Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.[F:37][CH2:38][C:39](OCC)=[O:40]>C1COCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:39](=[O:40])[CH2:38][F:37])[CH:31]=1
Reactant: CCOC(=O)CF
Reactant: Fc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(CF)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A 2.0 M solution of LDA in heptane/THF/ethylbenzene (100 mL, 200 mmol) was added dropwise via syringe to a solution of 1-bromo-4-fluorobenzene (20 mL, 182 mmol) in THF (600 mL) at −78° C. After stirring for 2.5 hours at −78° C., ethyl monofluoroacetate (18.47 mL, 191 mmol) was added dropwise via syringe, and the reaction was stirred at −78° C. for 20 minutes and then stirred at −45° C. for 30 minutes before being quenched with saturated aqueous ammonium chloride at −45° C. The mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous ammonium chloride, water, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was dissolved in a minimal amount of methanol and placed in a −20° C. freezer overnight. The resulting solid was collected and washed with cold methanol to afford the title intermediate (12.07 g, 51.6 mmol, 28% yield) as a white solid.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CCCCCCCCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(n-Octyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and n-octyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.Cl>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][C:11]=4[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 22 h
Yield: 83.7 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (408 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (125 g) were dissolved in N,N-diethylaniline (1.5 L) at 160° C. (internal temperature). A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL) in N,N-diethylaniline (400 mL) was added dropwise over 30 min, and the mixture was stirred at 180° C. (internal temperature) for 22 hr. The reaction mixture was cooled to room temperature, and ethyl acetate (1 L) and 3M hydrochloric acid (1 L) were added. The mixture was transferred into a separatory funnel with ethyl acetate (2 L) and 3M hydrochlorid acid (1 L). The organic layer was successively washed with 3M hydrochloric acid (2 L) twice and brine (2 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound as a brown solid (246 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([SH:18])=[CH:10][C:9]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[CH:21]([Li])(CC)C.CN(C=O)C>C1COCC1>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[CH:10][C:11]([SH:18])=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=2)[CH:19]=[CH:21]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Reactant: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(S)c(C(C)(C)C)cc21
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acid tert-butyl ester (prepared in Example EE; 20 g, 68 mmol) was dissolved in 100 mL of THF, cooled to −40° C., and treated dropwise with sec-butyllithium (1.3 M, 156 mL, 203 mmol). After the addition was complete, the reaction mixture was stirred at −30° C. to −45° C. for 30 minutes. To the mixture was added DMF (14.8 g, 203.39 mmol), and the solution was stirred at −35° C. for 30 minutes. The reaction mixture was slowly warmed to room temperature and was quenched with saturated NH4Cl solution. EtOAc (200 mL) was added; the organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was dissolved in 100 mL of THF and 2 mL of concentrated HCl and stirred at room temperature for 1 hour. The solution was diluted with EtOAc, washed with NaHCO3 solution and brine, and dried (MgSO4). The crude product was purified by flash silica gel chromatography to give the title compound. MS(APCI): 304 (M−H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[H][H].C1OCCOCCOCCOCCOC1.Br[CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32]>CN(C=O)C.O>[CH3:32][O:31][CH:30]([O:33][CH3:34])[CH2:29][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Oc1cccc(I)c1
Reactant: [H][H]
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1cccc(I)c1)OC
Temperature: 130 °C
Yield: 84.9 %

Procedure:
3-Iodophenol (5.35 g, 24.3 mmol) was added to a suspension of NaH (1.46 g, 36.5 mmol, 60% in mineral oil) in anhydrous DMF (30 mL) at 0° C. After hydrogen evolution had ceased, 15-crown-5 (0.535 g, 2.43 mmol) and 2-bromo-1,1-dimethoxyethane (7.1 g, 42 mmol) were added. The resulting mixture was heated at 130° C. for 3 h, cooled to room temperature, poured into water (200 mL), and extracted with Et2O (3×150 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:50) to afford the title compound (6.36 g, 85%). 1H NMR (DMSO-d6, 400 MHz): δ 7.32 (s, 1H), 7.30-7.26 (m, 1H), 7.07 (t, 1H), 7.00-6.94 (m, 1H), 4.66 (t, 2H), 3.98 (d, 1H), 3.33 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[NH2:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[NH:27][S:46]([C:43]1[CH:44]=[CH:45][C:40]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:41][CH:42]=1)(=[O:48])=[O:47])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a stirring solution of (2S)-(2-amino-5-bromo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 2 mmol) prepared above dissolved in DCM containing pyridine (1.58 g, 4 mmol), was added 4-tert-butylbenzenesulfonyl chloride (1.20 g, 2.5 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h, extracted with DCM, washed with 1M HCl and brine, and was concentrated in vacuo, followed by column chromatography purification (silica, CH2Cl2) giving 3-biphenyl-4-yl-2-[5-bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-propionic acid methyl ester (1.25 g) as a white solid which was hydrolyzed according to Procedure C yielding the title compound (1.23 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.Cl[S:13]([C:16]1[C:25]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14].[O-:32][C:33]#[N:34].[Na+].N1C=CC=CC=1>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:33]([NH:34][S:13]([C:16]2[C:25]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:32])[N:7]=1
Reactant: N#C[O-]
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)CNc1cccc(C(=O)OC)c1S(=O)(=O)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)CNc1cccc(C(=O)OC)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In succession, 0.54 g of 2-amino-4,6-dimethoxypyrimidine and 1.50 g of methyl 2-chlorosulfonyl-3-(N-methoxycarbonylmethylamino)benzoate are added at room temperature to a suspension of 0.61 g of sodium cyanate, 0.8 ml of pyridine and 18 ml of acetonitrile. The reaction mixture is stirred at room temperature for 3.5 h and then poured into ice-water. For purification the sulfonylurea which is separated out is stirred in a little methanol, separated off by means of filtration and dried. The resulting N-[(4,6-dimethoxypyrimidin-2-yl)amino-carbonyl]-2-methoxycarbonyl-6-(N-methoxycarbonylmethylamino)benzenesulfonamide is obtained as a colorless solid (1.35 g) 150°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Cl)=[CH:4][CH:3]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCCc1ccc(Cl)cc1
Product: Clc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]

Procedure:
Combine 15.0 g (0.086 mole) of 2-(4-chlorophenyl)ethyl chloride and 20.98 g (0.08 mole) of triphenylphosphine. Heat the mixture under a nitrogen atmosphere at 110°-120° C. for 3.5 days. Follow the progress of the reaction by thin layer chromatography on silica gel (hexanes). At the completion of the reaction triturate the resulting solid with 250 ml of anhydrous ether to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)#[N:2].II.CS(C)=[O:14]>>[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1)=[O:14]
Reactant: CS(C)=O
Reactant: Cc1ccc(C#N)cn1
Agent: II
Product: N#Cc1ccc(C=O)nc1
Temperature: 150 °C

Procedure:
A mixture of 5-cyano-2-methylpyridine (400 mg, 3.38 mmol) and iodine (0.8 g, 3.15 mmol) in DMSO (2 mL) was heated to 150° C. under nitrogen for 20 min. The reaction mixture was cooled to room temperature and quenched with 10% aqueous NaHCO3 solution. The organic product was extracted with EtOAc and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get the crude 6-formylnicotinonitrile (400 mg), which was carried through without further purification. 6-Formylnicotinonitrile (400 mg, 3.03 mmol) was dissolved in 1,2-dichloroethane (5 mL) and cooled to 0° C. A solution of tert-butyl 2-methylpiperazine-1-carboxylate (606 mg, 3.03 mmol) in 1,2-dichloroethane (5 mL), followed by sodium triacetoxyborohydride (1.1 g, 5.4 mmol) were added and the reaction mixture was allowed to warm up to room temperature and further stirred for 8 h. The reaction mixture was quenched with 10% aqueous NaHCO3 solution and the product was extracted with EtOAc.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2].[Se](=O)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH:14]=[O:24])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cn(CC)c2nc(C)c(OCC)cc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(C=O)c(OCC)cc2c1=O
Yield: 62.5 %

Procedure:
20.2 g of the Compound VIII obtained as above was heated at 175°-185° C. under a nitrogen stream to melt and 10 g of selenium dioxide was added in several portions. Under a nitrogen stream, the mixture was reacted under the same conditions for 20 minutes. After allowing to cool, chloroform was added to the reaction mixture and the insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was recrystallized from ethanol to yield 13.2 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 169°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:19])[C:5]=2[NH:4][N:3]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[C:28]=1[CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:36](=O)[CH2:37]CCl)[CH2:32][CH2:31]1>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:19])[C:5]=2[N:4]([C:20](=[O:23])[CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:28]3[C:41]([CH3:46])=[CH:42][C:43]([CH3:45])=[CH:44][C:27]=3[CH3:26])[CH2:31][CH2:32]2)[N:3]=1
Reactant: COc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: Cc1cc(C)c(CN2CCN(C(=O)CCCl)CC2)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(Cc5c(C)cc(C)cc5C)CC4)c3C2=O)cc1

Procedure:
A target compound (81.2 mg, 0.153 mmol, 32.9%) was yielded as white solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (120 mg, 0.464 mmol) with potassium carbonate (96.2 mg, 0.696 mmol) and 1-{4-(2,4,6-trimethylbenzyl)piperazin-1-yl}-3-chloropropan-1-one (157.5 mg, 0.510 mmol).
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:9][S:10]([O:8][CH2:7][C:5]1[N:6]=[C:2]([Cl:1])[O:3][CH:4]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1coc(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1coc(Cl)n1
Reaction time: 1 h

Procedure:
A solution of (2-chloro-1,3-oxazol-4-yl)methanol (5 g, 37.44 mmol, 1 eq, prepared according to the method described in Tetrahedron Lett. (2004), 45, 3797-3802) in dichloromethane (250 ml) is reacted with methanesulfonyl chloride (3.19 ml, 41.19 mmol, 1.1 eq) in the presence of triethylamine (5.79 ml, 41.19 mmol, 1.1 eq) at 0° C. After 1 h 30, the mixture is poured into a saturated solution of ammonium chloride and extracted twice with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to afford 7.9 g of (2-chloro-1,3-oxazol-4-yl)methyl methanesulfonate i59. This product is used in the next step without further purification or analysis.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1F)[C:6]([NH:8][C@H:9]([C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[N:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])#[N:2].C(C1C=C(C=CC=1F)C(O)=O)#N.C([N:48](CC)CC)C.F[P-](F)(F)(F)(F)F.[N:60]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:61]1>C1COCC1.O>[NH2:2][C:1]1[C:3]2[C:32](=[CH:31][CH:30]=[C:5]([C:6]([NH:8][C@H:9]([C:17]3[NH:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:48])[NH2:29])=[CH:24][CH:23]=4)[N:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:7])[CH:4]=2)[NH:61][N:60]=1
Reactant: N#Cc1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccc(F)c(C#N)c3)n2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCN(CC)CC
Agent: F[P-](F)(F)(F)(F)F
Agent: N#Cc1cc(C(=O)O)ccc1F
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)c1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccc4[nH]nc(N)c4c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Part B: 3-Cyano-N—{(S)-1-[4-(4-cyano-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-4-fluoro-benzamide: A mixture of the compound of Example 176 Part A (100 mg, 0.28 mmol), 3-cyano-4-fluorobenzoic acid (46 mg, 0.28 mmol), triethylamine (0.085 mL, 0.61 mmol) and BOP (0.18 g, 0.4 mmol) in THF (5 mL) was stirred at rt overnight under N2. Reaction mixture was diluted with water and extracted 3× with EtOAc. The combined extracts were washed with sat'd. NaHCO3 and brine and then dried over anhydrous Na2SO4, filtered and evaporated. Chromatography on silica gel (hexane/EtOAc) provided the amide product (88 mg, 72%). 1H NMR (500 MHz, CDCl3) δ 3.41 (dd, J=13.75, 7.15 Hz, 1H) 3.58 (dd, J=13.47, 7.97 Hz, 1H) 5.33 (q, J=7.70 Hz, 1H) 7.01-7.09 (m, 1H) 7.18-7.37 (m, 7H) 7.66 (d, J=8.25 Hz, 2H) 7.85 (d, J=8.25 Hz, 2H) 7.89-7.96 (m, 1H) 7.95-8.03 (m, 1H) 9.74 (s, 1H). m/z 436.1 (M+H)+.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:22][S:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH2:14][CH2:15][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[OH:11][N:12]([C@H:13]([CH2:22][S:23]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:34][N:33]=2)[CH2:30][CH2:31]1)(=[O:25])=[O:24])[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][CH:19]=[CH:20][N:21]=1)[CH:1]=[O:2]
Reactant: O=CO
Reactant: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)[C@@H](CCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 906.9 %

Procedure:
To formic acid (54 mL, 1.4 mol) at 8° C. was added acetic anhydride (11 mL, 100 mmol) and the mixture was stirred at RT for 10 minutes. The mixed anhydride was then recooled to 8° C., and added to a solution, pre-cooled to 0° C., 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine (16.32 g, 33.3 mmol) in DCM (170 mL) and formic acid (65 mL, 1.7 mol). The reaction was brought to room temperature and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×50 mL). The residue was then dissolved in MeOH/DCM (1:1, 250 mL) and stirred overnight at room temperature. The solution was then concentrated in vacuo, and partitioned between DCM (250 mL) and sat. NaHCO3 (250 mL). The DCM layer was then filtered through silica gel (20 g) washing with 5% MeOH/DCM and the volatiles removed in vacuo to give the racemic title compound as a pale yellow foam (15.68 g, 302 mmol, 91%).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][CH:36]([C:39]([NH:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[O:40])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][CH:36]([C:39]([NH:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[O:40])[CH2:35][CH2:34]1
Reactant: CCC(CC)NC(=O)C1CCN(c2cc(F)c(OC)cc2F)CC1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: CCC(CC)NC(=O)C1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 59.3 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-(2,5-difluoro-4-methoxyphenyl)-N-(1-ethylpropyl)-4-piperidine-carboxamide (167 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=12:1) to provide 1-(2,5-difluoro-4-hydroxyphenyl)-N-(1-ethylpropyl)-4-piperidinecarboxamide (95 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[N:28]1([C:33]2[N:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][N:34]=2)[CH:32]=[N:31][N:30]=[N:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[N:28]1([C:33]2[N:34]=[CH:35][C:36]([CH2:39][C:40]([N:18]3[CH2:17][CH2:16][N:14]4[CH2:15][C@H:10]([C:5]5[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=5[CH3:27])[N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:12][C@@H:13]4[CH2:19]3)=[O:41])=[CH:37][N:38]=2)[CH:32]=[N:31][N:30]=[N:29]1
Reactant: Cc1c([C@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (46 mg, 0.123 mmol) and 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetic acid (30.4 mg, 0.147 mmol) in DMF (2 mL) was added HATU (70.1 mg, 0.184 mmol) and diisopropylethylamine (64.4 μl, 0.369 mmol) and the resulting solution was stirred at rt for 1 h. Ethyl acetate (50 mL) was added and the organic phase was washed with brine (3×50 mL), dried over sodium sulphate, concentrated and the residue was purified on TLC using 10% methanol/methylene chloride to give title compound, LC/MS: [(M+23)]+=585.23; [(M+1-100-28)]+=435.20.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1cccnc1

Procedure:
Following General Procedure BF and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 62°-64° C. The reaction was monitored by tlc on silica gel (Rf=0.48 10% methanol/dichloromethane) and purification was by silica gel chromatography.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5](SC)C(C)[CH:3]1CN.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][NH2:23].[C:24](#[N:26])C>>[CH3:24][N:26]1[CH2:5][C:6]([N+:8]([O-:10])=[O:9])=[C:7]([NH:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[N:2]([CH3:1])[CH2:3]1
Reactant: CSC1=C([N+](=O)[O-])CN(C)C(CN)C1C
Reactant: NCc1ccccn1
Reactant: CC#N
Product: CN1CC([N+](=O)[O-])=C(NCc2ccccn2)N(C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 0.61 g of 1,3-dimethyl-4-methylthio-5-nitro-1,2,3,6-tetrahydropyridylmethylamine, 0.357 g of 3 pyridylmethylamine and 6 ml of acetonitrile was stirred at room temperature for 5 hours. The reaction mixture was then concentrated and purified by column chromatography (eluent: dichloromethane-methanol (10:1)) to give 0.33 g of 1,3-dimethyl-4-(pyridylmethylamino)-5 nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 31) as a syrup.