Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12.C(N(CC)CC)C.S(Cl)([Cl:36])=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:36])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12
Reactant: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCO
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCCl
Yield: 81.3 %

Procedure:
To a solution of 1000 mg of 5-hydroxy-N-β-hydroxyethylbenzo[a]phenazine-6-carboxyamide in 30 ml of dry chloroform was added 300 mg of triethylamine, followed by 660 mg of thionyl chloride. The mixture was heated at reflux for 30 minutes and evaporated to dryness under reduced pressure. The residue was dissolved in chloroform, washed with water, dried and the solvent was evaporated. The resulting residue was recrystallized from dimethylformamide to obtain 856 mg (91.8% yield) of 5-hydroxy-N-β-chloroethylbenzo[a]-phenazine-6-carboxyamide as yellow needles, m.p. 183°-186° C., Anal. Calcd. (%) for C19H14N3O2Cl: C, 64.87; H, 4.01; N, 11.94; Found: C, 64.60; H, 4.03; N, 11.66
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH2:11])=[CH:9][N:10]=2.[H-].[Na+].[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH:11][C:18]([NH:17][CH2:15][CH3:16])=[S:19])=[CH:9][N:10]=2
Reactant: CCN=C=S
Reactant: Nc1cnc2ccc(Cl)nc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)Nc1cnc2ccc(Cl)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A total of 5.0 g 6-Chloro-pyrido[2,3-b]pyrazin-3-ylamine (27.7 mmol; 1 eq) was dissolved in 150 mL of dry DMF. 1.32 g NaH (60% dispersion in mineral oil; 33.2 mmol; 1.2 eq) was added and the dark brown solution was stirred at room temperature for 1 hour. 2.4 g (27.7 mmol; 1 eq) ethyl isothiocyanate was then added and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into 500 mL of water. The solution was neutralized with 1 N HCl whereas the product crystallizes. The brown solid was filtered of and recrystallised from dichloromethane/diethyl ether to afford 3.6 g (48.5% yield) of 1-(6-Chloro-pyrido[2,3-b]pyrazin-3-yl)-3-ethyl-thiourea.
Reaction SMILES: C[Si](I)(C)C.[F:6][C:7]([F:22])([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:8][O:9]CC1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[F:6][C:7]([F:22])([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:8][OH:9]
Reactant: COCCCC(F)(F)COCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC(F)(F)CO
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Trimethylsilyliodide (5.2 g, 26 mmoles) is added to a solution of 2,2-difluoro-1-benzyloxy-5-methoxypentane (6.3 g, 25.8 mmoles) in dry dichloromethane (30 ml), kept under nitrogen at room temperature. After standing for 1 hour at 25° C., the reaction mixture is treated with triethylamine (5 ml) during 1 hour, diluted with dichloromethane and washed with 1N HCl and twice with diluted brine. Bulb to bulb distillation of the crude oil obtained (4.2 g) (110°-150° C., 15 mm) gives the title compound (2.7 g, contaminated with 10% of 2,2-difluoro-1-benzyloxy-5-hydroxy pentane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C@@H:41]([C:43]2[CH:44]=[C:45](B(O)O)[C:46]([F:49])=[N:47][CH:48]=2)[CH3:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CC([O-])=O.[K+]>O1CCOCC1.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:45]3[CH:44]=[C:43]([C@H:41]([N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)[CH3:42])[CH:48]=[N:47][C:46]=3[F:49])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.766 g, 1.996 mmol), (5-((1R)-1-(4-(tert-butoxycarbonyl)-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 146, Step 4) (0.705 g, 1.996 mmol), PdCl2AmPhos (0.071 g, 0.100 mmol), and KOAc (0.588 g, 5.99 mmol) in a mixture of dioxane (16.6 mL) and water (3.3 mL) was sparged with nitrogen and then heated at 100° C. for 2.5 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (60 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were then dried over Na2SO4 and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.570 g, 0.868 mmol, 43.5% yield) as light-yellow foam. m/z (ESI, +ve) 657.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.22 Hz, 1H); 8.18 (s, 1H); 7.18 (d, J=7.24 Hz, 4H); 6.82-6.89 (m, 5H); 4.75 (br. s., 4H); 3.79 (s, 6H); 3.60 (d, J=7.04 Hz, 1H); 3.43 (br. s., 4H); 2.63 (s, 3H); 2.30-2.53 (m, 4H); 1.44 (s, 12H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[NH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])=[CH:18][C:13]=2[N:12]=[C:11]1[NH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1.[O:43]1C[CH:44]1[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])O>C(#N)C.ClCCl>[OH:43][CH:44]([NH:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:20])=[CH:18][C:13]=2[N:12]=[C:11]1[NH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCN)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCNC(O)Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Lithium perchlorate (16 mg, 3 eq) then after 5 minutes 1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxy phenyl)amino]-1H-benzimidazole-5-carboxamide (25 mg, 1 eq) are added, at a temperature of approximately 20° C. to a solution of 2,3-epoxypropylbenzene (7 mg, 1 eq) in acetonitrile (0.5 ml). The mixture is heated under reflux for 24 hours then cooled down to ambient temperature and hydrogen carbonate and dichloromethane saturated water is added. After decanting and extracting, the organic phases are combined and washed with salt water, followed by drying over sodium sulphate and evaporating under reduced pressure at 40° C. Purification of the oil obtained by flash chromatography on silica gel (100% dichloromethane to dichloromethane/methanol 80:20) produces the expected compound in the form of an oil (31 mg, 55% yield)
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][NH:13][OH:14])(=[O:8])[O:5]CC)C.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[OH:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(COCCNO)OCC
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: O=P(O)(O)COCCNO
Temperature: 100 °C
Reaction time: 16 h

Procedure:
With reference to K-L. Yu, J. J. Bronson, H. Yang, A. Patick, M. Alam, V. Brankovan, R. Datema, M. J. M. Hitchcock, J. C. Martin, J. Med. Chem. 1992, 35, 2958-2969 0.5 mol [2-(N-hydroxyamino)-ethoxy]methylphosphonic acid diethylester and 1 mol 2,4,6-collidine in 5 ml of absolute methylenechloride are stirred under argon for one hour at a temperature of 0° C. After allowing to stand for 16 hours at room temperature the solution is concentrated in vacuum, taken up in watery acetone and stirred for 14 hours. Subsequently it is taken up in in NaOH and heated to 100° C. for 2 h. After cooling-off it is concentrated and the raw product purified by chromatography.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1(OB(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: OB(O)Oc1ccccc1
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromo-3-nitrobenzoic acid (1.0 g, 2.5 mmol) was dissolved in 1,4-dioxane (30 mL), and, thereto were added phenyl boric acid (610 mg, 5.0 mmol), cesium carbonate (6.5 g, 20.0 mmol), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (204 mg, 0.10 mmol), and purified water (10 mL). The reaction mixture was stirred under a nitrogen flow at 80° C. overnight. The reaction solution was filtered through celite, alumina, and Florisil, and, thereafter, was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-nitro-4-phenylbenzoic acid as a crude material.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:15](=[O:16])[O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: COc1ccc(SCCN)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCSc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of compound 1-HCl (0.466 g) in CH2Cl2 (20 mL) cooled to ˜0° C. was added methyl chloroformate (1.1 eq.) and triethylamine (2.5 eq.). The reaction mixture was stirred for 2 hours at 0° C. and washed with 1N HCl, and sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 7 as white solid with a yield of 480 mg, 98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24](O)=[O:25])=[CH:23][N:18]2[CH:17]=1>>[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][C:11]([F:13])([F:12])[F:14])[CH:4]=3)=[O:25])=[CH:23][N:18]2[CH:17]=1
Reactant: NCc1ccc(F)c(OC(F)(F)F)c1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1ccc(F)c(OC(F)(F)F)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-fluoro-3-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([C:6]([F:21])([F:20])[CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=2)[C:35]#[N:36])O1>>[NH2:17][C:11]1[O:12][CH2:13][C:14]([F:16])([F:15])[C@@:9]2([C:18]3[C:5](=[CH:4][CH:3]=[C:2]([C:30]4[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=4)[C:35]#[N:36])[CH:19]=3)[C:6]([F:21])([F:20])[CH2:7][CH2:8]2)[N:10]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: NC1=N[C@@]2(CCC(F)(F)c3ccc(Br)cc32)C(F)(F)CO1
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CCC3(F)F)N=C(N)OCC2(F)F)c1
Yield: 51 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-4,4,5′,5′-tetrafluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.4) with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile yielded the title compound (51% yield) as a yellow solid. MS (ISP): m/z=390.3 [M]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N+:11]([O-])([OH:13])=[O:12]>O>[N+:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: c1ccc2ccccc2c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1cccc2ccccc12

Procedure:
To a 2-liter resin flask equipped with a stirrer, thermometer, a dropping funnel, a N2 sparge tube and a condenser vented to a caustic scrubber was added 1025 g (8.0 moles) naphthalene. The reactor contents were heated until the naphthalene became molten, at which time agitation was started, and the heating was stopped. 680 ml nitric acid (72.5% concentration, 10.0 moles) was introduced over a period of 3 hours. During the first 40 minutes of addition time the temperature was gradually reduced to about 62° C. and for the remaining addition period the reaction temperature was maintained between 50° and 60° C. By using reduced pressure (ca. 25 mm Hg) water and excess nitric acid were distilled off at 60°-75° C. for about 1.25 hours, and residual water and HNO3 was driven off by sparging the molten reaction product with nitrogen gas while maintaining reduced pressure. During the 30 minutes sparging period the temperature was kept at 75°-80° C. The molten product (1408.5 g, 100% of theory) was removed from the reactor.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:4][CH2:5][CH:6]=[CH:7][C:8]([CH3:10])=[CH2:9])[CH3:3].[C:12](OC(C)=C)(=[O:14])[CH3:13]>CCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:12]([O:11][C:2]([CH3:1])([CH2:4][CH2:5][CH:6]=[CH:7][C:8]([CH3:10])=[CH2:9])[CH3:3])(=[O:14])[CH3:13]
Reactant: C=C(C)C=CCCC(C)(C)O
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Product: C=C(C)C=CCCC(C)(C)OC(C)=O
Yield: 39.9 %

Procedure:
6.7 g of 2,7-dimethyl-5,7-octadien-2-ol, 13 g of isopropenyl acetate and 0.1 g of p-toluenesulphonic acid are heated at reflux for 3 hours in a three-necked flask provided with a thermometer, stirrer and reflux condenser. The mixture is taken up in 100 ml of hexane and washed with a saturated sodium bicarbonate solution and with water. The solvent is distilled off and the residue fractionally distilled. There are obtained 3.4 g of 2,7-dimethyl-5,7-octadien-2-ol acetate of boiling point 60° C/0.2 mm Hg; nD20 = 1.4675; d420 = 0.9077. The yield is 40% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:10]([SH:14])[C:11](O)=[O:12]>C1(C)C=CC=CC=1>[SH:14][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:12]
Reactant: O=C(O)CS
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)CS)c1
Temperature: 25 °C

Procedure:
Freshly distilled 3-methoxyaniline (7.6615 g) was dissolved in toluene (35 ml) and treated with thioglycollic acid (4.75 ml). The mixture was heated under reflux, and water collected in an Dean and Stark apparatus overnight. Upon cooling to room temperature crystals formed which were collected at the pump. The title compound (which was sufficiently pure for the next reaction) was obtained as a white solid, yield 9.233 g.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([N:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]1=[O:36])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[C:37]([C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])[CH:44]=O)([CH3:40])([CH3:39])[CH3:38]>C1C=CC=CC=1>[CH:29](=[N:28][N:25]1[CH2:26][CH2:27][N:23]([C@@:5]2([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[O:11])[S:4][C@H:3]3[N:7]([C:8](=[O:9])[C@H:2]3[N:1]=[CH:44][C:43]3[CH:42]=[C:41]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:48]([OH:49])=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:46]=3)[CH2:6]2)[C:24]1=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C=N[C@@H]2C(=O)N3C[C@@](C(=O)OCc4ccc([N+](=O)[O-])cc4)(N4CCN(N=Cc5ccccc5)C4=O)S[C@H]23)cc(C(C)(C)C)c1O
Yield: 98.3 %

Procedure:
30 ml of benzene was added to 1.00 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxo-imidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane and 0.46 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde. The mixture was subjected to azeotropy and dehydration under reflux for 1 hour using a Dean-Stark aparatus. The reaction mixture was cooled, and the solvent was removed by distillation under reduced pressure to obtain 1.40 g (yield: 98.6%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[N:6]=[CH:5][CH:4]=[C:3]3[C:2]([F:1])([F:14])[F:15])(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: Nc1cccc2c(C(F)(F)F)ccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 60.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-trifluoromethyl-quinolin-8-ylamine (Intermediate 469) (325 mg, 1.53 mmol), 4-chloro-2-nitrobenzenesulfonylchloride (Intermediate 454) (507 mg, 1.99 mmol), DMAP (cat.), pyridine (0.5 ml), and DCM (5 ml) gave the title compound (400 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:42]3[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:36])[F:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Reactant: O=C1CNCCN1
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCNC(=O)C2)c(OCC(F)(F)F)c1

Procedure:
4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 697.4 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[S:37]([NH:40][CH2:41][CH2:42][OH:43])(=[O:39])=[O:38]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:37]([NH:40][CH2:41][CH2:42][OH:43])(=[O:38])=[O:39])=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccc(C(F)(F)F)cc2S(=O)(=O)NCCO)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C20H15F4N5O3S, 481.08; m/z found, 482.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.35-8.31 (m, 1H), 8.26 (s, 1H), 8.10-8.05 (m, 1H), 7.91-7.86 (m, 1H), 7.71 (d, J=7.9, 1H), 7.68-7.63 (m, 1H), 7.46 (dd, J=10.9, 1.7, 1H), 7.43-7.36 (m, 3H), 4.75 (t, J=5.4, 1H), 3.40-3.33 (m, 2H), 2.88-2.78 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To 4-chloro-3-nitrophenol (1.74 g, 10 mmol) and benzyl bromide (2.05 g, 12 mmol) in 25 mL of acetone was added K2CO3 (2.76 g, 20 mmol). The mixture was heated at 60° C. for 4 h under Ar atmosphere and cooled to rt. It was filtered and the solid was washed with ether (80 mL) and the combined filtrate was concentrated and chromatographed (EtOAc in hexane, 3% to 30% gradient) to afford 4-(benzyloxy)-1-chloro-2-nitrobenzene as a light-yellow solid (2.5 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=2.8 Hz, 1H), 7.42-7.34 (m, 5H), 7.11 (dd, J=8.8, 2.8 Hz, 1H), 5.08 (s, 2H); MS (ESI) m/z 264 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:26])([CH2:23][NH:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[O:15].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:23][N:24]([C:30]([C:29]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:28]=1[Cl:27])=[O:31])[CH3:25])([OH:26])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: CNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(O)c1c(F)cccc1Cl
Product: CN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(F)cccc1Cl

Procedure:
Similarly prepared to Example 6 from 5-amino-1-(4-fluorophenyl)-N-{3,3,3-trifluoro-2-hydroxy-2-[(methylamino)methyl]propyl}-1H-pyrazole-4-carboxamide and 2-chloro-6-fluorobenzoic acid.