Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]#[N:39]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:37][C:38]#[N:39])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: N#CCBr
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(OCC#N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 95.3 %

Procedure:
2.0 g (5.23 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1), 2.21 g of K2CO3, 0.26 g (1.57 mmol) of KI and 0.52 ml (7.85 mmol) of bromoacetonitrile were stirred in 30 ml of dry THF for 5 hours. The inorganic salts were filtered off and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in CH2Cl2 and the organic phase was washed with H2O, sat. sol. NaHCO3, sat. sol. NaCl, separated, dried over Na2SO4 and evaporated in vacuo to dryness to afford 2.10 g of a brown oil which was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 70:30. The crude product was triturated with hexane, filtered, washed and dried to yield 0.75 g of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)#[N:10].C(OCC)C>C(#N)C>[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]=[CH:6]2)=[CH:13][CH:12]=1)#[N:10]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 4-nitroimidazole (2,25 g, 19.9 mmol) and 4-cyanobenzyl bromide (3.90 g, 19.9 mmol) in acetonitrile (10 ml) was stirred at 50° C. for 72 hrs. The reaction was allowed to cool to room temperature and diethyl ether (70 ml) was added. The precipitate was removed by filtration and the filtrate partitioned between EtOAc and NaHCO3 solution. The organic extract was dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, 5% MeOH in CH2Cl2) to afford a solid that was triturated with hot ethanol, and washed with diethyl ether, to afford the product as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[NH2:9][C:10]1[N:11]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[C:12]([SH:15])=[N:13][N:14]=1>CN(C=O)C>[NH2:9][C:10]1[N:11]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[C:12]([S:15][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])=[N:13][N:14]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCOC(=O)CCBr
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 60 °C

Procedure:
3-Bromo-propionic acid ethyl ester (158 μL, 224 mg; 1.239 mmol) was added to a solution of 5-Amino-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (0.35 g, 1.239 mmol) in DMF (2.5 mL). The resulting mixture was heated to 60° C. for 20 hours. The reaction mixture was concentrated and sonicated with ethyl ether several times, decanting the ethyl ether layer. The resulting light yellow oil was placed on high vacuum to afford crude ethyl 3-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate as a light brown oily foam which was used directly in the next step (0.409 g, 87%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[Cl:19][CH2:20][C:21]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NC1CCCc2sccc21
Reaction time: 0.25 h

Procedure:
A mixture of 7.59 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 60 ml of dry tetrahydrofuran and 10.1 g of triethylamine in 20 ml of dry tetrahydrofuran is added. After stirring under a nitrogen atmosphere for 15 minutes, 3.5 ml or 5.25 g of chloroacetyl chloride in 30 ml of dry tetrahydrofuran is added dropwise, while the temperature is maintained at 30° C. to 40° C. After an hour of stirring, the mixture is filtered, the filter cake is washed with tetrahydrofuran, and the filtrate is evaporated to dryness. The residue is then triturated with water and the title compound, m.p. 115° C. to 119° C., is collected and washed with water and hexane.
Reaction SMILES: [CH3:1][C:2]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:8]1[N:4]([CH2:3][C:2]([CH3:1])([O:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[CH3:12])[N:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(Cn1cc([N+](=O)[O-])cn1)O[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(Cn1ncc([N+](=O)[O-])c1Cl)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 1-(2-methyl-2-((trimethylsilyl)oxy)propyl)-4-nitro-1H-pyrazole (1 equiv) in THF (0.41 M) was cooled into −78° C., followed by addition of lithium bis(trimethylsilyl)amide (2.6 equiv). After 1 h, hexachloroethane (1.5 equiv) was added. The reaction mixture was stirred at −78° C. for 2 h then the mixture was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel flash chromatography (15% ethyl acetate in petroleum ether) to afford the title compound as a colorless oil (80.1% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.12 (s, 1H), 4.06 (s, 2H), 1.51 (s, 6H), 0.01 (s, 9H). MS (ESI) m/z 292.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=O)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=[S:21])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NCCCC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCCC(N)=S
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 149.2 %

Procedure:
A suspension of 4-methanesulfonylamino-butyramide (0.50 g, 2.8 mmol) and Lawesson's reagent (0.56 g, 1.4 mmol) in THF (50 mL) was stirred at room temperature for 45 minutes. During this time all of the solid dissolved. The solution was concentrated and purified by flash chromatography (79:1 EtOAc:MeOH) to afford the title compound (0.41 g); 1H NMR (400 MHz, CDCl3) δ63.29 (s, 3H), 3.07-3.11 (m, 2H), 2.91 (s, 3H), 2.62-2.66 (m, 2H), 1.93-1.99 (m, 2H); MS 197 (M++1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (0.620 g, 2.69 mmol), (4-hydroxy-phenyl)-acetic acid (0.242 g, 5.15 mmol), HATU (1.23 g, 3.23 mmol) and diisopropylethylamine (0.939 mL, 5.39 mmol) in 9 mL of DMF was stirred at room temperature for 6 hours, concentrated under reduced pressure and the residue dissolved in ethyl acetate and washed with aqueous NaHCO3 (×3), brine (×2), and water. The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue purified by flash chromatography (60–90% ethyl acetate (1% triethylamine) in hexanes) to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.62 (m, 4 H), 2.45 (m, 4 H), 2.83 (t, J=6.78 Hz, 2 H), 3.53 (d, J=5.76 Hz, 2 H), 4.38 (t, J=6.78 Hz, 2 H), 6.71 (m, 2 H), 7.13 (m, 3 H), 7.64 (m, 1 H), 7.94 (s, 1 H), 8.13 (m, 1 H), 9.25 (s, 1 H), 10.24 (s, 1 H); MS (ESI) m/z 365 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])=[CH:9][CH:8]=[C:7]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([O:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[CH:29]=[CH:28][C:26]=3[N:27]=2)[N:6]=1)(=O)C.C1COCC1.[OH-].[Li+].Cl>CO>[CH:34]1([CH2:33][O:32][C:30]2[CH:29]=[CH:28][C:26]3[N:27]=[C:23]([C:7]4[N:6]=[C:5]([O:4][CH3:1])[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH3:14])=[CH:9][CH:8]=4)[O:24][C:25]=3[CH:31]=2)[CH2:35][CH2:36]1
Reactant: CC(=O)Oc1nc(-c2nc3ccc(OCC4CC4)cc3o2)ccc1OC[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(-c2nc3ccc(OCC4CC4)cc3o2)ccc1OC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]pyridin-2-yl acetate (111 mg), THF (1 mL), methanol (1 mL) and 1M lithium hydroxide aqueous solution (1 mL) was stirred at 0° C. for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with toluene (2 mL), methyl iodide (0.021 mL) and silver(I) carbonate (92 mg), and the obtained mixture was stirred at 85° C. for 3 days. To the reaction mixture were further added methyl iodide (0.021 mL) and silver(I) carbonate (92 mg), and the mixture was stirred at 85° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (70.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Br)(Br)([Br:15])=O>O>[Br:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1ccc2cccc(Br)c2[nH]1
Reactant: O=P(Br)(Br)Br
Solvent: O
Product: Brc1ccc2cccc(Br)c2n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 8-bromoquinolin-2(1H)-one (5 g, 22 mmol) and phosphoryl tribromide (13 g, 45 mmol) was heated to 140° C. for three hours. The resulting mixture was poured onto 100 g of ice and 100 ml water. The mixture was stirred for 1 hour and the resulting solids were filtered to yield the title compound. (5.1 g, 80% yield) MS APCI (+) 286, 288, and 290 (M+1 of each isotope combination) detected.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](I)=[C:16]([CH3:19])[N:15]=[C:14]2[CH3:20])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.N.ClCCl.[CH3:25][N:26]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17]([C:25]#[N:26])=[C:16]([CH3:19])[N:15]=[C:14]2[CH3:20])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: CN1CCCC1=O
Reactant: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: ClCCl
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1C#N
Reaction time: 3 h

Procedure:
A mixture of 8-methyl-6-(2,4-dimethyl-5-iodoimidazol-1-yl)-2-(1H)-quinolone (0.1 g), cuprous cyanide (0.047 g) and palladium acetate (0.01 g), in N-methyl-2-pyrrolidone (1 cm3) was heated and stirred at 175° for 3 hours. The cooled mixture was poured into aqueous ammonia solution (10 cm3 ; S.G. 0.880) and dichloromethane (50 cm3) and the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of appropriate fractions afforded an oil which crystallised on trituration with ether to give the title compound, m.p. 334°-337° (0.03 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:8]([O:21][CH:22]([CH3:24])[CH3:23])[CH:7]=2.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>C(#N)C>[CH3:24][CH:22]([O:21][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:23]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.732 g, 3.09 mmol) and 4-(4-piperidinyl)morpholine (0.684 g, 4.02 mmol) in acetonitrile (30 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3, and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford methyl 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.6 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ8.40 (s, 1H), 7.98 (s, 1H), 7.87-7.93 (m, 2H), 7.75-7.83 (m, 2H), 5.11 (dt, J=6.02, 12.05 Hz, 1H), 4.00 (s, 3H), 3.61 (s, 2H), 3.51-3.56 (m, 4H), 3.41 (s, 3H), 2.62 (d, J=11.29 Hz, 2H), 2.38 (br. s., 4H), 1.95-2.05 (m, 1H), 1.81 (t, J=10.92 Hz, 2H), 1.62 (d, J=12.55 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 1.20-1.29 (m, 2H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[C:8]([N:9]=[C:10]4[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Clc1c2c(nc3ccccc13)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(COc2ccc(-c3c4c(nc5ccccc35)CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-chloro-1,2,3,4-tetrahydro-acridine (282 mg, 1.30 mmol), 4-Benzyloxyphenyl boronic acid (443 mg, 1.94 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol), and 2 M aq Na2CO3 (0.97 mL, 1.94 mmol) was heated to 80° C. in 1,2-dimethoxyethane (2 mL) with vigorous stirring overnight in a sealed vial. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and H2O (10 mL). The aq. layer was extracted with EtOAc (25 mL). The combined organic layers were washed with sat. aq. NaCl (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was triturated with hexanes (50 mL) and to give a mixture of the desired product and starting chloride, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:3][C:2]=2[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:11][CH2:12]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(-c2nccs2)c1

Procedure:
A mixture of EXAMPLE 329B (0.070 g), 2-(tributylstannyl)thiazole (0.090 g), and tetrakis(triphenylphosphine)palladium(O) (0.069 g) in dioxane (2 mL) was heated at 90° C. for 4 hours. After cooling, the mixture was loaded onto a silica gel column and eluting with 1:3 ethyl acetate:hexanes to give the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29]Cl)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][N:2]2[CH2:6][CH2:5][CH:4]([N:7]3[C:11](=[O:12])[C:10]4=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]4[C:8]3=[O:17])[CH2:3]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1C1CCNC1
Reactant: COc1ccc(CCCl)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1OC
Yield: 11.3 %

Procedure:
6.03 g of the hydrochloride was suspended into 100 ml of acetonitrile, to which 4.79 g of 2-(3,4-dimethoxyphenyl) ethyl chloride, 8.24 g of anhydrous potassium carbonate and n-tetrabutyl ammonium iodide (catalytic amount) were added and refluxed under heating for 20 hours. After allowing them to cool, the inorganic salts were filtered out and the solvent was distilled off. After adding ethyl acetate and washed with water, they were dried with anhydrous magnesium sulfate. The solvent was concentrated and purified on silica gel chromatography to obtain 1.03 g of the above-captioned compound (total yield: 6.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:11][C:12]([F:15])([F:14])[F:13])=O)=[CH:4][C:3]=1[N:16]1[C:20]([CH2:21][OH:22])=[CH:19][C:18]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:17]1>C(Cl)(Cl)Cl.CO.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:11][C:12]([F:14])([F:13])[F:15])=[CH:4][C:3]=1[N:16]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]([O:23][CH2:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[N:17]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CO)cc1S(=O)CC(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C=O)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.6 %

Procedure:
1.5 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-hydroxymethyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 30 mL of chloroform and 10 mL of methanol, and 3.0 g of manganese dioxide was added, followed by stirring at room temperature for 12 hours. Then, the reaction solution as subjected to filtration, the filtrate was distilled under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.02 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-formyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22].CCN(C(C)C)C(C)C>C(O)C>[OH:22][CH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: N[C@H]1CCC[C@H]1CO
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@@H]1CO
Temperature: 60 °C
Yield: 95.6 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-(methylthio)-pyrimidine-5-carboxylate (5.00 g, 21.49 mmol) and cis-(2-aminocyclopentyl)-methanol (2.60 g, 22.56 mmol) in ethanol (85 mL) was added DIEA (5.61 mL, 32.2 mmol) and heated to 60° C. for 2.5 h. Upon completion of reaction, as indicated by LCMS and TLC, the reaction was removed from heat and concentrated, then purified by silica gel chromatography (0-80% ethyl acetate/hexane). The desired product fractions were combined and concentrated to afford ethyl 4-(cis-2-(hydroxymethyl)cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (6.4 g, 96% yield) as a white solid. MS (ESI) m/z 312.4 [M+1]+.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: ClCc1cccc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc2ccccc12

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 1-chloromethylnaphthalene, in 42% overall yield. The crude product was crystallized from ether/EtOAc/hexane to afford a white solid, mp 100°-104° C.; IR (KBr) 3435, 2896, 1668, 1504, 1414, 1253, 1132, 1068, 768, 758 cm-1 ; 1H NMR (CDCl3) δ 1.92 (br s, 1H Plus HDO), 2.26-2.44 (m, 2H), 3.96 (t, J=5.6 Hz, 2H), 4.94 (dd, J=7.5, 5.6 Hz, 1H), 5.62 (ABq, JAB =16.9 Hz, 2H), 6.72 (dd, J=8.0, 1.1 Hz, 1H), 6.84 (td, J=8.1, 1.5 Hz, 1H), 6.96-7.11 (m, 3H), 7.36 (t, J=7.4 Hz, 1H), 7.54-7.64 (m, 2H), 7.78 (d, J=8.2 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H); MH+ at m/z=334; Anal. Calc'd for C21H19NO3 : C, 75.66; H, 5.74; N, 4.20. Found: C, 75.56; H, 5.80; N, 4.14.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[OH:10])=[N:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH:31](O)([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([O:10][CH:31]([CH3:33])[CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)O
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Temperature: 160 °C

Procedure:
The compound of Example 1 (123 mg) was dissolved in isopropanol (2 mL), and concentrated sulfuric acid (41 mg) was added thereto. The mixture was heated at 140° C. for one hour and at 160° C. for 2 hours by means of a microwave reaction apparatus. The reaction mixture was basified with a 10% aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (10% to 100% ethyl acetate/hexane), and thus the title compound (66 mg) was obtained as a colorless solid.