Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc2ncccc2c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Yield: 78.9 %

Procedure:
A suspension of #213 (1.5 g, 4.55 mmol, 1 eq.) and palladium on carbon (150 mg) in ethanol (20 mL) was stirred at 50° C. under 30 psi of hydrogen overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Gradient: 40% ethyl acetate in petroleum ether) to afford #214 (1.2 g, 80%) as an oil. 1H NMR (400 MHz, CDCl3): δ 6.70 (d, 2H), 6.40 (m, 1H), 4.95 (m, 1H), 4.49 (m, 1H), 3.77 (s, 3H), 3.28 (m, 2H), 2.97 (m, 2H), 2.71 (m, 2H), 1.95 (m, 2H), 1.26 (s, 9H), HPLC (Protocol Y): m/z 357.0 [M+Na+] retention time=5.304 minutes (purity >98%). Chiral HPLC retention time: 4.64 min (purity=98%)(Column: Chiralcel OJ-H, 150×4.6 mm, 5 μm; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% over 15 minutes; Flow rate: 2.5 mL/minute.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=O.S(N)([NH2:17])(=O)=O.O>S1(CCCC1)(=O)=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)#[N:17]
Reactant: NS(N)(=O)=O
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 135 °C
Reaction time: 0.08 h

Procedure:
5-Chlorocarbonylphthalid (24.3 g, 0.124 mole) was dissolved in sulfolane (51 g). Sulfamide (13.8 g 0.144 mole) was added and the temperature was raised to 135° C. for 3 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool and water (100 g) was added. The temperature was held at 85-90° C. for 5 min and then the solution was cooled to 60° C. The crystals were filtered off and washed with water (60 g) and acetic acid (30 g). Then the title compound was dried in vacuo. Yield: 19 g, 96%. Purity: 98.2% (hplc, peak area).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]1[CH:28]=[CH:27][C:17]2[N:18]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:19](=[O:22])[N:20]([CH3:21])[C:16]=2[CH:15]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]1[CH:28]=[CH:27][C:17]2[N:18]([CH:23]3[CH2:26][CH2:25][CH2:24]3)[C:19](=[O:22])[N:20]([CH3:21])[C:16]=2[CH:15]=1.[CH:23]1([N:18]2[C:17]3[CH:27]=[CH:28][C:14]([C:3]4[C:4]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)=[N:5][N:6]([CH3:7])[C:2]=4[NH:1][C:36](=[O:38])[CH3:37])=[CH:15][C:16]=3[N:20]([CH3:21])[C:19]2=[O:22])[CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)Cl
Agent: Cn1nc(-c2ccccc2)c(-c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(-c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c(-c2ccccc2)nn1C
Reaction time: 1 h

Procedure:
5-(5-Amino-1-methyl-3-phenyl-1H-pyrazol-4-yl)-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one is prepared according to the methods described in Example 336. 5-(5-Amino-1-methyl-3-phenyl-1H-pyrazol-4-yl)-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (0.05 g) is diluted with chloroform (0.5 mL) and is treated with triethyl amine (0.04 mL) and acetyl chloride (0.02 mL). The reaction is allowed to stir for 1 hour then is diluted with saturated sodium bicarbonate and extracted with ethyl acetate. After concentration of the organic layer the product is purified by silica gel chromatography to give N-[4-(1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-methyl-5-phenyl-2H-pyrazol-3-yl]-acetamide. Similar reaction conditions utilizing the appropriate isocyanate, chloroformate or sulfonyl halide can be used to prepare ureas, carbamates and sulfonamides.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[NH:15][C:16]([C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=1)=O>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[NH:15][CH2:16][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=1
Reactant: Cc1cc(C(=O)Nc2cc(O)ccc2Cl)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CNc2cc(O)ccc2Cl)n(C)n1
Yield: 71.5 %

Procedure:
In the same manner as in Reference Example 23 and using 3-amino-4-chlorophenol (920 mg, 6.4 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1170 mg, 7.4 mmol) and N,N-dimethylacetamide (13 mL) as starting materials, N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1190 mg, 4.5 mmol) was obtained. Using lithium aluminum hydride (1060 mg, 22 mmol), N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1190 mg, 4.5 mmol) and tetrahydrofuran (40 mL) as starting materials, the title compound (810 mg, 72%) was obtained as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:18]=[CH:17][NH:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:16]2[CH:17]=[CH:18][C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:9][CH:10]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc(Oc2ccc(-c3ccn(-c4ccc(Cl)cc4)n3)cc2)cc1

Procedure:
By the same procedure as Example 67 Part C, 3-[4-(4-methoxy-phenoxy)-phenyl]-1H-pyrazole and 4-chlorophenylboronic acid were converted to the title compound. MS m/z: ESI+ 377.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8].C(O)=O.[Cl-].[Na+]>O>[Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=C(Cl)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=C(Cl)CN(CC=O)C(=O)OCC

Procedure:
151 g (0.6 mol) of ethyl N-(2-chloroallyl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux for 3 hours with 60 ml of formic acid in 1.2 1 of water. The mixture is saturated with sodium chloride, and the aqueous phase is separated off and extracted twice with 300 ml of methylene chloride each time. The organic phases are washed with saturated sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]1(B(O)O)C=CC=CC=1.C([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[C:32]3[O:34][CH2:35][O:36][C:31]3=[CH:30][C:29]=1[Cl:37])[C:22]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:21]2[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)C1C=CC=CC=1>>[Cl:37][C:29]1[CH:30]=[C:31]2[O:36][CH2:35][O:34][C:32]2=[CH:33][C:28]=1[CH2:27][N:23]1[C:24]2[C:20](=[CH:19][C:18]([OH:17])=[CH:26][CH:25]=2)[C:21]([C:43]2[CH:44]=[CH:45][C:46]([CH3:1])=[CH:47][CH:48]=2)=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1c(-c2ccc(C)cc2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2

Procedure:
Following the procedure of Example 1(a)-1(c) except substituting 4-methylphenylboronic acid for phenylboronic acid in step (b), and the procedure of Example 9(a), except substituting ethyl 5-benzyloxy-1-(2-chloro-4,5-methylenedioxybenzyl)-3-(4-methylphenyl)indole-2-carboxylate for ethyl 5-benzyloxy-1-(2-chloro-4,5-methylenedioxybenzyl)-3-phenylindole-2-carboxylate, the title compound was prepared as a white solid (0.304 g, 81%). 1HNMR (400 MHz, CDCl3) δ 7.37 (m, 2H), 7.24 (s, 1H), 7.15 (d, 1H), 6.97 (m, 3H), 6.00 (s, 1H), 5.89 (s, 2H), 5.71 (s, 2H), 4.56 (s, 1H), 4.13 (q, 2H), 2.43 (s, 3H), 1.03 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:28])[N:12](CC4C=CC(OC)=C(OC)C=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:28])[NH:12][CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1NCCc2nc(-c3ccc(Cl)cc3)sc21
Yield: 70.6 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(3,4-dimethoxy-benzyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (376 mg, 0.91 mmol) in toluene (5.0 mL) and treat with para-toluene sulfonic acid (176 mg, 0.92 mmol). Stir the solution at reflux for 2 d, then concentrate and purify the crude material by flash chromatography, using 5% MeOH (2N NH3)/CH2Cl2 as eluent, to give the title compound as a white solid (170 mg, 70%). MS (ES+) 265.0 (M+1)+. 1H NMR (CDCl3): δ 8.02 (d, 2H, J=8.8 Hz), 7.94 (s, 1H), 7.60 (d, 2H, J=8.4 Hz), 3.52 (dt, 2H, J=7.1, 2.5 Hz), 3.04 (t, 2H, J=7.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1.[CH3:24][S-:25].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([S:25][CH3:24])[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1
Reactant: Nc1nc(Cl)nc(OCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(N)nc(OCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a 25 mL recovery flask was added 2-(4-Amino-6-chloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide (33 mg, 0.0950 mmol, 1.0 eq.) and CH2Cl2 (7 mL). Sodium thiomethoxide (20 mg, 0.285 mmol, 3.0 eq.) was added and the resulting solution was stirred at room temperature for 1 h. The reaction was diluted with CH2Cl2 (50 mL) and washed with H2O (1×50 mL) and brine (1×50 mL). The combined aqueous phases were extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown solid. The crude material was purified via preparative HPLC to give 2-(4-Amino-6-methylsulfanyl-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (6.2 mg, 24% yield). LC/MSD (HP Series 1100 MSD) Expected MW: 359.07, Observed M+H, 360.1, Retention time: 1.40. Analytical LC: 98%, Retention time: 4.87 (11 minute run). 1H-NMR, CH3OH-d4, Varian 400 MHz δ 8.01 (s, 1H), 7.81 (d, 1H), 7.51 (t, 1H), 7.40 (d, 1H), 4.94 (s, 2H), 2.46 (3H) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:27][CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:29][CH:30]=3)[CH:16]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2-c1ccc(OCCn2ccnc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2-c1ccc(OCCn2ccnc2)cc1

Procedure:
0.5 g of 5-(4-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine is hydrogenated for 22 h in a hydrogen atmosphere at normal pressure and about 50° C. in 15 ml of THF in the presence of 0.1 g of 5% palladium/carbon. After filtration through Celite and crystallization by addition of ether, 5-(4-hydroxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 210°-212° C. is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:23].[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:33](O)=[O:34])[C:27]=2[CH:26]=[CH:25]1.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[C:11]1([CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]2[CH:7]=[CH:6][C:5](=[O:23])[N:4]([CH2:3][CH2:2][NH:1][C:33]([C:28]3[C:27]4[CH:26]=[CH:25][NH:24][C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:34])[CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc2[nH]ccc12
Yield: 59 %

Procedure:
To a solution of 1-(2-aminoethyl)-5-(diphenylmethyl)-2(1H)-pyridinone (75.0 mg), a mixture of indole-4-carboxylic acid (39.7 mg), HOBt (36.6 mg) and DMF (3.0 mL) was added WSCD. HCl (52.0 mg) at ambient temperature and the mixture was stirred at the same temperature for 18 hours. The resulting mixture was diluted with water (10.0 mL) and extracted with EtOAc (15 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:MeOH=90:10) to afford N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-1H-indole-4-carboxamide (65 mg) as a yellow amorphous powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:14]([O:18]C)(OC)[CH3:15])[CH:3]=1.O=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(=O)OCC>[F:13][S:8]([F:10])([F:11])([F:12])([F:9])[C:6]1[CH:5]=[C:4]([C:14](=[O:18])[CH3:15])[CH:3]=[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=1
Reactant: C1CCNC1
Reactant: COC(C)(OC)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1cc(N2CCCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-3-(1,1-dimethoxyethyl)-5-(pentafluorosulfanyl)benzene (200 mg) was initially charged at RT in DME (30 ml) under argon. Two drops of water were added to the DME. A strong argon stream was used to displace the oxygen from the solution for 45 min. Then pyrrolidine (45 μl) was added dropwise through a septum, followed by (+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (5 mg), sodium tert-butoxide (73 mg) and palladium(II) acetate (1.2 mg). The reaction mixture was heated to 85° C. for 3 h. Then EA was added to the reaction mixture and, after removing the EA phase, the aqueous phase was extracted three times with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ACN/water and adjusted to pH 2 with 1N hydrochloric acid. After standing for 30 min, the mixture was concentrated and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 55 mg of the desired compound were obtained.
Reaction SMILES: [ClH:1].[CH:2]([O:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][S:18][CH3:19])[NH:8]C(OC(C)(C)C)=O)([CH3:4])[CH3:3]>CCOC(C)=O>[ClH:1].[CH:2]([O:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][S:18][CH3:19])[NH2:8])([CH3:4])[CH3:3]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CSCC[C@H](N)C(=O)OC(C)C
Temperature: -20 °C

Procedure:
HCl gas was bubbled into a solution of N-(t-Butoxycarbonyl methionine isopropyl ester (20.5 g, 0.07 mol) in EtOAc (200 mL) with stirring and cooling to -20° C. for 10 min. The flask was stoppered and stirred at -20° C. for 1 h, argon was bubbled into the solution to remove excess HCl, then the solution was concentrated to dryness to give a white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:12])[C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:12][C:5]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[S:3][CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1c(Br)csc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)Cc1c(Br)csc1-c1ccc(C(=O)O)cc1
Yield: 69.7 %

Procedure:
Pd(PPh3)4 (0.046 g, 0.4 mmol was added to a degassed solution of methyl (2,4-dibromothien-3-yl)acetate (2.51 g, 8 mmol) and 4-carboxybenzeneboronic acid (1.32 g, 8 mmol) in Na2CO3(40 mL, 0.4 M, 16 mmol) and CH3CN (40 mL). The mixture was heated to reflux overnight under argon for 16 h. The solution was filtered hot and the filtrate was concentrated to about half volume. The solution was extracted with CH2Cl2. The aqueous phase was acidified with concentrated HCl and the resulting solid was collected by vacuum filtration and washed with H2O to yield 4-(4-bromo-3-methoxycarbonylmethyl-thiophen-2-yl)-benzoic acid (1.98 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Oc1ccc2sc(Nc3ccc(Br)cc3)nc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3sc(Nc4ccc(Br)cc4)nc3c2)ccn1

Procedure:
The mixture containing 2-[(4-bromophenyl)amino]benzothiazol-5-ol (1 eq), Potassiumbis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=455
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](=[O:16])[C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[OH:2]
Reactant: COc1cccc(OC)c1C
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccccc2F)c(O)c1C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2,6-dimethoxytoluene (20.0 g) and o-fluorobenzoyl chloride (19.8 g) are dissolved in 250 ml of dichloroethane and chilled to 5° C. AlCl3 is added portiowise and when the addition is complete the reaction mixture is allowed to warm to room temperature over 30 minutes, then refluxed 30 minutes. It is then poured into 5% HCl and allowed to stand undisturbed 18 hours. Extraction with ether, followed by drying and concentration, gives crystalline material that is washed with hexane to give 2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone, mp 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10](O)=[O:11].[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:27]=1[C:21]1([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:20][CH:19]2[CH2:28][C:29]([O:31]CC)=[O:30]>>[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:27]=1[C:21]1([CH2:22][CH2:23][N:24]([C:10](=[O:11])[CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:25][CH2:26]1)[CH2:20][CH:19]2[CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)CCc1ccccc1Cl
Product: O=C(O)CC1CC2(CCN(C(=O)CCc3ccccc3Cl)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-chlorophenyl)propanoic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate followed by a procedure analogous to that in Example 2. LC-MS Method 1 tR=1.87, min, m/z=446
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccncc2)cc1-c1nc(-c2ccccn2)no1
Yield: 10 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), 4-pyridylboronic acid (48.8 mg, 0.4 mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105° C. Standard work up, afforded 6.6 mg (10%) of 3-(2-pyridyl)-5-[2-methoxy-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[CH:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.