Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23](OCC)=[O:24])(=O)[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][NH:34][NH2:35])=[CH:31][CH:30]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:24])[N:34]([CH2:33][C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)[N:35]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNCc1ccc(F)cc1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (65 mg, 0.18 mmol) and 4-fluorobenzyl hydrazine (0.12 g, 0.88 mmol), and acetic acid (3 drops) in toluene (40 mL) was heated in a sealed tube at 120° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluted with 1-5% methanol in ethyl acetate gradient to provide titled product.
Reaction SMILES: [O:1]1CCO[CH2:3][CH2:2]1.Cl.[C:8]1([CH:15]=[CH:14][CH:13]=[C:11]([OH:12])[CH:10]=1)[OH:9].[Cl:16]CC#N>[Cl-].[Cl-].[Zn+2].O>[Cl:16][CH2:3][C:2]([C:13]1[CH:14]=[CH:15][C:8]([OH:9])=[CH:10][C:11]=1[OH:12])=[O:1]
Reactant: N#CCCl
Reactant: Oc1cccc(O)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=C(CCl)c1ccc(O)cc1O
Temperature: 27 °C
Reaction time: 9 h

Procedure:
A 100L round bottomed flask (RBF) containing 34.0 L of 1,4-dioxane was charged with 5.0 kg of HCl gas through a subsurface line. Resorcinol (10.0 kg) was then added as a solid, followed by addition of solid ZnCl2 (6.20 kg). A slight exotherm from 21 to 29° C. occurred after the ZnCl2 addition. The mixture was cooled with an ice/water bath, and chloroacetonitrile (7.50 kg) was added in portions over 2 h while maintaining the temperature at <40° C. The reaction mixture was aged 9 h at room temperature, and then water (34 L) was charged over 0.5 h. An exotherm to 40° C. occurred at the beginning of the water addition, and the reaction eventually cooled to 27° C. by the end of the addition. The resulting slurry was aged for 11 h at room temperature. More water (14L) was added, and the slurry was cooled to 0° C. The slurry was filtered, washed with water (4×20L), and then dried under a fast flow of nitrogen. After 5 days of drying, the chloroketone 2 was isolated as a light pink solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=3)[NH2:19])[C:10]=2[CH:9]=[CH:8]1.CCN(C(C)C)C(C)C.[CH3:34][C:35](=[CH2:39])[C:36](Cl)=[O:37]>ClCCl>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:19][C:36](=[O:37])[C:35]([CH3:39])=[CH2:34])[CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc(N)c3)ncnc21
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (10.0 g, 29.4 mmol) in dichloromethane (200 mL), was added DIPEA (12.0 g, 92.9 mmol) followed by dropwise addition of a solution of 2-methylprop-2-enoyl chloride (4.60 g, 44.0 mmol) in dichloromethane (50 mL) at −5 to 0° C. The reaction was stirred overnight at room temperature, quenched by addition of water (150 mL), and extracted with dichloromethane (×3). The organic layers were combined, washed with water and HCl solution (0.5 M in water), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C22H29N4O2Si [M+H]+: 409, found 409.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)[CH:29]([C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)[OH:30]
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CSc1nccc(C=O)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(c1ccc(F)cc1)C(O)c1ccnc(SC)n1
Reaction time: 0.75 h
Yield: 76 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (21.4 mL of 2M solution in THF, 42.8 mmol) in THF (70 mL) is added dropwise a solution of methyl 4-fluorophenyl-acetate (6.0 g, 35.7 mmol) in THF (30 mL). The solution is stirred for 1 hour at −78° C. after which a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1, (6.0 g, 39.3 mmol) in THF (30 mL) is added dropwise to the reaction mixture. Stirring is continued for 45 minutes at −78° C. then the reaction is quenched by pouring the reaction solution into aqueous saturated NH4Cl. The aqueous phase is extracted with ethyl acetate. The organic phases combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue is purified over silica (33% EtOAc/hexanes) to afford 8.7 g (76%) of the desired product as a mixture (1:1) of diastereomers.
Reaction SMILES: [N:1]1([C:6]2[CH:21]=[CH:20][C:9]([CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12]([O:14]C)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:16]([CH2:17][CH3:18])=[N:27][C:26]4[C:28]([C:12]=3[OH:14])=[CH:29][C:23]([Br:22])=[CH:24][CH:25]=4)=[CH:20][CH:21]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccc(Br)cc1
Reactant: CCC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(-n2cccn2)cc1
Temperature: 220 °C
Reaction time: 2 h

Procedure:
A mixture containing methyl 2-(4-(1H-pyrazol-1-yl)benzyl)-3-oxopentanoate (2.7 g, 9.4 mmol, Intermediate 32: step b), 4-bromoaniline (1.6 g, 9.4 mmol), and para-toluenesulfonic acid monohydrate (162 mg, 0.943 mmol) in diphenyl ether (31 mL) was heated to 220° C. After 2 hours, the flask was cooled to 23° C. Diethyl ether (50 mL) was added resulting in the formation of a solid. The heterogeneous mixture was stirred at 23° C. After 30 minutes, the mixture was filtered through filter paper and the filter cake was rinsed with diethyl ether. The solids were collected and dried to afford the title compound which was taken onto the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[C:19]1(=O)[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:3]3[C:4](=[O:8])[NH:5][N:6]([CH3:7])[C:2]=3[NH:1][C:19]3[CH2:23][CH2:22][C:21](=[O:24])[C:20]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1CCC(=O)C1
Solvent: CCO
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.23 g, 2 mmol), prepared as described in (C. Taylor and J. Barton, J.Am.Chem. Soc., (1959) 81, 2448), 3-bromo-4-fluorobenzaldehyde (0.4 g, 2 mmol), and 1,3-cyclopentanedione (0.2 g, 2 mmol) in ethyl alcohol (4 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction was cooled and the resulting precipitate was filtered off to provide 0.6 g (79%) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.3 (t, 2H), 2.69 (m, 2H), 3.5 (s, 3H), 4.7 (s, 1H), 7.15 (m, 1H), 7.2 (t, 1H), 7.39 (dd, 1H), 9.56 (s, 1H), 10.42 (s, 1H); MS (ESI+) m/z 380 (M+H)+; Anal. calcd for C16H13N3BrFO2.C2H6O: C, 50.96; H, 4.51; N, 9.90. Found: C, 50.51; H, 4.58; N, 9.79.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(O)CCC>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: COc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1ccnc(N2CCN(C(=O)c3ccco3)CC2)n1
Yield: 70.2 %

Procedure:
A solution of 1.0 g (6.92 mmol) of 2-chloro-4-methoxypyrimidine, 1.49 g (8,30 mmol) of 1-(2-furylcarbonyl)piperazine and 1.39 g (13.84 mmol) of triethylamine in 20 mL of n-butanol is maintained under gentle reflux conditions overnight. The solvent is evaporated off under reduced pressure and the crude residue is diluted in chloroform and washed in water. The organic phase is dried over NaSO4 and evaporated to dryness to give a crude product which is purified using silica-gel chromatography eluting with ethyl acetate/petroleum ether 70:30 to yield an oil which solidifies when left to stand. The solid is suspended in petroleum ether to yield 1.4 g (4.86 mmol) of 2-[4-(2-furylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine. m.p.=85-86° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH:2]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Yield: 42.4 %

Procedure:
A solution of 6-hydroxymethyl-1H-indole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 31; 5.10 g, 20.6 mmol) and o-iodoxybenzoic acid (prepared by the literature procedure: Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022; 8.00 g, 28.6 mmol) in dimethylsulfoxide (25 mL) was stirred at room temperature for 4 h. Water (200 mL) was added and the solution was extracted with dichloromethane (3×100 mL). The combined extracts were washed with brine (200 mL), dried (MgSO4), filtered, evaporated in vacuo. The residual material was chromatographed over silica gel (20-30% ethyl acetate/hexanes) to give 6-formyl-1H-indole-1-carboxylic acid, 1,1-dimethylethyl ester (2.14 g, 42% yield) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30](=[O:29])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[N:8]3
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3nc(SCCCCCNC(=O)C(F)(F)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 231 mg (1.20 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 15 hours at room temperature, and the the solvent was distilled off. To the residue was added ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 245 mg (58.1%, a pale brown solid) of the desired compound.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([F:46])[C:43]([F:47])=[CH:42][C:41]=4[F:48])[C:38]([CH3:49])=[C:37]([OH:50])[C:36]3=[O:51])=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([F:46])[C:43]([F:47])=[CH:42][C:41]=4[F:48])[C:38]([CH3:49])=[C:37]([O:50][CH3:3])[C:36]3=[O:51])=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cc(F)c(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OCCO
Product: COC1=C(C)C(c2cc(F)c(F)cc2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 g, 267.8 mmol in water), diazald (20 g, 93.37 mmol 5 eq) ethylene glycol/Et2O (2/1 v/v, 140 mL), 1-(1H-benzo[d]imidazol-5-yl)-5-(2,4,5-trifluorophenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (2 g, 5.57 mmol, 1 eq) and MeOH (50 mL); yield: 1.05 g (50.55%); MS m/z: 374.0 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.44 (s, 1H); 8.17 (s, 1H); 7.66 (s, 1H), 7.52-7.10 (m, 4H); 6.00 (s, 1H); 3.96 (s, 3H); 1.78 (s, 3H); HPLC (METHOD [A]): rt 12.37 min (98.7%)
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:10])([CH3:9])[CH2:4][C:5](=[O:8])[O:6]2.[CH3:11][C:12]([CH3:15])([OH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:11][C:12]([CH3:15])([O:14][CH:7]1[O:6][C:5](=[O:8])[CH2:4][C:3]([CH3:10])([CH3:9])[CH:2]1[OH:1])[CH3:13]
Reactant: CC1(C)CC(=O)OC2OC21
Reactant: CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC1OC(=O)CC(C)(C)C1O
Temperature: 25 °C
Reaction time: 41 h

Procedure:
A mixture of 500 mg of 5,6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one, 5 ml of 1,1-dimethyl ethanol and 2.5 mg of p-toluene sulfonic acid was stirred for 41 hours at room temperature and 1 ml of pyridine was then added. The mixture was evaporated to dryness under reduced pressure to obtain 6-(1,1-dimethylethoxy)-5-hydroxy-4,4-dimethyl-tetrahydro-pyr-2-one which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.C([N:13]([CH2:17][CH3:18])C(C)C)(C)C.O.[C:20](OCC)(=O)C>O1CCCC1.C(N)CC>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH2:17][CH2:18][CH3:20])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CCOC(C)=O
Solvent: CCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-5-iodopyrimidine (5.77 g) synthesized according to the method described in WO2008/155140 A1 and N,N-diisopropylethylamine (7.86 mL) in tetrahydrofuran (83 mL), propylamine (3.55 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with 1.0 mol/L aqueous hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain oily 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 6.44 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C=O.O.[C:41]([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:41])[CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: CCN(c1cc(C#CC2CCNCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(c1cc(C#CC2CCN(C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(piperidin-4-ylethynyl)benzamide (100 mg, 0.198 mmol) in methanol (5 mL) was added 35% formaldehyde in H2O (0.155 mL, 1.98 mmol) at 0° C. After stirring at 0° C. for 10 min, sodium cyanoborohydride (24.9 mg, 0.396 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. LCMS indicated that the reaction was completed. The reaction was quenched with sat. NaHCO3/brine and extracted with EtAOc/Heptane. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (10 g column, MeOH/DCM=1:9, and then MeOH/7 M NH3 in MeOH/DCM=1:1:8) to afford the titled compound (96.0 mg, 93%). 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (brs, 1H), 7.08 (brs, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 3.94-3.87 (m, 2H), 3.35-3.30 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 3.04-2.97 (m, 1H), 2.79-2.71 (m, 2H), 2.67-2.58 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.28-2.21 (m, 2H), 1.97-1.91 (m, 2H), 1.78-1.67 (m, 4H), 1.64-1.54 (m, 2H), 0.85 (t, J=7.0 Hz, 3H); MS (ESI) [M+H]+519.4.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].FC(F)(F)C(O)=O.[NH:45]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:46]([C:55](O)=[O:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1>CN(C=O)C>[NH:45]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:46]([C:55]([NH:1][C@@H:2]([C:8]([NH:10][CH2:11][C:12]([N:14]([CH3:30])[C@H:15]([C:23]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:56])[CH2:47][C:48]1[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=1
Reactant: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reaction time: 15 h

Procedure:
0.60 g of BOC-(D)-Gln-Gly-MePhe-NHNHCSNH2 is treated with trifluoroacetic acid and dissolved in 10 ml of DMF. The solution is neutralized with 0.19 ml of TEA, and 0.54 g of Z-Tyr ONB is added. The mixture is stirred for 15 hours. The DMF is distilled off and the residue is treated with ethyl acetate and filtered to obtain a powder, which is further reprecipitated from methanol-ether. Yield 0.54 g; m.p. 128°-133° C.; [α]D24 -72.4° (c=1.1, DMF); Rf1 0.13.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:22][NH2:23].Br.C(S[C:28](=[NH:30])[NH2:29])C.[OH-].[Na+]>CO>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([C:3]2[N:30]=[C:28]([NH2:29])[N:23]([CH3:22])[CH:2]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCSC(=N)N
Reactant: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)CBr)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Cc2ccc(Br)cc2)c2cn(C)c(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
1-bromo-4-(4-bromophenyl)-3-(4-methoxyphenyl)butan-2-one (0.15 g, 0.36 mmol) was dissolved in methanol (1.8 mL) and methylamine (0.36 mL, 0.72 mmol, 2M solution in methanol) was added in one portion and the reaction was allowed to stir at 25° C. for 0.5 hour. S-ethylisothiourea hydrobromide (0.27 mg, 1.46 mmol) and NaOH (0.61 mL, 1.82 mmol, 3M solution in water) were added to the solution and the resulting solution was allowed to stir at 25° C. for 16 hours. The reaction was purified using reverse phase C-18 chromatography (acetontitrile and water system) to afford 140 mg of 4-[2-(4-bromophenyl)-1-(4-methoxyphenyl)ethyl]-1-methyl-1H-imidazol-2-amine as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 32 g of N-benzyloxycarbonyloxysuccinimide in 100 ml of tetrahydrofuran is reacted with 15 g of 6-amino-1-hexanol in 30 ml of 50% methanol:tetrahydrofuran. The reaction mixture is stirred overnight at room temperature, and poured into water. The resulting mixture is extracted with methylene chloride and the organic layer is washed with sodium chloride solution, dried over anhydrous magnesium sulfate. The magnesium sulfate is filtered and the solvent is removed by evaporation. The product is recrystallized from ethyl acetate/ether to provide N-(benzyloxycarbonyl)-6-amino-1-hexanol, mp 81.5°-83° C. having the following formula: ##STR32##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74-6.68 (m, 12H), 5.08-4.99 (m, 1H), 3.67-3.56 (m, br, 2H), 3.02-2.82 (br, 2H), 2.80-2.57 (m, br, 4H), 2.57-2.38 (m, br, 2H), 2.05-1.80 (m, br, 6H), 1.64-1.40 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C32H39Cl2FN2O2.1.3EtOAc: C, 64.93; H, 7.24; N, 4.07. Found: C, 65.01; H, 6.97; N, 3.85. ESMS m/e: 537.1 (M+H)+.