Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1[CH:43]=CC(C=O)=C[CH:37]=1>>[F:35][C:36]1[CH:43]=[CH:13][C:8]([CH2:7][N:5]2[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]3[NH:16][C:17](=[O:30])[C:18]4[CH:23]=[N:22][N:21]([CH:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[C:19]=4[N:20]=3)[CH2:4]2)=[CH:9][CH:37]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccc(F)cc2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 4-fluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.36-7.33 (m, 2H), 7.05-7.01 (m, 2H), 4.82-4.77 (m, 1H), 4.14-4.09 (m, 2H), 3.79-3.76 (m, 1H), 3.62-3.54 (m, 3H), 3.34 (t, J=8.3 Hz, 1H), 2.99 (d, J=9.9 Hz, 1H), 2.85-2.83 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.30 (m, 3H), 1.99-1.82 (m, 3H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 412.1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](B1C2CCCC1CCC2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:28]([C:13]1[N:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:21]=2)=[N:11][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)nc2OCc2ccccc2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1csc(Nc2ncc(Cc3ccccc3)nc2OCc2ccccc2)n1
Yield: 78.7 %

Procedure:
Methyl 3-(2-(3-(benzyloxy)-5-bromopyrazin-2-ylamino)thiazol-4-yl)propanoate (0.826 g, 1.84 mmol), 9-benzyl-9-bora-bicyclo[3.3.1]nonane (11.0 mL, 5.51 mmol), PdCl2(dppf) dichloromethane adduct (0.151 g, 0.184 mmol), were placed in DMF (25 mL), and water (2.5 mL) and heated to 60° C. for 90 minutes. Cooled reaction mixture to room temperature and partitioned between water and DCM. Layers were separated, dried, filtered, and concentrated. Purified by silica gel to give methyl 3-(2-(5-benzyl-3-(benzyloxy)pyrazin-2-ylamino)thiazol-4-yl)propanoate (0.667 g, 78.8% yield). 28 mg of this was dissolved in DCM and 2M HCl was added and concentrated to give methyl 3-(2-(5-benzyl-3-(benzyloxy)pyrazin-2-ylamino)thiazol-4-yl)propanoate hydrochloride (0.027 g, 93%) 1H NMR (DMSO-d6) δ 7.79 (s, 1H), 7.52 (m, 2H), 7.32 (m, 4H), 7.27 (d, 4H), 7.20 (m, 1H), 5.44 (s, 2H), 3.93 (s, 2H), 3.60 (s, 3H), 2.86 (m, 2H), 2.68 (m, 2H). Mass spectrum (apci) m/z=461.1.0 (M+H-HCl).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].N[C:18]1[CH:19]=[C:20]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)[CH:21]=[CH:22][CH:23]=1.CN(C=[O:33])C.[I-].[K+]>C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][O:33][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[N:27][N:26]=[N:25]3)[CH:19]=2)=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CN(C)C=O
Reactant: Nc1cccc(-n2cnnn2)c1
Reactant: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(COc1cccc(-n2cnnn2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
To a 50 mL recovery flask was added 2-chloro-N-(4-chloro-3-trifluoromethylphenyl)-acetamide (400 mg, 1.47 mmol, 1.0 eq.) and 1-(3-aminophenyl)-1H-tetrazole 11 (710 mg, 4.40 mmol, 3 eq.) and DMF (10 mL). A catalytic amount of potassium iodide was added. The reaction mixture was heated at 70° C. overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a succession of 10% aq. LiCl (3×50 mL) and sat'd aq. NaCl (50 mL). The combined aqueous phases were extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give a tan solid. The solid was recrystallized in methanol and acetonitrile (10:1) to give a white solid (63 mg). Subsequent crops were isolated from the mother liquor (91 mg). Total yield: 154 mg, 26%. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 397.1 (M+H)+1 1H-NM, Varian 400 MHz (DMSO-d6) δ 10.51 (s, 1H), 10.00 (s, 1H), 8.19 (d, 1H), 7.88-7.85 (dd, 1H), 7.65 (d, 1H), 7.34-7.30 (t, 1H), 7.09 (t, 1H), 7.05-7.03 (dd, 1H), 6.75 (dd, 1H), 6.74 (t, 1H), 4.00 (d, 2H) ppm.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].[C:28](OCC)(=O)C.CCCCCC>>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH3:28])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Product: CCCCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-hexylpyridine (Example 23) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 3 H), 7.04 (m, 1 H), 4.65 (m, 1 H), 3.73 (sept, J=6.6 Hz, 1 H), 3.19 (sept, J=6.6 Hz, 1 H), 2.18 (m, 2 H), 1.39 (d, J=6.6 Hz, 3 H), 1.30 (m, 13 H), 1.18 (m, 4 H), 1.09 (m, 4 H), 0.81 (t, J=7 Hz, 3 H). FAB-MS: calcd for (C25H36FNO) 385, found 386 (M+H). Anal. Calcd for C25H36FNO: C, 77.88; H, 9.41; N, 3.63. Found: C, 77.84; H, 9.49; N, 3.65. mp 96-99° C. Rf=0.3 (10% ethyl acetate/hexane).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)#[CH:2].Br[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:20][CH:19]=4)=[C:3]([C:1]#[C:2][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound 17a (0.23 g, 0.57 mmol) and 2-bromoquinoline (1.0 g, 4.8 mmol) in a vial was evacuated and back flushed with Argon. Dry DMF (5 mL) and DIEA (0.99 mL, 5.7 mmol) were added via syringe and the mixture was deoxygenated by bubbling Argon gas through the stirred solution for 5 min. To the mixture were added CuI (5.4 mg, 0.028 mmol) and dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.057 mmol). The resulting mixture was stirred at rt for 1 h, and was poured into water (50 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (2×20 mL). The organic layer was concentrated, and the resulting residue was purified by flash column chromatography on silica gel (20-60% EtOAc/heptane) to give tert-butyl 4-(8-morpholino-2-(quinolin-2-ylethynyl)imidazo[1,2-b]pyridazin-3-yl)benzoate as a yellow solid.
Reaction SMILES: [F:1][C@:2]12[C@@H:30]([OH:31])[CH2:29][C@@:28]3([CH3:32])[C@@H:12]([CH2:13][C@@H:14]([CH3:34])[C@:15]3([OH:33])[C:16](=[O:27])[CH2:17][O:18][C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:36])[CH:4]=[CH:5][C:6](=[O:35])[CH:7]=1.[CH3:37][I:38]>CC(C)=O>[I-:38].[CH3:37][N+:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([O:18][CH2:17][C:16](=[O:27])[C@:15]2([OH:33])[C@:28]3([CH3:32])[C@H:12]([C@H:11]4[C@:2]([F:1])([C@@H:30]([OH:31])[CH2:29]3)[C@:3]3([CH3:36])[C:8](=[CH:7][C:6](=[O:35])[CH:5]=[CH:4]3)[CH2:9][CH2:10]4)[CH2:13][C@H:14]2[CH3:34])=[O:20])[CH:22]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COC(=O)c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COC(=O)c1ccc[n+](C)c1
Product: [I-]
Reaction time: 48 h
Yield: 56 %

Procedure:
The product of Example 116 (0.74 g, 1.5 mmol) was dissolved in 50 mL of acetone to which 2 mL of methyl iodide was added. A small amount (10 mL) of CH3NO3 was subsequently added to increase solubility. The reaction was allowed to proceed for 2 days, then the solid was collected to give 0.54 g (56% yield) of the title compound melting at 218°-221° C. and having the formula ##STR145## The structure of the product was confirmed by elemental analysis.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CN(C)C=O>[ClH:48].[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([NH:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]4[N:18]=[C:17]([CH2:19][O:20][C:21]5[CH:34]=[CH:33][C:24]([CH2:25][CH:26]6[S:30][C:29](=[O:31])[NH:28][C:27]6=[O:32])=[CH:23][CH:22]=5)[N:16]([CH3:35])[C:15]=4[CH:36]=3)=[CH:37][CH:38]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNS(=O)(=O)c4ccc(Cl)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 118.3 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.4 g), N,N-diisopropylethylamine (0.27 g) and anhydrous N,N-dimethylformamide (15 ml) was added 4-chlorobenzenesulfonyl chloride (0.15 g) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and diluted with water and tetrahydrofuran and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To a solution of the residue in tetrahydrofuran (10 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added diethyl ether (10 ml) and this mixture was stirred at room temperature for 30 minutes and then was irradiated with ultrasound for 30 minutes. The precipitate was isolated by filtration and washed with acetone, ethyl acetate and n-hexane to afford the title compound (0.3 g, mp 155-160° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:30])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1.O1CCOCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:15]2[C:10]([C:8]([C:6]3[N:7]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:3]=[CH:4][CH:5]=3)=[O:9])=[N:11][CH:12]=[C:13]([Cl:30])[CH:14]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (52 mg, 0.1 mmol) in pyridine/1,4-dioxane (1:1, 4 mL) was treated with acetyl chloride (100 mg) and then stirred at 60° C. for 2 h. After evaporation of solvent under reduced pressure, to the mixture was added THF (5 mL), followed by NaOH (2 N, 2 mL) and stirred at room temperature for another 2 h. The mixture was diluted with EtOAc and the organics were washed with 1 N HCl, NaHCO3 (saturated), and brine; dried over MgSO4, concentrated under reduced pressure, and purified through automated normal-phase chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 8.37 (d, 1H), 8.22 (m, 2 H), 8.14 (s, 1H), 7.80 (m, 3H), 7.46 (m, 3H), 2.20 (s, 3H), 1.23 (s, 9H); MS (ES) (M+H)+ expected 487.1, found 487.1.
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH2:13][NH2:14])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]I.[H-].[Na+]>C1COCC1>[C:1]([CH:8]([CH2:12][CH2:13][NH:14][CH3:15])[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(CCN)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCC(C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
To a 0° C. solution of 5.00 g (24.6 mmol) of BOC-4-aminobutyric acid in 75 mL of dry THF, was added 12.2 mL (197 mmol) of methyl iodide followed by 2.95 g (73.8 mmol, 60% dispersion in mineral oil) of sodium hydride, portionwise. The reaction was rapidly stirred at room temperature for 12 h and quenched by the careful addition of water. The mixture was partitioned between ether and water, and the organic phase extracted with 1N aq sodium bicarbonate. The combined aqueous phases were chilled and acidified to pH 3 with 1N sodium hydrogen sulfate, then extracted with two portions of ethyl acetate. The combined organics were washed successively with water, 5% aq sodium thiosulfate, water, brine, and then dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 5.00 g (94%) of BOC-4-(N-methylamino)butyric acid. 1H NMR: (300 MHz, CDCl3) δ3.28 (2H, bt, J=7 Hz), 2.84 (3H, s), 2.36 (2H, t, J=7.5 Hz), 1.85 (2H, m), 1.45 (9H, s).
Reaction SMILES: O.CC(C)=[O:4].OS(O)(=O)=O.O=[Cr](=O)=O.[F:15][C:16](=[C:20]([F:22])[F:21])[CH2:17][CH2:18][OH:19]>CC(C)=O>[F:15][C:16](=[C:20]([F:22])[F:21])[CH2:17][C:18]([OH:4])=[O:19]
Reactant: CC(C)=O
Reactant: OCCC(F)=C(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(F)=C(F)F
Yield: 65 %

Procedure:
A mechanically stirred 12 L glass reactor clad with a jacket cooled with tap water was charged with 100 mL of acetone and 100 mL of Jones reagent. A solution of 3,4,4-trifluoro-3-buten-1-ol (85 g, 6.75 mol) diluted to a total volume of 5.0 L in acetone was added simultaneously with 5.0 L of Jones reagent via a twin head peristaltic pump capable of a pump rate ca. 120 mL/min. A reaction temperature of 51°-54° C. was maintained by adjusting the pump rate and the tap water cooling flow. Following the addition (45 min), the mixture was allowed to cool to 35°-40° C. over 30-60 min. The reaction mixture was transferred to a separatory funnel and layers separated. The upper layer was washed once with brine and concentrated. The lower layer was diluted with water (500 mL) and extracted with dichloromethane (3 L). The dichloromethane extract was combined with the above residue, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave 613 g (65%) of the desired product as a green oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[O:30][C:29](=[O:31])[O:28][N:27]=1)=[O:19]>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:21]([O:20][CH:18]=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[O:30][C:29](=[O:31])[O:28][N:27]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1O
Reactant: O=C(Cl)OCCCCCc1noc(=O)o1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=CCc1ccccc1C(CCCCc1noc(=O)o1)OC=O
Yield: 69.4 %

Procedure:
2-Allylphenol (4.70g = 0.035 moles) and 2.76g (0.035 moles) pyridine dissolved in 11 ml 1,4-dioxane are added over a 1 hour period to a well stirred solution of 8.25g (0.035 moles) 5-(chloroformyloxypentyl)-1,3,4-dioxazol-2-one in 25 ml 1,4-dioxane at 40° C. Stirring is continued at 53° C for 11/2 hours. The product is then dissolved in 150 ml chloroform, washed 3 times with ice water, dried over Drierite and evaporated under vacuum. The residue, 11.67g of yellow liquid is analyzed by IR and NMR spectroscopy and found to contain 69.4 wt. % of 5-[(o-allylphenyl)-formyloxypentyl]-1,3,4-dioxazol-2-one (yield = 69.4%), having the following structural formula: ##STR15##
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br>C1(C)C(C)=CC=CC=1>[Br-:20].[Br:20][CH2:21][CH2:22][CH2:23][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCCBr
Solvent: Cc1ccccc1C
Product: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 130 °C

Procedure:
Into a one-liter 3-necked flask equipped with stirrer, condenser, addition funnel, and thermometer there was charged 500 ml xylene and 100 g. triphenylphosphine. There was slowly added 77 grams of 1,3-dibromopropane to the stirred solution at 130° C. After heating for 20 hours at 130° C., the resulting suspension was cooled and filtered to give 131.2 g of (3-bromopropyl)triphenylphosphonium bromide (M.P. 229°-30° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:4].C(Cl)(Cl)Cl.[Br-:27]>N1C=CC=CC=1>[Br:27][C:8]1[S:7][C:6]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: [Br-]
Reactant: CCOC(=O)C(=CNc1sccc1C(=O)OC)C(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1sc(Br)cc1C(=O)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.3 parts of diethyl (3-methoxycarbonylthienyl)aminomethylenemalonate in a mixture of 20 parts by volume of chloroform and 4 parts by volume of pyridine, 0.6 part by volume of bromide is added dropwise. The solution is further stirred at room temperature for 15 minutes, after which the reaction mixture is washed with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution and water, followed by drying over Na2SO4. The solvent is distilled off to give diethyl (5-bromo-3-methoxycarbonylthienyl)aminomethylenemalonate. Recrystallization from ethanol gives light-yellowish needles melting at 129°-130°C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[N+:17]([O-])([OH:19])=[O:18]>>[CH3:16][C:10]1[C:9]([N+:17]([O-:19])=[O:18])=[CH:8][C:7]([F:6])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
116 ml of sulfuric acid is introduced and mixed in portions at −15° C. with 14.70 g (95.37 mmol) of 5-fluoro-2-methylbenzoic acid. A mixture of nitrating acid (4.79 ml of fuming nitric acid and 21.8 ml of concentrated sulfuric acid) is added in drops to this mixture, specifically at −15 to −10° C. during a period of 90 minutes. After three more hours of stirring, the reaction mixture is poured into ice water and stirred vigorously for about one-half hour. The precipitated crystallizate is suctioned off, washed neutral with water and dried. The yield is 8.56 g (45.1%) of a mixture of various regioisomers and by-products. This mixture is incorporated into the next stage (esterification) and purified in this stage.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-:10].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C(O)C>[CH2:13]([O:7][CH:6]([OH:10])[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCCCCCCCBr
Reactant: [OH-]
Reactant: OCc1ccc(O)cc1
Agent: [Na+]
Solvent: CCO
Product: C=CCCCCCCCCOC(O)c1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 64.3 %

Procedure:
First, 12.80 g (0.10 M) of 4-hydroxybenzyl alcohol (compound (6)) was dissolved in 190 mL of ethanol, and 4.0 g (0.10 M) of sodium hydroxide was added thereto. The resulting mixture was heated to 65° C. After heating, 24.14 g (0.11 M) of 10-bromo-1-decene (compound (22)) prepared in Synthetic example 1-1 was added dropwise, and the resulting mixture was aged at a mixture temperature of 760° C. for 6 hours. Next, the generated salt was removed by decantation, and the reaction solution was concentrated. After concentration, the resulting solution was diluted with 350 mL of diethyl ether and washed twice with 100 mL of deionized water. After washing, the organic layer was concentrated to produce crude crystals. The crude crystals were recrystallized twice from 25 mL of hexane. The recrystallized crystals were washed with hexane and dried. Thereby, 16.88 g of 9-decenoxybenzyl alcohol (compound (23)) was produced (yield: 64.3%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.ClC1N=C(Cl)C(Cl)=CN=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH2:7][N:8]([CH3:12])[C:9]2=[O:11]
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cccc2c1CN(C)C2=O
Yield: 129.9 %

Procedure:
7-Amino-4-methoxy-2-methyl-2,3-dihydroisoindol-1-one (292 mg, 1.52 mmol) was combined with 2,4,5-trichloropyrimidine (279 mg, 1.52 mmol), and N,N-diisopropyethylamine (294 mg, 2.28 mmol) in isopropanol (5 mL) and microwaved at 120° C. for one hour. The yellow solid produced was isolated by filtration, was washed with clean isopropanol, and was dried in vacuo to afford 7-(2,5)-dichoropyrimidin-4-ylamino)-4-methoxy-2-methyl-2,3-dihydroisoindol-1-one (350 mg, 68%) as a yellow solid.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[N:11]=[CH:10][C:9]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][N:25](C)[OH:26].ON1C2C=CC=C[C:32]=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:17]([NH:16][C:15](=[O:19])[NH:14][C:12]1[CH:13]=[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:20]([N:25]([O:26][CH3:32])[CH3:24])=[O:22])=[CH:10][N:11]=1)[CH3:18]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: CN(C)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)N(C)OC)cn1

Procedure:
4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid (i) (200 mg, 0.67 mmol), dimethylhydroxylamine hydrochloride (65 mg, 0.67 mmol), 4-dimethylaminopyridine (81 mg, 0.67 mmol) and N-hydroxybenzotriazole (90 mg, 0.67 mmol) were added to a dry RBF which was flushed with N2. DMF (1.5 mL) was added and the mixture stirred. 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (150 mg, 0.80 mmol) was dissolved in DMF (1.5 mL) in a separate vial and this solution added to the reaction mixture at RT. The mixture was stirred overnight at RT.