Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H]1CNC[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.[CH2:29]([C:31]1[C:32]([NH:51][C@H:52]2[C@@H:56]([O:57][CH2:58][CH3:59])[CH2:55][N:54](C(OCC3C=CC=CC=3)=O)[CH2:53]2)=[N:33][C:34]([CH2:49][CH3:50])=[C:35]([C:37]2[C:38]([C:45]([F:48])([F:47])[F:46])=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[N:36]=1)[CH3:30]>>[CH2:58]([O:57][C@H:56]1[CH2:55][NH:54][CH2:53][C@H:52]1[NH:51][C:32]1[C:31]([CH2:29][CH3:30])=[N:36][C:35]([C:37]2[C:38]([C:45]([F:48])([F:47])[F:46])=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)=[C:34]([CH2:49][CH3:50])[N:33]=1)[CH3:59]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting benzyl (3R,4S)-3-({3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate provided the title compound as an amber oil. 1H NMR (CDCl3) δ 1.13, 1.28, 2.41, 2.69, 3.14, 3.37, 3.51, 3.66˜3.75, 4.04, 4.16, 4.69, 5.29, 6.96, 7.54; IR (liq.) 2975 (s), 2417 (b), 2177 (b), 2029 (w), 1923 (w), 1609 (s), 1565 (s), 1479 (s), 1400 (s), 1341 (s), 1278 (s), 1239 (s), 1192 (s), 1177 (s), 1138 (s) cm−1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([CH3:10])[C:2]([NH:13][CH2:12][CH2:11][NH2:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(Br)c(C)n1
Reactant: NCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: COc1ccc(NCCN)c(C)n1
Yield: 78.1 %

Procedure:
3-Bromo-6-methoxy-2-methylpyridine (50 mg, 0.247 mmol), ethane-1,2-diamine (0.083 ml, 1.237 mmol), sodium tert-butoxide (47.6 mg, 0.495 mmol) and dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-thisopropylphenyl)phenyl]phosphane (6.64 mg, 0.012 mmol) were dissolved under argon in anhydrous 1,4-dioxane (2.5 ml). Next, Pd2(DBA)3 (11.33 mg, 0.012 mmol) was added and the mixture was heated in a sealed flask to 70 C overnight. The reaction mixture was filtered over kieselguhr, rinsed with EtOAc and the combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, gradient of 0.5% to 10% of [7N NH3 in MeOH] in DCM to yield 35 mg (0.193 mmol, 78%) of a yellow oil. MS(ESI) m/z=182.2 [M+1]+.
Reaction SMILES: [CH:1]([N:4]([CH:27]([CH3:29])[CH3:28])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[C:10]2[CH2:24][CH2:25][NH2:26])=[O:6])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[S:46][C:45]([CH:47]=O)=[CH:44][CH:43]=2)[CH:37]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH:27]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)=[C:10]2[CH2:24][CH2:25][NH:26][CH2:47][C:45]1[S:46][C:42]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)=[CH:43][CH:44]=1)=[O:6])([CH3:29])[CH3:28]
Reactant: O=Cc1ccc(-c2cccnc2)s1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(C(C)C)C(C)C)cc3c2CCN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(C(C)C)C(C)C)cc3c2CCNCc2ccc(-c3cccnc3)s2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisopropylamide in a mixture of dry chloroform and methanol at 0° C. is added magnesium sulfate followed by 5-pyridin-3-yl-thiophene-2-carbaldehyde and the mixture stirred at low temperature. After 40 minutes, acetic acid is added followed by a solution of sodium cyanoborohydride and the mixture allowed to warm to room temperature. After completion, the reaction is quenched by the addition of saturated aqueous sodium bicarbonate, extracted with methylene chloride and the combined organics washed sequentially with water and brine. Purification of the concentrate by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[N:28]=[C:27]([NH2:32])[C:26]3[N:33]=[C:34]([CH2:39][O:40][CH2:41][CH3:42])[N:35]([CH2:36][CH2:37][CH3:38])[C:25]=3[C:24]=2[CH:23]=1.O>ClCCl>[NH2:32][C:27]1[C:26]2[N:33]=[C:34]([CH2:39][O:40][CH2:41][CH3:42])[N:35]([CH2:36][CH2:37][CH3:38])[C:25]=2[C:24]2[CH:23]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCCCCCN)cc3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCCCCCNC(=O)C(C)C)cc3c21
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Isobutyryl chloride (0.236 mL, 2.25 mmol) was added dropwise, followed by triethylamine (0.2 mL, 1.4 mmol), to a stirred slurry of 8-(6-aminohexyloxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (0.900 g, 2.25 mmol) in dichloromethane (25 mL) at room temperature. After 30 minutes, water (15 mL) was added and the mixture was allowed to stir for 30 minutes. The layers were separated and the aqueous layer was extracted with dichlormethane. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient elution with 1-6% CMA in chloroform) followed by recrystallization from acetonitrile afforded 0.285 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}hexyl)-2-methylpropanamide as a white crystalline solid, mp 136-138° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(#N)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccs3)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1cncc(-c2cnc3[nH]cc(-c4nccs4)c3c2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A mixture of 2-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)thiazole (75 mg, 0.17 mmol), pyridine-3-ylboronic acid (27 mg, 0.22 mmol) 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (6.9 mg, 0.009 mmol), acetonitrile (1 mL) and saturated aqueous NaHCO3 (1 mL) were stirred in a sealed microwave tube at 140° C. for 30 minutes. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with brine and concentrated to dryness. Silica gel chromatography afforded 2-(5-(pyridine-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)thiazole (36 mg, 76% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.47 (m, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.81 (d, J=3.5 Hz, 1H), 8.10 (m, 1H), 8.24 (s, 1H), 8.55 (dd, J=2.0, 5.0 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), (d, J=2.0 Hz, 1H), 8.89 (m, 1H), 12.37 (s, 1H). MS: m/z 279.0 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:39]Br>C(O)(=O)C>[Br:39][C:13]1[N:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:11]2[N:10]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:16](=[O:17])[C:15]=2[N:14]=1
Reactant: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(C(F)(F)F)cc2)n1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(C(F)(F)F)cc2)n1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 84 %

Procedure:
1-(4-Chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one (50.0 mg, 0.107 mmol) and sodium acetate (300 mg) are dissolved in 10 mL of acetic acid. 250 μLs of bromine is added and the reaction mixture is stirred for 3 h. After the volatile is evaporated, the residue is partitioned with DCM and water. The organic layer is collected and evaporated to dryness. The crude material is purified by column chromatography, yielding 78 mg (84%) of 8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one. 1H NMR (DMSO, 400 MHz) δ 7.63 (m, 5H), 7.57 (d, 2H), 7.50 (d, 2H), 7.43 (d, 2H), 7.39 (d, 2H). HPLC-MS calculated for C24H13BrClF3N4O (M+H+) 545.0. Found 545.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][N:10]=1)=[O:4].P(Cl)(Cl)([Cl:15])=O>CN(C=O)C>[Cl:15][C:8]1[N:7]=[C:6]([CH3:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:10][CH:9]=1
Reactant: COC(=O)c1ncc[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(Cl)nc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
In a 1-L flask, the crude 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (step 2, 17.77 g, 106 mmol) was dissolved in DMF (300 mL). Neat phosphoryl trichloride (29.6 mL, 317 mmol) was added. The reaction mixture was heated to 100° C. After 1 h, the reaction mixture was concentrated to remove most of the DMF. The flask was cooled in an ice water bath, and 1 M aqueous Na2CO3 (300 mL) was added slowly, followed by 80% EtOAc-hexane (400 mL). The mixture was filtered through Celite. The resulting filtrate was partitioned and the aqueous phase was extracted further with 80% EtOAc-hexane (2×250 mL). The combined organic layers were dried over MgSO4 and concentrated. The material was purified through silica gel using 11% EtOAc-hexane to afford the title compound (4.29 g, 23 mmol, 22%). MS m/z=187 [M+H]+. Calculated for C7H7ClN2O2: 186. 1H NMR in CDCl3 δ: 8.51 (s, 1H), 4.01 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7](O)([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:5][N:6]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH2:8]([CH:7]([C:4]1[S:3][C:2]([SH:1])=[N:6][CH:5]=1)[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(O)(CC)c1cnc(S)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cnc(S)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-mercapto-1,3-thiazol-5-yl)pentan-3-ol (515 mg, 2.5 mmol) in 30 ml of CH2Cl2 at 0° C. was added triethylsilane (2.0 ml, 12.5 mmol) and TFA (2.0 ml, 25.9 mmol). The mixture was stirred for 1 h at 0° C. then warmed to room temperature. After 1 h, the reaction mixture was diluted with EtOAc and quenched with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and the solvent evaporated. The crude compound showed a mixture of alkene and desired product. The crude mixture was then resubmitted to the same reaction condition to get complete conversion. The crude was chromatographed on silica gel (hexane:EtOAc; 95:5 to 80:20) to the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1>>[CH:12]1([C:15]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:16])[CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccnc(N)c1
Product: COC(=O)c1ccnc(NC(=O)C2CC2)c1
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (1.60 g, a yellow solid) from methyl 2-aminoisonicotinate (1.20 g, 7.89 mmol) and cyclopropanecarbonyl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: C(OC(=O)CCC1C=CC(O)=CC=1C)C.ClC(C1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)CC(C)C.[CH3:39][C:40]1[C:45]([CH2:46][OH:47])=[CH:44][CH:43]=[C:42]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[N:41]=1>O=[Mn]=O>[CH3:39][C:40]1[C:45]([CH:46]=[O:47])=[CH:44][CH:43]=[C:42]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:50][CH:49]=2)[N:41]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: O=[Mn]=O
Agent: CCOC(=O)CCc1ccc(O)cc1C
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(Cl)CC(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C=O

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 60B]) was reacted with [rac]-3-(1-chloro-3-methyl-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (prepared from [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]) by i) oxidation with MnO2 in analogy to the procedure described in example 3A] to yield 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde; ii) treatment with isobutyl magnesium chloride and iii) reaction with SOCl2 in analogy the procedures described in examples 4A] and 4B]) to give [rac]-3-(2-methyl-4-{3-methyl-1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].C(O)CCC>C(Cl)Cl>[Cl:1][CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CCCCOC(=O)CC(=O)CCl
Solvent: ClCCl
Solvent: CCCCO
Product: CCCCOC(=O)C[C@H](O)CCl
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In a 100 ml Hastelloy-made autoclave having been purged with nitrogen were charged 38.8 g (0.2 mol) of n-butyl 4-chloroacetoacetate and 50 ml of n-butyl alcohol, and solution of 73 mg of Ru2Cl2 [(R)-(+)-BINAP]2Et3N in 2 ml of methylene chloride was added thereto. The mixture was stirred at 100° C. under a hydrogen pressure of 11 to 12 kg/cm2 for 2 hours to conduct hydrogenation. The solvent was evaporated, and the residue was distilled under reduced pressure to give 35.0 g (percent yield: 90%) of n-butyl (S)-(-)-4-chloro-3-hydroxybutyrate.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][NH2:16])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C1COCC1>[Br:1][C:2]1[C:3]2[N:4]([C:17](=[O:18])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1nccc(-c2ccc(Cl)cc2)c1Br
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Temperature: 0 °C
Reaction time: 10 h
Yield: 84.4 %

Procedure:
Crude 3-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (7 g, 23 mmol) was dissolved in dry THF (100 mL), and the resulting solution was cooled to 0° C. To this was added 1,1′carbonyldiimidazole (18 g, 111 mmol). The reaction mixture was stirred at room temperature for 10 h. The solvent was evaporated under vacuum, and water (10 mL) was added, which caused solid desired product to precipitate. This was filtered, washed with water (2×25 mL), and dried to obtain the title compound as a yellow solid (6.3 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](O)=[O:22])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)([F:4])[F:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]([F:63])([F:62])[C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:52][CH:51]=1.C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.C(OCC)C>[F:63][C:49]([F:48])([F:62])[C:50]1[CH:51]=[CH:52][C:53]([N:56]2[CH2:61][CH2:60][N:59]([C:21](=[O:22])[CH2:20][O:19][C@H:16]3[CH2:15][CH2:14][C@H:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([S:5][C:2]([F:1])([F:3])[F:4])=[CH:7][CH:8]=4)[CH2:18][CH2:17]3)[CH2:58][CH2:57]2)=[CH:54][CH:55]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CO[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-[Trans-4-(4-trifluoromethylsulfanyl-phenylamino)-cyclohexyloxy]-acetic acid (18 mg, 0.05 mmol, prepared in accordance with Example 30) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol) were dissolved in dry tetrahydrofuran (2 mL) and stirred at room temperature for 10 min. 1-(4-Trifluormethyl-phenyl)-piperazine (12 mg, 0.05 mmol) and diisopropylethylamine (18 μL, 0.10 mmol) were then added, and the solution was stirred at room temperature for 1.5 hr. Aluminium oxide was then added (1 spatula). Afterward, the mixture was diluted with diethylether (10 mL) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a solid (16 mg, 57% yield). The structure was confirmed using Protocol I-B. Calculated mass=562; observed mass=562; HPLC retention time=6.03 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O-].[Na+].[C:4]([N:6]=[C:7]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:9][CH3:10])#[N:5]>CO>[NH2:5][C:4]1[N:6]=[C:7]([CH2:8][CH2:9][CH3:10])[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCC(=NC#N)NCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(N)c(C(=O)OC)[nH]1
Temperature: 13 °C
Yield: 37.6 %

Procedure:
To stirred methanol at -2° C. was added sodium methoxide (108 g, 2.0 mol) in portions over a period of 40 minutes To this clear solution at -3° C. was added a solution of methyl N (N'-cyanobutyrimidoyl)glycinate (Example 3, 344 g, 1.9 mol) in methanol (600 mL) over a period of 30 minutes. The resulting orange solution was allowed to warm to 13° C. over a period of 1 hour, then refluxed for 1 hour. The dark solution was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (4×1 L) and the combined organic layers washed with a saturated aqueous solution of sodium chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate at -10° C. to afford 131 g (38% yield) of methyl 4-amino-2-propylimidazol-5-carboxylate, mp 133°-136° C. MS (DEI) 184 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][CH2:39][CH:40]1[O:44][C:43](=[O:45])[CH:42]=[C:41]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>O1CCCC1>[OH:36][CH2:37][CH2:38][CH2:39][CH:40]1[O:44][C:43](=[O:45])[CH:42]=[C:41]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)[Si](OCCCC1OC(=O)C=C1c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C=C(c2ccccc2)C(CCCO)O1
Reaction time: 3 h
Yield: 71.7 %

Procedure:
1M Solution of tetrabutylammonium fluoride in tetrahydrofuran (0.736 ml) was added to a solution of 5-[3-(t-butyldiphenylsilyloxy)propyl]-4-phenyl-2(5H)-furanone (280 mg) in tetrahydrofuran (3 ml) and the resulting mixture was stirred at same temperature for 3 hours. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine successively, dried over magnesium sulfate, and evaporated in vacuo to give 5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (96 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][C:3]=1[Cl:24].[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[Cl:24][C:3]1[CH:4]=[C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])[CH:6]=[CH:7][C:2]=1[C:27]1[CH:28]=[CH:29][O:25][CH:26]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccoc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccoc2)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromo-3-chlorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:4][CH2:3][CH2:2][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: FCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1cccc(OCCF)c1
Temperature: 25 °C

Procedure:
Combine 1-bromo-2-fluoroethane (4.575 g; 36.0 mmol), 3-hydroxybenzaldehyde (4.103 gm; 33.60 mmol), and K2CO3 (7.05 gm; 51.0 mmol) in 2-butanone (100 mL) and reflux. After 18 hour cool the mixture to ambient temperature, concentrate, and partition between 100 mL of water and 100 mL of dichloromethane. Separate the layers and extract the aqueous layer with dichloromethane (2×75 mL). Combine the organic layers and wash sequentially with brine (2×150 mL), 1 M NaOH (2×100 mL), NaHCO3 (saturated, 100 mL), and brine (150 mL), dried (MgSO4), concentrate, and chromatograph on silica gel (0–25% diethyl ether in hexanes) to give the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].N1C=CC=CC=1.[CH:17]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18]1>C(OC)(C)(C)C.O.Cl>[CH:17]1([C:21]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1ccccc1S
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: O=C(O)c1ccccc1SC(=O)C1CCC1
Yield: 96.4 %

Procedure:
Thiosalicylic acid (6.17 g, 40 mmol) was suspended in tert-butylmethyl ether (100 ml) at room temperature. While stirring under ice cooling, pyridine (7.91 g, 100 mmol) and then cyclobutanecarbonyl chloride (5.00 g, 42 mmol) were dropwise added to the suspension. After the reaction mixture was stirred for 2 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (100 ml×3) with tert-butylmethyl ether-tetrahydrofuran (3:1, v/v). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give the title compound (9.11 g, 96%). A part (1.0 g) of the compound was recrystallized from ethyl acetate-hexane to give colorless crystals (0.81 g).