Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15](OCC)(=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[Cl:14])=[CH2:15])[CH3:21]
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Product: C=C(C(=O)OCC)c1c(Cl)cnc2ccc(OC)nc12

Procedure:
Starting from 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (41.75 g, 152.6 mmol) and diethyl malonate (70.2 mL, 3 eq.), the title compound was obtained as a white solid (31.35 g, 107.2 mmol) using the procedures reported in WO 2007/071936 for the analogous methyl ester.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 3-[3-(piperidinomethyl)phenoxy]propylamine (0.28 g) and triethylamine (0.40 g) in ethanol (2 ml), at 0° C., under nitrogen, was added 2-chlorobenzoxazole (0.17 g). The reaction mixture was stirred for one hour at 0° C., stirred at room temperature for 16 hours, evaporated under reduced pressure and subjected to column chromatography on silica (chloroform:methanol 25:1) to give the title compound as an oil (0.35 g). This was treated with anhydrous oxalic acid (2.1 equivalents) in methanol (5 ml). Addition of diethyl ether gave 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]benzoxazole dioxalate (0.245 g), m.p. 172°-4° C. (recrystallised from isopropanol-ethyl acetate).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[CH3:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reactant: O=Cc1cccc(F)c1
Product: CN(Cc1cccc(F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1

Procedure:
As described for Example 75d, 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile was converted, using 3-fluorobenzaldehyde instead of 3,4-dichlorobenzaldehyde, to the title compound. MS m/e=512.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([NH:11][C:12](=[O:14])[CH:13]=1)=[O:10].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:14])[NH:11][C:9]1=[O:10]
Reactant: O=C1C=C(c2ccccc2Cl)C(=O)N1
Reactant: Nc1ccccc1
Solvent: CCO
Product: O=C1NC(=O)C(c2ccccc2Cl)C1Nc1ccccc1

Procedure:
A solution of 2-(2-chlorophenyl)maleimide (4.70 g) and aniline (3.069) in ethanol (50 ml) is refluxed for 38 hours. The reaction mixture is concentrated and the residue is subjected to silica gel chromatography, with elution being carried out with n-hexane-ethyl acetate (4:1-1:1) to give 2-(2-chlorophenyl)-3-anilinosuccinimide (oil) (3.71 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)([CH3:21])[CH3:20])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17](=[O:29])[NH:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH:23]=1)([CH3:21])[CH3:20])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (2.57 g, 14.6 mmols), tert-butyl[1-(3-hydroxyphenyl)-1-methylethyl]carbamate (3.21 g, 12.8 mmols), potassium carbonate (2.02 g, 14.6 mmols) and N,N-dimethylformamide (20 ml) was stirred at 100° C. for 2 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl[1-[3-(5-chloro-2-nitrophenoxy)phenyl]-1-methylethyl]carbamate (3.6 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
EX-656A) 3-Aminophenol (5.0 g, 45.8 mmol) and 4-bromo-α,α,α-trifluorotoluene (14.0 g, 62.2 mmol) were dissolved in anhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30 g, 92.3 mmol) and copper triflate benzene complex (200 mg) were added. The mixture was stirred and heated to 85° C. using a reflux condenser under an argon atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% NaOH and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 6.8 g (59%) of the desired 3-(4-trifluoromethylphenoxy)aniline product as a yellow oil, which solidified to a yellow powder, 98% pure by HPLC analysis. HRMS calcd. for C13H10F3NO: 254.0792 [M+H]+, found: 254.0798.
Reaction SMILES: C(O)C.C(O[C:7](=[O:37])/[C:8](=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]2)=[C:25]([O:35][CH3:36])[CH:24]=1)/[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)C.[OH-].[Na+].Cl>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[CH2:12][CH2:11][CH2:10][CH2:9]/[C:8](=[CH:22]\[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)/[C:7]1=[O:37]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCNCc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCCN(Cc3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a to ethanol (2.0 mL) solution of (E)-6-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)hexanoic acid ethyl ester (173 mg), 2N sodium hydroxide solution (2.0 mL) was added. After refluxing the reaction solution for 1 hour and confirming disappearance of the starting materials, 2N hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. IPEA (134 μL), EDC (98.2 mg), and HOBT (69.2 mg) were added to a DMF (5.0 mL) solution of the obtained carboxylic acid compound (112 mg) one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate), and 70.3 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: ClC1C(OC(=O)[C@H:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:35]([O:42][C:43](=[O:71])[C@H:44]([CH2:67][CH2:68][S:69][CH3:70])[NH:45][C:46](=[O:66])[C@H](CC1C2C(=CC=CC=2)NC=1)NC(OC(C)(C)C)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:71])[C@H:44]([CH2:67][CH2:68][S:69][CH3:70])[NH:45][C:46](=[O:66])[C@H:10]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(C)(C)C)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccc(C(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-p-t-butyl-L-phenylalanine pentachlorophenyl ester is substituted for the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 5 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-p-t-butyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>CN(C=O)C>[N:33]1([C:31]([NH:30][C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:17]3[N:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:6][CH2:7][N:2]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:16]=3)[CH2:25]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added DIEA (190 μL, 1.10 mmol) and then acryloyl chloride (30 mg, 0.33 mmol). The mixture was stirred at RT for 20 min, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (499), as HCl salt (35 mg). LC-MS (ESI): m/z (M+1) 562.3. UV: λ=258, 329, 337 nm.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]([O:48][CH2:49][CH3:50])(=[O:47])[CH:45]=[CH2:46].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:46][CH2:45][C:44]([O:48][CH2:49][CH3:50])=[O:47])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)OCC)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reaction time: 5.5 h
Yield: 91.5 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in ethanol (2 mL), and stirred for 5.5 hours under heat and reflux after adding ethyl acrylate (0.181 mL, 1.67 mmol) and sodium ethoxide (5.7 mg, 0.083 mmol). After cooling the reaction solution, the solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3) to give ethyl 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoate (107 mg, 91.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][C:4]3=[N:10][CH:9]=2)[CH:12]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccn2c(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)cnc2n1
Product: Cc1ccn2c(-c3cccc(-c4ccccc4F)c3)cnc2n1
Yield: 122.4 %

Procedure:
Trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl ester (0.1 g, 0.28 mmol) was coupled to 2-fluorobenzene-boronic acid (52 μl, 0.59 mmol) as described in Example 21 to give 3-(2′-fluorobiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine as a white solid (104 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.78 (1H, d, J 7), 7.17-7.28 (2H, m), 7.37 (1H, m), 7.46-7.54 (2H, m), 7.60 (2H, m), 7.71 (1H, s), 7.85 (1H, s), 8.56 (1H,: d, J 7); m/z (ES+) 304 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][P:9]2(=[O:15])[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[O:15]=[P:9]1([CH2:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)[O:10][CH2:11][CH2:12][CH2:13][O:14]1
Reactant: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CP2(=O)OCCCO2)cc1
Temperature: 50 °C
Yield: 81.5 %

Procedure:
To a solution of 2-(4-nitrobenzyl)-1,3,2-dioxaphosphinane 2-oxide (Compound 230D, 70 mg, 0.27 mmol) in anhydrous THF was added 10% Pd/C (10 mg). The resulting mixture was heated at 50° C. under 50 psi H2 atmosphere for 6 h. Catalyst was filtered off and the filtrate was concentrated to give the desired product (50 mg, yield: 80%). 1H NMR (CD3OD, 400 MHz): δ=1.72-1.76 (m, 1 H), 1.98-2.02 (m, 1 H), 3.19 (d, J=20.4 Hz, 2 H), 4.28-4.40 (m, 4 H), 6.68 (d, J=8.0 Hz, 2 H), 7.03 (d, J=8.4 Hz, 2 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12](OC)=[O:13])[CH:9]=[CH:10][C:2]1=2.O.[NH2:19][NH2:20]>CCO>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12]([NH:19][NH2:20])=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: NN
Reactant: COC(=O)C(OC)c1ccc2c(c1)OCCO2
Solvent: CCO
Solvent: O
Product: COC(C(=O)NN)c1ccc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
To a stirred solution of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxyacetate (18.3 mmol) in anhydrous EtOH (150 mL) was added hydrazine hydrate (73.2 mmol, 4 eq) and heated to 90° C. Stirring was then continued for 24 hours. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (3.5 g) that was used without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=2)[CH:35]=1)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29].[NH2:49][C:50]1[N:59]=[C:58]([N:60]2[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]2)[C:57]2[C:52](=[CH:53][C:54]([C:67](O)=[O:68])=[CH:55][CH:56]=2)[N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:49][C:50]1[N:59]=[C:58]([N:60]2[CH2:61][CH2:62][N:63]([CH3:66])[CH2:64][CH2:65]2)[C:57]2[C:52](=[CH:53][C:54]([C:67]([NH:26][CH:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[N:48])[CH:42]=4)[CH:35]=3)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[O:68])=[CH:55][CH:56]=2)[N:51]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: CN(C)C(=O)C(N)Cc1cccc(Oc2cccc(C#N)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4cccc(Oc5cccc(C#N)c5)c4)C(=O)N(C)C)ccc23)CC1
Reaction time: 1 h
Yield: 13.3 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of 2-amino-3-[3-(3-cyanophenoxy)phenyl]-N,N-dimethylpropanamide HCl salt (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=2) to give the desired compound (0.004 g, 10%) as a white amorphous solid TFA salt. 1H NMR (400 MHz, DMSO): δ 7.98 (d, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.14 (m, 2 h), 7.03 (s, 1H), 6.86 (d, 1H), 5.08 (m, 1H), 4.56 (m, 2H), 3.65 (m, 2H), 3.55 (m, 2H), 3.22 (m, 2H) 2.99 (m, 5H), 2.82 (s, 3H), 2.78 (s, 3H); Analytical LCMS (M+H)+: m/z=579.2.
Reaction SMILES: Cl.[CH2:2]([O:6][P:7]([O-:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH3:5].[CH2:14]([C:18]([CH3:20])=[O:19])[CH:15]([CH3:17])[CH3:16]>C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-]>[CH2:9]([O:8][P:7]([C:18]([OH:19])([CH3:20])[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:13])[O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOP([O-])OCCCC
Reactant: CC(=O)CC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CCCCOP(=O)(OCCCC)C(C)(O)CC(C)C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Into a two-liter four-necked flask provided with a stirrer, a thermometer, dropping device, a hydrochloric-acid-recovering device and a condenser, 213.4 g (1.1 moles) of dibutylphosphite, 5.6 g (0.06 moles) of triethylamine and 1.05 g (0.011 moles) of magnesium chloride were fed. While stirring the resulting mixed solution at 25° C., 120.0 g (1.2 moles) of methyl isobutyl ketone (MIBK) was added thereto in 1 hour. The resulting mixed solution was further stirred for 1 hour at the same temperature (25° C.) to complete the reaction. Thereafter, the mixed solution was washed to remove the low-boiling point portions, as in (synthesis of raw material 2) of Example 1, and thus, the triethylamine and the magnesium chloride was removed from the mixed solution, to obtain 298.8 g of dibutyl(1-hydroxy-1,3-dimethylbutyl)phosphonate (raw material 3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[O:22][N:21]=1>>[CH3:19][C:20]1[CH:24]=[C:23]([C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:10][CH:11]=2)=[O:26])[O:22][N:21]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Product: Cc1cc(C(=O)NCCCCc2ccc(-c3ccc(=O)[nH]n3)cc2)on1

Procedure:
By treating 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one and 3-methyl-5-carboxyisoxazole in the same manner as in Example 87, 6-{4-[4-(3-methylisoxazole-5-ylcarbonylamino)butyl]phenyl}pyridazin-3(2H)-one was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:24])[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].S(=O)(=O)(O)O>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:24][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:9])=[O:8]
Reactant: CCCCC/C=C\C/C=C\CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 8.7 g (45 mmoles) of p-toluenesulfonyl chloride in 60 ml pyridine was added dropwise at 0°-5° C., a solution of 5.8 g (31.8 mmoles) of (Z,Z)-3,6-dodecadienol (T. Kajiwara, J. Sekiya, Y. Odake and A. Hatanaka, Agric. Biol. Chem., 41, 1481 (1977)). The temperature was allowed to rise to 25° C., and the reaction mixture was stirred at room temperature overnight. The resulting suspension was slowly poured into a mixture of 1 N aqueous sulfuric acid and ice and the product extracted with ether. The ether extracts were combined, washed with 10% sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The residue (8.0 g) was chromatographed on a silica gel column. Elution with 1:1 hexane-ether gave 4.9 g (14.6 mmoles) (45.8%) of (Z,Z)-3,6-dodecadienyl tosylate, which was dissolved in 20 ml of acetone.
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=1[NH:19][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Temperature: 150 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)acetate obtained in Step 1 of Synthesis Example 1 and 16.8 g of 2-methoxy-5-nitroaniline was stirred in an oil bath at 150° C for four hours under a reduced pressure of 50 to 100 mmHg. The reaction mixture was recrystallized from acetonitrile to obtain 29 g (yield 85%) of Coupler (7) having a melting point of 138° to 140° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][OH:24])=[NH:22])=[CH:16][CH:15]=3)[C:10]([CH2:25][CH3:26])=[C:9]([CH3:27])[N:8]=2)=[CH:4][CH:3]=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].CCN(CC)CC>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20]/[C:21](=[N:22]\[C:29](=[O:30])[O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)/[NH:23][OH:24])=[CH:18][CH:19]=3)[C:10]([CH2:25][CH3:26])=[C:9]([CH3:27])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=N)NO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C/C(=N\C(=O)Oc2ccccc2)NO)cc1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A 18-mL vial was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-hydroxy-acetamidine (61 mg, 0.15 mmol), phenyl chloroformate (29 mg, 0.18 mmol, 1.2 eq.), Et3N (20 mg, 0.2 mmol, 1.3 eq.) and dichloromethane (5 ml). The mixture was stirred at 0 C˜rt until starting material was consumed (4 hr). The mixture was poured into saturated sodium bicarbonate solution (10 ml) and extracted with dichloromethane (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent under reduced pressure gave the title compound (80 mg, 100% yield). The product thus obtained was forwarded to the next step without any purification.