Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([OH:24])[C:14]([O:16]N1C(=O)CCC1=O)=[O:15])[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]2[C:56]3[C:51](=[C:52]([Cl:58])[CH:53]=[C:54]([Cl:57])[CH:55]=3)[CH2:50][N:49]([CH3:59])[CH2:48]2)[CH:42]=1)(=[O:40])=[O:39]>>[Cl:57][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([Cl:58])[CH:53]=1)[CH2:50][N:49]([CH3:59])[CH2:48][CH:47]2[C:43]1[CH:42]=[C:41]([S:38]([NH:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:3](=[O:5])[C@H:2]([OH:1])[C@@H:13]([OH:24])[C:14]([OH:16])=[O:15])(=[O:39])=[O:40])[CH:46]=[CH:45][CH:44]=1
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](O)[C@@H](O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)[C@H](O)[C@@H](O)C(=O)O)c2)C1
Yield: 31.9 %

Procedure:
Compound 221 was prepared by isolating the mono-addition byproduct from the procedure outlined in Example 168 using (2R,3R)-bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (70.4 mg, 0.205 mmol) and Compound 28 (223 mg, 0.409 mmol). Purification by preparative HPLC gave the title compound (44.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.89 (d, 1H), 7.81 (d, 1H), 7.63 (t, 1H), 7.55 (s, 1H), 7.50 (t, 1H), 6.84 (s, 0.5H), 3.88-3.84 (m, 1H), 3.64-3.34 (m, 22H), 3.14 (s, 4H), 3.07 (m, 2H). MS (m/z): 677.36 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[F:31]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[F:31]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (383 mg, 1.60 mmol) and 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (455 mg, 1.76 mmol) in DMF (12 mL) at rt was added TEA (445 μL, 3.20 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (180 mg; yield 24% over the 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.236 (s, 1 H), 7.803 (d, J=6.5 Hz, 2 H), 7.757-7.770 (m, 2H), 7.693-7.710 (m, 1H), 4.414 (d, J=18.0 Hz, 1 H), 4.316 (d, J=18.0 Hz, 1 H), 1.481 (s, 6 H) ppm; HPLC purity: 99.13% at 220 nm and 99.15% at 254 nm; MS: m/z=461.9 (M+1, ESI+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[C:19]1[N:20]=[CH:21][NH:22][CH:23]=1.C([O-])(O)=O.[Na+].ClCCl>O1CCOCC1.O.CO.ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Ic1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)c1cc(-c2c[nH]cn2)cc(C(F)(F)F)c1
Yield: 23.6 %

Procedure:
In a 35 mL, microwave vial, 3,5-bis(trifluoromethyl)phenylboronic acid (2.5 g, 9.69 mmol) and 4-Iodo-1H-imidazole (2.068 g, 10.66 mmol) was dissolved in 1,4-dioxane (18 mL). To this reaction mixture aq. solution of NaHCO3 (1.628 g, 19.38 mmol) was added at room temperature. The reaction mixture was degassed for 30 min and Pd(dppf)Cl2.dichloromethane (0.791 g 0.1 eq.) was charged in microwave for 16 h at 90° C. The progress of the reaction was monitored by TLC using methanol: dichloromethane (0.5:9.5) as mobile phase. Reaction mixture was poured into water (50 mL) and filtered through celite bed. The filtrate was extracted with EtOAc (3×20 mL). The combined organic layers was washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure using rotary evaporator to afford 2.5 g of crude compound which was purified by column chromatography. Compound was eluted at 40% ethylacetate in hexane to give 0.640 g of pure product (Yield 23.61%). The same batch was repeated with same quantities of chemicals to give 0.781 g of pure product (Yield 28.78%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)=[N:23][CH:24]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(-c2ccnn2C2CCCCO2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 122.6 %

Procedure:
To a mixed solution of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100.5 g, 0.36 mol), 2-bromo-5-fluoropyridine (56.5 g, 0.33 mol), and Pd(PPh3)4 (38.0 g, 32.6 mmol) in ethanol (300 mL) and toluene (300 mL), a 2M aqueous solution of Na2CO3 (0.49 L, 0.99 mol) was added, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, then water and EtOAc were added thereto, and the resulting mixture was stirred at room temperature for 30 minutes, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, then NH silica gel (400 g) was added thereto, and the resulting mixture was stirred for 15 hours. The mixture was filtered through acid silica gel (eluted with n-hexane:AcOEt=1:1→AcOEt) and the solvent was distilled off under reduced pressure to obtain the title compound (100 g) (pale yellow oil).
Reaction SMILES: [CH2:1]([CH2:6][C:7]([CH:9]=[C:10](C)C)=[O:8])[CH:2]=[C:3](C)[CH3:4].C(N)CN.[OH-].[Na+]>>[CH3:10][CH2:9][C:7](=[O:8])[CH:6]=[CH:1][CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=CCCC(=O)C=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Product: CCCC=CC(=O)CC
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A 500 ml flask was charged with 100.0 g of prenyl mesityl oxide (13% nonconjugated 79.7% conjugated isomer), 0.56 mole, 40.6 g ethylene diamine, and 0.5 g NaOH. This was then flushed thoroughly with nitrogen. The mixture was heated at between 95° and 105° C. and agitated for approximately four hours under a slight nitrogen pressure. Analysis by gas liquid chromatography indicated that 31.9% prenyl mesityl oxide remained unchanged after this time. Steam distillation of the pot mixture gave a true yield of 95.8% of methyl heptenone based on the prenyl mesityl oxide reacted, after the recovery of unreacted prenyl mesityl oxide.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[C:15]1([CH2:14][O:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NCCOc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCCOc2cc(OCc3ccccc3)ccc21
Temperature: 60 °C
Yield: 64.5 %

Procedure:
A mixture of 8-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Preparation 26) (8.66 g, 48.3 mmol), benzyl bromide (6.32 ml, 53.2 mmol) and potassium carbonate (20.04 g, 145 mmol) in DMF (80 ml) was stirred and heated at 60° C. for 2 hours. The cooled reaction was diluted with EtOAc/water (300 ml of each) and the aqueous extracted with EtOAc (2×75 ml). Combined organics were washed with 3×100 ml of water, dried (magnesium sulphate), evaporated, triturated with ether and filtered off to give the title compound (8.39 g) as a white solid. MS (ES) C16H15NO3 requires 269; found 270 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH:20]1([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=2[F:30])[NH2:26])[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:26][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[CH:27]=[CH:28][C:29]=2[F:30])[CH2:22][CH2:21]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(C2CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(C3CC3)c2)nc(N2CCOCC2)cc1=O
Yield: 24.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 220 mg of 3-cyclopropyl-4-fluoroaniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. After extractions with ethyl acetate and silica column purification, eluent 90/10 CH2Cl2/MeOH, the residue is taken up with ml of diisopropyl ether, and the precipitate is spin-filter-dried and dried under vacuum, so as to obtain 69 mg of N-(3-cyclopropyl-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC(C1C=CC=CC=1)=[O:12].OO.S(=O)(=O)(O)O.CC1C=C(C)C=C(O)C=1O>>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(=O)c1ccccc1
Agent: Cc1cc(C)c(O)c(O)c1
Agent: O=S(=O)(O)O
Agent: OO
Product: Cc1cc(O)cc(C)c1O

Procedure:
In a vessel used in Example 52 were placed 100 g. (819 m. moles) of 3,5-dimethylphenol, 2.64 g. (22.0 m. moles) of methylphenylketone, 1.81 g. (31.9 m. moles) of 60 percent hydrogen peroxide and 0.01 g. of sulfuric acid, and treated at 110° C. for 20 minutes in the same manner as in Example 52. 2.10 g. (15.2 m. moles) of 3,5-dimethylcatechol and 1.04 g. (7.5 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of the dihydric alkylphenols was 70.9 percent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:18][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(C(O)c2ccc(C)cc2)cc1

Procedure:
To the Grignard reagent prepared from 47.2 g of p-bromotoluene and 7.2 g of magnesium in 200 ml of ether was added dropwise 30 g of p-tolualdehyde in 50 ml of ether with cooling. When the addition was complete the reaction was refluxed for 15 minutes, cooled in ice, and 40 ml of saturated NH4Cl solution was added dropwise. The reaction was filtered and the ether was removed under reduced pressure to give a yellow oil which crystallized on standing. Recrystallization from petroleum ether gave 26.1 g of nearly colorless 4,4'-dimethylbenzhydrol, m.p. 70°-71°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH2:28]([S-:30])[CH3:29].[Na+]>O1CCOCC1.CN(C=O)C>[CH2:28]([S:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:29]
Reactant: CC[S-]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCSc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium ethanethiolate in dioxane and DMF. ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1>C1C=CC=CC=1.C(O)(=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH:26]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: COC(=O)CC(=O)OC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1)C(=O)OC
Yield: 86.7 %

Procedure:
To solution of dimethyl malonate (0.22 mL, 1.65 mmol) in benzene (15 mL) and acetic acid (3 drops) was added 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (330 mg, 1.38 mmol). The reaction mixture was heated at reflux overnight. The reaction was quenched with sat. KH2PO4 and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient. Obtained 424 mg (87% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)methylene)malonate. MS found: (M+H)+=355.
Reaction SMILES: CO.[Cl-].[NH4+].[CH3:5][NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:8]>[Fe].O>[CH3:5][NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:8]
Reactant: CNC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CNC(=O)n1ccc2cc(N)ccc21
Yield: 76 %

Procedure:
Methanol (6 ml), water (2 ml), iron (0.32 g) and ammonium chloride (0.64 g) were added to N1-methyl-5-nitro-1H-1-indolecarboxamide (0.32 g, 1.46 mmol) synthesized in Production example 218-1; and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue was filtrated with celite, and concentrated under reduced pressure to yield the title compound (210 mg).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:37])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[N:26]=[CH:25][C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[C:10]([CH3:37])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionic acid tert-butyl ester (130 mg) in methylene chloride (1 mL) is added TFA (0.8 mL) and two drops of water. The mixture is stirred for 2 h, and concentrated and purified by reversed phase HPLC (water-acetonitrile with 0.1% TFA) yield 120 mg of product. MS (ES): 477.2(M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.O.[CH3:18][N:19](C)[CH:20]=O>>[C:8]([C:7]1[C:2]([N:19]([CH3:20])[CH3:18])=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Solvent: O
Product: CN(C)c1ncc(-c2cc[n+]([O-])cc2)cc1C#N
Reaction time: 8 h

Procedure:
2-Chloro-3-cyano-5,4'-bipyridine-1'-oxide and 3 g N,N-dimethylammonium-N,N-dimethyl carbamate is heated in 50 ml dimethylformamide for 2 hours on the boiling water bath and then allowed to cool. The crystalline precipitate, formed on standing overnight in the refrigerator, is filtered off with suction, crystallized from dimethylformamide and dried at 110° C. Yield: 2.9 g (93.2% of the theoretical yield), with a melting point of 282° C.-284° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](C#N)[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].Cl.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(=O)[nH]c1C
Temperature: 175 °C
Yield: 48.4 %

Procedure:
A 100 mL Parr reactor was charged with 5,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (Example 475, 3.00 g, 20.3 mmol), concentrated hydrochloric acid (18 mL), and water (18 mL). The reactor was slowly heated to 175° C. for 9 h and then cooled to rt. The solution was basified with 1N NaOH in water and was extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo, yielding the title compound (1.21 g, 48%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (bs, 1H), 7.18 (d, 1H), 6.04 (d, 1H), 2.10 (s, 3H), 1.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][O:13][CH3:12])=[CH:17][CH:18]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: COCOc1ccc(I)cc1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Product: COCOc1ccc(-n2c(C)cc3cc(Cl)ccc32)cc1
Yield: 19 %

Procedure:
5-Chloro-2-methylindole (4.14 g, 25 mmol) and 4-methoxymethyloxy iodobenzene (6.20 g, 25 mmol) were reacted according to the procedure used in Example 1a above to afford a colorless liquid (19%): 1H NMR (DMSO-d6): δ 2.25 (3H, s), 3.44 (2H, s), 5.28 (2H, s), 6.40 (1H, s), 6.96 (1H, d, J=8.8 Hz), 7.02 (1H, dd, J=2.0 Hz, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.55 (1H, d, J=2.0 Hz); MS m/z (M+H)+ 302/304 (1 Cl). Anal. for C17H16ClN02: Calc'd: C, 67.66; H, 5.34; N, 4.64. Found: C, 67.49; H, 5.17; N, 4.51.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23]C(=O)C(C)(C)C.[H-].[Na+].O1CCCCC1OC1CCCCO1.I[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][OH:53].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:18])[CH3:19])=[C:13]([F:20])[CH:12]=3)=[CH:8][C:7](=[O:21])[C:6]=2[C:22]=1[NH:23][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][OH:53]
Reactant: CN(C)c1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)cc(F)c3o2)cc1F
Reactant: OCCCCCCI
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cc(=O)c3c(NCCCCCCO)c(F)cc(F)c3o2)cc1F
Temperature: 0 °C
Reaction time: 1.3 h
Yield: 70 %

Procedure:
1.0 g (2.99 mmol) of Compound 38 obtained in Example 38 was dissolved in 20 ml of dimethylformamide under argon atmosphere, 239 mg of sodium hydride (60% oil dispersion) and 1.87 g of tetrahydropyranyl ether of 6-iodo-1-hexanol were added under ice-cooling and the mixture was stirred at 0° C. for 1.3 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. 18 ml of ethanol and 2 ml of concentrated hydrochloric acid were added to the residue and the mixture was stirred at room temperature for 18 hours. The reaction solution was adjusted to pH 7 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol=40:1) and recrystallized from n-hexane/ethyl acetate to give 912 mg (70%) of Compound 60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:43][CH2:42]2)[S:9]1(=[O:18])=[O:17]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccccc3Cl)S2(=O)=O)CC1
Yield: 60.8 %

Procedure:
In an analogous manner as general procedure II, step 1, a solution of 1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.23 g, 0.8 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.32 g, 1.2 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.37 g, 1.6 mmol) were added followed by diisopropylazodicarboxylate (0.23 mL, 1.2 mmol) to provide tert-butyl 4-{2-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.24 g, 61%) as a white foam:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[K+].Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])(=O)C([O-])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=CCO)ccc1F
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: COc1cc(/C=C/COCCCN2CCCC2)ccc1F
Yield: 4.1 %

Procedure:
Following the procedure described in example 2, but starting from 3-(4-fluoro-3-methoxyphenyl)prop-2-en-1-ol (600 mg), potassium hydroxide (456 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (618 mg) in dimethylsufoxide (5 mL) affords 40 mg of trans-1-{3-[3-(4-fluoro-3-methoxyphenyl)allyloxy]-propyl}pyrrolidine, oxalate as a solid melting at 143-144° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.O.[NH2:21][NH2:22]>C(O)C>[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:21][NH2:22])[C:3]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:2]=2[F:1])[CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: NN
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCC(C(=NN)c2ccc(F)cc2F)CC1
Yield: 79.2 %

Procedure:
A solution of 15.0 g of 4-(2,4-difluorobenzoyl)-1-acetylpiperidine, 6.9 g of hydrazine hydrate and 140 ml of ethanol was heated under reflux for 4 hrs. The ethanol was removed in vacuo to give a solid. The solid was triturated with water, filtered and dried to yield 12.5 g (64%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine hydrazone, mp 139°14 142° C.