Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[CH3:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([C:20](OC)=[O:21])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:24].C(O)(=O)C>CO.CN(C=O)C>[OH:3][NH:2][C:20]([C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[N:9]([CH3:8])[C:10](=[O:24])[NH:11]2)=[CH:16][CH:15]=1)=[O:21]
Reactant: COC(=O)c1ccc2c(=O)n(C)c(=O)[nH]c2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c2cc(C(=O)NO)ccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (2.79 mL, 4.74 mmol) was added to a solution of methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.11 g, 0.47 mmol) in methanol (1 mL) and DMF (2 mL). After stirring for 4 h at rt, excess reagent was quenched by the addition of acetic acid (0.27 mL, 4.74 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford N-hydroxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (21 mg, 19%). LC-MS: (FA) ES+ 236; 1H NMR (400 MHz, DMSO) δ 10.87 (s, 2H), 7.95 (d, J=8.2 Hz, 1H), 7.56 (s, 1H), 7.48 (dd, J=8.2, 1.1 Hz, 1H), 3.25 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]([CH2:34][CH2:35][CH2:36][CH3:37])[O:29][C:30]2=[O:31])=[CH:26][CH:25]=1.N1C=CC=CC=1>CCOCC>[CH2:34]([CH:28]1[C:27]2[C:32](=[CH:33][C:24]([NH:23][C:8](=[O:10])[C:7]3[CH:11]=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=3)=[CH:25][CH:26]=2)[C:30](=[O:31])[O:29]1)[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCC1OC(=O)c2cc(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc21

Procedure:
2.50 g (10 mmol) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid are heated with 2.5 ml of thionyl chloride under reflux for 30 minutes. The reaction mixture is evaporated in vacuo and the residue is mixed with petroleum ether to remove the excess of thionyl chloride. 2.05 g (10 mmol) of compound obtained in Example 4 are mixed with 8.6 g of dry pyridine and dried ether. To this suspension there is added, dropwise, the ethereal solution of acyl chloride prepared above; the reaction mixture is refluxed for 30 minutes. The solvents are removed in vacuo. The residue is washed with water and dried. The title compound is crystallised from ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.CCCCCC.Cl[Si](CC)(CC)CC.CON(C)[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C1COCC1>[CH3:1][N:2]1[C:6]([C:29]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:36])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a heat-gun dried flask containing 1-methyl-1H-imidazole (1.55 mL, 19.5 mmol) and THF (20 mL) at −78° C. was added 1.6 M n-BuLi in hexane (12.8 mL, 20.5 mmol). After stirring at −78° C. for 30 min, chlorotriethylsilane (3.3 mL, 19.7 mmol) in neat was introduced slowly. The mixture was stirred at −78° C. for 30 min. 1.6 M n-BuLi in hexane (12.8 mL, 20.5 mmol) was added, and the mixture was stirred for 45 min. A solution of N-methoxy-N-methylnicotinamide (2.70 g, 16.2 mmol, Intermediate 10, step a) in THF (20 mL) was added via cannula, and the mixture was stirred at −78° C. to room temperature for 2 hours. The reaction was quenched with NH4Cl (aqueous), the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (40 g silica gel column, 50-100% EtOAc in heptane, then 5-10% MeOH in CH2Cl2) to obtain the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[NH4+]>[Ni].C(O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCc1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 93.2 %

Procedure:
A mixture of 7.20 g (38.9 mmole) 2-(3-trifluoromethylphenyl)acetonitrile, 0.75 g Raney Nickel, 30 ml ethanol and 4.0 ml concentrated ammonium hydroxide was flushed with nitrogen, then hydrogenated at 3.5 kg/cm2 for 18 hours. The catalyst was removed by filtration under nitrogen and the filtrate evaporated in vacuo to afford 6.86 g (93%) of the title amine as a red oil. 1H-NMR(CDCl3)ppm(delta): 0.65-1.40 (bs, 2H), 2.65-3.40 (m, 4H), 7.30-7.60 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][C:7]=12.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:7]=12
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc2ccnc(Cl)c2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 138) (1.0 g, 5.5 mmol) in THF (27.7 mL) was added 3.0 M phenylmagnesium bromide in Et2O (3.8 mL, 11.3 mmol) at −78° C. under a nitrogen atmosphere. After stirring for ca. 2 h, additional 3.0 M phenylmagnesium bromide in Et2O (0.92 mL, 2.7 mmol) was added. The reaction mixture was stirred for another 1.5 h. The reaction mixture was poured into a saturated NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were washed with saturated NaCl, and dried over Na2SO4. Filtration and concentration provided the crude material, which was purified by flash chromatography to provide (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (0.97 g, 67%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ5.99 (1H, s), 6.42 (1H, s), 7.25-7.48 (6H, m), 7.82 (1H, d, J=5.4 Hz); ESI MS m/z 259 [C14H11ClN2O+H]+; HPLC (Method A) >99% (AUC), tR=13.8 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[CH:27]3)=[O:23])[CH2:17][CH2:16]1)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[CH:27]3)=[O:23])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2ccc3[nH]ncc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (6.0 ml) was added to the trans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclo-hexylcarbamate (420 mg, 1.17 mmol) obtained in Example 158, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, ethanol (10 ml) was added to the concentration residue, followed by washing by repulping. The residue washed was filtered and then dried under reduced pressure to obtain N-(4-aminocyclohexyl)-1H-indazole-5-carboxamide trifluoroacetate (363 mg, 83%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[N:19]1([CH2:18][CH2:17][CH2:16][O:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCCN3CCCC3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H]1CC[C@H](OCCCN2CCCC2)CC1
Reaction time: 4 h

Procedure:
trans-N,N-Dibenzyl-4-[3-(pyrrolidin-1-yl)propoxy]cyclohexanamine (115 mg) was dissolved in ethanol (2.3 ml), and 20% palladium hydroxide/carbon 50% wet (20 mg) was added thereto, followed by catalytic reduction at room temperature for 4 hours at 3 atm under a hydrogen atmosphere. The catalyst was removed by filtration after nitrogen substitution, and then concentrated under reduced pressure to obtain trans-4-[3-(pyrrolidin-1-yl)propoxy]cyclohexanamine (48 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=O)=[O:14])=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.O1CCOCC1>[C:25]([C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[S:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7])=[CH:33][CH:32]=1)#[N:27]
Reactant: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
In a mixture of 5 ml of pyridine and 50 ml of dioxane was suspended 2.5 g of (E)-2-[2-[4-(2-heptenyloxy)benzoylamino]phenylthio]benzamide followed by dropwise addition of 2.2 g of trifluoroacetic anhydride with ice-cooling and stirring.. After completion of dropwise addition, the mixture was stirred at room temperature for an additional 3 hours. Then, ice-water was added and the crystals separated out therefrom were collected by filtration, washed with water and dried to give 2.4 g of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.Cl[CH2:8][CH2:9][CH2:10][OH:11]>[OH-].[Na+]>[OH:11][CH2:10][CH2:9][CH2:8][N:3]1[C:2]([NH2:1])=[N:6][N:5]=[N:4]1
Reactant: OCCCCl
Reactant: Nc1nnn[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nnnn1CCCO

Procedure:
5-Aminotetrazole (2.1 g.) and 3-chloropropanol (2.1 ml.) were added to aqueous sodium hydroxide (1 g. in 20 ml.) and the mixture heated at 90° for 18 hours. The resulting solution was evaporated and the residue extracted with hot EtOH. The EtOH extracts were evaporated and the residue extracted with EtOAc to give a colourless oil which was a mixture of isomers. These were separated on a column of silica gel using EtOAc/MeOH/aqueous ammonia (s.g. 0.880) 6:1:1 v/v/v as eluant to give 1-(3-hydroxypropyl-5-aminotetrazole as a white solid (0.2 g.) and 2-(3-hydroxypropyl-5-aminotetrazole as a gum (1.0 g.).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:12]([NH2:11])[CH3:13])=[CH:15][CH:16]=1
Reactant: COc1ccc([C@H](C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc([C@H](C)N)cc1

Procedure:
A solution of the above (29) (42.8 g) in methanol (300 mL) was hydrogenated over 5% Pd on carbon (~2 g) at 50 psi H2 for 4 h in a Parr shaker. The product (30) was obtained after filtration of the catalyst through Celite®, rinsing with fresh methanol and evaporation (22.9 g, 100%). GC RT 4.68 min (HP 530 mμ×20 m methylsilicone column, He carrier flow rate 20 mL/min, 100° C. isothermal); 1H NMR (CDCl3) δ1.37 (3H, d, J=7 Hz), 2.25(2H, br s), 2.78(3H, s), 4.08(1H, q), 7.15(4H, q).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][NH2:23])=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.[C:25](OCC)(OCC)(OCC)[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C(OCC)(=O)C.O>[CH3:25][C:26]1[N:19]([C:16]2[CH:17]=[N:18][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:24])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[CH:14][CH:15]=2)[C:20](=[O:21])[NH:22][N:23]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ccc(Oc2ccc(NC(=O)NN)cn2)c2c1OCC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(-n3c(C)n[nH]c3=O)cn2)c2c1OCC2(C)C
Temperature: 25 °C

Procedure:
The crude N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}hydrazinecarboxamide (330 mg, 1.0 mmol) was suspended in EtOH (4.5 mL) and triethyl orthoacetate (3 equiv) was added, followed by p-toluenesulfonic acid hydrate (0.1 equiv). The resulting solution was heated to reflux for 24 hrs and then evaporated to dryness. Since the reaction was not complete, the residue was re-dissolved in EtOH (4.5 mL), more triethyl orthoacetate (3 equiv) and p-toluenesulfonic acid hydrate (0.1 equiv) were added and the solution stirred at reflux for additional 18 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and water. Saturated Na2CO3 solution was added the layers were separated and the organic washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified via silica chromatography, eluting with cyclohexane/ethyl acetate from 5/5 to 3/7. The fractions containing the product were combined and evaporated to dryness. The residue was further purified by triturating with methyl tert-butyl ether/n-heptanes. The solid was collected and washed with n-heptanes to afford 5-methyl-4-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid (177 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)C[CH2:33][OH:34].C[OH:37]>>[NH2:21][C:22]([CH2:23][OH:29])([CH2:27][OH:37])[CH2:33][OH:34].[NH2:1][C:2]1[C:7]2=[C:8]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: OCCCO
Agent: COc1cccc2cc(-c3nc([C@H]4CC[C@H](C(=O)O)CC4)n4ncnc(N)c34)[nH]c12
Agent: COc1cccc2cc(-c3nc([C@H]4CC[C@H](C(=O)O)CC4)n4ncnc(N)c34)[nH]c12
Product: NC(CO)(CO)CO
Temperature: 25 °C

Procedure:
The compound trans-4-[4-Amino-5-(7-methoxy-1H-indol-2-yl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic acid can be prepared as known in the art, e.g., according to US 2007/0112005 (Example 258 thereof). This product (5.01 g, 12.3 mmol) was suspended in MeOH (75.0 mL) and heated to reflux. 1,3-Propanediol, 2-amino-2-(hydroxymethyl) (1.79 g, 14.8 mmol) was added and the reaction was heated at reflux for 1 h. The suspension was allowed to cool to RT and then filtered. The solid was washed with MeOH and then dried in vacuo overnight at 50° C. to provide the title compound as a tan solid (4.57 g, 70.2% yield). 1H NMR (400 MHz, CD3OD): δ 1.67 (dddd, J=12.8, 12.8, 12.8, 2.8 Hz, 2H), 1.87 (dddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 2.14-2.17 (m, 4H), 234 (tt, J=12.4, 2.8 Hz, 1H), 3.40 (tt, J=12.4, 3.2 Hz, 1H), 3.65 (s, 6H), 4.01 (s, 3H), 6.75 (d, J=7.2 Hz, 1H), 6.75 (s, 1H), 7.04 (dd, J=7.6, 7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.88 (s, 1H). 13C NMR (100 MHz, DMSO): δ 29.1, 29.6, 34.3, 43.9, 55.3, 59.0, 61.3, 102.3, 102.5, 110.9, 113.1, 120.1, 126.8, 127.2, 130.0, 132.1, 146.3, 146.7, 178.6. LCMS (ESI+): m/z 407 (MH+). Anal. Calcd. for C25H33N7O6: C, 56.92%; H, 6.30%; N, 18.58%; O, 18.20%. Found: C, 56.23%; H, 6.31%; N, 18.33%; O, 18.63%.
Reaction SMILES: [C:1]([C:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Product: CC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Temperature: 115 °C

Procedure:
A mixture of 3-acetyl-1,4-dihydro-8-nitro-4-oxoquinoline (500 mg) and phosphoryl chloride was heated at 115° C. for 15 minutes. After cooling, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 3-acetyl-4-chloro-8-nitroquinoline (485 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH:11]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(NCC)C.[C:39]([NH:47][C@@H:48]([CH:63]([CH3:65])[CH3:64])[C:49]([N:51]([CH2:59][C:60]([OH:62])=O)[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(#N)C.CCOC(C)=O.O.CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH:11][C:60](=[O:62])[CH2:59][N:51]([C:49](=[O:50])[C@@H:48]([NH:47][C:39](=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH:63]([CH3:64])[CH3:65])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)OCc1cccc2c1Cc1ccccc1-2)=NNC(N)=O
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: ClCCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3(S)-(1-fluorenylmethyloxycarbonylamino)-4-oxobutyric acid tert-butyl ester semicarbazone (678 mg, 1.5 mmol; Prepared in a similar manner to the benzyloxycarbonyl analog in Graybill et al., Int. J. Protein Res. , 44, pp. 173-82 (1994)) in acetonitrile (5.0 mL) was added diethylamine (780 μL, 7.5 mmol) and the reaction allowed to stir at rt for 1 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene (3×) in vacuo. To a suspension of the residue, compound 704 (555 mg, 1.5 mmol) and HOBT (224 mg, 1.66 mmol) in 1:1 CH2Cl2 :DMF (10 mL) at 0° C., was added EDC (318 mg, 1.66 mmol). The reaction was warmed to rt and stirred over night. The reaction was diluted with EtOAc and H2O. The layers were separated and the organic phase washed with sat. aq. NaHCO3, sat. aq. KHSO4, brine, dried over MgSO4, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 2-6% MeOH:CH2Cl2) provided 600 mg of compound 705. ##STR84##
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](OCC)[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)C>O>[CH3:11][CH:12]1[O:10][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][O:9]1
Reactant: OCC(O)c1ccccc1
Reactant: CCOCC
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1OCC(c2ccccc2)O1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 1 l stirrer fitted with reflux condenser, thermometer and dropping funnel was charged with 223 g (1.47 mol) of (±)-1-phenyl-1,2-ethanediol (3) (91% pure according to GC) from Example 1, 100 ml of diethyl ether and 2 g of para-toluenesulfonic acid and cooled to 5–10° C., and, at this temperature, 80.8 g (1.83 mol) of acetaldehyde were added over the course of 30 min. When the dropwise addition was complete, the mixture was then stirred firstly for 4 h at 5–10° C. and for a further 2 h at a maximum of 20° C. After this time, water was added, the organic phase was separated off, the aqueous phase was extracted with 1×100 ml of ether, and the combined organic phases were washed until neutral with sodium carbonate solution and water. Drying over Na2SO4 was then carried out, and the solvent was distilled off under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:14][CH2:13][C:12]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[CH:11]2[OH:33])=[N:7][C:8]=1[Br:9].[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([C:12]2([C:15]([F:17])([F:18])[F:16])[CH2:13][CH2:14][N:10]([C:6]3[N:7]=[C:8]([Br:9])[C:3]([CH2:2][NH:1][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34])=[CH:4][CH:5]=3)[CH:11]2[OH:33])[CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Yield: 64.9 %

Procedure:
The mixture of 1-[5-(aminomethyl)-6-bromopyridin-2-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-2-ol (90 mg), 3,3,3-trifluoropropionic acid (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg), dichloromethane (10 ml) and a catalytic amount of 4-dimethylaminopyridine was stirred overnight at room temperature. Upon the completion of the reaction, the solvent was distilled off and the residue was purified by silica gel chromatography to obtain N-[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]-3,3,3-trifluoropropanamide (70 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[N:1][C:2]2[C:7]([C:11]=1[OH:10])=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:14])[CH3:17]
Reactant: Nc1ccncc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2ccncc2c1O
Reaction time: 16 h

Procedure:
4-Aminopyridine (15.84 g) and diethyl ethoxymethylenemalonate (34.3 ml) were heated at 110° C. then allowed to stand for 16 h at room temperture. The resulting solid was collected by filtration, washed wtih diethyl ether then pentane and dried in vacuo. A sample of the resulting enamine (10.0 g) was added portionwise to refluxing Dowtherm A (400 ml ). After heating for a further 0.25 h the reaction mixture was cooled then diluted with pentane (400 ml). The precipitated solid was collected by filtration and washed wtih diethyl ether to afford the title compound as a beige solide (3.84 g).
Reaction SMILES: [H-].[Na+].[C:3]([OH:8])(=[O:7])C(O)=O.[NH2:9][CH2:10][CH2:11][CH:12]([O:19][C:20]1[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:21]=1[C:22]#[N:23])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:12][C:13]([O:8][C:3](=[O:7])[NH:9][CH2:10][CH2:11][CH:12]([O:19][C:20]1[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:21]=1[C:22]#[N:23])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:14])[CH3:18]
Reactant: N#Cc1cc(F)c(Cl)cc1OC(CCN)c1cccnc1
Reactant: O=C(O)C(=O)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Oc1cc(Cl)c(F)cc1C#N)c1cccnc1
Reaction time: 3 h
Yield: 143.3 %

Procedure:
Sodium hydride (34.2 mg, 60% dispersion in oil, 0.86 mmol) was added to a solution of the product from Example 58 (c) (219 mg, 0.54 mmol) and methyl iodide (0.2 ml, 3.2 mmol) in tetrahydrofuran (4 ml) and stirred for 3 h. Aqueous ammonium chloride was added and the mixture was extracted with dichloromethane (three times). The combined organic extracts were dried (sodium sulphate), evaporated and purified by chromatography on silica eluting; with petrol—acetone to give the sub-title compound as a colourless oil (157 mg, 69%).