Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH3:30][C:31]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)=[O:32]>ClCCl>[C:33]1([C:31]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=2)([OH:32])[CH3:30])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)c1cccc2ccccc12
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ccccc12

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (4.5 g, 10.3 mmol) in dichloromethane (50 mL) at 22° C. was treated with ethyl magnesium bromide (3.48 mL, 10.4 mmol, 3M in ether) and allowed to react for 1 h. Anhydrous CeCl3 (3.3 g, 13.4 mmol) was added and the mixture was stirred for 30 m. A solution of 1-acetonaphthone (commercially available from Aldrich) (2.6 g, 15.9 mmol) in dichloromethane was added via syringe at 22° C. and stirred for 16 h. The mixture was quenched with a sat. solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by chromatography on silica gel with 50% EtOAc:hexane to give 1-naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H1) as a solid, 2.44 g (49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:14][C:15]1[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]=[C:17]([CH3:24])[N:16]=1.N12CCN(CC1)CC2>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]=[C:17]([CH3:24])[N:16]=1)=[O:13])(=[O:10])=[O:9]
Reactant: Cc1nc(C)c(C#N)c(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1nc(C)c(C#N)c(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Reaction time: 72 h
Yield: 71.2 %

Procedure:
4.35 g of 2-Chlorobenzenesulfonyl isocyanate was dissolved in 10 ml xylenes and 25 ml methylene chloride. To this was added 2.96 g of 4-amino-2,6-dimethyl-5-pyrimidine carbonitrile and a catalytic amount of 1,4-diazabicyclo-[2.2.2]octane. The reaction was stirred under a CaSO4 drying tube for three days. The reaction was filtered to remove unreacted pyrimidine, and then the desired product was precipitated by addition of 1-chlorobutane, filtered off, rinsed well with 1-chlorobutane and dried in vacuo giving 5.2 g of the desired product, m.p. 125°-127°. IR: 2240 cm-1 (C≡N), 1730 cm-1 (C=O); NMR (DMSO-d6)δ: 2.6 (s, 6H), 7.4-8.1 (m, 4H) ppm indicating the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].C(#N)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nnc(Cl)cc1N1CCOCC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
4-Bromo-6-chloropyridazin-3-amine (2.0 g, 9.6 mmol) was placed in an 8 mL vial equipped with a stir bar, and ACN (5 mL) and morpholine (8.3 mL, 96 mmol) were added. The mixture was stirred at 70° C. for 18 h. The reaction was cooled to rt, the suspension obtained was filtered, and the filtercake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure and the residue obtained was dissolved in DCM (50 mL) and washed with saturated NaHCO3 solution (2×30 mL). The aqueous washings were combined and extracted with DCM (3×30 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude residue was triturated with EtOAc (30 mL) then the solid was isolated by filtration to give compound 19a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H11ClN4O: 215.1 (M+H). found: 215.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(OCC)(=O)C>[CH2:10]([NH:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccccc1
Yield: 96 %

Procedure:
Benzoyl chloride (10 mL, 86.2 mmol) in ethyl acetate (200 mL) was treated with propylamine. The precipitate was removed by filtration, and the solution was washed with 1M HCl, 5% NaHCO3, and brine, dried over MgSO4 and concentrated in vacuo to give the title compound in 96% yield.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[NH4+]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21

Procedure:
Prepared by reacting 1-acetyl-2-indolinone in concentrated sulphuric acid (5.7 ml/g) at -10° C. with 1.1 equivalents of ammonium nitrate which is added in batches with stirring. After the addition has ended the mixture is stirred for a further 15 minutes, poured onto ice water, the precipitate is filtered off, washed with water and dissolved in ethylacetate. The organic phase is extracted with water, dried, filtered and evaporated down in vacuo. The evaporation residue is stirred with petroleum ether.
Reaction SMILES: CO[CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]>CO.[Ni]>[CH3:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]
Reactant: COCNCC[C@H](O)c1cccs1
Agent: [Ni]
Solvent: CO
Product: CNCC[C@H](O)c1cccs1
Reaction time: 12 h

Procedure:
(S)-3-methoxymethylamino-1-(2-thienyl)propan-1-ol obtained in example 2 dissolved in 10 mL of methanol with 8 mg of Raney-nickel were provided in a glass autoclave. The resulting solution was hydrogenated at 50□ for 12 hours. Upon completion of hydrogenation, the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain objective compound as a crystal compound (122 mg, 90.8% by HPLC assay, 95% ee). The crude product was further purified by re-crystallization in toluene with optical purity as high as 100% ee.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.N[C:13]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].NC1C=CC=CC=1>CC#N>[CH2:3]([C:13]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH:1]=[CH2:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: CC(C)(C)ON=O
Solvent: C=CCBr
Solvent: CC#N
Solvent: Nc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-amino-5-nitrobenzophenone (727 mg, 3.0 mmol) was added during 20 minutes while maintaining the temperature of the reaction mixture at 28-32° C. At the end of the addition of the aniline, extra t-butylnitrite (360 μl, 3 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) gave 370 mg (46%) of 2-allyl-5-nitrobenzophenone as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.29, (dd, 1H, J=8.6, 2.5 Hz), 8.18, (d, 1H, J=2.4 Hz), 7.81-7.74, (m, 2H), 7.69-7.60, (m, 1H), 7.57-7.45, (m, 3H), 5.93-5.88, (m, 1H), 5.09-5.95, (m, 2H), 3.53, (m, 2H, J=6.6 Hz).
Reaction SMILES: [C:1](#[N:4])[CH2:2]O.[C:5]([O:9][C:10](=[O:15])[NH:11][CH2:12][CH2:13][NH2:14])([CH3:8])([CH3:7])[CH3:6]>C(O)C>[C:5]([O:9][C:10](=[O:15])[NH:11][CH2:12][CH2:13][NH:14][CH2:2][C:1]#[N:4])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#CCO
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNCC#N

Procedure:
Glycolonitrile (70%, 5.10 g, 62.5 mmol), tert-butyl-N-(2-aminoethyl)carbamate (10.0 g, 62.5 mmol), and ethanol (200 mL) were combined under Ar and heated at reflux for 4 h. Removal of the solvent in vacuo gave 111 as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH3:10][C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:23][CH2:22][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:15][C:11]=1[CH3:10]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: Cc1cccc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
1.1 g of 2,6-Dimethylphenol, 2.01 g of 2-(5-methyl-2-phenyl-oxazole-4yl)-ethanol 2.6 g of triphenylphosphin were dissolved in 30 ml THF and treated at 0° with 1.6 ml DEAD (Diethyl azodicarboxylate). The reaction mixture was kept overnight at RT. Water was added. Twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents provided a crude product, which was purified by chromatography (SiO2; ether/cyclohexane) to yield 0.89 g of the title compound as a slightly yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:2]1.I[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:18][CH2:19][OH:20])[CH2:2]3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1
Reactant: OCCI
Reactant: c1cc2[nH]ncc2cc1OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCCC(Oc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
A mixture of the 5-(piperidin-3-yloxy)-1H-indazole (43 mg, 0.20 mmol) obtained in Example 377, 2-iodoethanol (84 mg, 0.49 mmol), potassium carbonate (70 mg, 0.50 mmol) and N,N-dimethylformamide (1 ml) was stirred at room temperature for 24 hours. The precipitate was removed by filtration and the solvent was distilled off as an azeotrope with toluene. The residue oil was purified by a silica gel column chromatography (eluent: ethyl acetate/triethylamine/ethanol=20/1/1) to obtain 2-[3-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol (17 mg, 32%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15]>O1CCCC1>[CH:2]1([CH2:12][Si:13]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:15])[CH:1]=[CH:5][CH:4]=[CH:3]1
Reactant: C1=CCC=C1
Reactant: CO[Si](CCl)(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO[Si](CC1C=CC=C1)(OC)OC
Yield: 93 %

Procedure:
27.5 g (417 mmol) of freshly distilled cyclopentadiene are added dropwise to a solution of 167 ml of n-butyllithium (2.5 molar) (417 mmol) in 250 ml of absolute tetrahydrofuran at RT over a period of one hour. 71.11 g of (chloromethyl)trimethoxysilane are subsequently added dropwise over a period of 30 minutes. The solution becomes warm during this process. After taking off the solvent, the mixture is fractionally distilled under reduced pressure to give 72.2 g of (cyclopentadienylmethyl)trimethoxysilane (yield: 93%).
Reaction SMILES: Cl.CN.[C:4]([BH3-])#[N:5].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=1.[OH-].[Na+]>CO>[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][NH:5][CH3:4])[CH:12]=[N:13][CH:14]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cncc(Br)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
1.8 g (27 mmol) of methylamine hydrochloride and then 0.4 g (6 mmol) of sodium cyanoborohydride are successively added to a solution of 1 g (5.4 mmol) of 5-bromopyridine-3-carbaldehyde in 20 ml of methanol. The reaction medium is stirred at room temperature for 2 days. The precipitate is filtered off and the filtrate is evaporated to dryness. The residue is taken up in dichloromethane and washed with water. After extraction, the organic phase obtained is washed with aqueous hydrochloric acid solution. The aqueous phase thus obtained is brought to pH 9 with aqueous sodium hydroxide solution and then extracted with dichloromethane. The organic phase thus obtained is dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 9.5/0.5 dichloromethane/methanol mixture. 0.5 g (50%) of (5-bromopyrid-3-ylmethyl)methylamine is obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:27]4=[C:28]([CH:31]=[CH:32][C:25]5=[C:26]4[C:10]4[C:11]6[C:23](=[N:24]5)[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:15](=[O:16])[C:12]=6[CH:13]=[CH:14][C:9]=4[N:8]=3)[C:29](=[O:30])[C:4]2=[CH:3][CH:2]=1.O.[S:34](=[O:38])(=[O:37])([OH:36])[OH:35]>>[CH:20]1[CH:21]=[C:22]2[C:23]3[C:11]4=[C:12]([CH:13]=[CH:14][C:9]5=[C:10]4[C:26]4[C:27]6[C:7](=[N:8]5)[C:5]5[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=5)[C:29](=[O:30])[C:28]=6[CH:31]=[CH:32][C:25]=4[N:24]=3)[C:15](=[O:16])[C:17]2=[CH:18][CH:19]=1.[S:34]([O-:38])([O-:37])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)O
Agent: O=c1c2ccccc2c2nc3ccc4c(=O)c5ccccc5c5nc6ccc1c2c6c3c45
Solvent: O
Product: O=S(=O)([O-])[O-]

Procedure:
30 Parts of crude flavanthrone were dissolved in 300 parts of concentrated sulfuric acid. 36 Parts of water were added dropwise at 50°-70° C, the flavanthrone-sulfate crystals formed were suction-filtered via an acid-resistant filter at room temperature and washed with about 150 parts of 80% sulfuric acid. The filter cake was introduced while stirring into 300 parts of water, the dyestuff was filtered and washed with water until free from acid. 63 Parts of an aqueous filter cake were obtained having a content of solid body of 43%.
Reaction SMILES: CO.[CH3:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=1.[F:23][C:24]1[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:10]([C:9]3[C:4]([CH3:3])=[N:5][C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:7][CH:8]=3)=[N:31][C:26]=2[C:25]=1[CH3:32]
Reactant: Cc1c(F)ccc(N)c1N
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: O=[Mn]=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
[5-(5-Fluoro-4-methyl-1 H-benzoimidazol-2-yl)-pyrimidin-2-yl]-3-(1-methyl-piperidin-4-yl)-propyl]-amine. A mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 mg, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(I)CCCCC>>[CH2:1]([N:8]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O
Solvent: CCCCCCI
Product: CCCCCOc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O

Procedure:
3(a) 5-(N,N-dibenzylglycyl)-2-hexyloxybenzamide, m.p. 92°-94°, 53% (hexyl iodide).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:30](=[O:32])[CH3:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine were added. The reaction was shaken at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentration in vacuo afforded 27 mg of the title compound as hydrochloride salt. Yield 40% ES MS m/z 439
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:10]=[CH:9][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Yield: 61 %

Procedure:
First, into a 200-mL three-neck flask were placed 9.7 g of 4-bromoiodobenzene, 3.1 g of 2-naphthylboronic acid, and 0.35 g of tri(ortho-tolyl)phosphine (P(o-tolyl)3), to which 30 mL of toluene, 6 mL of ethanol, and 10 mL of a 2.0M aqueous potassium carbonate solution were added. The mixture in this flask was degassed under reduced pressure, and the air in the flask was replaced with nitrogen. To this mixture was added 0.037 g of palladium(II) acetate, and the mixture was refluxed under a nitrogen stream at 90° C. for 6 hours. After the reflux, organic substances were extracted from the aqueous layer of this mixture with toluene. The solution of the extract was combined with the organic layer of the mixture. The resulting mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and then saturated brine. After the washing, anhydrous magnesium sulfate was added for drying. The obtained mixture was separated by gravity filtration, and the filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography. In the column chromatography, hexane was first used as a developing solvent, and then a mixed solvent in which a hexane/ethyl acetate ratio was 20:1 (v/v) was used. The obtained fractions were concentrated to give a solid. The obtained solid was recrystallized using a mixed solvent of toluene and hexane to give 2-(4-bromophenyl)naphthalene (as a white solid in 61% yield). The synthesis scheme of Step (a-2) is illustrated below.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.O[N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43]>ClCCl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(ON1C(=O)CCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
201 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dehydrated dichloromethane (3.6 mL), and 162 mg of N-methylmorpholin was added, followed by cooling to 0° C. 198.8 mg of isobutyl chloroformate was added to the mixture, followed by stirring for 10 minutes, and subsequently 167 mg of N-hydroxysuccinimide was added, followed by further stifling for 0.5 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=1/2) to afford 161 mg of the title compound as a colorless solid (yield 59%).
Reaction SMILES: COC1C=C(C)C=CC=1C[N:6]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1)C(=O)C(N)=O.[CH3:26][O:27][C:28]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:29]=1[CH2:30][NH:31][C:32](=[O:36])[C:33]([O-:35])=O>[Ni]>[CH3:26][O:27][C:28]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:29]=1[CH2:30][NH:31][C:32](=[O:36])[C:33]([NH:6][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:35]
Reactant: COc1cc(C)ccc1CNC(=O)C(=O)[O-]
Reactant: COc1cc(C)ccc1CN(CCc1ccc(C)cn1)C(=O)C(N)=O
Agent: [Ni]
Product: COc1cc(C)ccc1CNC(=O)C(=O)NCCc1ccc(C)cn1

Procedure:
This method resulted in an improved yield of 85% when compared to the previous example (40%) yield by purification of compound 4 with column chromatography and by using H2/Raney Ni instead of BH3—SMe2. Further, the one-pot preparation of N′-(2-methoxy-4-methylbenzyl)-N2-(2-(5-methylpyridin-2-yl)ethyl) oxalamide shown in the previous example, was divided into two steps in this example. The yield was improved to 44% by purification of 2-(2-methoxy-4-methylbenzylamino)-2-oxoacetate in this example, from 30% yield without any purification of 2-(2-methoxy-4-methylbenzylamino)-2-oxoacetate in the one pot preparation described in the previous example.