Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]CCCC)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>O>[N:1]1([C:8]2[C:9]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed butyl 3-(azepan-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.36 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (71 mg, 1.77 mmol, 4.98 equiv), water (2 mL). The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, XbridgePrep Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 90% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 80 mg (61%) of 3-(azepan-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Na].[OH:2][C:3]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:4]#[N:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>CN(C)C=O.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][O:2][C:3]([C:6]([F:7])([F:9])[F:8])([C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: N#CC(O)(C(F)(F)F)C(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A solution of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrile sodium salt (4.3 g.) and 4-(4-chlorophenyl)-benzyl chloride (4.7 g.) in dimethylformamide (25 ml.) is stirred at ambient temperature for 10 days, then diluted with water. During this reaction, 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionitrile is formed and is subsequently hydrolysed to the corresponding amide. The mixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane, and the extract is dried with sodium sulphate, then evaporated. The residue is crystallised from cyclohexane to give 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionamide, m.p. 123°-124° C. (1.6 g.).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].O>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of 2.08 g (10 mmol) of 1-benzylbenzimidazole in 200 ml of dry tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 8.0 ml (20 mmol) of n-butyllithium. The resulting solution was warmed to 0° C. for 0.5 h, recooled to -78° C., and poured into a mixture of excess dry ice in 200 ml of tetrahydrofuran. After being allowed to warm, the solution was treated with 200 ml of water, washed with ether, neutralized, and washed with ether. The aqueous layer was concentrated in vacuo, after which the residue was triturated with 2% methanol in chloroform and filtered. The filtrate was dried over MgSO4 and concentrated to give 2.01 g (80%) of the desired compound as a white powder. Mass spectrum: (M-OH)+ =235.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (0.650 g, 2.99 mmol) in dichloromethane (10 mL) was added Et3N (1.25 mL, 8.98 mmol). MeSO2Cl (0.35 mL, 4.5 mmol) was added dropwise at 0° C. under N2 and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (1:1 hexane/EtOAc) to give (S)-tert-butyl 3-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (0.720 g, 81%) as a white solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:11][CH:12]=1)[CH3:6]>O.C(O)(=O)C>[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](=[O:22])[C:16](=[N:1][OH:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCOC(=O)CC(=O)CCc1cccc(CC)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of sodium nitrite (6.3 g) in water (10 ml) was added to a stirred solution of the product from step (iii) (20.6 g) in acetic acid (30 ml) at <30° C. The reaction mixture was stirred at room temperature for 18 hours. Water (150 ml) was added and the mixture was stirred for 2 hours and extracted with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[O:9][CH:8]=[CH:7][CH2:6]1)(=[O:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].CCOCC>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([CH2:11][N:23]=[N+:24]=[N-:25])[O:9][CH:8]=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC=CO[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC=CO[C@@H]1CN=[N+]=[N-]
Reaction time: 24 h
Yield: 60.2 %

Procedure:
4-O-Acetyl-3-deoxy-6-O-tosyl-D-glucal (550 mg.) and sodium azide (550 mg.) were dissolved in hexamethylphosphoramide (50 ml.) and the mixture was stirred at 25° for 24 hours. The reaction mixture was poured into ether and extracted with water and the ether extract was dried (MgSO4) and evaporated and the product was chromatographed on a silica gel column (58 × 2.5 cm) using 7% acetone in hexane as the eluent to give 4-O-acetyl-6-azido-3,6-dideoxy-D-glucal (200 mg.) as a colorless oil, (Found: C, 48.84; H, 5.33; N,21.49. C8H11N3O3 requires: C, 48.72; H, 5.62; N, 21.31%), [α]D26 = 158.8° (CH3OH), νmax (film) 2100, 1720, 1660, 1220, 1050 cm.-1, δ(CDCl3) 2.09 (3H, s, OAc), 4.72 (1H, ddd, H = 6Hz, J = 4.5Hz, J = 3Hz, H2) and 6.39 ppm (1H, ddd, J = 2Hz, J = H1. )
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[C:16](=[O:22])[CH2:15]2)[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH2:36])=[CH:34][C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1.[C:43]1(C)C=CC=CC=1>>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:43])[C:16](=[O:22])[CH2:15]4)[C:3]=3[CH3:23])=[CH:34][C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1
Reactant: CCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Reactant: Cc1ccccc1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Product: CCCN1CCN(c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)CC1=O

Procedure:
Essentially prepared according to Procedure H using 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-ethylpiperazin-2-one (35.0 mg, 0.088 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 4-(4-(2,5-dimorpholinopyridin-3-ylamino)-5,7-difluoro-3-methylquinolin-2-yl)-1-propylpiperazin-2-one. 1H NMR (TFA salt) (400 MHz, CDCl3) δ ppm 7.79 (1H, d, J=2.5 Hz), 7.72 (1H, d, J=10.8 Hz), 7.40 (1H, ddd, J=9.7, 2.4, 1.2 Hz), 6.88 (1H, ddd, J=13.5, 8.6, 2.5 Hz), 6.47 (1H, d, J=2.7 Hz), 5.94 (3H, br. s.), 3.96-4.35 (3H, m), 3.87-3.95 (4H, m), 3.77-3.86 (4H, m), 3.54-3.76 (2H, m), 3.12-3.54 (7H, m), 2.99-3.13 (4H, m), 2.14 (3H, s), 1.63 (2H, sxt, J=7.5 Hz), 0.93 (3H, t, J=7.4 Hz). Mass Spectrum (ESI) m/e=582.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[F:25])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH2:21])[C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)=[CH:9][CH:8]=1.C(O[C:31](=[O:56])[NH:32][CH:33]([C:50]1[O:54][N:53]=[C:52]([CH3:55])[N:51]=1)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=2)=[CH:37][CH:36]=1)(C)(C)C.[Cl:57][C:58]1[C:59]([O:77][CH3:78])=[C:60]([C:74](O)=[O:75])[CH:61]=[C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]([F:73])([F:72])[F:71])=[CH:66][CH:65]=2)[CH:63]=1.COC>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[F:25])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:21][C:74]([C:60]2[CH:61]=[C:62]([C:64]3[CH:65]=[CH:66][C:67]([C:70]([F:72])([F:73])[F:71])=[CH:68][CH:69]=3)[CH:63]=[C:58]([Cl:57])[C:59]=2[O:77][CH3:78])=[O:75])[C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)=[CH:9][CH:8]=1.[Cl:49][C:44]1[CH:43]=[C:42]([CH:47]=[CH:46][C:45]=1[F:48])[O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH:33]([NH:32][C:31]([C:60]2[CH:61]=[C:62]([C:64]3[CH:65]=[CH:66][C:67]([C:70]([F:73])([F:71])[F:72])=[CH:68][CH:69]=3)[CH:63]=[C:58]([Cl:57])[C:59]=2[OH:77])=[O:56])[C:50]2[O:54][N:53]=[C:52]([CH3:55])[N:51]=2)=[CH:36][CH:37]=1
Reactant: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: Cc1noc(C(N)Cc2ccc(Oc3ccc(F)c(Cl)c3)cc2)n1
Reactant: Cc1noc(C(Cc2ccc(Oc3ccc(F)c(Cl)c3)cc2)NC(=O)OC(C)(C)C)n1
Agent: COC
Agent: Cl
Product: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)NC(Cc1ccc(Oc2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Product: Cc1noc(C(Cc2ccc(Oc3ccc(F)c(Cl)c3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)cc(Cl)c2O)n1

Procedure:
5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.07 g) was prepared from 2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride [0.07 g, 0.182 mmol, which was prepared from [2-[4-(3-Chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester by the hydrolysis of BOC group using the general procedure N] and 5-Chloro 4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (as in example 42) (0.053 g, 0.18 mmol) following general procedure A. 5-Chloro-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-[4-(3-chloro-4-fluoro-phenoxy)-phenyl]-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (20 mg) was obtained upon methyl ether hydrolysis using the general procedure P. 1HNMR (400 MHz, CDCl3): 2.40 (s, 3H), 3.39 (m, 2H), 5.79 (dd, 1H), 6.84 (m, 1H), 6.90 (d, 2H), 7.02 (1 H), 7.04-7.17 (m, 4H), 7.50 (d, 1H), 7.61 (d, 2H), 7.71 (d, 2H), 7.78 (d, 1H), 12.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.Cl[CH2:12][CH:13]=O>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[CH:12]=[CH:13][N:10]=[C:4]2[CH:3]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: O=CCCl
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc2nccn12
Product: Cl
Temperature: 25 °C
Yield: 141.9 %

Procedure:
A solution of 6-chloro-2-(methylthio)pyrimidin-4-amine (25.17 g, 143.3 mmol) and 2-chloroacetaldehyde (27.73 mL, 215.0 mmol) (50% aqueous) in 1,4-dioxane (50 mL) was heated at 95° C. for 14 hours. The reaction mixture was allowed to cool to ambient temperature and then cooled in an ice bath. The reaction mixture was filtered and the solids washed with dioxane to afford 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (24.01 g, 101.7 mmol, 70.96% yield) as a tan powder. MS (apci) m/z=200.0 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].[C:9](=O)([O-])[O-].[K+].[K+].IC.[H-].[Na+]>O.CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([O:8][CH3:9])[CH3:7]
Reactant: C[C@@H](O)CCCCCl
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CO[C@H](C)CCCCCl
Temperature: 40 °C
Yield: 43 %

Procedure:
A mixture of (R)-1-chloro-5-hydroxyhexane, dimethylformamide (100 ml), powdered potassium carbonate (1 g), iodomethane (15.9 g, 112 mmol) and sodium hydride (2.0 g, 84 mmol) were combined was heated at 40° C. for 30 minutes. After cooling to room temperature, water (100 ml) was added cautiously and the mixture was extracted with hexanes (2×100 ml). The combined extracts were concentrated under vacuum and the residue was purified by column chromatography on silica gel eluting with hexanes followed by 10% ethyl acetate-hexanes to afford (R)-1-chloro-5-methoxyhexane (3.1 g, 43% yield for 2 steps) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 3H), 1.36-1.56 (m, 4H), 1.70-1.84 (m, 2H), 3.28 (s, 3H), 3.29 (m, 1H), 3.52 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(F)cc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(F)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Dissolve 3-fluoro-5-iodoaniline (600 mg, 2.53 mmol) (prepared as described in published PCT International Application WO96/23783 A1, published Aug. 8, 1996), methanesulfonyl chloride (896 mg, 7.83 mmol), triethylamine (1.91 g, 18.9 mmol), and N,N-dimethylamino-4-pyridine (31 mg, 0.253 mmol) in CH2Cl2 (10 mL) and stir at room temperature overnight. Dilute with 1.00N aqueous HCl (20 mL) and extract into ethyl acetate. Dry (MgSO4) and concentrate organics to a yellow solid. Dissolve solid in THF (50 mL) and add 1.0M tetrabutylammonium fluoride (2.8 mL). Heat to reflux for 3.5 h. Cool to room temperature, dilute with H2O, and extract into ethyl acetate. Dry (MgSO4) and concentrate organics. Chromatograph on silica gel (40 g), eluting with 20% to 35% ethyl acetate/hexanes affords 618 mg (78%) of the title compound as a white solid. MS (ES) 314 (M−H); HPLC shows 100% purity.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([F:18])([F:17])[C:6]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]#[N:10])=O>CO>[F:4][C:5]([F:18])([F:17])[C:6]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([NH2:10])[O:3][N:2]=1
Reactant: N#CC(C(=O)C(F)(F)F)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Nc1onc(C(F)(F)F)c1-c1ccccc1
Yield: 82.1 %

Procedure:
Methanol (53 ml) and 96% hydroxylamine hydrochloride (2.82 g, 0.0390 mole, 1.3 eq.) were added to -(trifluoroacetyl)phenylacetonitrile (6.96 g, 0.0300 mole) and the mixture was heated under reflux for 68 hours. After methanol was distilled off under reduced pressure and the resulting residue was neutralized with a 8% solution of sodium bicarbonate, the solution was extracted with methylene chloride. After being dried with anhydrous sodium sulfate, it was concentrated and purified by column chromatography on silica gel to give the title compound (5.62 g, 82.1%). The product was recrystallized from benzene-cyclohexane to recover the title compound (4.80 g, 70.1%) as pale yellow needles, m.p. 89°-91° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]([C:15](=[O:17])[CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.OS(O)(=O)=O>C(OC(=O)C)(=O)C>[CH3:16][C:15]1[O:17][C:6]([C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:8][C:9]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(NC(=O)c1ccc(C)cc1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(C)cc2)oc1C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
The intermediate prepared in Example 8 (280 g, 1.06 mol) was dissolved in acetic anhydride (650 mL) followed by slow addition of conc. H2SO4 (60 mL). The pot temperature reached 80° C. The reaction was then held at 85° C. for 1 hour, cooled, and the acetic anhydride removed in vacuo. The residue was poured into ice water (2 L) and extracted with EtOAc (4 L total). The organic layer was then stirred with 1N NaOH (500 mL) for 1 hour, separated, then dried with MgSO4 and concentrated to afford the title ester as a clear oil (223 g, 87%), which slowly solidified to a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH3:22])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17]S(C)(=O)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([N:32]2[CH:36]=[C:35](O)[CH:34]=[N:33]2)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:35]2[CH:34]=[N:33][N:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:38])([F:39])[F:24])[CH:27]=3)[CH:36]=2)[N:14]=1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1cnn(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2cnn(-c3cccc(C(F)(F)F)c3)c2)cs1
Temperature: 85 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
2-Methyl-2-[(4-{2-[(methylsulfonyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (1.0 g) synthesized in Example 5 and 1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-4-ol (600 mg) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (363 mg) was added, and the mixture was stirred at 85° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 4:1) to give the title compound (400 mg) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:4])=[O:3].[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(OCC)(=O)C>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:20][N+:21]1[CH:25]=[CH:24][N:23]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH2:7]2)[CH:22]=1
Reactant: Cn1ccnc1
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)[O-]
Product: C[n+]1ccn(C2CCN(c3ccc([N+](=O)[O-])cc3)C2)c1
Yield: 81.4 %

Procedure:
23 g (0.08 mol) of 1-(4-nitrophenyl)pyrrolidin-3-yl methanesulphonate (2) was heated for 8 hours at 85° C. in 150 g of 1-methylimidazole (1.82 mol). This solution was stirred in 2 l of ethyl acetate to the point of crystallization. After filtration and drying, 24 g of yellow powder (3) was obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1.C(N)(=O)C1C(=CC=CC=1)O.Br[CH:25]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]1>CN(C)C=O.O>[OH2:10].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:25]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:25]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: CN1CCC(Br)C1
Agent: NC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(Cl)cc2C(N)=O)C1
Yield: 34.1 %

Procedure:
To a cooled suspension of 2.4 g (0.41 mole) sodium hydride in 50 ml of dimethylformamide was added dropwise 17 g (0.1 mole) of 5-chlorosalicylamide dissolved in 50 ml of dimethylformamide at a rate such that the temperature did not exceed 20° C. After addition of the salicylamide was complete, 16.7 g (0.1 mole) of 3-bromo-1-methylpyrrolidine dissolved in 50 ml of dimethylformamide was added dropwise. The reaction mixture was stirred and heated at reflux for 19 hr. The cooled solution was diluted with 250 ml of water and extracted twice with 250 ml portions of chloroform. The chloroform was extracted thrice with 500 ml portions of 3N hydrochloric acid. The aqueous extracts were made alkaline with 50% sodium hydroxide and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate under reduced pressure gave 6 g (23%) of product as a beige solid. The solid was recrystallized from ethyl acetate, m.p. 126°-128° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32]CN[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.[C:48]([BH3-])#[N:49].[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:28][CH2:29][CH2:48][N:49]([CH:40]5[CH2:41][CH2:42]5)[CH2:32]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CCCN(C4CC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 39.9 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.20 mmol) in MeOH (2.3 mL) containing 3 Å molecular sieves was added AcOH (114 μL, 2.00 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (241 μL, 1.20 mmol) and sodium cyanoborohydride (57 mg, 0.90 mmol). The reaction was stirred at 60° C. for 17 h. Aqueous NaOH (1N, 15 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MOON and the filtrate was concentrated to provide 37 mg (40%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1 H), 7.60 (s, 1 H), 7.50 (d, 1 H), 7.29 (s, 1 H), 6.98-7.08 (m, 5 H), 6.84 (dd, 1 H), 6.31 (s, 1 H), 5.35 (s, 2 H), 2.96-3.05 (m, 1 H), 2.88 (d, 1 H), 2.60 (d, 1 H), 2.01 (t, 1 H), 1.93 (t, 1 H), 1.62-1.71 (m, 1 H), 1.12-1.41 (m, 4 H), −0.04-0.16 (m, 4 H); ES-MS m/z 463.31 [M+H]+, HPLC RT (min) 1.48.