Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH2:11]=[O:12].[OH-].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12])([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CCO
Temperature: 70 °C
Yield: 41.9 %

Procedure:
A mixture of 137 g (1 mole) of o-nitrotoluene, 60 g of paraformaldehyde and 400 ml of dimethyl formamide containing 0.5% by weight of water is heated to 70° C. under stirring. Thereafter 40 g of potassium hydroxide, covered with 100 ml dimethyl formamide, are added to the mixture at such a rate that the temperature of the reaction mixture does not increase above 120° C. The resulting mixture is stirred for 3 minutes at a temperature above 85° C., thereafter it is cooled and filtered through a sintered glass filter. The filtrate is acidified with hydrochloric acid to pH=3, filtered again, and the resulting filtrate is evaporated. 100 g of a residue, containing 80% by weight of 2-(o-nitrophenyl)-ethanol, are obtained. This residue is distilled in vacuo to obtain 70 g of 2-(o-nitrophenyl)-ethanol with a purity grade of 98%. 45 g of o-nitrotoluene are recovered. The product is analyzed by gas chromatography.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[N:14]=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]1=[O:26])=[O:7])(=O)C.[Li+].[OH-].Cl>O1CCCC1.CO>[Br:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:12](=[O:26])[N:11]2[CH2:10][CH2:9][NH:8][C:6](=[O:7])[CH2:5][OH:4])=[CH:16][CH:17]=1
Reactant: CC(=O)OCC(=O)NCCn1c(=O)c(C(C)(C)C)nc2ccc(Br)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2ccc(Br)cc2n(CCNC(=O)CO)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-(7-Bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethylamino)-2-oxoethyl acetate was dissolved in 4 mL of 1:1 tetrahydrofuran/methanol, and 0.99 mL of aq. 1N LiOH was added. After 30 minutes of stirring at room temperature the reaction was complete. Hydrochloric acid was used to adjust the pH to 6, and the solution was extracted with ethyl acetate 3 times, the combined organic layers washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide 197 mg of N-(2-(7-bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethyl)-2-hydroxyacetamide. The product was pure by TLC and was used in the next step (Suzuki coupling) without purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: Sc1ccccc1
Product: COc1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert 4-iodoanisole and thiophenol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (416 mg, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.29 (dt, J=7.72, 2H; Ha, Ha′), 7.13–6.97 (m, 5H; Hc, Hc′, Hd, Hd′, He), 6.77 (d, J=7.54, 2H; Hb, Hb′), 3.67 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 159.74 (C4), 138.54 (C8), 135.29 (C2, C6), 128.85 (C9, C13), 128.08 (C10, C12), 125.66 (C11), 124.17 (C1), 114.90 (C3, C5), 55.23 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.34; H, 5.70; S, 14.81.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[NH3:23]>C(O)CO.O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:23])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Reactant: N
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(N)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Into a 10 mL sealed tube, was placed 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (150 mg, 0.40 mmol). To this was added Cu2O (30 mg, 0.21 mmol), followed by a saturated solution of NH3 in ethylene glycol (4 ml). The resulting solution was stirred at 70° C. for 3 hours, then diluted with 30 mL of H2O and extracted three times with 20 mL of EtOAc. The organic layers were combined and dried over Na2SO4. Removal of the volatile components under reduced pressure afforded the product 5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v) (50 mg, yield 40%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using 2-bromo-5-methyl-pyridine (2.92 g, 16.95 mmol) and phenylboronic acid (3.09 g, 25.4 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:1) as eluent. White solid. Yield: 1.99 g, 70%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.38 (s, 3H), 7.37-7.43 (m, 1H), 7.44-7.51 (m, 2H), 7.54-7.60 (m, 1H), 7.60-7.67 (m, 1H), 7.95-8.00 (m, 2H), 8.51-8.55 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.1, 120.0, 126.7, 128.6, 128.7, 131.5, 137.3, 139.4, 150.1, 154.8; (ESI): m/z=169.97 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]([O:31][CH3:32])[CH:28]=[CH:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Yield: 59 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromoanisole, the hydrochloride salt of the title compound was formed in 59% yield as a white solid, mp 260-261C. elemental
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[O:23]1[CH2:27][CH2:26][CH:25]([NH:28][C:3]([C:5]2[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:24]1
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOC2)nn1
Yield: 92 %

Procedure:
As described for example 1e, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (120 mg, 0.39 mmol) was converted, using rac-tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (130 mg, 92%) which was obtained as a light yellow oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=361.5 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
4-bromomethylbenzoic acid (25 g, 116.25 mmol) was dissolved in CH2Cl2 (200 ml) and treated with oxalyl chloride (12.2 ml, 139.5 mmol). DMF (0.45 ml) was added slowly then stirred for 1 h. The solvent was removed to give the 4-bromomethylbenzoyl chloride as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:20]([O:22]CC)=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
23.9 g (72.8 mmol) of the compound of Example 40A are provided in 100 ml of 1,4-dioxane, 100 ml (200 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 50° C. for 1 h. The mixture is concentrated, the residue is diluted with water, a conc. aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred in a little diethyl ether, collected by filtration and dried under high vacuum. 22.0 g (100% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][C:12](=[CH2:14])[CH3:13].C(=O)=O.CC(O)C>>[F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])([OH:4])[CH2:13][C:12]([CH3:14])=[CH2:11]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C
Agent: O=C=O
Solvent: CC(C)O
Product: C=C(C)CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Yield: 82.9 %

Procedure:
Hexafluoroacetone (238 g) and 120 g of isobutylene were condensed into a lecture bottle using Dry Ice/2-propanol cooling. The temperature was raised in the sealed vessel to 20° C. while stirring in a water bath and temperature maintained overnight. The next morning the temperature was raised to 50° C. for 2 hours. After cooling, excess isobutylene was bled off and the product distilled at 100-115° C. to afford 264 g (83%) of a clear liquid. The identity of the product was confirmed using 1H NMR spectroscopy and HRMS.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:38]1[CH:42]=[C:41]([CH2:43]O)[CH:40]=[N:39]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([N:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:43][C:41]1[CH:42]=[N:38][NH:39][CH:40]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(NC(=O)C2CCc3c(OCc4ccccc4)cccc32)c(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Product: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCc3c(OCc4ccccc4)cccc32)c(OC)c1
Yield: 37.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 4-benzyloxy-N-(2,4-dimethoxyphenyl)indan-1-carboxamide (0.96 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.47 g) as starting materials, 4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(pyrazol-4-yl)methyl]indan-1-carboxamide (0.43 g) was obtained. By the reaction and treatment in the same manner as in Example 271 using this compound (0.43 g) and ethyl iodide (0.28 mL), 4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]indan-1-carboxamide (0.36 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound (0.36 g), N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxyindan-1-carboxamide (0.21 g) was obtained.
Reaction SMILES: [C:1]([C:9]1C=[CH:15][CH:14]=[C:11]2[CH2:12][CH2:13][C:10]=12)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:19]([OH:21])C>>[CH:12]1[C:11]2[CH:14]=[CH:15][C:1]([C:2]3([CH:3]=[CH:4][CH:5]=[CH:6][CH2:7]3)[CH2:19][OH:21])=[CH:9][C:10]=2[CH:13]=1
Reactant: CCO
Reactant: O=C(c1ccccc1)c1cccc2c1CC2
Agent: [BH4-]
Agent: [Na+]
Product: OCC1(c2ccc3c(c2)C=C3)C=CC=CC1

Procedure:
4-Benzoylbenzocyclobutene is reduced with sodium borohydride in 2 mL ethanol. 1-(4-Benzocyclobutenyl)benzyl alcohol is obtained.
Reaction SMILES: [C:1]([OH:15])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(Cl)([Cl:18])=O>C1CCCCC1>[C:1]([Cl:18])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCC(=O)O
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCC(=O)Cl
Temperature: 80 °C
Yield: 101.4 %

Procedure:
In a one L (liter) two-necked flask were placed 158.7 g (0.74 mol) of tridecanoic acid and 200 milliliter (mL) of cyclohexane, and the flask was equipped with a 100 mL dropping funnel containing 83.3 g (0.7 mol) of thionyl chloride and a reflux tube. Then, the tridecanoic acid was completely dissolved under heating and stirring of the flask in an oil bath at 80° C. Thereafter the thionyl chloride was added dropwise over a period of 2 hours, and further the oil bath was maintained at 80° C. for one hour. From the resultant reaction solution were removed the cyclohexane and the thionyl chloride under reduced pressure by means of an aspirator. The resultant reaction mixture was subjected to vacuum distillation. Thus 166.0 g (0.71 mol) of tridecanoyl chloride was obtained in a yield of 95.9% based on the fed tridecanoic acid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:18]([OH:19])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NO
Reactant: CCCCCCCc1c(C)oc(C)cc1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of trimethyl pyrone 1 (113 mg, 0.51 mmol), hydroxylamine hydrochloride (707 mg, 10.2 mmol), sodium acetate (835 mg, 10.2 mmol), water (1 mL), and ethanol (2 mL) was heated to reflux for 8 hr. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 5:1 ethyl acetate/methanol gave 3-heptyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-6): yield 63 mg (51%); silica gel TLC Rf 0.35 (3:1 ethyl acetate/methanol); 1H NMR (400 MHz, CDCl3) δ 0.84-0.88 (m, 3H), 1.24-1.45 (m, 10H), 2.36 (s, 3H), 2.47 (s, 3H), 2.60 (t, 2H, J=7.6 Hz) and 6.73 (s, 1H).
Reaction SMILES: C(OC([NH:8][C:9]([NH:32]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:40]>ClCCl.O1CCOCC1>[ClH:40].[ClH:40].[OH:24][CH2:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:32])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2ncccc2CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)phenyl)guanidine (300 mg) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 6 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-hydroxymethylpyridin-2-yl)-phenylguanidine dihydrochloride (1I40 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([Br:24])[CH:23]=1.[F-].[K+]>CN(C=O)C>[Br:24][C:22]1[CH:21]=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[CH:19]=[C:18]([NH:17][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH:23]=1
Reactant: Cn1cc(-c2ccc(F)c([N+](=O)[O-])c2)cn1
Reactant: CC(=O)Nc1cc(N)cc(Br)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Br)cc(Nc2ccc(-c3cnn(C)c3)cc2[N+](=O)[O-])c1
Yield: 35 %

Procedure:
A solution of 4-(4-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole (1.6 g, 7.239 mmol), N-(3-amino-5-bromophenyl)acetamide (1.98 g, 8.687 mmol) and potassium fluoride (0.503 g, 8.687 mmol) in DMF was heated at 130° C. for 48 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to yield the title product in 35% yield (1.1 g); LC-MS (API): Calculated mass: 430.1; Observed mass: 432 [M+H]+ (rt: 1.50 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:23]1[CH:22]=[N:21][C:20]([Cl:19])=[N:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Product: Clc1ccc(OCc2ccccc2)c(-c2cnc(Cl)nc2)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 16 step (ii) (3.2 g) and 2-chloro-5-bromopyrimidine (2.59 g). Yield 2.43 g
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][C:23]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:22][N:21]=4)=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:32]([O:37][CH2:38][CH2:39]Br)(=[O:36])[C:33]([CH3:35])=[CH2:34].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:32]([O:37][CH2:38][CH2:39][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[O:24][C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[CH:15][CH:16]=3)=[N:21][N:22]=2)[CH:26]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)OCCBr
Reactant: Oc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Reaction time: 23.5 h

Procedure:
To a solution of 3-(5-(4-carbazol-9-ylphenyl)-1,3,4-oxadiazol-2-yl)phenol (1.0 g, 2.48 mmol) and 2-bromoethyl methacrylate (0.5 g, 2.59 mmol) in DMF (20.0 ml) was added K2CO3 (4.0 g, 28.94 mmol) at room temperature under stirring. The reaction was carried out at room temperature for 23.5 h. Water (100.0 ml) was added. Brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.7:0.3) as eluent. After removal of solvent, white glass-like solid product was dissolved in acetone. The acetone solution was slowly dropped into methanol (60.0 ml) under stirring. After addition of acetone solution, water (30.0 ml) was added into this solution. White solid product was obtained and collected by filtration. After vacuum dry, the product as white solid in 0.98 g (76.6%) was obtained. 1H NMR (400 MHz, CDCl3, δ): 8.37 (d, J=8.0 Hz, 2H), 8.14 (dd, J1=8.0 Hz, J2=0.8 Hz, 2 Hz), 7.78-7.72 (m, 4H), 7.50-7.41 (m, 5H), 7.31 (m, 2H), 7.12 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 6.16 (d, J=0.4 Hz, 1H, C═C—H), 5.59 (t, J=0.8 Hz, 1H, C═C—H), 4.55 (t, J=4.8 Hz, 2H, OCH2), 4.33 (t, J=4.8 Hz, 2H, OCH2), 1.96 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 167.28, 164.57, 164.06, 140.94, 140.22, 135.89, 130.40, 128.59, 127.21, 126.21, 124.97, 123.78, 122.34, 120.58, 120.47, 119.79, 118.74, 112.47, 109.87, 66.22, 62.86, 18.30. [M]+ calcd for C32H25N3O4, 515.2. found 515.2. Anal. Calcd for C32H25N3O4: C, 74.55; H, 4.89; N, 8.15. Found: C, 74.29; H, 4.79; N, 8.13.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([O:31][CH3:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[C:24]([O:31][CH3:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc1C(=O)NC1CCN(C)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.22 (m, 14H) 2.66-2.88 (m, 2H) 3.05 (m, 2H) 3.33 (s, 3H) 3.46 (d, J=11 Hz, 2H) 3.86 (s, 3H) 4.05 (t, J=14 Hz, 3H) 4.81 (m, 1H) 7.49 (m, 2H) 7.64 (m, 1H) 7.93 (d, J=7 Hz, 1H) 8.28 (s, 1H) 9.69 (s, 1H). [M+H] calc'd for C27H35F2N7O3, 544. found 544.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[N:8]1([C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)N1CCOCC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (2.64 g, 2 mL, 18.5 mmol) was reacted with morpholine (1.69 g, 1.7 mL, 19.4 mmol) and pyridine (1.68 g, 1.72 mL, 21.2 mmol) in methylene chloride (25 mL) at room temperature overnight to give the crude product, 1-chloroethyl morpholine-4-carboxylate. A portion of 1-chloroethyl morpholine-4-carboxylate (670.1 mg, 3.46 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.5 mg, 0.325 mmol) in the presence of cesium carbonate (1.094 g, 3.36 mmol) in dimethylformamide (7 mL) overnight to give, 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylate as an off-white solid (186.5 mg, 74% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]: 773, found: 773
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccnc1Cl
Reaction time: 10 h

Procedure:
2-Chloro-3-pyridinesulfonyl chloride in THF (10 mL) was treated with a 2.0M solution of dimethylamine in THF (8 mL, 16 mmol). After stirring for 10 hours, the mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organics were concentrated under reduced pressure and the residue was purified by flash chromatography (30% ethyl acetate in hexanes) to provide the title compound.