Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[BrH:10].BrBr>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:10][CH2:8][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CC(=O)c1cnn(C)c1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-methyl-1H-pyrazol-4-yl)ethanone (0.602 g, 4.85 mmol) in chloroform (20 mL) and of 33% HBr in acetic acid (3.92 mg, 0.05 mmol) was added dropwise a chloroform solution containing Br2 (0.262 mL, 5.09 mmol) via an addition funnel. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude solid was triturated in ethyl acetate, filtered, washed and dried in vacuo. The free base was obtained by triturating the product in 5% NaHCO3 for 2 h. The solid that formed were collected by filtration, washed with water and isopropyl alcohol and then dried in vacuo. Isolation gave 874 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]([CH:13]([CH3:15])[CH3:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O.O1CCOCC1>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]([CH:13]([CH3:14])[CH3:15])[NH:12][S:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1)(=[O:34])=[O:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of D-valine benzyl ester hydrochloride (2.4 grams, 10 mmol) and triethylamine (2.5 grams, 3.5 mL, 25 mmol) in water (50 mL) and 1,4-dioxane (50 mL) is added 4-methoxybenzenesulfonyl chloride (2.3 grams, 11 mmol). The mixture was stirred at room temperature for 1 hour and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed successively with dilute hydrochloric acid solution, water and brine. The organic solution was dried over magnesium sulfate and concentrated to leave N-(4-methoxybenzenesulfonyl)-D-valine benzyl ester as a white solid, 3.6 grams (97%); m.p. 92-94° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.O.[CH3:16][N:17]1CCCC1=O>>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[N:17]
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Yield: 40 %

Procedure:
A solution of 3-bromo-9H-carbazole (23.08 g, 0.094 mol) and cuprous cyanide (9.33 g, 0.103 mol) in N-methyl-pyrrolidone (300 ml) was heated at 200° C. for 5 h. The cooled reaction mixture was poured on to water (600 ml) and the precipitate was filtered off and washed with ethyl acetate (3×50 ml). The filtrate was extracted with ethyl acetate (3×250 ml) and the combined ethyl acetate extracts were washed with water (150 ml), brine (150 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptanes and recrystallised from acetonitrile (70 ml) affording 7.16 g (40%) of 3-cyano-9H-carbazole as a solid.
Reaction SMILES: [Mg].CO[CH:4]([O:12]C)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=2)([OH:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Starting with 0.74 g of magnesium, 6.42 g of 4-bromobenzaldehyde dimethyl acetal and 50 ml of tetrahydrofuran, a Grignard reagent was prepared in a conventional manner. Then it was ice-cooled and 10 ml of a solution of 5.67 ml of 1-benzyl-4-piperidone in tetrahydrofuran was dropped thereinto in such a manner that the bulk temperature did not exceed 20° C. After stirring at room temperature for 1 hour, 50 ml of a saturated aqueous solution of ammonium chloride was added thereto and then 1 N-hydrochloric acid was added until the pH value reached about 2. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure and the tetrahydrofuran was distilled off. To the residue were added anhydrous potassium carbonate and ethyl acetate and the resulting mixture was stirred for 15 minutes. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.27 g of the title compound as a slightly yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl.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>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: OCCN1CCN(c2cncc(Cl)n2)CC1
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: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: OCCN1CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2 mmol, 1 eq) and 2-(4-(6-chloropyrazin-2-yl)piperazin-1-yl)ethanol (57) (49.5 mg, 0.2 mmol, 1 eq) in DME (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.4 mmol, 2 eq) followed by addition of Pd(PPh3)4 (1.0 mg, 0.04 mmol) and degassing and purging under argon for additional min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 3% MeOH/CHCl3 to obtain pale yellow solid compound 2-(4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-1-yl)ethanol 126 in 15 mg quantity. The compound 126 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 8.96 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.36 (m, J=289.99, 1H), 6.61 (m, J=301.8, 1H), 3.75 (m, J=5.0, 6H), 2.69 (m, J=4.84, 6H); MS m/z 324.9 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH2:11]([N:13]([CH2:57][CH3:58])[CH2:14][CH2:15][N:16]([C:31]([CH2:33][N:34]1[CH:39]=[C:38]([CH2:40][C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)[C:37](=[O:47])[N:36]=[C:35]1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)=[O:32])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:12]>CC(O)C>[OH:8][C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])=[O:7].[CH2:57]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][N:16]([C:31]([CH2:33][N:34]1[CH:39]=[C:38]([CH2:40][C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)[C:37](=[O:47])[N:36]=[C:35]1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)=[O:32])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:58]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCN(CC)CCN(Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)Cn1cc(Cc2cnn(C)c2)c(=O)nc1SCc1ccc(F)cc1
Solvent: CC(C)O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
A solution of L-tartaric acid (0.75 g, 1 equiv) in 2-propanol (12 ml) was added to a solution of the free base from Example 6 (3.43 g, 1 equiv) in 2-propanol (25 ml) with stirring. The mixture was evaporated to ca. one third volume, diluted with ether, then the solid was filtered off, washed with ether and dried in vacuo; yield 3.87 g. 1H-NMR (DMSO, ca. 60:40 rotamer mixture) δ 0.9–1.1 (6H,m), 2.5–2.8 (4H,m), 3.2–3.4 (6H,m), 3.76 (3H,s), 4.20 (2H,s), 4.39/4.43 (2H,2x s), 4.60/4.67 (2H,2x s), 4.92/5.08 (2H,2x s), 7.1–7.7 (15H,m); MS (APCI+) found (M+1)=687/689; C37H40ClFN6O2S requires 686/688.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and propanoyl chloride as starting materials in 31% yield. LCMS for C28H32ClN6O2 (M+H)+: m/z=519.2.
Reaction SMILES: [C:1]1([P:7](=[O:12])([CH:10]=[CH2:11])[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([N:20]1[CH2:11][CH2:10][P:7](=[O:12])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: C=CP(=O)(C=C)c1ccccc1
Solvent: O
Product: O=P1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Phenyl(divinyl)phosphine oxide (1.47 g, 8.25 mmol) and benzylamine (901 μL, 8.25 mmol) were combined in water (20 mL) and stirred at 90° C. for 1 h. A second portion of benzylamine (901 mL, 8.25 mmol) was added, and the reaction was stirred at 90° C. for an additional 1 h. The solution was cooled and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated. The crude residue was purified by flash chromatography (0-10% MeOH/CH2Cl2) to afford the desired product as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.79-7.73 (m, 2H), 7.55-7.46 (m, 3H), 7.35-7.30 (m, 4H), 7.27-7.23 (m, 1H), 3.63 (m, 2H), 3.04-2.89 (m, 4H), 2.21-2.14 (m, 2H), 2.08-1.99 (m, 2H). MS: cal'd 286 (MH+), exp 286 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6].[OH-].[K+].Cl.Cl[CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>CS(C)=O.C(Cl)Cl.O>[NH:17]1[CH:18]=[CH:19][N:20]=[C:16]1[CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(I)c(O)c1
Reactant: ClCc1ncc[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(I)c(OCc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a flask, were added 3-hydroxy-4-iodobenzaldehyde (200 mg, 0.806 mmol), KOH (43.0 mg, 0.766 mmol) and DMSO (2 ml). The mixture was stirred at rt for 2 h. 2-(chloromethyl)-1H-imidazole hydrochloride (105.4 mg, 0.689 mmol) in 1 ml of DMSO was added to this mixture and stirred overnight. The mixture was diluted with DCM and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated to afford crude product, which was purified on silica gel (MeOH/DCM=8/92) to afford desire product (97.4 mg, 0.297 mmol, 36.8% yield).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:35]([CH:20]1[C:19](=[O:24])[CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[O:22][C:21]1=[O:23])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.7 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (55 mg, 0.174 mmol, described below) in benzene (1.9 ml), under an atmosphere of argon. Benzyl bromide (21 ul, 0.174 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (9.0 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:32])[C:26]=3[N:25]([CH:33]([CH3:36])[CH2:34][OH:35])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1>>[F:32][C:31]1[C:26]2[N:25]([CH:33]([CH3:36])[CH2:34][OH:35])[CH:24]=[C:23]([C:21]([C:17]3[CH:16]=[C:15]([NH:14][C:9](=[O:11])[CH2:8][N:6]4[CH:7]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=[N:5]4)[CH:20]=[N:19][CH:18]=3)=[O:22])[C:27]=2[CH:28]=[N:29][CH:30]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cn1cc(C(F)(F)F)cn1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using [4-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Preparation 74) and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc. LCMS (5 minute run) Rt=2.85 minutes MS m/z 491 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[CH3:11][NH:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:13]/[NH:12][CH3:11]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: CNN
Product: CN/N=C/c1c(Br)cncc1Br
Temperature: 100 °C
Yield: 96.4 %

Procedure:
In analogy to GP 1, 2.15 g of 3,5-dibromo-pyridine-4-carbaldehyde (8.12 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 36 mL 1-propyl alkohol, treated with 0.65 mL N-methyl hydrazine (12.17 mmol, 1.5 eq.) and heated to 100° C. for 30 min (employing a Biotage Initiator® microwave oven in batch mode). The reaction mixture was concentrated, the residue partitioned between water and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 2.29 g of the desired product (7.82 mmol, 96% yield), which was used in the subsequent cyclization without further purification steps.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Br)=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2].[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:21]2[C:22]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)c(Br)s1
Reactant: OB(O)c1cccc2ccccc12
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: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)c(-c2cccc3ccccc23)s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-methyl-thiazole-2-carboxylic acid ethyl ester (60 mg, 0.24 mmol) in 1,4-dioxane (2 ml) is added 1-naphthaleneboronic acid (50 mg, 0.29 mmol), cesium carbonate (187 mg, 0.58 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol). The reaction mixture is stirred in a sealed tube at 110° C. overnight. After cooling to rt, the mixture is purified by PTLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=2)=[CH:6][N:7]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:22])[CH:9]=2)=[CH:6][N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCNC(=O)c1nc(-c2cccc(CO)c2)cnc1N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Reaction time: 7 h
Yield: 76.6 %

Procedure:
To a solution of 3-amino-N-ethyl-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carboxamide (566.1 mg, 1.0 eq) in dichloromethane (20 mL) were added carbon tetrabromide (749.8 mg, 1.1 eq), triphenylphosphine (600 mg, 1.1 eq) at ambient temperature. After being stirred for 7 h, the reaction mixture was partitioned with dichloromethane (10 mL×3), washed with brine. The organic layer was combined and dried over anhydrous magnesium sulfate. Filteration and concentration in vacuo gave a crude product. Purification by column chromatography afforded the 3-amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (534 mg, 77% yield): 1H NMR (400 MHz, DMSO-d6): δ 8.87 (m, 2H), 8.84 (s, 2H), 8.23 (m, 1H), 7.61 (bs, 1H), 7.45 (m, 1H), 4.77 (s, 2H), 3.38 (m, 2H), 1.16 (m, 3H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.C(O)CCC>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 100 °C
Yield: 52.8 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-iodobenzoic acid (248 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). After heated for a specified duration, the reaction was allowed to reach room temperature. Water and diluted HCl (10%) was added until ˜pH 3. Diethyl ether (2 mL) was added and the organic layer was analyzed by tlc. The reaction mixture was further extracted by diethyl ether (4×10 mL) and the combined organic phase was washed with brine and dried over Na2SO4. The solvent was rotary evaporated and the yellowish-brown residue was purified by column chromatography using a solvent mixture (diethyl ether/ethyl acetate=1/1, Rf=0.3) to afford 2-(N-benzyl)aminobenzoic acid (161 mg, 71% isolated yield) as light yellow solid. For aryl bromide substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-bromobenzoic acid (201 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (120 mg, 53% isolated yield) as light yellow solid. For aryl chloride substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and indicated >95% purity. See Chang, M. R.; Takeuchi, Y.; Hashigaki, K.; Yamato, M. Heterocycles 1992, 33, 147–152. Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.; Palermo, S.; Webster, W. J. Org. Chem. 1969, 34, 887–892.
Reaction SMILES: [OH-].[Na+].[CH:3](/[CH2:11][C:12]([OH:14])=[O:13])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Zn+2:16].[Cl-]>O>[CH:3](/[CH2:11][C:12]([O-:14])=[O:13])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Zn+2:16].[CH:3](/[CH2:11][C:12]([O-:14])=[O:13])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)C/C=C/c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C/C=C/c1ccccc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 77.4 %

Procedure:
A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of trans-styrylacetic acid (8.1 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 7.5 g (77%) zinc trans-styrylacetate as a fine white powder. IR absorption bands: 1526, 1436 and 1385 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[N+:32]([O-])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.NN>CO.[Fe](Cl)Cl>[C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[NH2:32])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2[N+](=O)[O-])cs1
Agent: Cl[Fe]Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2N)cs1
Yield: 79.6 %

Procedure:
2-[(4-{2-[(4′-Fluoro-3-nitrobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (2.0 g) obtained in Example 97-2 was dissolved in methanol (20 mL), a catalytic amount of iron chloride (III) (62 mg), activated carbon (1.0 g) and hydrazine monohydrate (580 mg) were successively added, and the mixture was heated under reflux for 3 hr. The mixture was filtered through celite, methanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.5 g).