Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]=2[N:10]=[CH:9]1.[Cl:22][C:23]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH:9]=[N:10][C:11]=2[CH:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:26]
Reactant: CCOC(=O)C1NCCc2c1ncn2-c1ccccn1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A mixture of ethyl 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylate hydrochloride (0.050 g, 0.18 mmol), 2-chloro-3-trifluoromethyl benzoic acid (0.045 g, 0.20 mmol), HATU (0.077 g, 0.20 mmol), and DIPEA (0.035 mL, 0.20 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH (NH3):DCM) gave the title compound (26 mg, 30%). 1H NMR (500 MHz, CDCl3) δ 8.58-8.45 (m, 1H), 8.10-7.98 (m, 1H), 7.94-7.82 (m, 1H), 7.82-7.72 (m, 1H), 7.63 (dd, J=7.6, 1.3 Hz, 1H), 7.55-7.28 (m, 3H), 6.23 (dd, J=12.3, 6.3 Hz, 1H), 5.25-5.00 (m, 1H), 4.48-4.06 (m, 2H), 4.01-3.60 (m, 3H), 3.50-2.85 (m, 3H). MS (ESI): mass calculated for C22H18ClF3N4O3, 478.1. m/z found 479.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[Br:23][CH2:24][C:25](Cl)=[O:26]>ClCCl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[Br:23][CH2:24][C:25]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:26]
Reactant: O=C(Cl)CBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2
Reaction time: 8 h

Procedure:
A mixture of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (0.19 g, 0.91 mmol) and triethylamine (0.5 mL, 3.7 mmol, Aldrich) in dichloromethane was treated with dropwise addition of bromoacetyl chloride (0.33 mL, 4.0 mmol, Fluka). A catalytic amount of 4-dimethylaminopyridine was added and the reaction stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-(bromoacetyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline which was taken directly to the next step without determination of yield. RF=0.3 (50% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:13]=[O:14])[C:11]=2[N:12]=1.[BH4-].[Na+].C1COCC1.O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([N:12]=1)=[C:10]([CH2:13][OH:14])[CH:9]=[CH:8][CH:7]=2
Reactant: COc1cnc2cccc(C=O)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cnc2cccc(CO)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred suspension of 3-methoxy-quinoxaline-5-carbaldehyde (prepared as described in WO 2006/032466, 5.0 g, 26.57 mmol) in EtOH (200 mL) cooled at 0° C., NaBH4 (1.1 g) was added in one portion. The reaction mixture was warmed to rt and THF (50 mL) was added. A clear solution was obtained. The mixture was further stirred at rt for 30 min. Water (200 mL) was added and the volatiles were removed in vacuo. The residue was filtered off, washed with water. The solid was dried under HV to afford the title alcohol as a brown solid (4.8 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.[NH2:17][NH2:18].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:17][NH2:18])[C:4]=2[CH:3]=1
Reactant: NN
Reactant: O=C1c2ccccc2-c2ccc(Cl)cc21
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NN=C1c2ccccc2-c2ccc(Cl)cc21
Yield: 100 %

Procedure:
A mixture of 2-chloro 9-fluorenone (18) (5 g, 23.3 mmoL), hydrazine monohydrate (6 mL, 120 mmoL, 5.2 eq) and acetic acid (1 mL) in ethanol (150 mL ) was refluxed for 2.5 h. The mixture was then evaporated to dryness to provide 5.3 g (100%) of product which was used without further purification: mp 139°-143° C..
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[CH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1(OC)C=CC=CC=1>[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1/[CH:20]=[CH:21]/[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=Cc1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C(=C/[C@@H]1CCCN1)\c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (1 mL) was added dropwise to a stirred ice-cold solution of (2S)-N-(tert-butoxycarbonyl)-2-(2-(3-pyridyl)vinyl)pyrrolidine (280 mg, 1.02 mmol) in anisole (2 mL). The reaction mixture was allowed to warm to room temperature, stirred for 16 h, then neutralized with saturated aqueous NaHCO3 solution, saturated with solid NaCl and extracted with chloroform (5×10 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated on a rotary evaporator to give a viscous dark oil, which was chromatographed with chloroform:methanol (9:1, v/v) and 1% triethylamine as eluant. Selected fractions containing the product were combined and concentrated on a rotary evaporator to give 130 mg (73.1% yield) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2C=CC[NH:9][CH2:8][C@H:7]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]1=[O:28].C(N(CC)CC)C.[C:37]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:14]2[CH:13]=[CH:18][CH:17]=[CH:16][C:15]=2[N:9]([C:45](=[O:46])[CH2:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][C@H:7]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:6]1=[O:28]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CNCC=Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of (3S)-2-oxo-3-(benzoylamino)-2,3,4,5-tetrahydro-1H-1,5-benzodiazecine-1-acetic acid methyl ester 200 mg, 0.57 mmol) in CH2Cl2(10 ml) was treated with triethylamine (1-9 mg, 1.13 mmol) and 3-phenylpropionyl chloride (114 mg, 0.68 mmol). The reaction was stirred at RT for 30 min and diluted with CH2Cl2. The solution was washed wIth*. aq. 10% HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo to give 240 mg (87%) of 602a as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.CC1C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:31][CH2:32][F:33])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCF)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (21.6 g) was dissolved in dry DMF (500 ml) and poptassium tert-butoxide (24.2 g) was added. The mixture was stirred at ambient temperature for 30 minutes, then 1-(4-methylphenylsulfonyloxy)-2-fluoroethane (see J. Med. Chem. (1980), 23(9), 985-90 for outline of synthesis, 25.9 g) added, and stirring continued at the same temperature for 24 hours. Solvent was evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was washed with water and evaporated. The residue was dissolved in isopropanol and diluted with iso-hexane, precipitating unchanged piperazinone starting material, which was removed by filtration. The solution was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 50% isopropanol in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-(2-fluoroethyl)-3-oxopiperazine (6.74 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>O.CO>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (250 mg, 0.5 mmol) was treated with 1 M of lithium hydroxide in water (2 mL) and methanol (1 mL). The reaction was stirred at room temperature for 12 h. Acidified by 10% aqueous citric acid to pH 5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated. The resultant 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid was used as is with no further purification steps. LC/MS (ESI+): m/z 462 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H), 8.36 (d, J=8.4, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.7, 1H), 7.35 (d, J=1.7, 1H), 5.82 (dt, J=13.1, 6.6, 1H), 4.52 (s, 4H), 2.25 (s, 3H), 1.78 (s, 6H), 1.45 (t, J=13.9, 6H)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)(C)(C)C.Cl.[CH3:32][P:33]1(=[O:44])[O:38][CH2:37][C:36]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][O:34]1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:41]2[CH2:42][CH2:43][C:36]3([CH2:35][O:34][P:33]([CH3:32])(=[O:44])[O:38][CH2:37]3)[CH2:39][CH2:40]2)=[CH:25][CH:26]=1
Reactant: CP1(=O)OCC2(CCNCC2)CO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP1(=O)OCC2(CCN(Cc3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2-(4-Bromomethyl-benzoylamino)-4-thiophen-2-yl-phenyl]-carbamic acid tert-butyl ester (150 mg, 0.31 mmol), 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride (89 mg, 0.37 mmol), and DIEA (107 μL, 0.62 mmol) were combined in DMF (4 mL) and stirred at room temperature for 18 h. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography of the crude (0-10% MeOH/CH2Cl2) afforded the desired product as a colorless solid. The solid was dissolved in a mixture of CH2Cl2 (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The solution was diluted with 1,2-DCE and evaporated. The crude was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated. The residue was triturated with EtOAc and filtered to afford the desired product as a colorless solid 1H NMR (DMSO-d6, 600 MHz) δ 9.69 (s, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.44 (s, 1H), 7.41 (d, J=7.8 Hz, 2H), 7.33 (d, J=5.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.22 (d, J=3.5 Hz, 1H), 7.02 (t, J=4.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.13 (s, 2H), 4.16-4.04 (m, 4H), 3.54 (s, 2H), 2.43-2.37 (m, 2H), 2.34-2.28 (m, 2H), 1.68-1.62 (m, 2H), 1.52 (d, J=17.0 Hz, 3H), 1.42-1.38 (m, 2H). MS: cal'd 512 (MH+), exp 512 (MH+).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][C:3](=[O:13])[CH2:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][C:3]1=[O:13]
Reactant: O=C1CSc2ccccc2C(=O)N1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSc2ccccc2C(=O)N1CCCCCBr
Reaction time: 2 h
Yield: 42.4 %

Procedure:
In 20 ml of DMF was dissolved 102 mg of 2,3,4,5-tetrahydro-1,4-benzothiazepine-3,5-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.116 ml (1.5 equivalent) of 1,5-dibromopentane and 27.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 2 hours with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 79.2 mg (yield: 42.4%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]2[NH:16][CH:17]=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(OCc2ccccc2)c1N
Reactant: O=CO
Solvent: ClCCl
Product: c1ccc(COc2cccc3nc[nH]c23)cc1

Procedure:
A mixture of 3-benzyloxy-1,2-diaminobenzene 1.6 g (0.0073 mol) and formic acid (2.6 g, 0.057 mol) was heated to reflux for 1.5 h. The resulting mixture was then cooled, dissolved in methylene chloride, washed with 10% sodium carbonate solution, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was recrystallized from acetonitrile to give the title compound in 0.75 g (46%) yield, m.p. 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[S:18][C:17]([I:19])=[CH:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:20])[C:12]3[S:18][C:17]([I:19])=[CH:16][C:13]=3[N:14]([CH3:23])[CH:15]=2)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)sc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(I)cc21
Temperature: 90 °C
Yield: 74 %

Procedure:
To a stirring mixture of N-(4-chlorobenzyl)-7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxamide (0.50 g, 1.12 mmol) in DMF (20 mL) in a pressure tube was added K2CO3 (0.31 g, 2.25 mmol). To the resulting suspension was added CH3I (0.335g, 2.36 mmol), the vessel capped and heated at 90° C. for 16 h. The resulting dark suspension was cooled to ambient temperature and poured into H2O (100 mL). The aqueous solution was extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried over MgSO4 and solvent removed to afford 0.38 g title compound as a yellow solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][NH:5][S:6]([C:9]1[C:18]2[C:13](=[C:14]([N:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl>CO>[O:2]=[CH:3][CH2:4][NH:5][S:6]([C:9]1[C:18]2[C:13](=[C:14]([N:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COC(CNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OC
Agent: Cl
Solvent: CO
Product: CN(C)c1cccc2c(S(=O)(=O)NCC=O)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acetal 11 (287 mg, 850 mop was dissolved in MeOH (1 mL) and coned HCl (0.5 mL) was added to the solution, which was stirred for 1 h at 25° C. The reaction mixture was then evaporated to dryness; the material left was dissolved in CH2Cl2 (10 mL) and the solution was washed with NaHCO3 (2 mL of a saturated aqueous solution). The organic layer was collected and was evaporated under low pressure to give the aldehyde as a light green foam, the total amount of which was used without further purification in the preparation of 12.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13]O)=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:19](#[N:21])C.C(N(CC)CC)C>ClCCl.[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][C:19]#[N:21])=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: OCc1ncnn1-c1cccc(F)c1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#CCc1ncnn1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole (1.7 g) is treated with thionyl chloride (10 mL) in dichloromethane (20 mL) at room temperature overnight. The solvent is then removed. To the residue is added acetonitrile (20 mL), tetraethylammonium cyanide (2.75 g, 17.6 mmol), and triethylamine (2.5 mL, 17.6 mmol). The mixture is stirred at room temperature for 2 h. The mixture is diluted with ethyl acetate, washed with aqueous bicarbonate, and then with saturated aqueous sodium chloride, dried (Na2SO4), concentrated and the residue purified by silica gel chromatography to give crude 1-(3-Fluorophenyl)-5-cyanomethyl-1,2,4-triazole. 1H NMR (CDCl3): δ 8.06 (s, 1H), 7.52-7.62 (m, 1H), 7.20-7.30 (m, 3H), 3.98 (s, 2H). LCMS 203.0 (MH+), 201.2 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([OH:36])[CH2:5][NH:6][C:7](=[O:35])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15](C(OC(C)(C)C)=O)[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([OH:36])[CH2:5][NH:6][C:7](=[O:35])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-3-(4-{[tert-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxypropionic acid methyl ester was dissolved in ethyl acetate (10 mL) and dry hydrogen chloride in ethyl acetate (3 M, 10 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was suspended in ethyl acetate (15 mL) and concentrated. This was repeated twice. The residue was then suspended in ethyl acetate (10 mL) and placed at 5° C. overnight. The precipitate was filtered and washed with ice-cooled ethyl acetate and dried in vacuo to afford 0.62 g of (R)-3-{4-[(4-cyclohexylphenylamino)-methyl]benzoylamino}-2-hydroxypropionic acid methyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:7]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc2c(c1)OCO2
Product: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of methyl 1,3-benzodioxole-5-carboxylate (9.3 g, 51 mmol) acetic acid (25 mL) and fuming nitric acid (50 mL) was stirred approximately 15 minutes and then poured into ice-water (600 mL). The mixture was allowed to stand 1 hour in an ice-bath and the solids were collected, stirred with water and recollected to give methyl 6-nitro-1,3-benzodioxole-5-carboxylate.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Br:63][C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66](O)=[O:67]>CN(C=O)C.O>[Br:63][C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:67]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 56 %

Procedure:
DIPEA (144 mg, 1.11 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (120 mg, 0.37 mmol) in DMF (5 mL). HOBT (60 mg, 0.45 mmol) and EDCI.HCl (178 mg, 0.93 mmol) were then added. After 2 minutes 2-bromobenzoic acid (89 mg, 0.45 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was precipitated and filtered. Purification by column chromatography using silica gel 60-120 mesh and 80% EtOAc in hexane as eluent afforded 105 mg (56% yield) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 96.78%, HPLC Purity: 97.31%. 1H NMR: (DMSO) δ 8.7 (t, 1H), 8.0 (d, 2H), 7.8 (m, 5H), 7.5 (m, 6H), 4.2 (dd, 2H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][OH:8])[CH2:5][CH2:4]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][C:18]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1>[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][O:8][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)[CH2:5][CH2:4]1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Reactant: OCC(c1ccc(Cl)cc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A stirred suspension of 0.1 gram (0.0044 mole) of sodium hydride in 5 mL of tetrahydrofuran was cooled to 0° C., and a solution of 0.8 gram (0.0041 mole) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol in 2.5 mL of tetrahydrofuran was added via syringe during a two minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes and then was heated to 55° C. where it stirred for 1.5 hours. The reaction mixture was cooled to ambient temperature, and a solution of 1.0 gram (0.0043 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 2.5 mL of tetrahydrofuran was added via syringe. Upon completion of addition, the reaction mixture stirred at ambient temperature for 20 hours and then was warmed to 60° C. where it stirred for 30 minutes. The reaction mixture was cooled, and 15 mL of water was added. The aqueous layer was removed and extracted with three 25 mL portions of hexanes. The organic materials were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by rotating disk thin layer chromatography using 5-10% ethyl acetate in hexanes for elution. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.65 gram of (4-fluoro3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether. The nmr and the ir spectra were consistent with the proposed structure.