Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
Dioxane is added under a nitrogen atmosphere to a mixture of 4-bromo-1-fluoro-2-nitrobenzene (220 mg, 1.00 mmol), benzeneboronic acid (143 mg, 1.20 mmol), potassium phosphate (636 mg, 3.00 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (55 mg, 0.05 mmol). The reaction may be heated to an appropriate temperature such as 90° C., stirred for an appropriate time, such as overnight, and filtered. The filtrate may be concentrated and purified by Biotage column chromatography to give 4-fluoro-3-nitrobiphenyl (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][O:15]C(=O)C)[C:8]=2[N:7]=[C:6]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].O.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][OH:15])[C:8]=2[N:7]=[C:6]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC(=O)OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (Example 103) (1.45 g, 3.38 mmol) dissolved in methanol (19 mL) and water (1.0 mL) was added K2CO3 (0.40 g). After 30 min, the reaction was concentrated, redissolved in EtOAc, and washed with NaHSO4 (10% soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. Recrystallization of the crude product from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxymethylbenzimidazole (1.25 g, 3.24 mmol, 96% yield). M.p. 157-158° C. 1H-NMR (300 MHz, CD2Cl2): δ 7.54 (m, 1H, H4′), 7.43 (d, J=7.9 Hz, 1H, H7), 7.30-7.22 (m, 2H, H6,4″), 7.18 (d, J=7.5 Hz, 1H, H5), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.37 (s, 2H, CH2PhF2), 5.06 (d, J=5.4 Hz, 2H, CH2O), 3.51 (t, J=5.4 Hz, 1H, OH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cc(C#N)ccc1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)c1cc(C#N)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.6 g (16.3 mmol) of methyl (2-benzyloxy-5-cyano-phenyl)-acetate are dissolved in 10 ml of dimethylformamide and 1.9 g (17 mmol) of potassium tert. butoxide are added. Then 2 ml (16.8 mmol) of benzylbromide are added dropwise while cooling gently with ice and the mixture is then stirred for another two hours at ambient temperature. It is stirred with ice water and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. The crude product is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (0-7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C[O:12][C:13](=[O:42])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:31]1[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:42])=[O:12])=[C:17]([CH3:41])[CH:18]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccccc1Cl
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3Cl)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-chlorophenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 122 mg (66%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H22O4F3Cl 526, found 527 and 529 (M+1 and M+3,100%).
Reaction SMILES: 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.[Cl:47][C:48]1[C:49](Cl)=[N:50][CH:51]=[C:52]([CH:58]=1)[C:53]([O:55][CH2:56][CH3:57])=[O:54].[NH2:60][CH:61]1[CH2:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH2:62]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:47][C:48]1[C:49]([NH:60][CH:61]2[CH2:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH2:62]2)=[N:50][CH:51]=[C:52]([CH:58]=1)[C:53]([O:55][CH2:56][CH3:57])=[O:54]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: NC1Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(NC2Cc3ccccc3C2)c(Cl)c1
Temperature: 10 °C
Yield: 58.4 %

Procedure:
Palladium(II) acetate (25 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (106 mg) in dioxane (10 mL) was stirred at ambient temperature for 15 minutes. To this suspension was added ethyl 5,6-dichloronicotinate (500 mg), 2-aminoindane (363 mg), and cesium carbonate (1.1 g), and the mixture was heated at 10° C. for 8 hours. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 v/v) to give ethyl 5-chloro-6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (420 mg) as a pale tan solid.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:31])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].O>C(O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([OH:31])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C(CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CC(O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (8.0 mg, 0.21 mmol) was added to 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanone (20 mg, 0.050 mmol) in ethanol (1 mL) and stirred at RT for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc, twice with brine, then was dried over MgSO4, and evaporated to dryness. The crude material was purified by preparative TLC using 5% (10% NH4OH in MeOH): 95% DCM solvent system to yield 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanol.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7][C@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:5]1.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([CH2:28][N:5]2[C@@H:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]2=[O:3])[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](c2ccccc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 14.4 mg, 0.36 mmol) was added to a solution of tert-butyl (3R,7R)-2-oxo-7-phenylazepan-3-ylcarbamate (100 mg, 0.33 mmol) and cyclopropylmethyl bromide (0.08 mL, 0.82 mmol) in N,N-dimethylformamide (1 mL) at 0 □C, and the mixture was allowed to warm to ambient temperature. After 6 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (82 mg). MS 359 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH2:19][C:12]3=[C:11]([CH:20]=[C:21]([N+:23]([O-])=O)[CH3:22])[C:10]=2[CH:9]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].Cl>C1COCC1>[ClH:7].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH2:19][C:12]3=[C:11]([CH2:20][CH:21]([NH2:23])[CH3:22])[C:10]=2[CH:9]=1
Reactant: CC(=Cc1c2n(c3ccc(Cl)cc13)CCC2)[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: CC(N)Cc1c2n(c3ccc(Cl)cc13)CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a stirred solution of lithium aluminium hydride (1.0 M in THF, 2.7 mL, 2.7 mmol) in added THF (5 mL) under argon was added dropwise a solution of 1-(7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2-nitro-1-propene (0.5 g, 1.8 mmol) in THF (10 mL). The mixture was heated under reflux for 4 h and cooled to 0° C. To the mixture was added dropwise aqueous potassium sodium tartrate solution (50 mL) and the mixture was stirred for 30 min and filtered through kieselguhr. The filtrate was extracted with dichloromethane (3×30 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate), concentrated in vacuo, treated with ethereal hydrogen chloride (1.0 M, 2 mL, 2 mmol) and concentrated in vacuo. The concentrate was recrystallised (2-propanol) to give the title compound as a white solid (0.23 g, 45%): mp 272-273° C.; Found: C, 57.86; H, 6.37; N, 9.41%. C14H17ClN2.HCl. 0.25H2O requires: C, 58.03; H, 6.39; N, 9.67%.
Reaction SMILES: C([O-])(C)C.[NH2:5][C:6]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:7]=1[C:8](NNS(C1C=CC=CC=1)(=O)=O)=[O:9].C(O)CO.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[NH2:5][C:6]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:7]=1[CH:8]=[O:9]
Reactant: Cc1cc(C)c(C(=O)NNS(=O)(=O)c2ccccc2)c(N)n1
Agent: CC(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: OCCO
Product: Cc1cc(C)c(C=O)c(N)n1
Temperature: 160 °C

Procedure:
N1 -(2-amino-4,6-dimethylnicotinoyl)-N2 -benzenesulfonyl hydrazine isopropanolate (62.0 g., 0.163 mole) is divided into two portions. To each portion, ethylene glycol (300 ml.) is added and the mixture heated to 160° C. prior to the addition of anhydrous sodium carbonate (30 g.) in one portion with vigorous stirring. The mixture is allowed to cool and then is poured into water. The two runs are combined and the product isolated by extraction with chloroform. Following recrystallization from carbon tetrachloride the product melts at 152°-158° C. Further recrystallization from the same solvent raises the melting point to 162°-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]([NH:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[CH2:20]([N:27]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[C:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:19])[N:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CNc2ccncc2)cc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N(Cc2ccccc2)c2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(benzylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:30])#[N:25]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccc(C#N)c4)nc3cc21

Procedure:
3-Cyano-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-cyano-benzoyl chloride (146 mg, 0.89 mmol). The title compound was obtained as light brown powder (90 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][CH:5]=[C:6]([CH3:9])[C:7]=1Cl.[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:7]1[C:6]([CH3:9])=[CH:5][N:4]=[C:3]([CH2:10][OH:11])[C:2]=1[Cl:1]
Reactant: Cc1cnc(CO)c(Cl)c1Cl
Reactant: CNC
Solvent: CCO
Product: Cc1cnc(CO)c(Cl)c1N(C)C
Temperature: 2000 °C

Procedure:
3,4 -dichloro-5 -methyl-2 -hydroxymethylpyridine (4 g) was dissolved in 33 % dimethylamine in ethanol (11 ml), placed in a sealed vessel and heated to 2000° C. for 4 hours. On cooling, the reaction mixture was evaporated under reduced presure and the residue dissolved in water (15 ml) and ether extracted. Etherial extracts were dried (K2CO3 ), filtered and stripped to yield 4 -dimethylamino-3 -chloro-5 -methyl-2 -hydroxymethylpyridine, 4.08 g as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[N:11]=[C:10](Cl)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CS(C)=O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c(=O)n2Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)nc(N1CCC[C@@H]1C)c(=O)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 1-benzyl-3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (3 g, 9.15 mmol, 1.00 equiv), (S)-2-methylpyrrolidine (1.55 g, 18.24 mmol, 2.00 equiv), DMSO (16 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20). This resulted in 2.2 g (64%) of (S)-methyl 1-benzyl-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][NH2:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCCCCCC>[C:1]([NH:18][CH2:17][CH:16]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCCCCCCCCCC(CCCCCCCC)CNC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
62 ml of pivaloyl chloride were dissolved in 180 ml of heptane and then added to 150 g of 2-octyldodecylamine at a temperature of 60° C. After addition of 70 ml of triethylamine, the reaction medium was stirred for 2 hours and then purified on silica. 118 g of the desired amide were thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4](I)[CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.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[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH:11]=[CH2:12])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)c(Cl)cc1N
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A mixture of 4,5-dichloro-2-iodobenzenamine (6 g, 20.8 mmol), tributyl(vinyl)stannane (6.6 g, 20.8 mmol), Pd(PPh3)4 (2.4 g, 2.1 mmol) in toluene (60 mL) was stirred at reflux under argon for 6 h. The mixture was allowed to cool to room temperature, quenched with aqueous KF solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desired product (3.0 g, 76.7% yield) as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13](C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].Br.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20]>>[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CCSc1nccn1-c1ccc(C)cc1
Agent: Br
Agent: Cl
Product: CCSc1nccn1-c1ccc(O)cc1
Yield: 72.5 %

Procedure:
A mixture of 14 parts of 2-(ethylthio)-1-(4-methylphenyl)-1H-imidazole monohydrochloride and 113 parts of hydrobromic acid solution 48% in glacial acetic is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is dissolved in water. The solution is neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from 2-propanol, yielding 8.3 parts (72.5%) of 4-[2-(ethylthio)-1H-imidazol-1yl]phenol; mp. 165.2° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:15]([O:17]CC)=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:24])([S:20]([CH3:23])(=[O:21])=[O:22])[C:15]([OH:17])=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCCC2)cn1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@](CCn1cc(C2=CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of ethyl (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (370 mg, 1.04 mmol, 1.0 eq) in MeOH/THF (3 mL:3 mL) was added LiOH (52.5 mg, 2.19 mmol, 2.1 eq) in H2O (1.5 mL) and the mixture allowed to stir at RT overnight. The mixture was diluted with 5 mL of H2O and washed with Et2O. The aqueous layer was then acidified with 1 M HCl which precipitated out a white solid. The solid was filtered off and washed with heptane to give (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (339 mg, 99.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.75-7.66 (m, 1H), 7.41-7.35 (m, 1H), 6.05-5.96 (m, 1H), 4.78-4.59 (m, 1H), 4.55-4.38 (m, 1H), 3.14 (s, 3H), 2.77-2.64 (m, 1H), 2.51-2.37 (m, 1H), 2.28-2.19 (m, 2H), 2.18-2.06 (m, 2H), 1.80-1.69 (m, 2H), 1.64 (s, 5H). LC-MS M+H+327.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[F-].[K+].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1>[C:17]([C:18]1[CH:23]=[CH:22][C:21]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)=[CH:20][CH:19]=1)([O:16][CH3:15])=[O:25]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2cccc(C(C)=O)c2)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 3-acetylphenyl boronic acid (246 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and methyl-4-chlorobenzoate (171 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 229 mg (90%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]([C:26]1[O:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1)=[O:25]>CN(C=O)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:28]2[O:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:30][CH:29]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(C(=O)c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
To a stirred solution of 4-hydroxybenzophenone (198.2 mg, 1.0 mmol) in DMF (3 mL) at 0° C. under nitrogen was added potassium carbonate (207 mg, 1.5 mmol) followed by methyl-5-chloromethyl-2-furoate (175 mg, 1.0 mmol). The reaction was allowed to warm to room temperature and the mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with 10% aqueous K2CO3 solution, water, brine, dried over MgSO4, filtered and the solvent removed in vacuo to yield the title compound (330 mg, 98.2%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C>Cl.O1CCOCC1>[ClH:25].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-[1-(4-Chloro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (475 mg, 1.2 mmol) was dissolved in 4M HCl-dioxane (5 mL) at 0° C. The mixture was stirred for 1.5 hour at 25° C., concentrated and the residue triturated with ether. Yield, 422 mg, 105%; TSPMS 283 (MH+, 100%).