Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:8]([CH:9]=O)=[C:7]([CH3:11])[O:6][N:5]=1.Cl.[NH2:13][CH2:14][C:15]1[N:16]=[C:17]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[O:22])[S:18][CH:19]=1>CO>[CH3:3][C:4]1[C:8]([CH2:9][NH:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[O:22])[S:18][CH:19]=2)=[C:7]([CH3:11])[O:6][N:5]=1
Reactant: NCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reactant: Cc1noc(C)c1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1CNCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 6 h

Procedure:
NaBH4 (35 mg, 1 mmol) was added in portions to a MeOH (5 mL) solution of 3,5-dimethylisoxazole-4-carbaldehyde (65 mg, 0.5 mmol) and 1-(4-(aminomethyl) thiazol-2-yl)-3-(3-fluorobenzyl)urea hydrochloride (157 mg, 0.5 mmol) at 0 C. The mixture was stirred for 6 hours then quenched with dilute HCl solution. Basic aqueous work-up with CH2Cl2 followed by flash chromatography afforded Intermediate 61: 1-(4-(((3,5-dimethylisoxazol-4-yl)methylamino)methyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea. 1H NMR (400 MHz, CDCl3): δ 8.2 (1H, br), 7.27 (m, 1H), 6.92 (m, 3H), 6.60 (s, 1H), 4.37 (d, 2H), 3.66 (s, 2H), 3.33 (s, 2H), 2.22 (s, 3H), 2.11 (s, 3H). MS (ES+): M/Z 390 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2)=[O:12]
Reactant: O=C(O)c1ccc2c(c1)CCN2
Reactant: CNC
Product: CN(C)C(=O)c1ccc2c(c1)CCN2

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using indoline-5-carboxylic acid and dimethylamine; MS: 191.1 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.BrBr.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.CCCCC>[NH2:20][C:18]1[S:19][C:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(N)=S
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
To a solution of compound tert-butyl 4-oxopiperidine-1-carboxylate (24.0 g, 120.6 mmol) in dry CHCl3 (500 mL) at 0-5° C., was slowly added a solution of Br2 in CHCl3 (100 mL) over 1.5 hours. The reaction mixture was warmed to RT and stirred for 3 hours. The reaction mixture was concentrated to obtain solid, which was thoroughly washed with Et2O. The resulting intermediate tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate was used immediately in the next reaction. Accordingly, this intermediate (20 g, 72 mmol) was suspended in pentane, filtered, washed with pentane, and the solid so obtained dried in vacuo and dissolved in EtOH (100 mL). Thiourea (5.46 g, 72.0 mmol) was added and the reaction mixture heated for 4 hours at 70-75° C. The reaction mixture was concentrated to yield a residue, which was treated with aq. Na2CO3 solution, adjusted to pH=10, extracted with EtOAc, washed with water, washed with brine solution, dried (Na2SO4), filtered, and concentrated. The residue was washed with pentane to obtain tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (8.7 g, 28% yield)
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH:22]([CH3:24])[CH3:23])=[CH:11][C:10]=1[CH:25]([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH:25]([C:10]1[CH:11]=[C:12]([CH:22]([CH3:24])[CH3:23])[CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:9]=1[OH:8])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(C)c1cc(-c2ccc(F)cc2)c(OCc2ccccc2)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(O)c(C(C)C)c1
Yield: 92.9 %

Procedure:
4 g of 10% Pd on carbon are added to a solution of 49.3 g (0.136 mol) of the benzyl ether from step 4 in 1 l of ethyl acetate and 100 ml of glacial acetic acid and the mixture is shaken in a hydrogen atmosphere (vigorous absorption of H2) for 20 minutes. The catalyst is filtered off, the filtrate is concentrated, the residue is taken up several times in toluene and the solution is in each case concentrated in vacuo. 34.4 g of the title compound are obtained as a colorless oil, b.p. 115° C./0.1 torr.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][OH:11])[C:7]([CH:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:6][CH:5]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:19])[CH3:18]>>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][C:17](=[O:19])[CH3:18])[C:7]([CH:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCO
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1C=CN(C)C

Procedure:
2,26 g. (0.01 mole) of 5-nitro-1-(2-hydroxyethyl)-2-(2-dimethylaminovinyl)-imidazole and 0.79 g. (0.01 mole) of acetyl chloride were reacted as described in Example 11. After pouring the reaction mixture on ice water, it was extracted with chloroform and the chloroform solution evaporated. The crude red oil exhibited the characteristic UV maxima in methanol:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>O>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[C@H:13]([CH3:17])[CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1c1ncccc1C(F)(F)F
Temperature: 250 °C

Procedure:
A mixture of the piperazine from step (a) above (80 mg, 0.25 mmol), 2-chloro-3-trifluoromethyl-pyridine (54 mg, 0.3 mmol, Aldrich) and NAN-diisopropylethylamine (0.5 mL, 2.9 mmol, Aldrich) was heated in a microwave synthesizer for 120 min at 250° C. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 35% EtOAc/hexane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[OH:21][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
A solution of 4-bromobenzoic acid (4.02 g, 20.0 mmol) in tetrahydrofuran (100 mL) was purged with argon for 5 min. n-Butyllithium (16.0 mL of 2.5 M in hexanes, 40 mmol) was added dropwise at −78° C., resulting in a yellow thick syrup. The mixture was stirred at −78° C. for 30 min. Cyclopentanone (3.89 mL, 44.0 mmol) was added dropwise. The reaction was quenched immediately with saturated NH4Cl and allowed to warm to room temperature. The mixture was acidified with 1 N HCl to pH ˜3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue was suspended in hexanes, filtered, and the solid washed with additional hexanes. The solid was re-suspended in dichloromethane followed by hexanes. The resulting precipitate was filtered, washed with hexane and air dried to yield 4-(1-hydroxycyclopentyl)benzoic acid (1.25 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.93 (s, 1H), 1.93-1.71 (m, 8H).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:18]([C:21]1[CH:22]=[C:23]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:30]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])=[C:19]=[O:20]>C(Cl)Cl>[C:3]1([CH2:2][O:9][NH:10][C:19]([NH:18][C:21]2[CH:22]=[C:23]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])[CH2:30]3)[CH:24]=[CH:25][C:26]=2[O:27][CH3:28])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N=C=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1NC(=O)NOCc1ccccc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
1.68 g of O-benzyl-hydroxylamine hydrochloride suspended in 30 ml of methylene chloride were added to 1.52 ml of triethylamine and then 3.2 g of the product of Step A in 10 ml of methylene chloride were added dropwise with stirring for 2 hours, followed by evaporating to dryness under reduced pressure. The residue was chromatographed on silica, (eluent: methylene chloride-ethyl acetate 96-4) to obtain 3.75 g of the expected product melting at 134° C. after crystallization from a 1-1 mixture of methylene chloride and isopropyl ether.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)CCC>[Br:12][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)Cn1cccc(Br)c1=O
Solvent: O
Solvent: CCCCO
Product: NNC(=O)Cn1cccc(Br)c1=O
Yield: 62 %

Procedure:
As described for example 112a, (3-bromo-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at reflux for 16 h. The precipitate was filtered and triturated with hot methanol to afford the title compound as an off-white solid (yield: 62%). MS: m/e=244.2/246.2 [M−H]−.
Reaction SMILES: [OH-].[Na+].[C:3]1(CC(=O)C(O)=O)C=CC=CC=1.CI.Cl.[O:18]=[C:19]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]>CN(C)C=O>[O:18]=[C:19]([C:23]([CH3:3])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 59 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) and 30 ml of dimethylformamide were added to 1.64 g (10.0 mmoles) of phenylpyruvic acid to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellowish white solid. Analysis of its NMR spectrum showed that 2-oxo-3-phenylbutanoic acid formed in a yield of 59%, and 2-oxo-3-methyl-3-phenylbutanoic acid, in a yield of 21%. The NMR spectrum of the former is shown in Example 1, and that of the latter is shown in Example 73.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: O
Solvent: COCCOC
Product: Cc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 78.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.054 g (79%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethylphenylacetic acid (150.0 g), n-octanol (130.0 g), p-toluenesulphonic acid (9.5 g) and benzene (800 ml) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (3×500 ml) and with water (3×500 ml). After drying over magnesium sulphate, the solvent is evaporated in vacuo. The residue is distilled (95°-97°/2.10-2Torr) to yield n-octyl 3-trifluoromethylphenylacetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][Zn+])=[CH:30][CH:29]=1.O1CCCC1>CCOC(C)=O.[Cl-].[NH4+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][C:2]2[CH:3]=[C:4]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:30][CH:29]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Br)n1
Reactant: Clc1ccc(C[Zn+])cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Bis(tri-t-butylphosphine)palladium(0) (4.38 mg, 0.00857 mmol) and 4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (0.075 g, 0.17 mmol) were combined in a dry round bottomed flask fitted with a stirbar and sealed with a septum. The flask was evacuated/refilled with nitrogen three times then a solution of 4-chlorobenzylzinc chloride in tetrahydrofuran (0.50M, 0.720 mL, 0.360 mmol) was added dropwise via a syringe. A nitrogen line was attached and the reaction was stirred at rt for 30 minutes, then at 60° C. for ˜2 hours. The reaction was cooled to rt, diluted with EtOAc and saturated ammonium chloride solution, then the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice more with EtOAc. The organics were combined, washed with bicarbonate solution, then brine, then dried over sodium sulfate. The mixture was filtered then evaporated in vacuo and the residue was purified by column chromatography on silica, elution 100% hexane to 100% EtOAc to afford the title compound as a light yellow oil. Yield 63 mg (76% yield). LCMS: (FA) ES+, 483, 485.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>CO.[Pd]>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=[CH:15][N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C=Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ethyl 3-[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]propenoate (579 mg) was dissolved in methanol (20 mL), 10% palladium on carbon (60 mg) was added to the solution, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Oc1ccc2ccccc2c1

Procedure:
A well stirred mixture of 37.2 g. (0.15 mole) of o-iodobenzoic acid, 21.6 g. (0.15 mole) of β-naphthol and 20.6 g. (0.15 mole) of potassium carbonate in 300 ml. of pyridine is heated at 50° C. for 1 hour. Cuprous chloride (5 g.) is added and the mixture is refluxed for about 18 hours. The mixture is poured in 1200 ml. of water and filtered. The filtrate is acidified and extracted with methylene chloride. The extracts are dried, evaporated and the residue crystallized from carbon tetrachloride to yield 2-(2-naphthyloxy) benzoic acid.
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:25]([CH:27]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:28](OC)=O)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:28]=[C:27]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:25](=[O:26])[N:24]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: COC(=O)CC(C=O)C(=O)OC
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 130 °C

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (437 mg, 0.861 mmol) and dimethyl 2-formylbutanedioate (450 mg, 2.58 mmol) in NMP (5 mL) was added K2CO3 (357 mg, 2.58 mmol). The mixture was heated at 130° C. for 1.5 h. Purification via reverse phase flash chromatography then afforded the title compound, together with ethyl ester (102 mg, 0.211 mmol, 24.55% yield).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]([CH3:22])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:10]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C#Cc1nc(Br)cnc1N)cn2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3[nH]1)cn2C
Reaction time: 5 h
Yield: 45.5 %

Procedure:
5-Bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl) ethynyl)pyrazin-2-amine (3.25 g, 9.10 mmol) in DMF (35 mL) was treated with NaH (60% dispersion in mineral oil, 0.36 g, 9.1 mmol). After about 5 h at ambient temperature, the mixture was treated with another portion of NaH (60% dispersion in mineral oil, 0.036 g, 0.91 mmol) and stirred for about 16 h. The mixture was concentrated and stirred with water (50 mL) and EtOAc (40 mL). The mixture was filtered and the solids were washed until an insoluble tar remained. The filtrate layers were separated and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The material was dissolved in a minimum amount of warm DMF and purified by silica gel chromatography (120 g silica gel column) eluting with 95:5 DCM/MeOH. The product-containing fractions were combined and concentrated to give an oil which was purified by silica gel chromatography (120 g silica column) eluting with EtOAc. The product-containing fractions were combined and concentrated to give an oily residue which was triturated with EtOAc (20 mL) then filtered to give a yellow solid. The material was dried to give 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (1.48 g, 45%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 357 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=12>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([S:33][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=5)[N:35]=[CH:36][N:37]4[CH:41]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(Sc3ccccn3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Sc5ccccn5)c4s3)[C@H](C)[C@H]12
Yield: 12.2 %

Procedure:
The procedure of Example 1a) was repeated, except that 576 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 872 mg of 7-(pyridin-2-yl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 112 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)=O>C(OCC)C>[Br:20][C:16]1[CH:15]=[C:14]([C:12]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH2:11])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: C=C(c1ccc(OC)cc1)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
4-Bromoanisole (2.2 mL, 0.017 mol) in diethyl ether (10 mL) was added to a mixture of magnesium turnings (0.5 g, 0.02 mol) in diethyl ether (5 mL), at room temperature. The resulting mixture was heated to reflux for 1 h. The mixture was then cooled to room temperature. A solution of 3-bromoacetophenone (3.4 g, 0.017 mol) in diethyl ether was then added dropwise causing a gentle reflux. After 3 h heating to reflux the reaction mixture was examined by LC-MS which showed complete conversion to the desired product. The mixture was quenched with 1 N HCL solution (20 mL). Ethyl acetate (20 mL) was added and the aqueous phase was separated. The aqueous phase was then extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The crude was then dissolved in toluene (10 mL) and a catalytic amount of p-toluene sulfonic acid (30 mg) was added and refluxed for 3 h. The solvent was removed and the crude residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (3.7 g, 74%).