Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][Br:29])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[Br-:29].[F:1][C:2]([F:19])([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][P+:36]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Fc1ccc(OC(F)(F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC(F)(F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
217 mg (0.46 mmol) of 2-(bromomethyl)-4-fluorophenyl difluoro[4′-(trifluoromethyl)biphenyl-4-yl]methyl ether from Example 41A and 148 mg (0.57 mmol) of triphenylphosphine are stirred in 5 ml of THF at RT for 12 hours. The reaction mixture is concentrated and the residue is washed with diethyl ether and n-hexane. The crude product is employed without further purification in the subsequent stage.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[BrH:22].[Br:23]Br.C([O-])(O)=O.[Na+]>>[Br:22][C:18]1[C:16]2[C:15](=[N:14][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:17]=2)[C:21]([Br:23])=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: CCCCCCCCCCCCn1nc2ccccc2n1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCCCCCCn1nc2c(Br)ccc(Br)c2n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Dodecylbenzotriazole (3.7 g, 13.1 mmol) and an aqueous HBr solution (5.8 M, 15 ml) were added to a flask, and the mixture was stirred for 1 h at 100° C. Bromine (5.9 g, 36 mmol) was added, and the mixture was stirred for 12 h at 135° C. After cooling the mixture to room temperature, an aqueous solution of NaHCO3 was added and the product was extracted with CHCl3. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. With column chromatography, 4,7-dibromo-2-dodecylbenzotriazole was obtained as light yellow oil (4.3 g, 75%). 1H NMR (400 MHz, CDCl3, δ): 7.36 (s, 2H), 4.60 (t, J=7.0 Hz, 2H), 2.10 (m, 2H), 1.38-1.12 (m, 18H), 0.80 (t, J=6.9 Hz, 3H). 13CNMR (100 MHz, CDCl3, δ): 143.7, 129.4, 109.9, 57.4, 31.8, 30.1, 29.5, 29.5, 29.4, 29.4, 29.3, 28.9, 26.4, 22.6, 14.0.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[N:6]1[C:22](=[O:34])[C@@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH3:25])=[O:4].O.[OH-].[Na+].ClCCl>CO>[C:30]([O:29][C:27]([NH:26][C@@H:23]([CH2:24][CH3:25])[C:22]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:34])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2(R/S)-carboxylic acid methylester (2.75 g, 5.76 mmol) in methanol (20 mL), was added the water solution of sodium hydroxide (0.46 g, 11.52 mmol) under nitrogen at 10-15° C. The solution was stirred at room temperature for fourteen hours, then poured into dichloromethane and washed with potassium hydrogen sulphate solution, water. The organic layer was separated and dried over magnesium sulphate, solvent removal gave a yellow foam which was pure enough for the next step.
Reaction SMILES: [H-].[Na+].N1[C:12]2[C:7](=C[CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])C1=O.[CH3:15]I.O.[CH3:18][N:19]([CH:21]=[O:22])[CH3:20]>>[CH3:18][N:19]1[C:20]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]([CH3:15])[C:5](=[O:13])[C:21]1=[O:22]
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c(=O)n(C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of NaH (2.5 g) in DMF (200 mL) was added quinoxaline-2,3(1H,4H)-dione (5 g) in portions, followed by the slow addition of methyl iodide (3.8 mL). The reaction mixture was stirred at ambient temperature for 4 hours, then water was added (200 mL). The resulting precipitate was collected by filtration and washed with water to afford 1,4-dimethylquinoxaline-2,3(1H,4H)-dione as a white solid in 95% yield. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.50(s, 6H), 7.25(m, 2H), 7.38(m, 4H).
Reaction SMILES: [CH2:1]([Li])[CH3:2].C(Br)C.[Li].[CH3:8][O:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21])=[O:13].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:8][O:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21])([OH:13])[CH2:1][CH3:2]
Reactant: [Li]CC
Reactant: COc1ccccc1C(=O)c1ccc(O)cc1O
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ethyl lithium solution prepared from 29.4 g. of ethyl bromide and 3.7 g. of lithium in 33o ml. of dry ether, under argon atmosphere, which is cooled to -10° C., a solution of 11 g. of 2-methoxy-2',4'-dihydroxy-benzophenone in 60 ml. of dry tetrahydrofurane is added dropwise, taking care that the temperature does not exceed -5° C. Thereafter the reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for two hours. The reaction mixture is decomposed with a 10% aqueous ammonium chloride solution, the phases are separated, and the aqueous phase is extracted with ether. The combined ethereal phases are washed to neutral with water, dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off in vacuo, after decoloring with activated carbon. Crystallization of the solid residue from a mixture of n-hexane and ethyl acetate yields 8.3 g. of the named compound, melting at 141° to 142° C.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)[C:8](Cl)=[O:9].[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:8]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:9])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1
Reactant: CC(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A suspension of Example B7 (0.059 g, 0.673 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.059 mL, 0.673 mmol), stirred at RT for 1 h, warmed to 80° C. for 2.5 h, cooled to RT and added drop-wise to a solution of Example A2 (0.15 g, 0.561 mmol) in THF (4 mL) and pyridine (0.226 mL, 2.81 mmol). The mixture was stirred at RT overnight, treated with satd. Na2CO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resulting material was dissolved in MeCN/H2O, frozen and lyophilized to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (89 mg, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.85 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26-8.25 (m, 2H), 8.09 (d, J=9.0 Hz, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.73 (dd, J=9.0, 3.0 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.43 (m, 1H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 381.1 (M+H+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C([O-])([O-])=O.[K+].[K+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[N+:29]([O-:31])=[O:30]>CS(C)=O.O>[NH2:28][C:24]1[C:23]([N+:29]([O-:31])=[O:30])=[C:22]([O:14][C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]([NH2:3])=[CH:13][CH:12]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Nc1ccc(O)c2ncccc12
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nccc(Oc2ccc(N)c3cccnc23)c1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred solution of 5-aminoquinolin-8-ol dihydrochloride (2.00 g, 8.60 mmol) in DMSO (30 mL) under N2 was added K2CO3 (3.79 g, 27.5 mmol) and after 1 hr at RT the mixture was treated with 4-chloro-3-nitropyridin-2-amine (1.34 g, 7.72 mmol) in a single portion. The reaction mixture was heated to 70° C. for 2 hr and was then cooled to RT and diluted with water (500 mL). A precipitate formed which was isolated by filtration, washed with water (2×20 mL) and then dried in vacuo at 40° C. to afford the title compound, Intermediate H1 as a dark brown solid (1.50 g, 53%); Rt 0.99 min (Method 2); m/z 298 (M+H)+ (ES+).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[CH:25](Cl)[C:26]([O:28]C)=[O:27].Cl>O.CN(C)C=O>[C:9]1([C:6]2[C:5]3[CH:15]=[CH:16][C:2]4[O:1][CH:25]([C:26]([OH:28])=[O:27])[O:17][C:3]=4[C:4]=3[O:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Cl)Cl
Reactant: Oc1ccc2c(-c3ccccc3)noc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1Oc2ccc3c(-c4ccccc4)noc3c2O1
Reaction time: 5 h
Yield: 57.3 %

Procedure:
A mixture of 6,7-dihydroxy-3-phenyl-1,2-benzisoxazole (2.1 g), potassium carbonate (7.7 g), methyl dichloroacetate (2.7 g) and N,N-dimethylformamide (50 ml) was stirred at 90°-100° C. for 5 hours. After addition of water (100 ml), the mixture was stirred at 90°-100° C. for 30 minutes, and after acidifying it with hydrochloric acid, extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from acetonitrile to give 1.5 g of 3-phenyl-1,3-dioxolo[4,5-g]-1,2-benzisoxazole-7-carboxylic acid. m.p.: 187°-190° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16](CC(O)=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-:37])=[O:36])[CH2:24]1.[CH3:38]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:22][C@@H:23]1[CH2:27][N:26]([C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[O:10][C:11]=3[CH:17]=2)[C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:24]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C([O-])CCCCCOC[C@@H]1C[C@H](F)CN1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOC[C@@H]1C[C@H](F)CN1c1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 0 °C

Procedure:
In DMF (10 ml), 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (282 mg, 1.00 mmol), 6-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)hexanoate (247 mg, 1.00 mmol), EDC•HCl (288 mg, 1.50 mmol), HOBT (203 mg, 1.50 mmol) and triethylamine (0.70 ml, 5.00 mmol) were stirred at room temperature for 22 hours. The reaction mixture was poured in ice water (50 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue thus obtained was purified by thin-layer silica gel chromatography, followed by separation by using chloroform/acetone (10/1), whereby the title compound (330 mg, 65%) was obtained as a yellow oil.
Reaction SMILES: C(N=C=O)CCCCC[N:7]=[C:8]=[O:9].[C:13]([O:17]CCO)(=[O:16])[CH:14]=[CH2:15].C1(C=[CH:27][C:25]([OH:26])=CC=1)O>>[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15].[NH2:7][C:8]([O:26][CH2:25][CH3:27])=[O:9]
Reactant: Oc1ccc(O)cc1
Reactant: O=C=NCCCCCCN=C=O
Reactant: C=CC(=O)OCCO
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
500 g of polyethylene glycol having a molecular weight of about 1,000 and 168 g (1 mole) of hexamethylene diisocyanate were placed in a reaction vessel and reacted for 2 hours at 80° C. Moreover, 116 g (1 mole) of 2-hydroxyethyl acrylate and 1.7 g of hydroquinone were added thereto and reacted for 3 hours at 80° C. while blowing in air to obtain a urethane acrylate (A-2) having acryloyl groups on both ends of a molecule thereof. The weight average molecular weight of the urethane acrylate (A-2) was 1,900.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[O:8]=[C:9]1[C:17]2C(=[CH:13][CH:14]=[CH:15][CH:16]=2)C(=O)[N:10]1[CH2:19][CH:20]([S:41]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][N:22]1[C:30]([C:31]2[S:32][CH:33]=[C:34]([CH3:36])[N:35]=2)=[C:29]2[C:24]([N:25]([CH3:40])[C:26](=[O:39])[N:27]([CH3:38])[C:28]2=[O:37])=[CH:23]1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:86][C:87]1[O:91][C:90]([CH:92]=O)=[CH:89][CH:88]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:86][C:87]1[O:91][C:90]([CH:92]2[C:23]3=[C:24]4[N:25]([CH3:40])[C:26](=[O:39])[N:27]([CH3:38])[C:28](=[O:37])[C:29]4=[C:30]([C:31]4[S:32][CH:33]=[C:34]([CH3:36])[N:35]=4)[N:22]3[CH2:21][CH:20]([CH2:19][N:10]3[C:3](=[O:5])[C:2]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]3=[O:8])[S:41]2)=[CH:89][CH:88]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=Cc1ccc(Cl)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2C(=O)c4ccccc4C2=O)SC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (0.399 ml, 5.18 mmol) was added to a solution of 6-(3-(1,3-dioxoisoindolin-2-yl)-2-(tritylthio)propyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (764 mg, 1.035 mmol) in toluene (15 ml) and the mixture was stirred at room temperature for 30 minutes. Bismuth triflate (340 mg, 0.518 mmol) and 5-chlorofuran-2-carbaldehyde (203 mg, 1.553 mmol) were then added and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with ethyl acetate (150 ml) and washed with water (150 ml), saturated NaHCO3(aq) (150 ml) and brine (150 ml). The organic layer was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[O:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[C:21]([C:26]([NH2:28])=[O:27])=[N:22][C:23]=1[CH2:24][CH3:25].O.NN.O1CCCC1>C(O)C>[NH2:3][C@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[O:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:37][CH2:38][CH:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:40][CH2:41]3)=[CH:34][CH:35]=2)[C:21]([C:26]([NH2:28])=[O:27])=[N:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCC[C@@H]1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A mixture of 5-{[(1R,2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopentyl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (322 mg), hydrazine monohydrate (99 mg), tetrahydrofuran (6.44 mL), and ethanol (6.44 mL) was stirred at 80° C. overnight. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; chloroform:methanol=99:1-97:3) to obtain 5-{[(1R,2S)-2-aminocyclopentyl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (117 mg) as a pale yellow solid.
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12]C=2)=CC=1.[NH:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[O:15]1[CH2:14][CH2:9][CH:10]([N:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C2CCOCC2)C1

Procedure:
The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl piperidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate on EXAMPLE 1A.
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[CH:27]=O)=[CH:22][CH:21]=1>CO.CCOC(C)=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([C:27]#[CH:3])[CH3:30])=[CH:22][CH:21]=1
Reactant: CC(C)(C=O)c1ccc(F)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC(C)(C)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Next, a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.4 eq.) in MeOH (0.6 M) was treated at 0° C. with K2CO3 (2.4 eq.) and 2-(4-fluorophenyl)-2-methylpropanal (1.0 eq.). The reaction mixture was stirred for 1 hour, diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated giving 1-fluoro-4-(2-methylbut-3-yn-2-yl)benzene: 1H NMR (600 MHz, CDCl3) δ 7.48-7.50 (m, 2 H), 6.97-7.00 (m, 2 H), 2.33 (s, 1 H), 1.57 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([CH3:26])=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([CH3:26])=[CH:25][C:16]=12
Reactant: Cc1cc2c(Cl)c(C#N)cnc2s1
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(C)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (0.15 g, 0.73 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-methylthieno[2,3-b]pyridine-5-carbonitrile (0.06 g, 0.29 mmol) is added. The reaction mixture is heated at reflux for 3 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 3:7 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 79 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 179–181° C.; 1H NMR (DMSO-d6) δ 2.57 (s, 3H), 3.85 (s, 3H), 7.32 (s, 1H), 7.39 (s, 1H), 7.74 (s, 1H), 8.35 (s, 1H), 9.61 (s, 1H); MS 362.1 (M−H)−
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.Cl[P:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]3[CH:21]=[CH:22][CH:23]=[C:13]([C:14]=23)[O:12]1.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][NH:3][P:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]3[CH:21]=[CH:22][CH:23]=[C:13]([C:14]=23)[O:12]1
Reactant: CCN(CC)CC
Reactant: ClP1Oc2cccc3cccc(c23)O1
Agent: CN
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CNP1Oc2cccc3cccc(c23)O1
Temperature: 5 °C

Procedure:
Under a nitrogen atmosphere, 0.4 ml triethylamine was added to 1.5 ml methylamine (2 M in THF) in 20 ml dry toluene. To the resulting solution was cooled to 5° C. and 250 mg 2-chloronaphtho[1,8-de][1,3,2]dioxaphosphinine (available from Hansa Fine Chemicals GmbH, Bremen, Germany) was slowly added. After stirring overnight at room temperature 20 ml hexane was added. The precipitate was removed by centrifugation. The solvents were removed under vacuum. The product N-methylnaphtho[1,8-de][1,3,2]dioxaphosphinine-2-amine was isolated as an oil and used as such. 31P-NMR C6D6 δ 121.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([Cl:40])[C:34]=1[CH:41]([OH:43])C.O[C:45]1[C:46]([N+:51]([O-:53])=[O:52])=[N:47][CH:48]=[CH:49][CH:50]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([Cl:40])[C:34]=1[CH2:41][O:43][C:45]1[C:46]([N+:51]([O-:53])=[O:52])=[N:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ncccc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of triphenyl phosphine (8.2 g, 0.03 mol) and DEAD (13.65 mL of a 40% solution in toluene) in THF (200 mL) at 0° C. was added a solution of 1-(2,6-dichloro-3-fluoro-phenyl)ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate-hexanes (20:80) to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (6.21 g, 0.021 mol, 98%) as a pink solid. 1H NMR (CDCl3, 300 MHz) δ1.8-1.85 (d, 3H), 6.0-6.15 (q, 1H), 7.0-7.1 (t, 1H), 7.2-7.21 (d, 1H), 7.25-7.5 (m, 2H), 8.0-8.05 (d, 1H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)(C)=O.[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:42])[C:25](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:43])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:42])[C:25]([CH:35]4[CH2:8][CH:36]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:43])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)/C=C/c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a 6 ml DMSO suspension of 200 mg of 60% sodium hydride was added 1.1 g of trimethylsulfoxonium iodide, followed by stirring for 30 minutes. To the reaction mixture was added 242 mg of ethyl (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acrylate, followed by stirring at room temperature for 1 hour and at 60° C. for 1 hour. To the reaction mixture was added water, followed by extraction with diethyl ether. The organic layer was washed with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg of ethyl 2-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]cyclopropanecarboxylate.