Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.[N+:16]1([O-:29])[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:20]=2[N:19]=CN=1)[CH2:26][CH2:25][CH2:24]3.N>C(Cl)Cl>[N+:16]([C:21]1[CH:22]=[C:23]2[C:27]([CH2:26][CH2:25][CH2:24]2)=[CH:28][C:20]=1[NH:19][C:10](=[O:11])[CH3:12])([O-:29])=[O:1]
Reactant: [O-][n+]1ncnc2cc3c(cc21)CCC3
Reactant: OO
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 1.1 mL, ca. 21 mmol) was added dropwise to a stirred solution of TFAA (3.0 mL, 21 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a solution of 1-oxide 64 (0.40 g, 2.1 mmol) in DCM (20 mL) at 0° C. and the solution was stirred at 20° C. for 4 h. Dilute aqueous NH3 solution (10 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-30%) of EtOAc/DCM, to give (i) starting material 64 (68 mg, 17%) and (ii) 1,4-dioxide 65 (213 mg, 49%) as a tan solid: mp (EtOAc/pet. ether) 179-181° C.; 1H NMR δ 8.81 (s, 1H, H-3), 8.31 (s, 1H, H-9), 8.28 (s, 1H, H-5), 3.13-3.22 (m, 4H, H-6, H-8), 2.26 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 155.2, 152.0, 141.0, 139.1, 134.5, 116.1, 114.1, 33.4, 33.0, 25.5. Anal. calcd for C10H9N3O2: C, 59.1; H, 4.5; N, 20.7. Found: C, 58.9; H, 4.6; N, 20.5%.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][CH:4]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)nc3)nc-2c1=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(N4CCOCC4)nc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 22), 60 mg, 0.13 mmol] was dissolved in dimethyl sulfoxide (1 mL) and treated with morpholine (35 mg, 0.40 mmol, 3 equiv) and potassium carbonate (19 mg, 0.13 mmol, 1 equiv). The vessel was sealed and placed into an oil bath preheated at 100° C. for 9 hours. The mixture was cooled to ambient temperature, poured into water (5 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed three times with water and once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.29 (1H, br s), 7.69-7.59 (3H, m), 7.57-7.51 (2H, m), 7.44 (1H, m), 7.38-7.29 (3H, m), 6.59 (1H, d, J=9.1 Hz), 5.73 (2H, s), 3.79 (4H, m), 3.50 (4H, m), 2.35 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 453.2038 [(M+H)+; calculated for C26H25N6O2: 453.2034].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In N,N-dimethylformamide (40 mL) was dissolved 4-bromo-2-methyl-phenol (1.87 g), potassium carbonate (4.15 g) and benzyl bromide (1.3 mL) were added to the solution, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate, and the liquids were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2 to 95:5) to obtain 1-benzyloxy-4-bromo-2-methylbenzene (2.73 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]([OH:17])[C:15]#[CH:16])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].I[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]([OH:17])[C:15]#[C:16][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH3:12])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(O)c1ccc(N(C)C)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1ccc(C(O)C#Cc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Yield: 62.2 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 900 mg (3.8 mmol) of 1-(3-tert-butyl-4-dimethylaminophenyl)prop-2-yn-1-ol with 805 mg (3.2 mmol) of 4-iodobenzoic acid, 30 mg (0.16 mmol) of copper iodide and 56 mg (0.08 mmol) of bis(triphenylphosphine)palladium chloride. 700 mg of 4-[3-(3-tert-butyl-4-dimethylaminophenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a beige solid (Mp=139° C., yield=64%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[N:20][CH:21]=1.C1C[O:26][CH2:25]C1>>[Br:15][C:16]1[CH:17]=[C:18]([CH:25]=[O:26])[C:19]([F:22])=[N:20][CH:21]=1
Reactant: Fc1ccc(Br)cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a stirred solution of DIPEA (44.1 mL, 312 mmol) in dry THF (500 mL) at −78° C. was added dropwise n-BuLi (2.5M in hexanes, 125 mL, 313 mmol). The temperature was warmed to rt and stirred for 10 minutes. The solution was cooled to −78° C. and a solution of 5-bromo-2-fluoro-pyridine (1) (50.0 g, 284 mmol) in THF (500 mL) added dropwise. The reaction mixture was stirred at −78° C. for 45 minutes then quenched with 10% citric acid in THF (250 mL) at −78° C. The solution was warmed to rt then diluted with H2O (250 mL). The solution was extracted with EtOAc (3×250 mL) and the combined organics washed with saturated brine solution (250 mL), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-pet ether) to provide the title compound as a white solid (36.0 g, 62%); Rf: 0.7 (10% EtOAc-pet ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C2CCCCO2)=[C:5]([CH2:20][CH2:21][CH:22]=[CH:23][O:24]C)[CH:4]=1.O1CCCC1.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH:23]([CH2:22][CH2:21][CH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:13])=[O:24]
Reactant: COC=CCCc1cc(OC)c2ccccc2c1OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(CCCC=O)c(O)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 140.6 %

Procedure:
A solution of 947 mg of (3EZ)-4-methoxy-2-(4-methoxy-3-butenyl)-1-[(tetrahydro-2-H-pyran-2-yl)oxy]-naphthalene dissolved in 10 ml of 3:1:1, acetic acid:tetrahydrofuran:water is stirred at 40° C. for 3 hrs. TLC analysis still indicates unhydrolyzed starting material. The temperature is increased to 50° C. and continued stirring for 1 hr affords complete hydrolysis. The solution is poured into 25 ml water and solid sodium bicarbonate is added portionwise until gas evolution ceases. This mixture is extracted with ether and the organic phase is washed with saturated aqueous sodium bicarbonate and brine (pH adjusted to 7), dried with magnesium sulfate, filtered and concentrated to give 0.95 g of crude title product as an orange colored oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: Brc1ncccn1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=S(=O)(CCc1ccc(F)cc1)N1CCC(CNc2ncccn2)CC1

Procedure:
A mixture of 0.3 g of C-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine, 0.3 g of 2-bromopyrimidine, 25 mL of 2-propanol and 0.3 mL of N,N-diisopropylethylamine was heated to reflux overnight. Purification of the residue obtained after concentration under reduced pressure by preparative chromatography, eluting with ethyl acetate gave a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[F:16].O1CCOCC1.[NH3:23]>O>[NH2:23][C:4]1[C:3]([F:16])=[C:2]([NH2:1])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: N
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Reaction time: 1.33 h
Yield: 100.1 %

Procedure:
To a stirred solution of methyl 4-amino-2,3-difluoro-5-nitrobenzoate (4) (33.0 g, 142.15 mmol) in 1,4-dioxane (165 mL, 1.93 moles), in a 250 mL glass pressure vessel, was added an aqueous solution of ammonia (39 g, 711 mmol, 42.9 mL, 16.5 M). The vessel was then heated in an immersion bath at a bath temperature between 79 and 105° C., for 80 minutes, over which time the internal pressure ranged between 0.2 and 2.7 bar. The pressure was then released slowly and the mixture was treated with water (330 mL, 10 vol). The resultant suspension was stirred for 20 minutes and then filtered under vacuum, and the solid was washed with water (33 mL, 1 vol). The solid was sucked dry, then dried in a vacuum oven at 50° C. to provide methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (32.6 g, 92% yield) as a yellow solid. 1H NMR (500 MHz, d6 DMSO) δ 3.83, (3H, s, OMe), 7.20 (2H, br, NH2), 7.37 (2H, br, NH2), 8.47 (1H, s, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 52 (CH3), 101 (C), 122 (C), 126 (CH), 134 (C), 137 (C), 142 (C), 166 (C═O). νmax/cm−1 3474, 3358, 1697, 1633, 1528, 1435, 1317, 1285.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].[NH2:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:10](=[O:12])[CH3:11])=[CH:3][C:2]=2[N:1]=[C:28]1[NH:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][C:24]([F:27])([F:25])[F:26])[CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CNc1ccc(C(C)=O)cc1N
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 68.8 %

Procedure:
1-[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-ethanone (69 mg) was prepared by following General Procedure D starting from 1-(3-amino-4-methylamino-phenyl)-ethanone (41 mg), 2-amino-6-(trifluoromethoxy)-benzothiazole (59 mg), 1,1′-thiocarbonyldiimidazole (44 mg), and EDC (48 mg). LC/MS: m/z 408.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=2)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[O:18])=[CH:10][N:9]=1>C1COCC1>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=2)[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)=[O:18])=[CH:12][N:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc(Cl)nc2)c1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc(OCCO)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH 60% in oil (12.19 mg, 0.508 mmol) in THF (200 μL) was added ethylene glycol (21.24 μL, 0.381 mmol). A solution of 3-(2-chloropyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1, 50 mg, 0.127 mmol) in THF (2.5 mL) was then added and the RM was stirred at RT overnight. Additional ethylene glycol (200 μL, 3.59 mmol) was added and the reaction was stirred at RT for 4 h. The reaction was quenched with HCOOH and the solvent was evaporated off under reduced pressure. The residue was treated with saturated aq. NaHCO3 (10 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH+1% NH4OH, from 1% to 12% MeOH+1% NH4OH) to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=2.44 min, m/z=420.1 [M+H]+, m/z=418.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.76 (dd, 2H) 4.40 (t, 2H) 4.92 (t, J=5.5 Hz, 1H) 7.39 (d, J=8.6 Hz, 2H) 7.64-7.70 (m, 1H) 7.91 (d, J=9.0 Hz, 2H) 7.97 (d, J=8.1 Hz, 2H) 8.28 (s, 1H) 9.04 (s, 2H) 10.48 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@H:23]([CH2:24][OH:25])[C@@H:22]2[CH2:26][C@H:19]1[CH2:20][CH2:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C@H:23]([CH:24]=[O:25])[C@@H:22]2[CH2:26][C@H:19]1[CH2:20][CH2:21]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C=O
Reaction time: 0.75 h

Procedure:
To a cold (−60° C.) solution of oxalyl chloride (60.8 mmol) in dry DCM (130 mL) is added dropwise DMSO (111 mmol) within 5 min. After 15 min a solution of (1R,3S,4S)-3-hydroxymethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (50.7 mmol) in dry DCM (40 mL) is added dropwise within 15 min. Stirring is continued for 45 min at −55° C., then DIPEA (253 mmol; dried over 3 A molecular sieve) is added during 5 min. The reaction mixture is allowed to reach rt and diluted with water (250 mL). The layers are separated and the organic layer is washed twice with aq. citric acid (5%, 200 mL each) and twice with brine. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3, 2 rotamers): δ=1.31-1.37 (m, 1H); 1.44 & 1.50 (2 s, 9H); 1.58-1.84 (m, 5H); 2.78 & 2.81 (2 bs, 1H); 3.60 & 3.74 (2 bs, 1H); 4.26 & 4.41 (2 bs, 1H); 9.55 & 9.60 (2 bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][C:35](=[O:41])[C@@H:36]([NH2:40])[CH:37]([CH3:39])[CH3:38])([CH3:33])([CH3:32])[CH3:31].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>C(Cl)Cl>[C:30]([O:34][C:35](=[O:41])[C@@H:36]([NH:40][C:27]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[C@H:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]1)=[O:28])[CH:37]([CH3:38])[CH3:39])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1)C(=O)OC(C)(C)C
Yield: 32.4 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (215.7 mg, 0.50 mmol) prepared in Example 1d was reacted with (S)-2-amino-3-methyl-butyric acid tert-butyl ester (125.4 mg, 0.60 mmol), HATU (210.1.0 mg, 0.60 mmol) and iPr2NEt (129.3 mg, 1.00 mmol) in CH2Cl2 (5 mL) at rt overnight to give (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (95.0 mg, 32.4%) after column separation. HRMS (ES+) m/z Calcd for C32H41Cl2N3O3+H [(M+H)+]: 586.2602. found: 586.2598.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([CH3:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].[NH4+].[Cl-]>C(Cl)Cl>[CH3:37][S:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([CH3:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=[O:40])=[O:39]
Reactant: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 380.3 %

Procedure:
To a solution of 4-(9-hydroxynonyl)-7-methoxy-3-methyl-3-(4-pyridyl)chroman (108 mg, 0.272 mmol) in methylene chloride (2 mL) were added under ice-cooling triethylamine (0.057 mL, 0.41 mmol) and methanesulfonyl chloride (0.032 ml, 0.41 mmol), which was then stirred for 30 minutes. After the reaction was completed, saturated aqueous NH4Cl solution was added, the resulting mixture was then extracted with methylene chloride and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4-(9-methanesulfonyloxynonyl)-7-methoxy-3-methyl-3-(4-pyridyl)chroman (492 mg, yield 38%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][N:23]([CH3:25])[NH2:24]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:25])[NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN(C)N
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol) in 100 mL CH2Cl2 was cooled to 0° C. and treated with triethylamine (8.40 mL, 60.0 mmol) and N,N-dimethylhydrazine (5.65 mL, 74.4 mmol) under an atmosphere of nitrogen. After 18 h, the mixture was diluted with 2% Na2CO3 solution and CHCl3 and separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 4-(2,2-dimethylhydrazino)-3-nitroquinoline (5.33 g) as a yellow/orange crystalline solid.
Reaction SMILES: [C:1]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:52][O:53][CH2:54][CH2:55]Br)[C:47]([O:49]CC)=[O:48])[N:45]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1C=CC=C[CH:23]=1.CS(C)=O>O>[C:21]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:52][O:53][CH2:54][CH2:55][NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:47]([OH:49])=[O:48])[N:45]=1)([C:22]1[CH:23]=[CH:3][CH:2]=[CH:1][CH:8]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)C(=NOCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 82 h

Procedure:
A mixture of 75 g of tritylamine, 50 g of syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate and 100 ml of dimethylsulfoxide was stirred under argon at 60° C. for 82 hours and after the temperature returned to room temperature, 10 volumes of water were added thereto. The mixture was vacuum filtered and the recovered product was washed with water and dissolved in a liter of chloroform. The solution was washed with water, with an aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure at less than 40° C. The residue was added to a mixture of 320 ml of dioxane, 2 liters of absolute ethanol and 200 ml of sodium hydroxide solution and the mixture was stirred at room temperature for 24 hours and was evaporated to dryness under reduced pressure at not more than 40° C. The residue was empasted 5 times with 60 ml of a 1-7 dioxane-ethanol mixture and was then added to a liter of water and a liter of chloroform. The pH of the mixture was adjusted to 2 by stirring with sufficient N hydrochloric acid and the decanted organic phase was washed with water and with aqueous saturated sodium chloride solution, was dried and evaporated to dryness under reduced pressure at less than 40° C. The residue was suspended in 300 ml of dichloroethane and the mixture was heated at 50° C. for 15 minutes and was then vacuum filtered at room temperature. The product was successively rinsed with dichloroethane, isopropyl ether and ether and dried to a constant weight to obtain 40 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-tritylaminoethoxyimino)acetic acid in the form of a powder melting at 176° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2>CC#N>[CH:23]([O-:24])=[O:22].[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][CH2:3][CH2:2][N+:14]23[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]2)[C@@H:16]([O:22][C:23]([C:25]2([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:15]3)=[CH:7][CH:8]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: COc1ccc(COCCBr)cc1
Solvent: CC#N
Product: COc1ccc(COCC[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)cc1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 148.6 %

Procedure:
A mixture of 1-(2-bromo-ethoxymethyl)-4-methoxy-benzene (42 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 16 h then heated to 80° C. under nitrogen overnight. A further 1.1 equivalents of 1-(2-bromo-ethoxymethyl)-4-methoxy -benzene were added and the mixture was heated at 80° C. for a further 48 h. The volatiles were evaporated and the crude product was purified by silica gel chromatography eluting with 0-10% of a 10% conc. NH3/MeOH solution in dichloromethane give 61 mg of an oil that was purified further by reverse phase HPLC (Gemini 5 μM C6 phenyl column) eluting with 5-95% MeOH/H2O containing 0.1% formic acid over 30 min with UV detection at 220 nm. The relevant fractions were combined and evaporated to afford the title compound (34 mg) as an oil.