoro-2-methyl-phenyl)-acetamide in 30 mL of concentrated sulfuric acid was added dropwise 2.74 g of 70% nitric acid (d=1.42) while keeping the inner temperature at 3° C. After stirring for 40 minutes at this temperature, the reaction solution was poured dropwise into ice water under stirring. After collecting the precipitated powder by filtration, the powder was dissolved in 100 mL of ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate (twice) and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was crystallized from ethanol, to afford 3.68 g of the title compound as yellow needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH2:38](Br)[CH2:39][CH3:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:38][CH2:39][CH3:40])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CCCBr
Product: CCCOc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with propyl bromide
Reaction SMILES: C[C@@:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1CCCBr.[N-]=[N+]=[N-].[Na+]>C1COCC1.O>[C:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(S(N)(=O)=O)C=CC=CC1CCCBr
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 94 %

Procedure:
To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-bromopropylbenzene-sulfonamide (1.188 g, 2.295 mmol) in THF/H2O (20/4, 24 mL) was added sodium azide (1.49 g, 22.9 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was extracted with ether (3×60 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.941 g of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-azidopropyl]]benzenesulfonamide as a colorless oil in 94% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl.Br[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.N.[Cu]I>[N:14]1[CH:15]=[CH:16][C:11]([N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:13]=1
Reactant: Brc1ccncc1
Reactant: Cc1ccc(=O)[nH]c1
Agent: [Cu]I
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(=O)n(-c2ccncc2)c1

Procedure:
Compound 22 was synthesized by condensation of 5-methyl-2(1H)-pyridone (327.4 mg, 3 mmol) with 4-bromopyridine hydrochloride (778 mg, 4 mmol) in the presence of CuI (60 mg, 0.3 mmol) and K2CO3 (1.36 g, 10 mmol) in DMF (3 ml) at 135° C. overnight. The reaction mixture was diluted with 10% ammonia (15 ml) and extracted with ethyl acetate. Organic extract was washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. Column chromatography (5% MeOH-DCM) afforded 197 mg (35%) of the target compound as a yellowish solid. The 1H NMR spectra was consistent with the structure of Compound 22.