Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:19][CH:16]([CH3:18])[CH3:17])=[O:5]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 1.00 g of Boc-Pro-OH, 0.40 ml of isopropylamine, 0.71 g of HOBt and 1.06 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 28 (Process 2) to give 654 mg of the title compound.
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][C:11]([CH3:18])([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH3:12]>O1CCCC1>[C:11]([C:13]([OH:17])([CH2:14][CH2:15][CH3:16])[C:8]#[C:7][CH:6]([OH:9])[CH3:5])([CH3:18])([CH3:12])[CH3:10]
Reactant: C#CC(C)O
Reactant: CCCC(=O)C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCCC(O)(C#CC(C)O)C(C)(C)C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Over a period of 30 min, a solution of 40.7 g (374 mmol) of ethyl bromide in 100 mL of dry tetrahydrofuran was added dropwise to a stirred suspension of 9.08 g (374 mmol) of magnesium turnings in 5 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. The reaction mixture was then stirred for additional 3 h at reflux. The reaction was allowed to cool down to room temp., and a solution of 12.6 g (180 mmol) of but-3-yn-2-ol in 80 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again heated to reflux for 4 h, prior to removal of the heating bath. At room temp., a solution of 25.0 g (195 mmol) of 2,2-dimethylhexan-3-one in 90 mL of dry tetrahydrofuran was added with stirring within 35 min, and the reaction mixture was refluxed for another 2 d with stirring. The reaction mixture was then allowed to cool to room temp., and quenched with 500 mL of an aqueous satd. NH4Cl solution. The aqueous layer was extracted three times with 500 mL of ether each, the combined organic extracts were dried with sodium sulfate, and the solvent was evaporated on a rotary evaporator to provide 32.3 g (90%) of crude 5-tert-butyloct-3-yne-2,5-diol as a slightly yellowish oil, which was employed without further purification. A solution of 20.8 g (105 mmol) of this product in 300 mL of ethanol was hydrogenated by stirring at ambient pressure and temp. in an atmosphere of hydrogen in the presence of 3.11 g (2.92 mmol) of 10% palladium on barium sulfate and 300 mg (2.32 mmol) of quinoline. After 10 h of stirring, the catalyst was filtered off over a pad of Celite, and the solvent was removed on a rotary evaporator to provide 20.7 g (99%) of crude (3Z)-5-tert-butyloct-3-ene-2,5-diol, of which 19.6 g (98 mmol) was heated for 45 min in a Kugelrohr apparatus to 155° C./280 mbar in the presence of 2.00 g (14.7 mmol) of KHSO4. The evaporating reaction product was trapped in a bulb at −80° C., and further purified by flash chromatography (400 g of silica-gel, pentane/ether, 98:2) to afford 7.26 g of product. This was then distilled in a Kugelrohr apparatus to furnish at 70-80° C./20 mbar 6.24 g (34%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:25][CH3:26])=[O:6].N1C=CC=CC=1.[C:41](Cl)(=[O:45])[O:42][CH2:43]C>O1CCCC1.O>[CH3:43][O:42][C:41](=[O:45])[NH:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:19])[F:17])=[CH:10][C:9]=2[CH2:25][CH3:26])[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: CCOC(=O)Cl
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(NC(=O)OC)c1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3-Amino-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methyl-phenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (0.2 g) and pyridine (0.05 g) were dissolved in tetrahydrofuran (5 ml). To the solution, ethyl chlorocarbonate (0.04 g) was added under ice cooling. After adjusting to room temperature, the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain methyl[5-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)-6-methylphenyl]carbamoyl}-2-(1H-1,2,4-triazol-1-yl)phenyl]carbamate (0.14 g, yield 58%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH:28][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:32][CH:33]=1
Reactant: NCc1cccc(COc2ccc(Cl)cc2)c1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCc2cccc(COc3ccc(Cl)cc3)c2)c(Nc2ccncc2)c1=O
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 3-(4-chlorophenoxy-methyl)-benzylamine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1C(OC(C)(C)C)=O)[CH3:3].C(O)(C(F)(F)F)=O.C(Cl)[Cl:30]>>[ClH:30].[CH3:1][N:2]([CH3:3])[CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1
Reactant: ClCCl
Reactant: CN(C)C[C@@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C[C@@H]1Cc2ccccc2CN1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl 3-((dimethylamino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Edwards, P. J., European Patent Application No. 1598341 (2005)) (66 mg, 0.23 mmol) in CH2Cl2 (2.3 mL) was added TFA (1.4 mL, 18.1 mmol). After stirring for 3 h at room temperature, the reaction mixture was concentrated in vacuo. Next, HCl (1N solution in Et2O) was added and the mixture was concentrated in vacuo (3×) to give a crude oil which was used without purification in the preparation of Example 108. MS(ESI+) m/z 790.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][Mg]Br.[CH2:7]([O:9][C:10]([C:12]1[C:13](OS(C(F)(F)F)(=O)=O)=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8].CCOC(C)=O.CCCCCC>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:13]([CH:1]=[C:2]([CH3:6])[CH3:3])=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1C
Reactant: CC(C)=C[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=C(C)C)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
5.6 ml (2.8 mmol, 2M in THF) (2-methylprop-1-enyl)magnesium bromide was added in drops at 0° C. to a solution of 600 mg (1.4 mmol) 4-methyl-7-(trifluoromethyl)-2-(trifluoromethylsulfonyl-oxy)quinoline-3-carboxylic acid ethyl ester and 75 mg (0.1 mmol) Ni(dppp)Cl2 in THF (10 ml). The mixture was subsequently stirred for 16 h at RT and thereafter quenched at 0° C. with a sat. aq. NH4Cl sol. It was then extracted with EtOAc and the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:19) of the residue, 200 mg (0.6 mmol, 43%) 4-methyl-2-(2-methylprop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:13]=1[C:14]([OH:16])=[O:15])=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1.C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of 2-(2-tert-butoxycarbonylamino-ethylamino)-6-nitro-benzoic acid (0.22 g, 0.00068 mol) in THF at 0° C. was added 4N HCl in dioxane (0.68 mL). The reaction was stirred at 0° C. for 2 h then warmed to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-(2-amino-ethylamino)-6-nitro-benzoic acid (0.12, 76% yield). 1H NMR (400 MHz, CDCl3) δ 11.6 (s, 1H), 7.57 (t, 1H, J=7.6 Hz), 7.05 (d, 1H, J=7.8 Hz), 6.80 (d, 1H, J=7.8 Hz), 4.0 (broad s, 3H), 3.63 (m, 2H), 3.07 (m, 2H); MS (m/e) 226 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](C(O)=O)[C:15]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[N:24]=2)=[CH:14]3)[N:8]([CH3:10])[N:9]=1)=[O:4].[Li+].[OH-]>O1CCCC1.CO.O>[CH3:10][N:8]1[C:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[N:24]=2)=[CH:14]3)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[N:9]1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)cc(-c2nc(C)no2)n3C(=O)O)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2cc3cc(-c4cc(C(=O)O)nn4C)ccc3[nH]2)n1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 5-(5-Methoxycarbonyl-2-methyl-2H-pyrazol-3-yl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-indole-1-carboxylic acid (2.7 g) in tetrahydrofuran (40 ml) and methanol (40 ml) at room temperature is added a solution of LiOH (3M, 103.3 mmol) in water over 5 minutes. The reaction is stirred for 30 minutes and the organic solvents are evaporated in vacuo. The reaction mixture is diluted 3x with water and washed with dichloromethane (100 ml). The aqueous layer is acidified with HCl (12 N) and the product extracted 3× with 200 ml of ethyl acetate. The combined ethyl acetate washings are dried (Na2SO4), filtered, and evaporated in vacuo to give the title compound 1.9 g, 57%, LC/MS ESI m/z (M+H)+=324.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:11]([O-])([OH:13])=[O:12].O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 3,5-difluoroanisole (30 g, 208 mmol) in 260 mL dichloromethane was added HNO3 (>90% fuming, 60 mL) dropwise at 0° C. The resulting solution was stirred at 0° C. for 3 hours, then washed water. The aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and condensed on a rotavap. The residue was recrystallized in hexane and ethyl acetate to provide 28.5 g (72% yield) of 1,5-difluoro-3-methoxy-2-nitrobenzene as an off-white powder. 1H NMR (400 MHz, DMSO) δ ppm 7.20 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:14]CCC(C1C=CC=CC=1)=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:14]1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: Nc1cccc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 47.4 %

Procedure:
A stirred mixture of 1.411 g of 1,8-diaminonaphthalene, 1.629 g of 4-chlorobutyro-phenone, 3 mg of p-toluenesulfonic acid monohydrate, and 10 mL of toluene was heated to reflux under a nitrogen atmosphere using a Dean-Stark trap to remove the water evolved from the reaction for 10 hr. The mixture was filtered to remove unreacted starting material, partioned between ethyl acetate and 5% sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2.04 g of crude product. This was further purified by chromatography on silica gel, eluting with 1:1 diethyl ether/petroleum ether, and collecting the initial band to yield 0.719 g of dihydroperimidine intermediate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:6][N:5]2[CH:16]=[N:17][N:18]=[C:4]2[CH:3]=1.N1C=CC=CC=1.[SH2:25]>C(N(CC)CC)C>[CH3:1][C:2]1[C:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[S:25])=[CH:10][CH:9]=2)=[N:6][N:5]2[CH:16]=[N:17][N:18]=[C:4]2[CH:3]=1
Reactant: S
Reactant: Cc1cc2nncn2nc1-c1ccc(C#N)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc2nncn2nc1-c1ccc(C(N)=S)cc1

Procedure:
A 2.1 g. portion of p-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared as in Example 1) is partially dissolved in a solvent mixture of 50 ml. of pyridine plus 5.0 ml. of triethylamine. Hydrogen sulfide gas is bubbled into the reaction mixture over a 3 hour period during which time the color of the reaction mixture changes from yellow to green. A solid begins to form in the reaction mixture approximately 15 minutes after the addition of the hydrogen sulfide gas is begun. The mixture is then filtered and the yellow solid is washed with petroleum ether to afford the product of the example as a bright yellow solid, m.p. 268°-272° C.
Reaction SMILES: C([N:9]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH3:23])[C:11]=2[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)C>CCOCC.O>[CH3:23][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:19](=[O:22])[C:20]2[CH2:21][NH:9][CH2:10][C:11]1=2
Reactant: Cn1c2c(c(=O)c3ccccc31)CN(C(=O)c1ccccc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cn1c2c(c(=O)c3ccccc31)CNC2

Procedure:
A mixture of 10 g of 2-benzoyl-1,2,3,4-tetrahydro-4-methyl-9H-pyrrolo[3,4-b]quinolin-9-one, 10 g of potassium hydroxide, 10 ml of water and 100 ml of ethanol is heated at reflux for 17 hours, cooled, diluted with 50 ml each of ether and water and filtered. The recrystallisation of the residue from methanol and ether yields 1,2,3,4-tetrahydro-4-methyl-9H-pyrrolo[3,4-b]quinolin-9-one. M.P. 209°-213° (decomposition).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([CH3:23])[CH:14]=1>C(C(C)=O)C>[I-:1].[CH2:2]([N+:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH2:12])=[CH:14][C:15]=1[CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: CCCCCCCCCCI
Solvent: CCC(C)=O
Product: CCCCCCCCCC[n+]1c(C)cc(N)c2ccccc21
Product: [I-]

Procedure:
This compound was prepared by mixing commercially available iododecane and 4-aminoquinaldine in methyl ethyl ketone, and refluxing for 72 h. The solid product was collected by filtration and recrystallized twice in absolute ethanol. 1H NMR (in DMSO-d6): δ 0.85 (t, J=5.1 Hz, 3H), 1.24 (br, 12H), 1.43 (m, 2H), 1.70 (m, 2H), 2.73 (s, 3H), 4.45 (t, J=8.09 Hz, 2H), 6.73 (s, 1H), 7.72 (dd, 1H), 8.02 (dd, 1H), 8.15 (d, J=8.94 Hz, 1H), 8.43 (d, J=8.37 Hz), 8.81 (br, 2H). Elemental analysis Calcd for C20H31N2I: C, 56.33%; H, 7.33%; N, 6.57%. Found: C, 56.23%; H, 7.41%; N, 6.42%. MS, [M-I−]=299 (m/z) (calcd 299.47 for C20H31N2).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([F:31])[CH:24]=1.[BH4-].[Na+]>CO.ClCCl>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:14][C@H:11]2[CH2:12][CH2:13][N:9]([C:6]3[N:7]=[CH:8][C:3]([Br:2])=[CH:4][N:5]=3)[CH2:10]2)=[C:25]([F:31])[CH:24]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NC1CCN(c2ncc(Br)cn2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1cc(Br)ccc1CN[C@H]1CCN(c2ncc(Br)cn2)C1

Procedure:
Dissolve 1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride (60 mg, 0.22 mmol) in methanol (10 mL) and dichloromethane (1 mL). Add triethylamine (100 μL, 0.72 mmol) and 4-bromo-2-fluorobenzaldehyde (87 mg, 0.43 mmol) and stir overnight at room temperature. Add sodium borohydride (25 mg, 0.66 mmol) and stir 1 h. Dilute the mixture with methanol and pour onto a column of Dowex® 50wx4-200. Wash with methanol, then elute with 10% triethylamine in methanol. Concentrate and chromatograph on silica gel, eluting with 20:80 to 1:1 ethyl acetate:hexanes to give the title compound as a residue. Dissolve the residue in methanol and add 1 N HCl in methanol (0.75 mL). Concentrate and dry in a vacuum oven at 60° C. overnight to give the title compound as its hydrochloride salt, as a white solid (80 mg, 80%). 1H NMR (400 MHz, MeOH-d4) 8.45 (s, 2H), 7.57-7.52 (m, 3H), 4.42-4.34 (m, 2H), 4.15-4.09 (m, 1H), 4.04-3.99 (m, 1H), 3.87-3.77 (m, 2H), 3.69-3.62 (m, 1H), 2.63-2.54 (m, 1H), 2.36-2.27 (m, 1H), MS (ES): m/z=429 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:8])=[N:4][O:5][C:6]=1[CH3:7].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:19]N1C(=O)CCC1=O>C(N(CC)CC)C>[C:9]1([S:15]([O:8][C:3]2[C:2]([Cl:1])=[C:6]([CH2:7][Br:19])[O:5][N:4]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1onc(O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1noc(CBr)c1Cl)c1ccccc1

Procedure:
4-Chloro-3-hydroxy-5-methylisoxazole was reacted with benzenesulphonyl chloride in the presence of triethylamine to give 3-benzenesulphonyloxy-4-chloro-5-methylisoxasole, which was then reacted with N-bromosuccinimide to give 3-benzenesulphonyloxy-5-bromomethyl-4-chloroisoxazole. This was then treated by the procedure described in Preparation 10, to afford benzhydryl 4-chloro-3-hydroxyisoxazol-5-ylmethylthioacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (25 g, 0.159 mmol) in acetonitrile (500 mL) and methanol (500 mL) was treated with diisopropyl ethylamine (28 mL). The reaction mixture was cooled in an ice-bath and after 30 minutes, trimethylsilyldiazomethane was added dropwise. The mixture was stirred at room temperature for 18 hours then evaporated under vacuum to afford the product as an oil (29.4 g, 100%). MS (+ve ion electrospray) m/z 172 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([O-:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]([F:37])([F:36])[C:22]1[CH:27]=[C:26]([Sn](C)(C)C)[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[N:23]=1.CN(P(N(C)C)(N(C)C)=O)C.O1CCO[CH2:51][CH2:50]1>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>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([C:26]4[CH:27]=[C:22]([C:21]([F:37])([F:36])[F:20])[N:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([O:17][CH2:50][CH3:51])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1COCCO1
Reactant: C[Sn](C)(C)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: O=C([O-])c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C(F)(F)F)nc(C(F)(F)F)c3)c(F)cc2c1=O

Procedure:
Ethyl 1-cyclopropyl-6-fluoro-7-[2,6-di(trifluoromethyl)-4-pyridinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate was prepared from 4 g 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 5 g 2,6-di(trifluoromethyl)-4-(trimethylstannyl)pyridine, 400 mg dichlorobis(triphenylphosphine)palladium and 2 ml HMPA in 60 ml dioxane according to the procedure of Example 1, part (h), and was obtained (2.8 g) as a solid with m.p. 239°-241° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6](Cl)=[N:7][CH:8]=[N:9][C:10]=1[Cl:11])=[O:4].[SH:13][CH2:14][C:15]([O:17][CH2:18]C)=[O:16].C(N(CC)CC)C.Cl>C(#N)C.O>[CH3:18][O:17][C:15]([C:14]1[S:13][C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[C:3]=1[OH:4])=[O:16]
Reactant: COC(=O)c1c(Cl)ncnc1Cl
Reactant: CCOC(=O)CS
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2ncnc(Cl)c2c1O
Temperature: 50 °C
Yield: 92 %

Procedure:
To a solution of 4,6-Dichloropyrimidine-5-carboxylic acid methyl ester (0.5 g, 2.5 mmol) (prepared as disclosed in Lee, C.-H., et. al. Bioorganic & Medicinal Chemistry Letters (2001), 11(18), 2419) and mercaptoacetic acid, ethyl ester (0.29 g 2.5 mmol) in acetonitrile (50 mL) was added triethylamine (2 mL) and the solution warmed to 50° C. for one hour. The reaction mixture was diluted with water (100 mL), made acidic (pH 2) with 2N HCl and the precipitate collected by filtration, giving product as a white solid, (0.6 g, 2.3 mmol, 92 percent) yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:4]=1[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[NH:8][CH:7]=1.ClCCCl.C(N(CC)CC)C.Cl.[F:38][C:39]([F:46])([F:45])[CH2:40][CH:41]([CH3:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:20]1[CH:19]=[CH:18][C:4]([CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:17])[NH:43][CH2:42][CH:41]([CH3:44])[CH2:40][C:39]([F:46])([F:45])[F:38])[CH:13]=3)[NH:8][CH:7]=2)=[C:3]([O:2][CH3:1])[CH:21]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)O)cc23)c(OC)c1
Reactant: CC(CN)CC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 3-(2-methoxy-4-methoxycarbonyl-benzyl)-1H-indole-5-carboxylic acid (1.7 grams, 5.00 mmol) in methylene chloride (50 mL), was added 4-dimethylaminopyridine (0.67 grams, 5.50 mmol), 1,2-dichloroethane (1.06 grams, 5.50 mmol), triethylamine (0.73 mL, 5.25 mmol) and 4,4,4-trifluoro-2-methylbutylamine hydrochloride (0.93 grams, 5.25 mmol). The resulting solution was stirred 12 hours, at room temperature, then diluted with methylene chloride. The solution was washed with 1 M hydrochloric acid (aq), then the organics were dried over magnesium sulfate. Concentration in vacuo followed by trituration of the crude product in a 2:1 ratio of ether:hexanes gave 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid methylester (1.88 grams, 82% yield).