Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-3) 1.33 g (4.6 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 2.22 g (4.84 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=4:6) to obtain the title compound 2.41 g (68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C[CH2:40][N:41]=[C:42]=[N:43]CCCN(C)C.Cl.NCC#N.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[O:25])[N:41]([C:42]#[N:43])[CH3:40])=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: N#CCN
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C#N)C(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 500.8 %

Procedure:
4-{[tert-Butoxycarbonyl-(4-tert-butylphenyl)amino]methyl}benzoic acid (4.1 g, 10.7mmol) was dissolved in DMF (40 ml). Hydroxybenzotriazole (1.59 g, 11.8 mmol) and EDAC (2.25 g, 1.8 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. Aminoacetonitrile hydrochloride (1.38 g, 15 mmol) and diisopropylethylamine (2.55 ml, 15 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (150 ml) and extracted with water (125 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×50 ml) and a mixture of water and saturated sodium chloride (1:1, 3×50 ml), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (150 g) using ethyl acetate/n-heptane (3:7) as eluent to afford 3.8 g of N-(4-tert-butylphenyl)-N-[4-(cyano-methylcarbamoyl)benzyl]carbamic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:9][NH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][NH:8][CH:9]=1
Reactant: CCOC(=O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Yield: 108.1 %

Procedure:
A solution of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (205 mg; 0.72 mmol) and lithium hydroxide monohydrate (125 mg; 2.9 mmol) in 1:1 THF/water (10 ml) was heated at 60° C. overnight. The THF was removed by evaporation, the aqueous phase acidified with 1M hydrochloric acid then extracted with ethyl acetate (20 ml). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to give 200 mg of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid. (LC/MS: [M+H]+ 256.85).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1COCC1>[C:8]1([C:14]2[N:1]([CH2:4][CH2:5][CH2:6][OH:7])[N:2]=[N:3][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=NCCCO
Reactant: C#Cc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCCCn1nncc1-c1ccccc1
Yield: 82 %

Procedure:
3-Azidopropanol (101 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (8 mg, 0.01 mmol, 1 mol %). Solvent: THF, 10 mL, 60° C., 2 hours. White microcrystalline product was obtained in 82% yield (167 mg). ESI-MS: m/z 204, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16](OC2C=CC=CC=2Cl)=[O:17])[CH2:12][C:11](=[O:26])[N:10]([CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][C:31]([O:36][CH3:37])=[CH:30][C:29]=2[O:38][CH3:39])[CH2:9]1.CN(C)C=O.Cl.[C:49]([O:53][C:54]1[CH:58]=[C:57]([CH:59]([NH2:62])[CH2:60][CH3:61])[O:56][N:55]=1)([CH3:52])([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:62][C@@H:59]([C:57]2[O:56][N:55]=[C:54]([O:53][C:49]([CH3:50])([CH3:52])[CH3:51])[CH:58]=2)[CH2:60][CH3:61])=[O:17])[CH2:12][C:11](=[O:26])[N:10]([CH2:27][C:28]2[C:29]([O:38][CH3:39])=[CH:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=2[O:34][CH3:35])[CH2:9]1
Reactant: CCC(N)c1cc(OC(C)(C)C)no1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1cc(OC(C)(C)C)no1
Reaction time: 15 h
Yield: 43 %

Procedure:
To the compound S141C described in WO 06-059801A, that is, (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxylate (395 mg) in an N,N-dimethylformamide (0.64 ml) solution, the compound S94 described in WO 06-059801A, that is, 1-(3-tert-butoxyisoxazol-5-yl)propylamine hydrochloride (150 mg), 4-dimethylaminopyridin (78 mg) and N,N-diisopropylethylamine (0.111 ml) were added at 0° C., and the mixture was stirred at that temperature for 15 hours. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was combined, successively washed with saturated aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and brine, dried over sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=50/50 to 35/65) to obtain (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-(3-tert-butoxyisooxazole-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide (189 mg) (compound S49a) and (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1S)-1-(3-tert-butoxyisooxazol-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide (compound S49b).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromopyridine (1.00 g) in toluene (10 mL) and ethanol (5 mL) was added phenylboronic acid (515 mg), sodium carbonate (1.34 g) and tetrakis (triphenylphosphine)palladium(0) (24 mg) and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted into ethylacetate (2×30 mL). The organic layers were washed with brine (40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 5-bromo-2-phenyl-pyridine as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[NH2:20])=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
reacting the 4-(quinolin-2-ylmethoxy)phenylhydrazine product of step (4) with p-chlorobenzyl chloride, tetrabutylammonium bromide and diisopropyl ethyl amine to yield 1-(p-chlorobenzyl)-1-[4-(quinolin-2-ylmethoxy)phenyl]hydrazine;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]=1Cl.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][C:5]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1NCc1ccc(OC)cc1
Yield: 43.6 %

Procedure:
A solution of 2,5-dichloro-nicotinic acid methyl ester (71) (25 g, 121 mmol) in anhydrous methanol was purged with argon and added p-methoxybenzylamine (34.5 mL, 266 mmol) at room temperature. The solution was refluxed overnight under argon. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was taken in dichloromethane, sonicated briefly and undissolved solids were filtered off. The filtrate washed by water, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with hexane:CH2Cl2 (1:1) to yield 16.2 g (44%) of 5-chloro-2-(4-methoxy-benzylamino)-nicotinic acid methyl ester (72) as a white solids. Mp 94° C. 1H-NMR (DMSO-d6): δ 3.71 (s, 3H), 3.82 (s, 3H), 4.59 (d, J=5.6 Hz, 2H), 6.87 (m, 2H), 7.24 (m, 2H), 8.06 (d, J=2.8 Hz, 1H), 8.27 (m, 1H), 8.32 (d, J=2.8 Hz, 1H); EIMS m/z 307 (M+1).
Reaction SMILES: CN[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].[Li]CCCC.C1C[O:19]CC1.C(#N)C1C=CC(OC)=CC=1>C1COCC1>[CH3:10][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[C:3]([OH:19])=[O:4]
Reactant: C1CCOC1
Reactant: CNC(=O)c1ccsc1C
Agent: COc1ccc(C#N)cc1
Agent: [Li]CCCC
Product: Cc1sccc1C(=O)O
Temperature: -70 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (36.0 g) in THF (500 ml) was added dropwise 2.5M n-BuLi/THF solution (200 ml) at −70° C. The reaction solution was stirred at −70° C. for 2 hr. followed by the addition of anisonitrile (31.0 g) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, and then the mixture was further stirred for 1 hr. The resulting white precipitates were collected by filtration, washed with water, ether and n-hexane in this order, and then dried, to give the title compound (17.9 g, yield; 30%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>ClCCl>[CH:31]([O:30][C:28]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:29])([CH3:33])[CH3:32]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC([C@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine by treatment with isopropyl chloroformate in the presence of triethylamine using dichloromethane as a solvent. LC (method 6): tR=1.33 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: N(C(C)(C)C#N)=N[C:3](C)(C)C#N.[C:13]([O:17][CH2:18]CCC)(=[O:16])[CH:14]=[CH2:15].CN(C)C=O.CC[CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)(Cl)Cl>[C:13]([O:17][CH3:18])(=[O:16])[C:14]([CH3:3])=[CH2:15].[C:13]([O:17][CH:31]([CH2:30][CH3:29])[CH3:32])(=[O:16])[CH:14]=[CH2:15]
Reactant: CCCCCC
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC
Product: C=CC(=O)OC(C)CC
Temperature: 60 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Along with 230 mg (0.055 mmole) of poly(methyl methacrylate) macroinitiator prepared in Example 80, 0.9 mg (0.005 mmol) of 2,2′-azobis(isobutyronitrile), 0.70 g (5.5 mmole) of n-butyl acrylate (same as above) and 1 ml of N,N-dimethylformamide (DMF) were placed into a glove box with the inside air replaced by nitrogen, followed by stirring at 60° C. for 3 hours. After the completion of the reaction, the reaction mixture was dissolved in 5 ml of chloroform, and the solution was then poured into 300 ml of hexane which was being stirred. The resulting polymer precipitate was collected by suction filtration and dried to obtain block copolymer of poly(methyl methacrylate-b-n-butyl acrylate) (yield 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[CH:12]=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[CH:12]=[N:11][CH:10]=2)=[CH:4][CH:3]=1)#[N:29]
Reactant: CN(C)C=O
Reactant: O=c1ccccn1-c1ccc(Cn2cncc2Oc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Oc2cncn2Cc2ccc(-n3ccccc3=O)cc2)cc1

Procedure:
A mixture of 1-{4-[5-(4-bromophenyloxy)imidazol-1-ylmethyl]-phenyl}-1H-pyridin-2-one (145 mg, 0.35 mmol) and zinc cyanide (24 mg, 0.2 mmol) in DMF (3 mL) was purged with argon for 10 min. A solution of tetrakis(triphenylphosphine)palladium(0) (40 mg, 35 μmol) in DMF (1 mL) was added. The resultant mixture was stirred under argon at 80° C. overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the titled compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:14])[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH2:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:21])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1cc(Br)ccc1-c1ccccc1
Yield: 89 %

Procedure:
4-bromo-2-methylbiphenyl (5 g, 20.23 mmol) was suspended in pyridine (23 mL) and water (35 mL). Potassium permanganate (16 g, 101 mmol) was added portion wise over a period of 20 min. The mixture was refluxed overnight. The reaction mixture was cooled and MnO2 was filtered off. Conc. HCl was added to the filtrate until the product precipitated. The product was extracted with DCM, washed with water and brine, collected, dried (MgSO4), filtered and evaporated to give 4-bromobiphenyl-2-carboxylic acid (5 g, 18.04 mmol, 89% yield) as a white solid. LCMS: rt=1.39 min.; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:20][CH2:19]2)[CH2:11]3)=[CH:4][N:3]=1.Cl[CH:22]([C:25]1([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)[CH2:27][CH2:26]1)[CH:23]=O>C(O)(C)C>[CH:18]1([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([C:5]4[CH:4]=[N:3][C:2]5[N:7]([C:22]([C:25]6([C:28]7[CH:29]=[C:30]8[C:35](=[CH:36][CH:37]=7)[N:34]=[CH:33][CH:32]=[CH:31]8)[CH2:27][CH2:26]6)=[CH:23][N:1]=5)[CH:6]=4)[CH:9]=3)[C:13]2=[O:17])[CH2:20][CH2:19]1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc3c(c2)CN(C2CC2)C3=O)cn1
Solvent: CC(C)O
Product: O=C1c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2CN1C1CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(2-aminopyrimidin-5-yl)-2-cyclopropylisoindolin-1-one (20 mg, 0.075 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (18 mg, 0.075 mmol) in isopropyl alcohol (0.5 mL) was stirred at 90° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=458.1.
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][O:15][N:14]=[C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCON=C(c1ccccc1)c1ccccc1
Yield: 73.5 %

Procedure:
Benzophenone oxime (3.94 g, 20 mmol), 1-bromo-2-chloroethane (28.7 g, 200 mmol) a nd dried, powdered potassium carbonate (5.53 g, 80 mmol) in acetone (60 ml) were heated at reflux for 72 h. The reaction mixture was cooled and filtered and the filtrate was evaporated to an oily residue which was purified by "flash" chromatography (eluting with heptane/ethyl acetate 19/1) to provide diphenylmethanone O-(2-chloroethyl)oxime (3.82 g, 73%) as an oil, tlc rf 0.36 (SiO2, heptane/ethyl acetate 9/1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26](CC)([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34]C1C(C(O)=O)CCNC1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH:27]([CH3:34])[CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Reactant: CC1CNCCC1C(=O)O
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1CN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CCC1C(=O)O
Yield: 2 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using 3-Methyl-piperidine-4-carboxylic acid (0.154 g, 1.08 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol) and Acetic acid (0.18 mL, 3.1 mmol) in Methanol (1.8 mL, 44 mmol) and sodium cyanoborohydride (84.101 mg, 1.3383 mmol) to give 6 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-3-methyl-piperidine-4-carboxylic acid (2%). ESI-LCMS 438 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.73-8.05 (m, 3H), 7.50-7.67 (m, 1H), 7.44 (s, 1H), 7.12-7.30 (m, 1H), 4.45 (br. s., 3H), 2.99-3.49 (m, 3H), 2.59-2.74 (m, 1H), 1.70-2.28 (m, 7H), 1.03-1.48 (m, 6H), 0.96 (d, J=6.8 Hz, 3H), 0.89 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](O)[C:12]3=[CH:11][C:10]=2[CH3:20])=[C:5]([CH3:21])[CH:4]=1.P(Br)(Br)[Br:23].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][C:17]1[C:12]2[N:13]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:21])=[C:10]([CH3:20])[CH:11]=2)[N:14]=[C:15]([CH3:19])[CH:16]=1
Reactant: COc1ccc(-c2c(C)cc3c(O)cc(C)nn23)c(C)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Brc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(C)cc3c(Br)cc(C)nn23)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 7-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (0.16 g, 0.567 mmol) and phosphorus tribromide (0.27 mL, 2.83 mmol) in bromobenzene (3.0 mL) was refluxed for 5 h. After cooling down to room temperature, the mixture was diluted with CHCl3. Saturated NaHCO3 solution was added to neutralize and separated immediately. The aqueous layer was extracted with CHCl3 (2×). The combined CHCl3 solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (silica gel, 1/20 EtOAc/hexane) to afford 0.14 g (64%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8 Hz, 1H), 6.82 (d, J=3 Hz, 1H), 6.76 (dd, J=3, 8 Hz, 1H), 6.59 (s, 1H), 6.49 (s, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H); MS m/z 347.1 (M++H).
Reaction SMILES: [CH:1]1[C:6]([C@H:7]2[O:16][C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([OH:18])[C:10]=3[CH2:9][C@H:8]2[OH:19])=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[OH:21][C:3]1[CH:2]=[CH:1][C:6]([C@@H:7]2[C@H:8]([OH:19])[CH2:9][C:10]3[C:15](=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[OH:18])[O:16]2)=[CH:5][C:4]=1[O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc(O)c2c(c1)O[C@H](c1ccc(O)c(O)c1)[C@H](O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc([C@H]2Oc3cc(O)cc(O)c3C[C@H]2O)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (−)-epicatechin (1.16 g, 4 mmol) and potassium carbonate (1.1 g, 8 mmol) in DMF (10 mL) at −20° C. was added ethyl bromoacetate (490 mL, 4.4 mmol). The reaction was stirred at the same temperature for 2 hr, allowed to warm to RT, and stirred for 2 hr. The reaction was diluted with ethyl acetate, washed with citric acid then brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative reverse phase HPLC using a gradient of 10% to 80% acetonitrile/(0.2% formic acid/water) over 20 min, analyzing at 280 nm. The appropriate fractions were frozen and lyophilized to give as white powders: