Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:33]1[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:42]2[C:43]3[NH:44][C:45]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]=3[CH:39]=[CH:40][CH:41]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:32])=[O:31]
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1C
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)c1ccccc1NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 39.5 %

Procedure:
To a solution of 2-[(2-(2-methylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water (3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.11 g, 39%). HRMS calcd for C37H32N2O4: 568.6692. Found: 568.6689. MA calcd for C37H32N2O4: C, 78.15%; H, 5.67%; N, 4.93%. Found: C, 77.96%; H, 5.68%; N, 4.90%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH-].[Na+].Br[CH2:21][CH2:22][CH:23]=[CH2:24]>CN(C)C=O>[CH2:24]([O:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:23][CH:22]=[CH2:21]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(O)c1
Reactant: C=CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCCOc1cc(C(=O)OCC)ccc1C(=O)OCC
Yield: 41.3 %

Procedure:
3.55 g of this diethyl hydroxyterephthalate was dissolved in 100 mL dimethylformamide and combined with 640 mg crushed sodium hydroxide. 4.03 g 4-bromo-1-butene dissolved in 20 mL dimethylformamide was added dropwise in while cooling on an ice bath. After stirring the reaction for 16 hours, purification by the usual methods gave 1.8 g diethyl 2-(3-butenyloxy)terephthalate.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:10]1([S:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[I-:43].[K+]>O>[I-:43].[CH3:8][C:2]1[CH:3]=[C:4]([S+:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:7])[C:1]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [I-]
Solvent: O
Product: Cc1cc([S+](c2ccccc2)c2ccccc2)cc(C)c1O

Procedure:
To a mixture of 36 g of 2,6-xylenol and 60 g of diphenyl sulfoxide was added 300 mL of a solution consisting of diphosphorous pentoxide/methanesulfonic acid=1/10. The resultant reaction mixture was reacted at 40° C. for 4 hours and then poured on ice. This aqueous solution was washed with ethyl acetate. To the aqueous phase was added a solution prepared by dissolving 200 g of potassium iodide in water. The particles precipitated were taken out by filtration and washed with acetone. As a result, 3,5-dimethyl-4-hydroxyphenyldiphenylsulfonium iodide was obtained in an amount of 80 g. To 7.1 g of the 3,5-dimethyl-4-hydroxyphenyldiphenylsulfonium iodide obtained were added 300 mL of chloroform and 2.0 g of triethylamine. To this solution was dropwise added 10 g of nonafluorobutanesulfonic anhydride over 30 minutes with cooling with ice. After the resultant reaction mixture was reacted at room temperature for 1 hour, water was added thereto. The organic phase was washed with 5% aqueous NaOH solution and subsequently with water and then concentrated to obtain a crude reaction product, which was recrystallized from ethyl acetate/dilsopropyl ether. As a result, acid generator (Bb-1) was obtained in an amount of 10.0 g.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[BH4-].[Na+]>CO.O.Cl[Ni]Cl>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[N:7][C:2]=1[Br:1]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])c(Br)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1ccc(N)c(Br)n1
Reaction time: 0.01 h
Yield: 97.5 %

Procedure:
To a solution of methyl 6-bromo-5-nitropyridin-2-ylcarbamate (700 mg, 2.5 mmol) in CH3OH (20 mL) was added NiCl2 (1.2 g, 5.1 mmol) and NaBH4 (300 mg, 7.6 mmol) successively at 0° C. The mixture was stirred for 20 seconds. The reaction mixture was diluted with water and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 5-amino-6-bromopyridin-2-ylcarbamate (600 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.4 Hz, 1H), 7.13 (brs, 1H), 7.09 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]1([OH:21])[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19].C1(C)C=CC=CC=1>O>[CH3:1][S:2]([O:21][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])(=[O:4])=[O:3]
Reactant: Cc1cccc(C)c1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OS(C)(=O)=O

Procedure:
12.5 Parts of methanesulphonyl chloride and 11.0 parts of triethylamine were added separately and simultaneously to a solution of 12.2 parts of 2,6-xylenol (the material available commercially from Synthetic Chemicals Limited and containing at least 92% 2,6-xylenol) in 65 parts of toluene over 40 minutes. The reaction mixture was mechanically agitated and the temperature was maintained at 40°-50° C. with external cooling. After agitating for a further 30 minutes, 24 parts of water were added, and the two phase mixture was separated. Evaporation of the organic phase gave 19.7 parts of 2,6-xylyl methanesulphonate. The product was purified by distillation at 188°-191° C. at 30 mm. On cooling the ester solidified, remelting at 26°-27° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Reactant: Brc1ccccn1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1Oc1ccccn1
Yield: 24.5 %

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with 2-bromopyridine (18.6 μL, 30.8 mg, 0.20 mmol) as described in Example 47, except that heating at 150° C. overnight was required, affording 5-[4-fluoro-3-(pyridin-2-yloxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine (15.1 mg, 24%). δH (400 MHz, CDCl3) 7.04-7.09 (2H, m), 7.30-7.35 (1H, m), 7.38-7.43 (2H, m), 7.60 (1H, d, J 4.7), 7.73-7.79 (1H, m), 7.83 (1H, d, J 8.6), 8.17 (1H, dd, J 5.1 and 2.0), 8.64 (1H, d, J 8.6), 9.27 (1H, d, J 4.3). m/z (ES+) 386 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[Cl:33][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([CH2:11][NH:12][C:13]([C:15]3([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)c2cc(CNC(=O)C3(C)CCCCC3)ccc2C)ccc1Cl
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-5-[(1-methylcyclohexylcarbonylamino)methyl]benzoyl chloride (0.266 g, 0.864 mmol) in 5 mL THF was added to methyl 5-amino-2-chloro-benzoate (0.160 g, 0.864 mmol) and 0.42 mL TEA in 10 mL THF. The mixture was stirred overnight and concentrated. EtOAc was added to the residue and the organic phase was washed with water and 2 M aq. HCl solution and dried with Na2SO4. The crude mixture was purified via MPLC. Yield: 0.21 g (53%). MS [M+H]+=457 (Cl isotope pattern); TLC: Rf=0.44 (silica gel, DCM:EtOH 19:1).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([N:7]([CH2:18][CH3:19])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH2:18][CH3:19])=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1)#[N:2]
Reactant: CCN(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
4′-Cyano-N-ethyl-p-toluenesulfonanilide (6.95 g (23.1 mmol) was dissolved in concentrated sulfuric acid (20.0 ml) under cooling with ice. To this, 97% fuming nitric acid (1.00 ml (23.4 mmol)) was added dropwise and the mixture was stirred for 30 minutes under cooling with ice. The resulting mixture was poured into ice-water, followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 1.25 g (28%) of 4-cyano-N-ethyl-2-nitroaniline as yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br-:9].[K+].B(O[O-])=O.[Na+].O>C(O)(=O)C.[NH4+].[NH4+].O.O.O.O.[O-][Mo]([O-])(=O)=O>[Br:9][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[I:1]
Reactant: Nc1ccccc1I
Reactant: [Br-]
Agent: O=[Mo](=O)([O-])[O-]
Agent: O=BO[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: BrNc1ccccc1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A vigorously stirred suspension of 2-iodoaniline (10.0 g, 45.7 mmol), potassium bromide (6.52 g, 54.8 mmol), and ammonium molybdate tetrahydrate (0.57 g, 0.46 mmol) in acetic acid (54 mL) was cooled to 0° C., treated with sodium perborate (7.74 g, 50.3 mmol), and stirred for two hours as the reaction warmed to room temperature. After adding water and stirring one additional hour, the reaction mixture was poured into ice-water and filtered. The filtered solid was washed with water, dissolved in ethyl acetate (250 mL), and washed with a saturated, aqueous, potassium carbonate solution (2×75 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the intermediate, 4 bromo-2-iodoaniline, as a red solid (12.56 g, 92%).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(S(C)(=O)=O)cc3)ccc21

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.18 g (5 mmol) of 4-bromophenylsulfonylmethane, 610 mg (31%) of the expected sulfone compound, with a melting point of 112°-113° C., were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:31][O:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:34][CH2:33][O:32][CH3:31])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 2-bromoethyl methyl ether and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-(2-methoxy-ethyl)-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 550.8 ([M+NH4]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:35][CH:34]=3)[O:29][CH:30]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1)[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:35][CH:34]=3)[O:29][CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCCn2ccnn2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [4-(4-[1,2,3]Triazol-1-yl-butyl)-phenyl]-carbamic acid tert-butyl ester (0.297 g, 0.94 mmol) in N,N-dimethyl formamide (5 ml) sodium hydride (0.050 g, 2.1 mmol) was added and the mixture stirred for 30 min at r.t. To this mixture a solution of 2-(4-chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole 0.3 g, 0.94 mmol) in N,N-dimethyl formamide (5 ml) was added and stirring continued for 16 h. The mixture was then poured on water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic extracts was washed with water, brine and dried over sodium sulfate. After concentration in vacuo the crude product was purified on silica gel (iso-hexanes/ethyl acetate 1:2) to yield [4-(4-[1,2,3]Triazol-1-yl-butyl)-phenyl]-[2-(5-trifluoromethoxy-1H-indol-2-yl)-oxazol-4-ylmethyl]-carbamic acid tert-butyl ester as light yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[N:11][C:10]2[C:9](=O)[NH:8][CH:7]=[N:6][C:5]=2[CH:4]=1.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>CCOC(C)=O.O>[Cl:34][C:9]1[C:10]2[N:11]=[CH:12][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(C(F)(F)F)cnc12
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cnc2c(Cl)ncnc2c1
Temperature: 115 °C
Yield: 95.5 %

Procedure:
A pressure bottle was charged with 7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (540 mg, 2.51 mmol), toluene (10.000 mL) and Hunig's base (1.315 mL, 7.53 mmol). POCl3 (0.702 mL, 7.53 mmol) was added, and the bottle was sealed. The mixture was heated to 115° C. for 4 h. After cooling to RT, the mixture was diluted with EtOAc and water, and the layers were separated. The aqueous portion was extracted with additional EtOAc, and the combined organic portions were washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. 4-chloro-7-(trifluoromethyl)pyrido[3,2-d]pyrimidine (560 mg, 2.397 mmol, 96% yield) was isolated as a brown solid. LC/MS (ESI+) m/z=234.0 (M+H).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)(=O)C.[N+:23]([O-])([O-:25])=[O:24].[K+].N>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2CC(=O)O
Temperature: 0 °C
Yield: 69.3 %

Procedure:
57.5 g (0.19 mol) of 7-acetamido-1-(ethoxycarbonylmethyl)quinoxaline-2,3(1H,4H)-dione were dissolved in 575 ml of concentrated sulfuric acid. The solution was cooled to 0° C., and 19.0 g (0.19 mol) of potassium nitrate were added in portions. The cooling was then removed, and the mixture was stirred. After reaction was complete, the mixture was poured into 2 l of ice-water and heated on a waterbath for 2 h. The pH was then adjusted to about 4-5 with aqueous ammonia solution, and the precipitate was filtered off with suction. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (mobile phase: methanol:tetrahydrofuran:water=5:4:1+2.5% glacial acetic acid). The resulting product was combined with the first precipitate to afford 36.9 g (70%) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:50][C:51]1([CH3:57])[CH2:53][C@@H:52]1[C:54](O)=[O:55].CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:54]([C@H:52]6[CH2:53][C:51]6([CH3:57])[CH3:50])=[O:55])[CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Reactant: CC1(C)C[C@@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of the hydrochloride salt of ((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (60.0 mg, 0.0775 mmol) and (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (10.6 mg, 0.093 mmol) in N,N-dimethylformamide (1.5 mL, 19 mmol) at RT was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yOuronium hexafluorophosphate (35.4 mg, 0.093 mmol) and N,N-diisopropylethylamine (54.0 uL, 0.310 mmol). The reaction mixture was stirred at RT overnight, and then concentrated. The residue was redissolved in 1:1 acetic acid:water (6 mL), filtered and purified by reverse phase preparative HPLC. Desired fractions were combined and freeze dried to give a white solid 34.1 mg). (m/z): [M+H]+ calcd for C43H52N8O5 761.42 found 761.7. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.18-8.20 (m, 1H), 7.76-7.86 (m, 7H), 7.68-7.7 (m, 2H), 6.95-6.99 (m, 1H), 5.22-5.26 (t, 1H, J=16), 4.59-4.73 (m, 1H), 4.03-4.38 (m, 5H), 3.82-3.89 (m, 1H), 3.69-3.74 (m, 1H), 3.65 (s, 3H), 3.12-3.2 & 3.3-3.5 (m, total 2H), 2.53-2.6 (m, 1H), 2.0-2.3 (m, 4H), 1.75-1.78 & 1.82-1.85 (m, total 1H), 1.25 (s, 3H), 1.12 (s, 3H), 1.07-1.1 & 1.14-1.17 (m, total 1H), 0.96 (s, 3H), 0.88-0.96 & 1.21-1.27 (m, total 6H), 0.76-0.8 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22][C:23]2[C:24](B(O)O)=[CH:25][C:26]3[C:27]([CH3:36])([CH3:35])[CH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[C:31]=3[CH:32]=2)=[CH:19][CH:18]=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:6]=1[C:24]1[C:23]([O:22][CH2:21][C:20]2[CH:40]=[CH:41][C:17]([Cl:16])=[CH:18][CH:19]=2)=[CH:32][C:31]2[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:35])[C:26]=2[CH:25]=1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)c(OCc3ccc(Cl)cc3)cc21
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C=CC(=O)O)ccc3O)c(OCc3ccc(Cl)cc3)cc21
Yield: 32.5 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 2.05 g (5.5 mmol) of 3-(4-chlorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained above, 590 mg (30%) of the expected compound were obtained in the form of a white solid having a melting point of 152°-154° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].OS([O-])(=O)=O.[K+]>C1COCC1>[CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)CC2CCCC2)cc1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
The product of Example E (2.2 g, 0.01 mole) was dissolved in THF (50 mls) and cooled under argon to 0° C. Lithium tri-t-butoxyaluminum hydride (2.7 g) was added portionwise over 1/2 hour at 0° C. and stirred for 2 hours at 0° C. The mixture was allowed to stir a total of 4 hours until thin layer chromatography indicated the reaction was complete. The mixture was then poured into 0.5N KHSO4 and extracted with ethyl acetate. After drying the organic layer over Na2SO4, the solvent was removed to give 2.2 g of title compound (97% yield) as an oil.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26]O>>[C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23][CH3:26])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reaction time: 2 h

Procedure:
A solution of crude 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-carboxyimidazole (30 g.) in methanol (600 ml.) is heated to reflux, and then heating is discontinued as hydrogen chloride is bubbled rapidly through the solution with stirring for a half hour, followed by two and a half hours at reflux. Bubbling of hydrogebn chloride is continued for another two hours followed by another hour at reflux and then the reaction mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is then concentrated to dryness under reduced pressure. The residue is dissolved in water (150 ml.) and the pH is adjusted to 8 with saturated sodium carbonate solution. The basic mixture is extracted with ethyl acetate and the extracts are dried, filtered, and concentrated under reduced pressure to yield a solid which is recrystallized from acetonitrile to yield the methyl 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a cream-colored solid, m.p. 168-172° C.