Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([P:8]([OH:10])[OH:9])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][CH2:13][CH2:14]O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CCOCC>[OH:1][C:2]([PH:8](=[O:10])[O:9][CH2:14][CH2:13][O:12][CH3:11])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)(O)P(O)O
Reactant: COCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)[PH](=O)OCCOC
Reaction time: 3 h

Procedure:
1-Hydroxy-1,4-dimethylbutylphosphonous acid prepared as described in Example 8 (0,166 g. 0,001M), 2-methoxyethanol (0.076 g. 0,001M) and dimethylaminopyridine (0.01 g.) are stirred in THF (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g., 0,001M) is added portionwise and the mixture is stirred for 3 hours. Ether (10 ml.) is added and the dicyclohexylurea is filtered off. The filtrate is evaporated and the residue is dissolved in chloroform and washed with water. Evaporation of the chloroform gives an oil which is purified on silica using ethyl acetate as eluant. There is obtained 2-methoxyethyl (1-hydroxy- 1, 4-dimethylbutyl)phosphinate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][OH:37].O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:35][CH2:36][OH:37])[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1cccc(O)c1)nn2-c1c(F)cccc1F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1cccc(OCCO)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenol (30 mg), potassium carbonate (7 mg) and 2-bromoethanol (21 μL) in DMF (3 mL) was stirred at 70° C. for 5 hr. The mixture was allowed to be cooled to room temperature, potassium carbonate (107 mg) and 2-bromoethanol (55 μL) were added thereto, and the mixture was stirred overnight at 7° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])([O-:3])=[O:2].[F-:18].[K+]>CS(C)=O>[N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([F:18])=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])([O-:3])=[O:2]
Reactant: [F-]
Reactant: N#CCOc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A suspension of 2,4-dinitro-5-chlorophenoxyacetonitrile (5.0 g) and potassium fluoride (1.7 g) in dimethylsulfoxide (25 g) was stirred at 83° to 85° C. for 1 hour. The reaction mixture was poured into ice-water (300 ml) and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and washed with ether to give crystalline 2,4-dinitro-5-fluorophenoxyacetonitrile (4.18 g; yield, 89.3%). M.P., 118°-118.5° C. (recrystallized from methanol).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24]C)=[CH:22][CH:23]=3)[N:13]=[C:12]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:11]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br.Br.C(OC(=O)C)C.Cl>C(OCC)(=O)C>[ClH:1].[NH:26]([C:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][CH:19]=2)[N:13]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(CNc2nc(Nc3ccccc3)nc(Nc3ccc(F)cc3)n2)cn1
Agent: Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1ccc(CNc2nc(Nc3ccccc3)nc(Nc3ccc(F)cc3)n2)c[nH]1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 565 mg portion of the N-(4-fluorophenyl)-N′-[(6-methoxypyridin-3-yl)methyl]-N″-phenyl-1,3,5-triazine-2,4,6-triamine hydrochloride synthesized in Invention Example 753 was mixed with 5 ml of 25% hydrobromic acid acetic acid solution and 1 ml of 48% hydrobromic acid aqueous solution and stirred at 80° C. for 6 hours. After evaporation of the reaction solution under a reduced pressure, the residue was mixed with ethyl acetate and sodium bicarbonate aqueous solution in that order and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel column chromatography and eluted with chloroform:methanol (99:1) to obtain a crude product. This crude product was dissolved in ethyl acetate and mixed with 4 M hydrochloric acid ethyl acetate solution, and the thus formed crystals were collected by filtration and dried to obtain 195 mg of 5-[({4-anilino-6-[(4-fluorophenyl)amino]-1,3,5-triazin-2-yl}amino)methyl]pyridine-2(1H)-one hydrochloride as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:22]=1[CH3:23])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8].[F:26][C:27]([F:32])([F:31])C([O-])=O.[Na+].CN1CCCC1=O>CCOCC.O.[Cu]I>[CH3:23][C:22]1[C:6]([C:7]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=2[O:20][CH3:21])=[O:8])=[C:5]([O:24][CH3:25])[CH:4]=[CH:3][C:2]=1[C:27]([F:32])([F:31])[F:26]
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(C(F)(F)F)c2C)c(OC)c1OC
Temperature: 160 °C

Procedure:
A mixture of 63C (6.15 g, 0.015 mol), sodium trifluoroacetate (9.52 g, 0.07 mol), copper-(I)iodide (13.37 g, 0.07 mol) and 1-N-methyl-2-pyrrolidinone (100 ml) is heated to 160° C. for 118 hours. The reaction mixture is cooled to room temperature and diluted with ether and water. The organic phase is separated and concentrated and the residue is purified by column chromatography (petrol ether:ethyl acetate, 95:5 v/v) yielding the pure product as white crystals, 1.3 g, (22%) having a melting point of 95-96° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[CH:12].N>>[C:13]1([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: c1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-benzene (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.70 (m, 3H), 7.78 (s, 1H), 7.87-7.98 (m, 2H), 9.34 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(OCC)(=O)C.ClCCl>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Reactant: Brc1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccccn1
Yield: 14.8 %

Procedure:
Heat a mixture of ethyl 3-aminoindole-2-carboxylate (250 mg, 1.2 mmol) and 2-bromopyridine (1.0 mL, 10 mmol) at 150° C. for 1 h. Cool the reaction and partition between aqueous ammonium chloride and ethyl acetate. Separate the organic layer and concentrate to afford a crude mixture. Flash chromatograph the mixture on silica gel eluting with 25% ethyl acetate/dichloromethane to afford 50 mg of the title compound: MS 282(M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[S:11][C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=1>>[CH2:1]([NH:8][C:16]([C:12]1[S:11][C:10]([Br:9])=[N:14][C:13]=1[CH3:15])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Yield: 60 %

Procedure:
Following the procedure as described in Preparation 7, making variations as required to use benzylamine in place of pyridin-3-ylmethanamine to react with 2-bromo-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a yellow solid in 60% yield: 1H NMR (300 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 5.99 (br s, 1H), 4.56 (d, J=5.7 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 311.2 (M+1), 313.2 (M+1).
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].Cl[C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CC(N(C)C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: COC(=O)c1csc(Cl)n1
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (5.3 g, 13.86 mmol) and methyl 2-chlorothiazole-4-carboxylate (2.5 g, 14 mmol) in DMA (60 mL) was added Cs2CO3 (25 g, 70 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to rt, acidified with 5% HCl, extracted with DCM, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% MeOH in DCM to provide 4.2 g (67%) of the desired product methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (1C): LC/MS (APCI): m/z 451.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[C@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]4)[C:20]3=[O:28])[CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: ClCCN1CCCCC1
Product: O=C1N(CCN2CCCCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 70 starting from with 1-(2-chloroethyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H25ClN2O: 380, observed (M+H)+: 371.2 1HNMR (400 MHz, MeOD-d4) δppm 1.62 (br. s., 1 H) 1.89 (br. s., 3 H) 2.05 (br. s., 2 H) 2.21-2.30 (m, 2 H) 3.09 (br. s., 2 H) 3.30 (t, J=8.59 Hz, 1 H) 3.48-3.62 (m, 2 H) 3.76 (br. s., 1 H) 3.93 (br. s., 1 H) 4.22-4.32 (m, 1 H) 4.34-4.46 (m, 1 H) 6.15 (d, J=7.58 Hz, 1 H) 6.84 (t, J=7.58 Hz, 1 H) 7.15-7.21 (m, 1 H) 7.23-7.31 (m, 3 H) 7.33-7.40 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:19][OH:20])=[C:15]([CH3:18])[CH:16]=3)[O:11][C:10](=[O:21])[CH:9]=2)=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:19]=[O:20])=[C:15]([CH3:18])[CH:16]=3)[O:11][C:10](=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc2c(-c3ccc(F)cc3)cc(=O)oc2cc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc2c(-c3ccc(F)cc3)cc(=O)oc2cc1C=O

Procedure:
4-(4-Fluorophenyl)-7-(hydroxymethyl)-6-methyl-2H-chromen-2-one (0.487 g, 1.71 mmol) in CH2Cl2 (350 mL) was stirred with activated MnO2 (2.23 g, 25.7 mmol) for 65 h at rt. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to afford the title compound. 1H NMR (500 MHz, acetone-d6): δ 10.40 (s, 1H), 7.86 (s, 1H), 7.70 (m, 2H), 7.46 (s, 1H), 7.42 (m, 2H), 6.53 (s, 1H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[NH:15][CH2:16][CH3:17])[N:11]=[C:10]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[N:15]([CH2:39][CH3:40])[CH2:16][CH3:17])[N:11]=[C:10]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:30])([CH3:31])[CH2:23]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCNc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)c1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
To a solution of 2-[5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl]-N-ethylaniline (Example 70) (25 mg, 0.06 mmol, 1 eq) in acetone (2 mL) was added potassium carbonate (84 mg, 0.6 mmol, 10 eq) and iodoethane (0.049 mL, 0.6 mmol, 10 eq), the solution heated to 60° C. overnight. The reaction was 50% complete, added iodoethane (0.049 mL) and heated to 60° C. overnight. Added water, extracted with DCM, dried over MgSO4 and concentrated. Purification by silica gel column chromatography (8 g) eluting with 7 to 15% EtOAc/hex, then purification by RP-HPLC eluting with 10 to 100% acetonitrile/H2O gave the title compound (12.4 mg, 46%).
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=O)C.[CH2:27]([O:34][CH2:35][CH2:36][NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:19]([O:18][C@@H:8]1[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6][C@H:5]2[C@H:10]([N:11]=[C:12]([NH:37][CH2:36][CH2:35][O:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:13]2)[C@H:9]1[O:14][C:15](=[O:17])[CH3:16])(=[O:21])[CH3:20]
Reactant: NCCOCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (9.8 g, 25 mmol) in dichloromethane (100 mL) was added 128 (4 g, 26 mmol) at 0° C. After stirred for 2 hours, trifluoroacetic acid (15.4 g, 159 mmol) was added. The resulting solution was stirred for 12 hours at room temperature, then quenched with ice-water (200 mL) and neutralized by the addition of NaHCO3 (26 g, 318 mmol). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by silica gel column, eluted with 10%-50% ethyl acetate in petroleum ether to afford 129 as a white syrup (9.8 g, 77%). (ES, m/z) [M+H]+ 481.0; 1H NMR (300 MHz, CDCl3) δ 7.31-7.38 (m, 5H), 6.24 (d, J=6.3 Hz, 1H), 5.41-5.43 (m, 1H), 4.94-4.98 (m, 1H), 4.55 (s, 2H), 4.34-4.37 (m, 1H), 4.14-4.16 (m, 3H), 3.83-3.87 (m, 1H), 3.64 (t, J=5.4 Hz, 2H), 3.53 (t, J=5.1 Hz, 2H), 2.12 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]N.COCCOCCN(CCOCCOC)CCOCCOC>CS(C)=O>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:1][C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)CCN
Reactant: Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(NCCN(C)C)c1
Yield: 80 %

Procedure:
To a stirred solution of 3,4-dinitrotoluene (3.64 g, 20 mmol) and N,N-dimethylethylenediamine (1.76 g, 20 mmol) was heated at 80° C. in dimethyl sulfoxide and catalytic amount of TDA-1 for 2 hours. N,N-Dimethyl-2-(5-methyl-2-nitroanilino)ethanamine was isolated in 80% yield (3.6 g, 16 mmol) after aqueous work-up. Quaternization was achieved in quantitative yield with methyl iodide and dimethylformamide. Its melting point was 225°-7° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[C:10]([CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)[N:11]=1.[Br:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[CH2:44][CH2:43]2>C1COCC1>[Br:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45]([CH2:6][C:7]1[N:8]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=[C:10]([CH2:12][C:13]3([C:16]([F:17])([F:18])[F:19])[CH2:14][CH2:15]3)[N:11]=1)([OH:49])[CH2:44][CH2:43]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: Cc1nc(CC2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (14.8 mL, 23.7 mmol) was added to a solution of 2-methyl-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazole (7.05 g, 15.8 mmol) in THF (30 mL) at −78° C. After 5 min, a solution of 5-bromoindan-1-one (5 g, 23.7 mmol) in THF (2 mL) was added dropwise to the reaction mixture. The solution was stirred at −78° C. for 2 h. The reaction was quenched with the addition of saturated aqueous NH4Cl. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography eluting with 0-100% EtOAc/hexanes to give 5-bromo-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Oc1cnccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccncc3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (100 mg, 0.23 mmol), 2-hydroxypyrazine prepared above (43 mg, 0.45 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMSO (1 mL) was degassed before being charged with CuI (21 mg, 0.11 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the title compound (15 mg). MS 412.0 and 414.0 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][N:2]([C@@H:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][CH3:25])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].Cl>CCOCC.O1CCOCC1>[CH3:1][N:2]([C@@H:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:24][CH3:25])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl 4-[4-[[methyl[(1R)-1-phenylpropyl]amino]carbonyl]-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step D) (3.6 g, 8.1 mmol) was dissolved in 100 mL of ether and treated with 20 mL of 4 N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 4 h during which time a precipitate formed and was collected. The mother liquid was concentrated under reduced pressure, treated with 20 mL of 4 N HCl in dioxane, stirred at ambient temperature for 1 h and concentrated under reduced pressure. The residue was combined with the previously collected precipitate, dissolved in water and washed with ether. The aqueous layer was basified with 1 N aqueous NaOH solution and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure to give 2.33 g of the title compound as an orange oil suitable for use in subsequent reactions.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[S:38])[CH3:28].N1CCCCC1>ClCCl>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:17]/[C:15]2[O:16][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=3)=[CH:13][CH:14]=2)/[S:34][C:33]1=[S:38])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\SC(=S)N(CC(=O)OCC)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (7 mg, 0.015 mmol) and ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (3.5 mg, 0.016 mmol) synthesized by the same method as in Example 1 were dissolved in dichloromethane (2 mL), piperidine (5 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give labeling precursor 1 in a yield of 6 mg (yield 56.6%).