Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:48])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:51]1([CH2:55][CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:54][CH2:53][CH2:52]1.C(N(CC)CC)C.O>CN(C)C=O>[N:51]1([CH2:55][CH:56]2[CH2:61][CH2:60][N:59]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:30][CH:31]=4)[CH:22]=[CH:21][N:20]=3)=[O:48])[CH2:58][CH2:57]2)[CH2:54][CH2:53][CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: C1CN(CC2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(CN2CCC2)CC1
Reaction time: 62 h
Yield: 78.9 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (70.2 mg), triethylamine (0.0862 ml) and water (0.100 ml) were added thereto in this order, followed by stirring for 62 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (35.8 mg, 78.9%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:3]=1.S(=O)(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1nc(COc2ccc([N+](=O)[O-])cc2)no1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(COc2ccc(N)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
O-(5-Methyl-1,2,4-oxadiazol-3-yl)methyl-4-nitrophenol (1 g) was dissolved in THF (40 mL) and water (40 mL). Sodium bisulfate (3.8 g), sodium bicarbonate (1.4 g), K2CO3 (1.8 g) were added to the solution. It was stirred at rt for 30 min, then diluted with water (80 mL). The aq. solution was extracted with EtOAc (2×100 mL). The organic layers were combined, dried, evaporated to give 4-(5-methyl-1,2,4-oxadiazol-3-yl)methoxyaniline.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:20])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:20][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cccc(N)c1-c1nnnn1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Reaction time: 8 h
Yield: 98.7 %

Procedure:
2-(1-Benzyl-1H-tetrazol-5-yl)-3-methylphenylamine (Intermediate 16, 0.15 g) was dissolved in pyridine (5 mL) and benzenesulfonyl chloride (0.07 g, 0.4 mmol) was added. The mixture was stirred overnight, then diluted with ethyl acetate and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white powder (0.16 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][CH2:15][C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][CH2:15][C:16]1[O:20][C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:18][CH:17]=1
Reactant: COCc1ccc(C=O)o1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COCc1ccc(C=C2N=C(c3cccs3)OC2=O)o1
Temperature: 90 °C
Yield: 50.7 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 5-(methoxymethyl)-2-furancarboxaldehyde (46 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 44 mg of the above-captioned compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1.S(Cl)([Cl:22])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CCCCOCCCCBr)cc1
Product: O=C(Cl)c1ccc(CCCCOCCCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-{4-[(4-bromobutyl)oxy]butyl}benzoic acid (0.91 g, 2.77 mmol, e.g. which can be as prepared in Intermediate 25) in thionyl chloride (SOCl2, 2 ml) was stirred at room temperature for 1 hour and then at 100° C. for 2 hours. The reaction mixture was cooled and the excess thionyl chloride was removed by evaporation, followed by co-evaporation with dichloromethane (2×30 ml) to give the title compound as a brown oil (1.03 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.5-2.0 (10H, m); 2.75 (2H, m); 3.45 (4H, m); 7.35 (2H, d); 8.05 (2H, d). The compound was not pure by 1H NMR (CDCl3), but it was not purified further.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:20]=[C:19]([OH:21])[C:10]3[C:11]4[CH2:18][CH2:17][S:16][C:12]=4[C:13](=O)[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH:1]1([CH2:4][CH:5]([C:7]2[CH:20]=[C:19]([OH:21])[C:10]3[C:11]4[CH2:18][CH2:17][S:16][C:12]=4[C:13]([CH2:3][CH2:2][CH2:1][CH2:4][CH2:5][CH3:6])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1
Reactant: CC(CC1CC1)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reactant: CCCCCC[Mg]Br
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(O)c2C2=C1SCC2

Procedure:
By reacting 7-(3-cyclopropyl-2-propyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran with n-hexyl magnesium bromide, using the procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-4H-thieno[2,3-c] [1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: [Li+].[OH-].O.[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[S:14]([NH:17][CH:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:19][C:20]([O:22]C)=[O:21])(=[O:16])=[O:15]>CO.O>[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[S:14]([NH:17][CH:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:19][C:20]([OH:22])=[O:21])(=[O:15])=[O:16]
Reactant: COC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LiOH×H2O (0.25 g, 18 mmol) was added to a solution of the methyl 3-(naphthalene-2-sulfonamido)-3-phenylpropionate (3.3 g, 9 mmol) in a methanol/water mixture (3:1, 90 ml) at a reaction temperature of 0° C. The reaction mixture was stirred at RT for 16 h. The solvent was removed under reduced pressure, the residue was taken up in water and the mixture was washed with MC. The aqueous phase was then cautiously acidified with HCl (1 N) and extracted with ethyl acetate. The organic phase was washed with water and sat. NaCl solution and dried over Na2SO4. After removal of the solvent, the product was obtained in an adequate purity.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])[CH:2]=1.C([O-])=O>>[CH:2]1[C:8]2[C:6](=[CH:5][CH:4]=[CH:3][CH:7]=2)[CH:5]=[CH:4][C:3]=1[CH:7]([OH:11])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(O)c1cccnc1
Agent: O=C[O-]
Product: O=C(O)C(O)c1ccc2ccccc2c1

Procedure:
(−)-3-pyridylglycolic acid This Reaction was performed in 100 mM anmonium formate buffer at pH 8. To isolate the product, the reaction mixture was filtered through a 10,000 MWCO membrane to remove enzyme and then concentrated in vacuo. 1H NMR (DMSO-d6, 500 MHz) δ 8.56 (s, 1H), 8.36 (d, J=4.57 Hz, 1H), 8.25 (s, 1H), 7.71 (m, 1H), 7.25 (dd, J=4.98, 4.80 Hz 1H), 5.45 (s, 1H). 13C NMR DMSO-d6, 125 MHz) δ 165.911, 147.862, 147.251, 139.118, 133.381, 122.746, 71.508. MS calc'd for [C7H7NO3] 153.04, found 154.0 ((MALDI TOF). ee=92% [HPLC], 84% yield, [α]20598=−65.2 (c=0.5, H2O).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)(Cl)Cl>[CH3:45][S:46]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[N:13]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:12]=[CH:11][N:10]=1)(=[O:48])=[O:47]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3S(C)(=O)=O)Cc3nccn3S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (52.9 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.0 ml). The solution was added with triethylamine (0.054 ml) and then added with methanesulfonyl chloride (manufactured by Kanto Kagaku) (0.027 ml), followed by stirring at room temperature for 17 hours. After completion of the reaction, chloroform (3.0 ml) was added to the solution, and the whole was washed with water. The organic layer was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (31.7 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:39])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[CH:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:7]=1.CC[N:42]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.N>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:39])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH2:42])=[O:28])[CH:20]=[CH:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:7]=1
Reactant: COc1ccc(CC(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(N)=O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reaction time: 16 h

Procedure:
A mixture of {3-[5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-phenyl}-acetic acid (Example 60) (0.177 mmol), EDC.HCl (0.222 mmol), HOBt (0.131 mmol) and Et3N (0.621 mmol) in CH2Cl2 (1.3 mL) at rt was treated with an ammonia solution (0.4N/THF) (0.52 mmol). After stirring for 16 h, the reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic layers were successively washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 7.08 min (HPLC 2); ESI-MS: tR=1.16 min, [M+H]+ 562/564 (LC-MS 1); TLC: Rf=0.14 (EtOAc).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])=[CH:10][N:11]2[CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O.Cl>O1CCOCC1.O>[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([F:21])[CH:18]=1)[CH2:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[C:9]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:10]1
Reactant: COC(=O)c1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 1-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indole-6-carboxylic acid methyl ester (150.0 mg, 0.33 mmol) in dioxane (20 mL) and water (15 mL) was added LiOH.H2O (83.1 mg, 2.0 mmol) in 5 ml water. The reaction mixture was stirred overnight at 60° C. The mixture was then acidified to pH 4 by addition of 15% aqueous HCl and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as yellow/orange crystals (129.3 mg, y=89%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:5][S:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1O>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:4]2[C:3]([CH2:2][O:1][C:26]3[C:25]([F:28])=[CH:24][C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:22][C:21]=3[F:20])=[C:7]([C:8]([F:11])([F:9])[F:10])[S:6][N:5]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: N#Cc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Product: N#Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting from 4-[4-(hydroxymethyl)-5-(trifluoromethyl)-1,2-thiazol-3-yl]benzonitrile, following Steps 4-6, and using ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-propanoate. Upon hydrolysis, the desired compound 261 was afforded as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.98 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.88 (d, J=9.6 Hz, 2H), 5.23 (s, 2H), 2.87 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H). 19F NMR (300 MHz, CD3OD) δ: −56.54, −77.52, −129.65. Mass spectrum (ESI, m/z): Calcd. for C21H13F5N2O3S, 467.0 (M−H). found 466.9.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[H-].[Na+].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29]>CN(C)C=O>[N+:25]([C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[CH:16]=[C:17]([C:28]([F:29])([F:30])[F:31])[C:18]=1[N:8]1[C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][C:5](=[O:10])[NH:6][C:7]1=[O:9])([O-:27])=[O:26]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)n(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c(=O)[nH]1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
1.0 g of 6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added to 10 ml of dimethylformamide, followed by addition of 0.65 g of sodium hydride (purity: 55%) with stirring at 0° C. The mixed solution was stirred at room temperature for 30 minutes, then cooled to 0° C. and added dropwise with a 5 ml dimethylformamide solution of 1.89 g of 2-chloro-3,5-dinitrobenzotrifluoride. After the solution was further stirred at room temperature for 3 hours, the solvent was distilled away under reduced pressure. After addition of cooled dilute hydrochloric acid thereto, the residue was extracted with 100 ml of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then the solvent was distilled away under reduced pressure to form a crude product. This crude product was recrystallized from a mixed solvent of chloroform and petroleum ether to obtain 0.77 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29].N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CC(C)=CCBr
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Agent: N
Product: CC(C)=CCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (26 mg, 76%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 4-bromo-2-methyl-2-butene (25 mg, 0.16 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.68 (s, 3H), 1.81 (s, 3H), 2.12–2.23 (m, 3H), 2.26–2.42 (m, 1H), 2.55–2.70 (m, 2H), 2.78 (t, J=6.6 Hz, 2H), 3.10–3.45 (m, 6H), 3.63–3.77 (m, 2H), 5.42–5.55 (br, 1H), 6.99 (s, 1H), 7.03 (s, 1H), 7.24–7.217.29 (m, 2H), 7.47 (d, J=1.8 Hz, 1H) ppm. MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.O>NC(CC)CO>[CH2:6]([C:5]1[N:4]=[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)=[N:4][N:3]2[CH:8]=1)[CH3:7]
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Agent: CCC(N)CO
Solvent: O
Product: CCc1cn2nc(-c3cccc(C(F)(F)F)c3)ccc2n1

Procedure:
A 2.58 g sample of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine in 3.56 g of 2-amino-1-butanol was heated at 120° C. (internal temperature) for 18 hours, cooled and poured into cold water. The mixture was extracted with dichloromethane and the extracts washed with water, dried over anhydrous sodium sulfate and concentrated. The residue in ethyl acetate was chromatographed on silica gel with ethyl acetate to give 2.2 g of yellow oil. Crystallization from dichloromethane-hexane gave 2-{[6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl]amino}-1-butanol as crystals, mp 84°-87° C.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][NH2:24])[N:18]=1>CCOCC>[Br:16][C:17]1[N:18]=[C:19]([NH:23][N:24]=[C:2]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]2)[CH:20]=[CH:21][CH:22]=1
Reactant: NNc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(=NNc2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-oxoazepane-1-carboxylate (1.7 g, 8.1 mmol) was added to a solution of 2-bromo-6-hydrazinylpyridine (1.5 g, 8.1 mmol) in Et2O (27 mL), and the resulting solution was stirred at ambient temperature for 1.5 h. The solution was concentrated under reduced pressure to provide the title compound (3.1 g, 99%) as a light orange solid: 1H NMR (300 MHz, DMSO-d6) δ 9.89-9.68 (m, 1H), 7.50-7.45 (m, 1H), 7.04-7.01 (m, 1H), 6.89-6.85 (m, 1H), 3.48-3.28 (m, 4H), 2.59-2.50 (m, 4H, overlaps with H2O), 1.69-1.53 (m, 2H), 1.38-1.36 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CS(C)=O.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>[OH-].[Na+]>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of p-hydroxybenzoic acid (19.2 g., 150 mmole) in 10% aqueous sodium hydroxide (120 ml.) is added to DMSO (480 ml.) previously heated to 80° C. n-Octyl bromide (28.95 g., 150 mmole) is added dropwise to the solution. The reaction mixture is stirred for 4 hours at room temperature after which it is poured into ice water (1200 ml.). Conc. hydrochloric acid (30 ml.) is added, and the mixture is allowed to stand until precipitation is complete. The precipitate is collected, dried, and crystallized from acetonitrile-water. m.p. 97°-99° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Oc1cccc(Nc2nc(F)ncc2F)c1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-fluoro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20–7.10 (m, 2H), 7.00–6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (CDCl3): −47229; LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (MH+).