Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A solution of N-[(1,3-Dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-(2′,6′-dichloro-benzyloxy)pentanoic acid, t-butyl ester (49 mg) in anisole (0.2 mL) and methylene chloride (2 mL) was treated with TFA (1 ml) and stirred for 30 minutes under a nitrogen atmosphere at room temperature. The resultant solution was concentrated and chased with methylene chloride to give a white solid as the crude product. The crude product was triturated with ether to yield the title product as a white powder (34 mg). MS(EI) for C28H31Cl2N3O6; MH+=576/578; (MH)−=574/576.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19].CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([NH:19][CH2:18][CH:17]([OH:16])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH3:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CCC(C)=O)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(CCC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-carbomethoxyphenyl) butan-2-one (3.0 g) and 2-hydroxy-2-(3-trifluoromethylphenyl) ethanamine (3.0 g) in dry benzene (100 ml) was refluxed under Dean and Stark conditions for 2 hours. The solvent was replaced with methanol (100 ml) and sodium borohydride (2.0 g) was added portionwise with ice cooling. The mixture was stirred at ambient temperature for 2 hours, the solvent was evaporated and the residue was partitioned between water (100 ml) and chloroform (100 ml). The organic phase was dried (MgSO4) and evaporated to an oil, which was chromatographed on silica gel 60 in 3% methanol/chloroform. The title compound was obtained as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C[N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([NH2:45])=[CH:40][CH:41]=2)[CH2:36]1>CC(O)C.Cl>[NH2:35][CH:44]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[C:39]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:38]=2)[CH2:43]1
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Product: NC1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (100 mg, 0.22 mmol) (prepared according to a procedure similar to that described in Example 27, Step C) and 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (44 mg, 0.27 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was stirred at 90° C. overnight, and the reaction mixture was partitioned between saturated aqueous NaHCO3 and 4:1 CHCl3/MeOH. The organic layer was dried over MgSO4, filtered, and purified by flash chromatography to give the title compound as a yellow oil (76 mg, 59% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.95 (s, 1H), 9.44 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.55-7.65 (m, 1H), 7.45-7.49 (m, 2H), 7.35-7.39 (m, 1H), 7.26 (t, J=8.1 Hz, 2H), 7.14 (t, J=6.8 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.52 (d, J=5.3 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 3.30 (s, 2H) 2.75 (t, J=5.5 Hz, 2H), 2.52-2.63 (m, 2H), 2.26 (s, 3H). MS (ESI) m/z=588 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.C(=O)([O-])[O-:33].[Cs+].[Cs+]>CN(C=O)C.O.CS(C)=O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([OH:33])([CH2:14][OH:13])[C:15]([F:16])([F:17])[F:18]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C(O)(CO)C(F)(F)F)c(Cl)c1F
Yield: 379 %

Procedure:
250 mg (0.54 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on are stirred with 353 mg (1.1 mmol) Caesium carbonate in 3 ml DMF, 1.9 ml water and 0.5 ml DMSO. Water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (methanol in dichloromethan 0 to 5%) yields 0.98 g of the title compound.
Reaction SMILES: [CH:1]1([PH:7](=[O:9])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)CCC>[CH:1]1([PH:7](=[O:8])[O:9][CH2:6][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[PH](O)C1CCCCC1
Solvent: CCCCO
Product: CCCCO[PH](=O)C1CCCCC1

Procedure:
The title compound was prepared from cyclohexylphosphinic acid and n-butanol according the the method described in Procedure 43. The compound was used without further purification.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: Cc1cc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)ccc1C#N
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
(S)-tert-butyl 4-(1-amino-3-(4′-cyano-3′-methylbiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 19, step (i), 127 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (119 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the mixture was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:1) to afford the sub-titled compound (105 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Br:50][C:51]1[CH:52]=[C:53]([NH2:58])[C:54]([NH2:57])=[N:55][CH:56]=1>CN(C)C=O.C(OCC)(=O)C>[C:2]1([CH2:1][O:8][C:9](=[O:10])[N:11]([CH2:12][C:13]([NH:58][C:53]2[C:54]([NH2:57])=[N:55][CH:56]=[C:51]([Br:50])[CH:52]=2)=[O:15])[CH3:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: Nc1cc(Br)cnc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)Nc1cc(Br)cnc1N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]acetic acid (0.42 g, 1.88 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.75 g, 1.97 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.72 mL, 4.12 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature, followed by the addition of 5-bromo-2,3-diaminopyridine (0.35 g, 1.86 mmol), then stirred for 16 hours. It was diluted with ethyl acetate (50 mL), washed with aqueous lithium chloride (2×20 mL) and brine, dried over sodium sulfate, filtered and concentrated. Gradient flash chromatography (35% to 85% ethyl acetate in hexane) provided phenylmethyl{2-[(2-amino-5-bromopyridin-3-yl)amino]-2-oxoethyl}methylcarbamate (0.70 g, 96%). MS (EI) for C16H17BrN4O3: 394 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].Br[CH:31]1[CH2:35]C[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:33][CH2:32][CH2:31][CH2:35]3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2
Temperature: 75 °C
Yield: 87.2 %

Procedure:
A mixture of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 300 mg, 0.888 mmol), bromocyclopentane (397 mg, 2.66 mmol) and K2CO3 (491 mg, 3.55 mmol) in CH3CN (40 ml) was stirred at 75° C. Further bromocyclopentane (397 mg, 2.66 mmol) and catalytical amount of KI were added over three days. The solvent was removed and the residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-cyclopentyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (286 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>C1COCC1>[CH3:2][C:3]1[N:4]=[C:5]([NH:9][C:27]([C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[O:28])[S:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)C23CC4CC(CC(C4)C2)C3)sc1C
Yield: 74 %

Procedure:
To a solution of 4,5-dimethyl-thiazol-2-ylamine hydrochloride (1.65 g, 10.0 mmol) in THF (100 mL) was added triethylamine (4.2 mL, 30 mmol) and adamantane-1-carbonyl chloride (2.2 g, 11 mmol). The mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1M NaHCO3, dried (Na2SO4), filtered and concentrated. Purification by column chromatography (SiO2, 10% ethyl acetate:90% hexanes) afforded 2.15 g (74%) of the title compound. MS (ESI+) m/z 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>CO>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Solvent: CO
Product: Nc1ccc(Oc2ccc(Cl)cc2Cl)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl22H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2[OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=[O:26])[CH3:25]>C(C(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:17])[C:11]([CH3:16])=[C:12]([CH3:15])[CH:13]2[O:14][C:24](=[O:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1=C(C)C(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)OC1C(C)=C(C)C(=O)N1c1ccc(Cl)c(Cl)c1

Procedure:
27.2 g of N-(3',4'-dichlorophenyl-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (see Example 3) is refluxed together with 20.7 g of K2CO3 in 150 ml of methyl ethyl ketone. After cooling, there is added dropwise 8.2 g of acetyl chloride, with the temperature of the reaction mixture rising from 15° to 35°. The reaction mixture is filtered after 24 hours, and the filtrate is concentrated by evaporation. The residue is recrystallised from methanol to give 23.9 g (76% of theory) of the above product in the form of colourless crystals, m.p. 109°-110°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1[OH:34].[O-]O.C1(C(C)C)C=CC=CC=1>CN(C=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:34])=[N:15][CH:16]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 22 °C

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) is solubilised in anhydrous DMF (0.65 mL). Titanium isopropoxide (IV) (22 μl, 0.076 mmol) and (1R,2S)-(+)-1-amino-2-indanol (22.8 mg, 0.151 mmol) in anhydrous DMF are added under stirring at 22° C., followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23](#N)[CH3:24].O>>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:1][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])[CH:24]=[CH:23][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC#N
Solvent: O
Product: O=C(O)c1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
The title compound was prepared analogously to 4-(octyloxy)-3-(trifluoromethyl)benzoic acid (11a) in >95% yield. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) is 3.14 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:22])[CH2:15][CH2:16]N(CC)CC)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(OC1C=C(CCCC(=O)C=C)C=CC=1)(=O)C.[CH3:40][CH:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47].CO>[OH-].[K+].C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:22])[CH2:15][CH2:16][C:41]2([CH3:40])[C:45](=[O:46])[CH2:44][CH2:43][C:42]2=[O:47])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC(C)=O)c1
Reactant: CC1C(=O)CCC1=O
Agent: C=CC(=O)CCCc1cccc(OC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1

Procedure:
Reflux a mixture of 6-(m-acetoxyphenyl)-1-diethylaminohexan-3-one and 6-(m-acetoxyphenyl)hex-1-en-3-one (1 g), with 2-methylcyclopentane-1,3-dione (1.5 g) in 0.12% methanolic potassium hydroxide (6 cc) for 18 hours. Remove methanol (2 cc) under reduced pressure and add chloroform (60 cc). Wash the solution in turn with dilute sulfuric acid (25 cc), saturated potassium bicarbonate solution, and brine; dry and evaporate the solvent. The product (0.8 g) is the adduct 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione in admixture with some of the corresponding free phenol; infrared absorption: 2.86 to 3.08 (broad low-intensity band), 5.71, 5.81, 5.85, and 8.26 μ.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:2].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:4]=1[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a suspension of 2′-cyano-p-toluenesulfonanilide (2.67g (9.80 mmol) in acetic anhydride (7.0 ml), 97% fuming nitric acid (0.45 ml (10.5 mmol) was added with stirring at room temperature. After stirring for one hour at 50° C., crystals began to separate. Water was added to decompose excess acetic anhydride, and the crystals were filtered, washed with water, dried in the air and then, washed with diethyl ether and collected by filtration to give 3.05 g (98%) of 2′-cyano-4′-nitro-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[N:14]=[N:15][C:16]([C:19](=[O:26])[NH:20][CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:17][CH:18]=2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C1(CCNC(C2N=NC(NC3CNC3)=CC=2)=O)CC1.[F:53][C:54]([F:65])([F:64])[C:55]1[CH:63]=[CH:62][CH:61]=[CH:60][C:56]=1C(Cl)=O>ClCCl.C(N(CC)CC)C>[CH:23]1([CH2:22][CH2:21][NH:20][C:19]([C:16]2[N:15]=[N:14][C:13]([NH:12][CH:10]3[CH2:9][N:8]([C:6](=[O:7])[C:56]4[CH:60]=[CH:61][CH:62]=[CH:63][C:55]=4[C:54]([F:65])([F:64])[F:53])[CH2:11]3)=[CH:18][CH:17]=2)=[O:26])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(NCCC1CC1)c1ccc(NC2CNC2)nn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(NC2CN(C(=O)c3ccccc3C(F)(F)F)C2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
3-[6-(2-Cyclopropylethylcarbamoyl)pyridazin-3-ylamino]azetidine-1-carboxylic acid tert-butyl ester dissolved in dichloromethane (15 mL) was treated with trifluoroacetic acid. The isolated 6-(azetidin-3-ylamino)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.026 g, 0.100 mmol) was dissolved in dichloromethane (8 mL) and then 2-trifluoromethylbenzoyl chloride (0.022 g, 0.110 mmol) was added at ambient temperature in the presence of triethylamine (0.2 mL). The mixture was stirred at ambient temperature for 15 minutes. The solvent was evaporated and the residue was purified by column chromatography. The title compound was obtained as a white solid in 57% yield (0.0246 g). 1H NMR (300 MHz, CDCl3) (8.0 (d, J=9.0 Hz, 1H), 7.9 (br., t, 1H), 7.7 (d, J=7.0 Hz, 1H), 7.6-7.5 (m, 2H), 7.4 (d, J=7.0 Hz, 1H), 6.8 (d, J=9.0 Hz, 1H), 5.7 (br., s, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.5 (q, J=7.0 Hz, 2H), 1.5 (q, J=7.0 Hz, 2H), 0.7 (m, 1H), 0.4 (m, 2H), 0.06 (m, 2H). MS (ES+) m/z 434 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([NH:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][N:20]=[CH:21]4)[CH:14]=2)C=CC=CC=1>C1COCC1.O.Cl>[CH:21]1[C:22]2[C:17](=[C:16]([NH:15][C:13]3[CH:12]=[N:11][CH:10]=[C:9]([NH2:8])[CH:14]=3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: c1ccc(C(=Nc2cncc(Nc3cccc4cnccc34)c2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cncc(Nc2cccc3cnccc23)c1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A mixture of Example 23D (145 mg; 0.36 mmol) in 3 mL THF at room temperature was treated with 10 drops of water and 3 drops of conc. HCl, stirred for 2 hours, and concentrated. The residue was partitioned between ethyl acetate and concentrated NaHCO3 (aq). The aqueous layer was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to provide the desired product (59 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.FC(F)(F)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][CH2:42][C:43]([F:46])([F:45])[F:44])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC(NCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 31.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (200 mg, 0.488 mmol) and ethyldiisopropylamine (0.166 mL, 0.976 mmol) in N,N-dimethylformamide (10 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.0774 mL, 0.54 mmol) at room temperature. The mixture was stirred at room temperature for 20 hr. To the reaction mixture was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.030 mL, 0.208 mmol) at room temperature and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 25-45% ethyl acetate/n-hexane gradient mixture to give the title compound (76.4 mg, 0.155 mmol, 32%) as a colorless solid.