Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Oc2cc(F)cc(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.6 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester (3e) (1 g, 0.0045 mol), 3,5-difluorophenylboronic acid (1.07 g, 0.0068 mol), Cu(OAc)2 (0.9 g, 0.005 mol), freshly activated 4 Å molecular sieves (4 g) and Et3N (4 mL) in CH2Cl2 (25 mL) was stirred at room temperature under N2 for 48 hrs. The mixture was filtered through Celite and the filter cake was washed with CH2Cl2. The filtrate was concentrated to give a dark liquid. The crude liquid was purified by column chromatography eluting with EtOAc/petroleum ether (1/5) to give the title compound (0.4 g, 26.6%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.18 (s, 1H), δ 7.14 (s, 1H), 6.47(m, 1H), δ 6.36 (dd, 2H), 3.81 (s, 3H), 2.83 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([NH:41][CH:42]([C:48](O)=[O:49])[CH2:43][S:44][C:45](=[O:47])[CH3:46])(=[O:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:48](=[O:49])[CH:42]([CH2:43][S:44][C:45](=[O:47])[CH3:46])[NH:41][C:38](=[O:40])[CH3:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline tert-butyl ester (0.85 g.) and hydroxybenzotriazole (0.67 g.) in methylene chloride (10 ml.) chilled in an ice bath, dicyclohexylcarbodiimide (1.03 g.) and N,S-diacetyl-D,L-cysteine (1.7 g.) are added in that order. After fifteen minutes, the ice bath is removed and the mixture is stirred at room temperature overnight. The precipitate is filtered off and the filtrate is washed with 10% potassium bisulfate, water, saturated sodium bicarbonate, and water. The organic phase is dried and concentrated to dryness in vacuo to give N,S-diacetyl-D,L-cysteinyl-L-proline tert-butyl ester as an oil. Rf =0.25 (silica gel, ethylacetate).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:10]=2[O:9][C:8]1([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)Cc2cccc(Br)c2O1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2c(Br)cccc2C1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirring mixture of 7.0 grams (0.031 mole) of 7-bromo-2,3-dihydro-2,2-dimethylbenzofuran and 5.5 grams (0.031 mole) of N-bromosuccinimide in 150 mL of carbon tetrachloride is heated to reflux while irradiating with a sun lamp. The refluxing reaction mixture is stirred for about three hours, then it is cooled to ambient temperature. After this time the reaction mixture is washed with two 50 mL portions of aqueous 5% sodium bicarbonate solution, and one 50 mL portion of water. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 3,7-dibromo-2,3-dihydro-2,2-dimethylbenzofuran.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:33][CH2:34][C:35](=N)OCC.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([O:8][CH2:9][C@H:10]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:35]1[CH2:34][Cl:33])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 70 °C
Yield: 85.4 %

Procedure:
N4-[(1S)-2-(Benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]quinoline-3,4-diamine (1.66 g, 3.80 mmol) was dissolved in 40 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (1.80 g, 11.4 mmol) was then added and the reaction mixture was heated to 70° C. After stirring overnight, the reaction mixture was cooled and treated with 20 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20-50% ethyl acetate/hexanes) gave 1.61 g of 1-[(1S)-2-(benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline as a golden syrup.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[C:24]2[C:21](=[CH:20][CH:19]=1)[CH:22]=[C:2]1[C:1]([O:14][C:5](=[O:7])[C:4]3[C:3]1=[C:12]2[CH:11]=[CH:10][CH:9]=3)=[O:13]
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: O=C1OC(=O)c2cc3ccc(C(F)(F)F)cc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and p-(trifluoromethyl)benzaldehyde:
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].CCN(CC)CC.[Si:14](Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C1C=CN=CC=1)C>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:6][C:2]([CH3:3])([C:4]#[CH:5])[CH3:1]
Reactant: C#CC(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)O[Si](C)(C)C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 2-methylbut-3-yn-2-ol (140 g, 1.67 mol) was added DMAP (20 g 0.17 mol), Et3N (927 ml, 3.33 mol) and TMS-Cl (289 g, 2.66 mol) at 5 degree under a nitrogen atmosphere. After being stirred one hour, the mixture was washed with water, dried (MgSO4), filtered, concentrated, and distilled to obtain trimethyl[(2-methylbut-3-yn-2-yl)oxy]silane (150 g, 0.96 mol).
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[N:4]=[C:3]1[C:17]([F:20])([F:19])[F:18].S(Cl)([Cl:23])=O>CN(C)C=O.O>[Cl:23][C:7]1[C:6]2[N:2]=[C:3]([C:17]([F:20])([F:19])[F:18])[NH:4][C:5]=2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)n(O)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2[nH]c(C(F)(F)F)nc2c1Cl
Reaction time: 8 h

Procedure:
Crude 1-hydroxy-4,6-dinitro-2 -(trifluoromethyl)-benzimidazole (about 5 grams) was mixed with about 50 milliliters of thionyl chloride and several drops of dimethylformamide added. The reaction mixture was stirred overnight, then poured slowly into water and filtered. The solid was dissolved in benzene and eluted off a silica column with benzene. As a result of the foregoing operations, the desired 7-chloro-4,6-dinitro-2-(trifluoromethyl) benzimidazole product was obtained, m.p., 189° -91° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)c[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 2.75 g ethyl-4-phenylimidazole-2-carboxylate in 20 mL tetrahydrofuran was added a suspension of 0.5 g lithium aluminum hydride in 30 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature overnight, poured into 100 mL of ice water and extracted with 2×100 mL of ethyl acetate. The combined extracts were washed with 2×100 mL of brine, dried over anhydrous sodium sufate and the solvent removed under reduced pressure to yield 2 g of 2-hydroxymethyl-4-phenylimidazole which was used in the next step without further purification or characterization.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[O:23]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:38][CH:37]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 4-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (451 mg, 69%).
Reaction SMILES: O.Cl.CS[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([CH3:9])[C:6]([OH:8])=[O:7]>[Zn].C(OCC)C>[O:16]([C:12]1[CH:11]=[C:10]([CH:5]([CH3:9])[C:6]([OH:8])=[O:7])[CH:15]=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 100.3 %

Procedure:
Water (1.5 ml) and 1.5 ml of conc. hydrochloric acid were added to 432 mg of α-methylthio-α-(m-phenoxyphenyl)propionic acid, and then 300 mg of zinc powder was added. With stirring, the mixture was heated under reflux for 2.5 hours. Water (10 ml) and 30 ml of diethyl ether were added to the reaction mixture. The insoluble matter was separated by filtration. The filtrate was extracted three times with 30 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 364 mg of α-(m-phenoxyphenyl)propionic acid as an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[O:10]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)[CH2:11]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:11][C:12]2([OH:10])[CH2:13][CH2:14][N:15]([C:18](=[O:33])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)CO3)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(O)(Cn3cc([N+](=O)[O-])nc3Cl)CC2)CC1
Yield: 60.5 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1.29 g, 8.76 mmol), tert-butyl 4-{2-(1-oxa-6-azaspiro[2,5]octan-6-yl)-2-oxoethyl}piperazine-1-carboxylate (2.97 g, 8.76 mmol) and sodium hydrogencarbonate (809 mg, 9.64 mmol) in ethanol (10 ml) was stirred under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and a saturated sodium hydrogencarbonate solution was added. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-{2-[4-(2-chloro-4-nitroimidazol-1-ylmethyl)-4-hydroxypiperidin-1-yl]-2-oxoethyl}piperazine-1-carboxylate (2.58 g, yield 61%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[N:12]([Sn](C)(C)C)=[N+:13]=[N-:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]1[N:12]=[N:13][NH:14][N:5]=1
Reactant: N#Cc1c(F)cc(Cl)cc1Br
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Fc1cc(Cl)cc(Br)c1-c1nn[nH]n1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-bromo-4-chloro-6-fluoro-benzonitrile (4 g, 17.06 mmol) and azidotrimethyltin (3.86 g, 18.77 mmol) in toluene (100 ml) was heated to 120° C. for 72 h. After completion of the reaction, the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml). The organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure to afford the title compound (4.2 g, 87%) as red solid.
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[N:31]=[CH:30][CH:29]=[N:28]4)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Reactant: OB(O)c1ccc2nccnc2c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc3nccnc3c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 46 using (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1) and quinoxalin-6-ylboronic acid. LC-MS (Condition 6) tR=1.64 min, m/z=496.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]2[NH:15][C:16]([C:18]3[C:19](=[O:34])[NH:20][CH:21]=[CH:22][C:23]=3[NH:24][CH2:25][C@@H:26]([OH:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N>C1COCC1>[OH:33][C@@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][NH:24][C:23]1[CH:22]=[CH:21][NH:20][C:19](=[O:34])[C:18]=1[C:16]1[NH:15][C:14]2[C:9]([NH:8][C:42](=[O:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Triethylamine (0.058 g, 0.416 mmol) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) and phenylacetyl chloride (0.051 g 0.32 mmol) in THF (2 ml) and the reaction stirred at room temperature. After 20 hours methanolic ammonia was added (5 ml) and the reaction stirred for a further 20 hours. The reaction mixture was concentrated under reduced pressure and the crude solid washed with acetonitrile water (1:1; 10 ml) to give the desired product (0.034 g; 43%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.94 G. of 1-acetamido-4-hydroxy-2-nitrobenzene, 5.13 g. of benzyl bromide and 4.2 g. anhydrous potassium carbonate are refluxed overnight in acetone with stirring, evaporated to dryness, the excess benzyl bromide removed under vacuum, water added and the product extracted with dichloromethane to give 1-acetamido-4-benzyloxy-2-nitrobenzene.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Reactant: COc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(SCCCCCCCc2ccccc2C(=O)O)cc1

Procedure:
The compound of Example 14(a), 2-(7-bromoheptyl)benzoic acid (1 g., 3.34 mm) was reacted with 4-methoxybenzenethiol (0.618 ml, 5.03 mm), and triethylamine (1.87 ml, 13.42 mm) in DMF (40 ml) as in Example 14(b) to afford the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[Br:39])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Br
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4Br)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 2-Bromo-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(2-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (8 mg, 14%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 6.77 (m, 2 H) 6.94 (m, 3 H) 7.24 (m, 1 H) 7.44 (m, 1 H) 7.54 (dd, J=7.74, 1.84 Hz, 1 H) 7.73 (dd, J=8.09, 1.50 Hz, 1 H) 7.86 (d, J=8.46 Hz, 1 H) 8.01 (dd, J=8.64, 2.02 Hz, 1 H) 8.15 (d, J=2.21 Hz, 1 H) 8.89 (s, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.06 (s, 1 H) 11.37 (s, 1 H); MS (ESI+) m/z 570, 572 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[CH2:4][CH:5]=[CH2:6].[OH-].[K+].O.Cl>CO>[CH2:1]=[CH:2][CH:3]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCC(C=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCC(C=C)OCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
9.3 g of the compound (2), 4.0 g of potassium hydroxide and 1 ml of water were dissolved in methanol, and reflux was carried out for one hour. After addition of 50 ml of water, reflux was further carried out for three hours. The reaction mixture was adjusted to pH 2 by adding diluted hydrochloric acid. The precipitate was collected by filtration and was then washed with water, to obtain 8.1 g of the objective compound (3). (Yield: 90%)
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:37]=[CH:36][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]#[N:35])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]([NH2:35])=[O:39])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:36][CH:37]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1-H-pyrazole-3-carbonitrile (0.070 g, 0.145 mmol) in DMSO (1.0 mL). To this was added potassium carbonate (0.024 g, 0.174 mmol) and hydrogen peroxide (0.445 mL, 14.5 mmol) and the mixture was stirred at 20° C. for 3 days and quenched with water. The product was extracted into EtOAc, washed 1× saturated NaHCO3, 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was purified using a Gilson reverse phase liquid chromatography system. The product fractions were extracted into CH2Cl2. The organic layers were washed organics 1× saturated NaHCO3, 1×H2O, dried with Na2SO4, filtered through fritted funnel and concentrated to yield 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1-H-pyrazole-3-carboxamide as light yellow solid. MS m/z=500 [M+1]+. Calc'd for C29H21N7O2: 499.52.
Reaction SMILES: [CH2:1]([C:4]12[CH2:11][O:10][C:7]([CH2:12][C:13]([O-:15])=[O:14])([O:8][CH2:9]1)[O:6][CH2:5]2)[CH2:2][CH3:3].[Na+].[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O>[CH2:1]([C:4]12[CH2:9][O:8][C:7]([CH2:12][C:13]([O:15][CH2:19][C:18]#[CH:17])=[O:14])([O:6][CH2:5]1)[O:10][CH2:11]2)[CH2:2][CH3:3]
Reactant: C#CCBr
Reactant: CCCC12COC(CC(=O)[O-])(OC1)OC2
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC(=O)CC12OCC(CCC)(CO1)CO2
Reaction time: 24 h

Procedure:
A mixture of sodium 2-{4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl}acetate (1.0 g) and propargyl bromide (1.8 ml of 80% solution in toluene, supplied by Aldrich) in dry dimethylformamide (30 ml) was stirred at 20° for 24 hours. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica (pre-eluted with 1:3 dichloromethane:hexane containing 3% triethylamine) and eluting with 1:3 dichloromethane:hexane containing 3% triethylamine.