Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[C:19](OC(Cl)=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20].O>O1CCOCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19]([N:9]3[C:10]4[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=4)[CH:7]=[CH:8]3)=[O:20])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)OC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)n1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
5-Nitroindole (2.0 g, 12.3 mmol) was dissolved in dioxane (25 mL) and 10% wt./vol Na2CO3 solution (2.5 g, water 25 mL) was added. FMOC-chloroformate (3.19 g, 12.3 mmol) was added to the mixture and the reaction was stirred overnight. The reaction mixture was transferred into water, filtered as a yellow solid and dried in vacuum oven at 50° C. for 2 hours. Obtained (4.07 g, 86% y). NMR (400 MHz, CDCl3), δ 8.61 (d, J=2.2 Hz, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.12 (dd, J=7.3, 5.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.62 (m, 4H), 7.60-7.30 (m, 8H), 6.74-6.69 (m, 2H), 4.94 (d, J=5.4 Hz, 2H), 4.41 (t, J=5.1 Hz, 1H), 4.05 (d, J=5.6 Hz, 2H). MS 384 [M−H] APCI.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][C:15]2([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][C:15]3([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
Prepared by coupling 3-fluorophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium(0) with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water. Work up in the usual manner followed by recrystallization from ethanol gave a gray solid: mp 190-192° C. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.57 (s, 1H), 7.50 (m, 4H), 7.15 (m, 1H), 6.95 (d, 1H J=8.2 Hz), 2.39 (s, 2H), 1.29 (s, 6H); MS (APCI(−)) m/z 268 [M−H]− Anal. Calc. For C17H16FNO 0.25 H2O: C, 74.57, H, 6.07, N, 5.12. Found: C, 74.86, H, 5.97, N, 5.06.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]([C:12]2([CH:22]3[CH2:24][CH2:23]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:8]2[CH:7]=[C:6]([C:33]3[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:34]=3)[CH:11]=[CH:10][CH:9]=2)([CH:22]2[CH2:23][CH2:24]2)[N:13]=1
Reactant: COc1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: NC1=NC(c2cccc(Br)c2)(C2CC2)c2ccccc21
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(-c2cccc(C3(C4CC4)N=C(N)c4ccccc43)c2)c1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine acetate (Scheme #15, O) and 4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: 1H NMR (DMSO-d6) δ 7.89-7.84 (m, 2 H), 7.75-7.68 (m, 1 H), 7.68-7.63 (m, 1 H), 7.56-7.51 (m, 1 H), 7.43-7.35 (m, 4 H), 7.12 (dd, J=8.66, 2.64 Hz, 1 H), 7.06 (d, J=2.51 Hz, 1 H), 3.89 (s, 3 H), 1.92-1.83 (m, 4 H), 0.49-0.38 (m, 2 H), 0.25-0.16 (m, 1 H), −0.04-0.03 (m, 1 H): MS (ES) m/z 380 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11](=[CH2:23])[CH:12](O)[CH:13]([NH:19][CH:20]=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].S(Br)([Br:26])=O.O>C(Cl)Cl>[Br:26][CH2:23][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:13]([NH:19][CH:20]=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=C(CCCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CBr
Reaction time: 0.17 h

Procedure:
5 g (15.1 mmol) of ethyl 7-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-heptanoate are dissolved in 50 ml of CH2Cl2 and 1.4 ml (18.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours 50 ml of water are added and the batch is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted once with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and the filtrate is concentrated by evaporation giving ethyl 4-bromomethyl-7-ethoxycarbonyhnethoxy-2-formylamino-hept-3-enoate as a yellow oil which is further reacted without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.[NH2:17][N:18]1[C:27](=O)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=2)[N:20]=[C:19]1NN.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:17][N:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([CH3:29])=[CH:25]2)=[N:20][CH:19]1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: Cc1ccc2nc(NN)n(N)c(=O)c2c1
Reactant: CCOC(=O)N1CCN(CCCCN)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(CCCCNC2N=c3ccc(C)cc3=CN2N)CC1
Temperature: 180 °C

Procedure:
A mixture of 10 g of ethyl 4-(4-aminobutyl)-piperazine-1-carboxylate, 5 g of 3-amino-2-hydrazino-6-methylquinazolin-4-(3H)-one and 0.5 g of p-toluenesulfonic acid was heated to 180° C. (bath temperature of reaction mixture 160° C.) for 4 hours. After cooling to 100° C., the reaction mixture was dissolved in 250 ml of toluene and was washed twice with 100 ml of water. The mixture filtered through `celite` and the product was retained in the toluene solution for use in the next stage.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[CH3:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: CC(F)(F)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(C)(F)F)c1

Procedure:
Prepared from 460 mg (1.03 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1,1-difluoro-ethyl)-benzenesulfonamide, 355 mg of potassium carbonate and 195 μL of methoxymethyl chloride in 2 mL THF using procedure x. Yield: 162 mg of a white solid. LC-MSD, m/z for C15H13BrCl2F2N2O3S [M+H]+=488.8, 490.8, 492.8; HPLC retention time: 2.9 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ncnc(Cl)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2ccc(CBr)cc12
Temperature: 80 °C
Yield: 47.5 %

Procedure:
A flask containing 4-Chloro-6-methylquinazoline (0.91 g, 5.09 mmol), NBS (0.95 g, 5.35 mmol), benzoyl peroxide 70% (0.09 g, 0.2545 mmol) and carbon tetrachloride (25 mL) is refluxed at 80° C. for 20 h. The solution is cooled to RT, filtered and concentrated. Purification by flash chromatography (7.5% EtOAc/hexanes) yields the title compound as a white solid (0.62 g, 2.42 mmol). 1H NMR (CDCl3, 300 MHz) 9.06(s, 1H), 8.25(s, 1H), 8.07(d, 1H), 8.00(d, 1H), 4.67(s, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([NH2:17])=[CH:12][C:13]=32)[CH2:6]1)(=[O:4])=[O:3].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.C(O)(C)C.C(=O)(O)[O-].[Na+]>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(S(C)(=O)=O)C2)ncc1Cl
Temperature: 130 °C
Yield: 31.1 %

Procedure:
Into a microwave tube was dissolved 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (58.0 mg, 0.194 mmol) in isopropyl alcohol (1 mL, 10 mmol). The tube was heated in the microwave at 130° C. for 20 minutes. The reaction solution was poured into saturated sodium bicarbonate solution and was extracted with methylene chloride (6×20 ml). The reaction was dried over magnesium sulfate filtered and was rotovaped to a clear oil. The crude product was chromatographed on silica gel (12 g Isco column) and eluted with a gradient of 0-15% methanol in methylene chloride to yield -[5-Chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (31.0 mg, 31%) as a white powder. MP: 163.5-165.0° C.; 1H-NMR (CDCl3) δ 10.97 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.55-7.42 (m, 2H), 7.21-7.09 (m, 3H), 6.40 (br s, 1H), 3.40-3.28 (m, 3H), 3.18 (br s, 1H) 3.10 (br s, 1H), 3.02 (dd, J=5.05, 3H), 2.42-2.30 (m, 1H), 2.08-2.00 (m, 1H), 1.90 (s, 3H), 1.81 (d, J=10.9 Hz, 1H), 1.32-1.21 (m, 2H), 0.90-0.81 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](B(O)O)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl.Cl.Br[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[C:36]1[N:41]=[C:40]([N:42]2[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]2)[CH:39]=[N:38][CH:37]=1>>[CH3:1][O:2][C:3]1[C:12]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][N:31]=[C:30]3[C:36]2[N:41]=[C:40]([N:42]3[CH2:43][CH2:44][CH:45]([NH2:48])[CH2:46][CH2:47]3)[CH:39]=[N:38][CH:37]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1B(O)O
Reactant: NC1CCN(c2cncc(-c3n[nH]c4ccc(Br)cc34)n2)CC1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1nc2ccccc2cc1-c1ccc2[nH]nc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 150 °C

Procedure:
To a 5 mL conical vial was added 2-methoxyquinolin-3-ylboronic acid (Frontier Scientific, 89 mg, 0.437 mmol), potassium phosphate (Aldrich, 285 mg, 1.345 mmol), PdCl2(AmPhos) (23.80 mg, 0.034 mmol), and 1-(6-(5-bromo-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine dihydrochloride salt (Example 1) (150 mg, 0.336 mmol) which was sealed, evacuated and back-filled with N2 3×. Dioxane (2.8 mL) and water (0.6 mL) were added, and the reaction mixture was heated at 150° C. for 30 min with microwave irradiation. After the reaction mixtures were filtered, the crude reaction mixture was concentrated and purified on silica gel (eluent: 0 to 4% MeOH (with 2M NH3) in DCM) to afford the title compound. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[CH2:12][CH2:13]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCN(c3ncccn3)CC2)nc1
Temperature: 80 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (500 mg, 3.2 mmol) and 2-piperazin-1-yl-pyrimidine (520 mg, 3.2 mmol) in DMF (15 mL) was added diisopropylethylamine (2.70 mL, 15.5 mmol). The mixture was heated in a sealed tube at 80° C. for 24 hours. The mixture was concentrated to dryness and triturated in methanol to give 2-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. The NMR spectrum on this sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][C:25](O)=[O:26])[N:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:25](=[O:26])[CH2:24][N:21]4[CH:22]=[CH:23][C:19]([C:18]([F:28])([F:17])[F:29])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1ccc(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.026 g, 0.12 mmol), 2-(3-(trifluoromethyl)-pyrazol-1-yl)acetic acid (0.024 g, 0.12 mmol) and NEt3 (0.060 mL, 0.43 mmol) in DMF (0.5 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.035 g, 74%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.64 (m, 1H), 7.43 (m, 2H), 7.15 (dd, J=8.8, 8.4 Hz, 2H), 6.62 (d, J=2.4 Hz, 1H), 5.23 (s, 2H), 3.82 (m, 2H), 2.84 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][N:16]=1.N>>[F:14][C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: NC(=NO)c1ccc2nccn2c1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccc4nccn4c3)no2)cn1

Procedure:
The title compound was prepared according to Method C using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 6-fluoronicotinic acid (Frontier). 1H NMR (300 MHz, DMSO-d6) δ 7.55 (ddd, J=8.5, 2.7, 0.7 Hz, 1 H), 7.70 (d, J=1.4 Hz, 1 H), 7.73-7.86 (m, 2 H), 8.20 (s, 1 H), 8.75 (ddd, J=8.1, 2.5 Hz, 1 H), 9.08 (dt, J=1.7, 0.8 Hz, 1 H), 9.46 (dd, J=1.7, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:33](Br)([CH3:35])[CH3:34].CN(C)C=O>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:33]([CH3:35])[CH3:34])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane, 1.5 g of K2CO3, 3 ml of isopropyl bromide and 20 ml of dimethylformamide was stirred at 130° C. for two hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: benzene) to give 0.3 g of 1-(3-phenoxyphenyl)-4-(4-isopropoxyphenyl)-4-methylpentane.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1)(=[O:39])=[O:38]
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: COc1ccc(CN2Cc3c(Oc4ccc(NS(=O)(=O)c5ccccc5F)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (45 mg, 0.11 mmol) and 2-fluorobenzenesulfonyl chloride (24 mg, 0.12 mmol) were suspended in pyridine (1 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=553, obsd.=553).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].Cl.[NH2:14][OH:15].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5](=[N:14][OH:15])[NH2:6]
Reactant: NO
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C(N)=NO)ccc1[N+](=O)[O-]

Procedure:
To a solution of 3-methyl-4-nitrobenzonitrile (5 g) in ethanol (100 ml) at room temperature was added hydroxylamine hydrochloride (2.25 g) followed by triethylamine (4.5 ml). The mixture was heated under reflux for 2.5 hours. On cooling the mixture was evaporated to a third of its original volume and poured on to water (200 ml). The mixture was filtered to give the title product as a solid, m.p. 127-9° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.[OH-].[K+]>O>[CH:4]1[CH:2]=[C:2]2[CH:4]=[C:6]3[C:11](=[N:1][C:8]2=[CH:7][CH:6]=1)[CH:10]=[CH:9][CH:8]=[CH:7]3
Reactant: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2nc3ccccc3cc2c1
Temperature: 50 °C

Procedure:
Isatin (1) (1.88 g) was slowly added to a solution of potassium hydroxide (5.07 g, 0.09 mole) dissolved in water (3.5 ml). The reaction flask was heated to about 50° C. in an oil bath. About 10 ml more water was added dropwise. Resorcinal (2) (10 g, 0.089 mole) was added and the temperature was raised to 100° C. as stirring was continued, resulting in the formation of a molten mixture. More isatin (1) (1.88 g) was added. The reaction flask (3-necked round bottom) was attached to a nitrogen inlet and the water vapors were flushed out by the stream of nitrogen. The mixture was stirred for 4 hours at 125° C. Water (70 ml) was added and the contents were dissolved by continued stirring. After transferring the mixture to an erlenmeyer flask the volume was brought up to 200 ml with water. The pH was adjusted to 2.0 with concentrated hydrochloric acid. Filtration and washing of the solids with water gave the crude acridine acid. It was then dissolved in 2N NaOH (100 ml) and the solution was filtered through celite. The celite bed was washed with 200 ml of 1N NaOH. The filtrate was acidified with concentrated HCl to pH 2.0. The precipitate of 2-hydroxy-acridine-9-carboxylic acid (3) was filtered, washed with water and was dried in vacuum over P2O5 (yield=42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in CH2Cl2 (30 mL) was stirred for 1 h at 0° C. and at ambient temp for 2 h. The solution was diluted with CH2Cl2 (40 mL) and the organic phase was washed with 0.1 N HCl and brine, dried over Na2SO4 and evaporated to dryness. The resulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. The solution was evaporated and the resulting orange oil was left in the freezer overnight to give a yellow solid. The crude solid was recrystallized from EtOH to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (5.3 g, 86.8% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCCCCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A mixture of ethyl 7-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate (16 g., 0.035 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50 ml.) is stirred and refluxed for 6 hours. The mixture is poured into water (400 ml.) where upon the product slowly solidifies. The product is removed by filtration, dried and recrystallized from a mixture of tetrahydrofuran, ether and petroleum ether (50, 100 and 200 ml., respectively) to give 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoic acid, 12.1 g., m.p. 107°-110° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23](OCC)=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:20][CH2:21]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 5 and was obtained as an off-white solid: 1H NMR (CDCl3) δ 10.36 (1H, br t, J=5 Hz), 8.59 (1H, d, J=1.3 Hz), 7.46 (1H, s), 7.34 (2H, m), 7.26 (1H, m), 7.20 (2H, d, J=7 Hz), 4.16 (2H, s), 4.08 (2H, d, J=7 Hz), 3.64 (2H, q, J˜5 Hz), 3.58 (2H, t, J˜5 Hz), 3.40 (3H, s), 1.00 (1H, m), 0.46 (2H, m), 0.39 (2H, m); HRMS calcd for C23H25N3O4+H+: 408.1923. Found: 408.1914.