Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OCCC1C=C[C:37]([C:38]#[N:39])=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[NH2:39][CH2:38][CH2:37][C:9]1[CH:10]=[CH:2][C:3]([C:4]#[N:5])=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN)cc1
Reaction time: 1 h

Procedure:
A mixture of phthalimide (20.0 g) and triphenylphosphine (35.65 g) was added dropwise to a mixture of 4-(2-hydroxyethyl)benzonitrile (20.0 g) and diethylazodicarboxylate (21.4 ml) in THF (650 ml) with stirring over one hour. The mixture was stirred at ambient temperature for 4 days. The solvent was removed under reduced pressure. Methanol (500 ml) and hydrazine hydrate (13 ml) were added to the residue and the mixture was boiled under reflux with stirring for 5 hours. The solvent was removed under reduced pressure and aqueous acetic acid (420 ml of glacial acetic acid in 1030 ml of water) was added to the residue. This mixture was stirred for 1 hour and then filtered. The filtrate was added to ice and basified with solid potassium hydroxide. The mixture was extracted with dichloromethane to give an oil which was purified by flash column chromatography to give 4-(2-aminoethyl)benzonitrile, as an oil. A sample was dissolved in ethereal hydrogen chloride to give the hydrochloride salt, m.p. 211-213° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH:9]([CH:15]=[N:16][O:17][CH2:18][CH3:19])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([CH2:21][S:22]([CH3:24])=[O:23])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH:9]([CH:15]=[N:16][O:17][CH2:18][CH3:19])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([CH2:21][S:22]([CH3:24])(=[O:33])=[O:23])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCON=CC(C(=O)c1ccc(Br)cc1CS(C)=O)C(=O)C1CC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCON=CC(C(=O)c1ccc(Br)cc1CS(C)(=O)=O)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.8 %

Procedure:
A mixture of 1-[4-bromo-2-(methylsulphinylmethyl)phenyl]-3-cyclopropyl-2-(ethoxyiminomethyl)propan-1,3-dione (350 mg) and m-chloroperbenzoic acid (50-60%, 400 mg) in dichloromethane was stirred at room temperature for one hour. 1M sodium metabisulphite was added and the mixture cooled to 0° C. and filtered. The filtrate was diluted with ether, washed with 25% sodium acetate and brine, dried (anhydrous sodium sulphate) and evaporated. The residue was purified by column chromatography on silica gel, eluting with acetone and hexane, giving as a brown gum 1-[4-bromo-2-(methylsulphonylmethyl)phenyl]-3-cyclopropyl-2-(ethoxyiminomethyl)propan-1,3-dione (compound 9, 10 mg), NMR (CDCl3) δ 1.0-1.2(7H, m), 2.45(1H, m), 2.8(3H, s), 4.05(2H, q), 4.6(2H, q), 7.5-7.6(2H, m), 7.65-7.7(2H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[C@H:25]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[O:24]2)[CH3:21])[CH2:17]1.C(O)(=O)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:29][C@@H:30]2[C@@H:23]([CH2:22][N:20]([CH3:21])[CH:18]3[CH2:17][CH:16]([CH2:15][CH2:14][C:13]4[NH:1][C:2]5[CH:7]=[CH:6][C:5]([CH:8]6[CH2:9][O:10][CH2:11]6)=[CH:4][C:3]=5[N:12]=4)[CH2:19]3)[O:24][C@@H:25]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[C@@H:26]2[O:27]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2cc(C3COC3)ccc2N)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4COC4)ccc3[nH]2)C1
Temperature: 65 °C
Yield: 64.8 %

Procedure:
N-(2-amino-5-(oxetan-3-yl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (0.446 g, 0.752 mmol) was taken up in acetic acid (7.7 mL, 140 mmol) and heated at 65° C. for 3.5 h; HPLC/LC MS indicated complete conversion. At 3.75 h the acetic acid was removed by distillation with minimal warming to afford an orange oil, which was taken up in CH2Cl2 (45 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The aqueous layer was treated with NaCl until saturated and extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford a light orange oil. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.28 g, 65%) as a light orange foam: MS (ESI+) for C30H38N8O4 m/z 575.3 (M+H)+; MS (ESI−) for C30H38N8O4 m/z 573.3 (M−H)−; HPLC purity >95% (ret. time 2.142 min).
Reaction SMILES: FC1C=C(C=CC=1OC)C(NNC(C1OC=C(C2C=CC=CC=2)C=1C1C=CC=CC=1)=O)=O.[NH2:33][C:34]1[CH:35]=[C:36]([CH:60]=[CH:61][C:62]=1[O:63]C)[C:37]([NH:39][NH:40][C:41]([C:43]1[O:44][CH:45]=[C:46]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:47]=1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:42])=[O:38]>>[NH2:33][C:34]1[CH:35]=[C:36]([CH:60]=[CH:61][C:62]=1[OH:63])[C:37]([NH:39][NH:40][C:41]([C:43]1[O:44][CH:45]=[C:46]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:47]=1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:42])=[O:38]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1N
Agent: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1F
Product: Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Yield: 96.2 %

Procedure:
A reaction and treatment was carried out in the same manner as in Example 32 except that the compound of Example 31 used in Example 32 was replaced with the compound of Example 41 (1.00 g), thereby giving 0.93 g of the desired compound. Melting point: 268-270° C. (Recrystallized from methanol)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>C1COCC1>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (1.13 g, 6.31 mmol) and Et3N (965 ml, 6.92 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (953 ml, 6.31 mmol) and the reaction mixture was stirred at room temperature for 2 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%) as white needles. mp 137-139° C.; 1H-NMR (CDCl3) δ1.25-1.29 (m, 3 H), 3.59 (s, 2 H), 4.15-4.20 (m, 2 H), 7.05 (br s, 1 H), 7.13-7.23 (m, 6 H), 7.47-7.51 (m, 1 H), 7.54-7.56 (m, 1 H), 8.01-8.03 (m, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([NH:19][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Product: CC(C)(C)Nc1ncnc2c([N+](=O)[O-])cccc12
Yield: 51 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 500 mg, 2.39 mmol), and tert-butylamine (350 mg, 4.78 mmol) in pyridine (5 mL) was stirred at rt for 3 h. Then the reaction mixture was concentrated and the residue was dissolved in EtOAc. Then the solution was washed with water and brine, separated, dried, filtered, concentrated and purified by column chromatography to afford 300 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.67 (d, J=8.4 Hz, 1H), 8.53 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.63-7.58 (t, J=8.0 Hz, 1H), 1.54 (s, 9H); MS [M+H]+: 247.18.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([CH:23]=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:23][C:22]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:14][C:15]2[C:20]([C:21]=1[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1c(C=O)c(-c2ccc(F)cc2)nc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1c(C=C(Br)Br)c(-c2ccc(F)cc2)nc2ccccc12
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of carbon tetrabromide (2.958 gm, 8.92 mmol) in CH2Cl2 (10 ml) was added over a 15 minute period to a cold (-10° C.) solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde (1.744 gm, 5.95 mmol) (the preparation of which is described in Example 2) and triphenylphosphine (4.680 gm, 17.84 mmol) in CH2Cl2 (34 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow-orange oil. The oil was chromatographed (flash, Merck SiO2, 30% CH2Cl2 in hexane followed by 1:1 CH2Cl2 in hexane followed by straight CH2Cl2) to give 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as a colorless foam (2.572 gm, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Yield: 98.6 %

Procedure:
7.1 g of (3-Chloro-4-fluoro-phenyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine was reduced using Raney nickel catalyst in THF, then filtered and evaporated to give 6.4 g N4-(3-Chloro-4-fluoro-phenyl)-7-methoxy-quinazoline-4,6-diamine (99% yield). This product was reacted with 4-Chloro-but-2-enoyl chloride as described in Scheme 1 to provide 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=2)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[N:30][NH:31]2)=[CH:27][CH:26]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=4)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:33]=2)[CH:29]=[N:30]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CNC(=O)COc1cccc(Nc2nc(Cl)nc3[nH]ccc23)c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNC(=O)COc1cccc(Nc2nc(Nc3ccc4cn[nH]c4c3)nc3[nH]ccc23)c1
Temperature: 115 °C
Yield: 8.7 %

Procedure:
To a mixture of 2-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.062 g) in nBuOH (0.6 mL) was added 6-aminoindazole (0.028 g) and TMSCl (0.013 mL). After heating at 115° C. for 15 h, the mixture was purified by prep HPLC to give 2-(3-(2-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.007 g, MS calcd for C22H20N8O2 428.4, found [MH] 429.1; UV 238.1, 311.6 nm).
Reaction SMILES: N[OH:2].[C:3]1([CH:9]([OH:12])CO)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:9]([OH:12])(=[O:2])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: OCC(O)c1ccccc1
Product: O=C(O)c1ccccc1
Yield: 77 %

Procedure:
Results for the oxidation of a variety of alcohols as represented in the reaction scheme are summarized in Table 1. ##STR10## Oxidation of phenethanol (1a) gave phenylacetic acid (2a) in 96% yield (entry 1). Similarly, substrates with electron rich aromatic rings, such as 1b and 1c, were converted into the carboxylic acids 2b and 2c in excellent yields (entry 2,3). Most notably, chiral alcohol id was cleanly oxidized to 2d (95%) without any evidence of racemization based on chiral HPLC assay (entry 4). This was perhaps attributed to the fact that the aldehyde intermediate was very short lived under the reaction conditions. In all cases examined, the aldehyde intermediates were not observed in more than 5% during the reactions (HPLC). The cyclopropyl group in alcohol 1e was intact under the reaction conditions to give 2e in 90% yield (entry 5). Amidoacetal in 1f also survived to give the desired product 2f in 73% yield (entry 6). Cbz-protected amino alcohol 1g was oxidized to the Cbz-protected amino acid 2g in good yield without racemization (83%, entry 7). In this case, the reaction was carried out at r.t. due to the low solubility of the substrate at 0° C. For the vicinal diol, 1-phenyl-1,2-ethanediol (1h), carbon-carbon bond cleavage occurred to give benzoic acid in 77% yield (entry 8). To our surprise, oxidation of benzylic alcohols such as benzyl alcohol, 4-methoxybenzyl alcohol and furfuryl alcohol gave unsatisfactory results. Interestingly, electron deficient 4-nitrobenzyl alcohol (1i) gave a quantitative yield of 4-nitrobenzoic acid (entry 9). Substrates with very electron rich aromatic groups, such as 2,4,6-trimethoxybenzyl alcohol and 2-(3',4'-dimethoxyphenyl) ethanol, gave complex reaction mixtures. No reaction was observed for cinnamyl alcohol and 3-phenyl-2-propyn-1-ol. As expected, secondary alcohols, sec-phenethanol (1j) and 1-phenyl-2-propanol (1k), were oxidized to acetophenone and phenylacetone respectively in quantitative yield (entry 10, 11). Only 1.25 equivalents of periodic acid and 0.6 mol % CrO3 were required in these cases.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]2)[CH2:6]1.Cl.C(#N)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(CC(=O)C(C)(C)C)CC(C1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)CN1CC2CNCC(C1)O2
Temperature: 0 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of tert-butyl 7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (i) above; 0.265 g, 0.812 mmol) in ethyl acetate (10 mL) was treated, at 0° C., with ethyl acetate saturated with gaseous hydrochloric acid. The mixture was stirred at 0° C. for 5 h, and then evaporated. Acetonitrile (15 mL) and K2CO3 (1 g, 7.2 mmol) were added, and the mixture was stirred overnight before being filtered and evaporated to yield 0.159 g (86%) of the sub-title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10].[C:11]([S:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15][C:16](=[O:21])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[F:10])[C:18](=[O:20])[CH3:19])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: Fc1ccc(CBr)c(F)c1
Product: CC(=O)C(Cc1ccc(F)cc1F)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2,4-difluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17])([CH3:7])[C:3]([NH:5][NH2:6])=O.FC(F)(F)C(O)=O.[CH2:25]([N:27]=[C:28](SC)[N:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1)[CH3:26].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:25]([N:27]1[C:3]([C:2]([CH3:7])([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[CH3:1])=[N:5][N:6]=[C:28]1[N:29]1[CH2:30][CH2:31][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]1)[CH3:26]
Reactant: CCN=C(SC)N1CCC(C(=O)OCC)CC1
Reactant: CC(C)(Oc1c(F)cc(F)cc1F)C(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2CC)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
2-methyl-2-(2,4,6-trifluorophenoxy)propanohydrazide (500 mg) and trifluoroacetic acid (0.08 ml) were added to a solution of ethyl 1-[(ethylimino)(methylsulfanyl)methyl]piperidine-4-carboxylate (600 mg) in toluene (10 ml), followed by stirring at 120° C. for 8 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate and the solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (using basic silica:hexane:ethyl acetate=100:0 to 50:50 to 0:100) to obtain ethyl 1-{4-ethyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}piperidine-4-carboxylate (254 mg), as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[N:4]1)[CH3:2].Cl>CO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[N:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(OC)nc2)c2ncccc21
Agent: Cl
Solvent: CO
Product: CCn1nc(-c2ccc(O)nc2)c2ncccc21
Yield: 79.4 %

Procedure:
A mixture of 1-ethyl-3-(6-methoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine (120 mg), MeOH (10 mL) and concentrated HCl (5 mL) was stirred at reflux for 24 h and then evaporated. The residue was treated with saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was suspended in IPE and collected by filtration to give the title compound (90 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][C:11]2=[O:12]
Reactant: O=C(Cl)CCc1ccc(F)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(F)cc(F)cc21
Temperature: 0 °C

Procedure:
To a mixture of 3-(2,4-difluorophenyl) propanoic acid (28.7 g, 0.15 mol) and dimethylformamide (5 drops) at ambient temperature was added dropwise oxalyl chloride (50 mL, Aldrich). The mixture was stirred at ambient temperature for 18 h. The excess oxalyl chloride was removed by distillation in vacuo to give 3-(2,4-difluorophenyl)propionyl chloride. A solution of the 3-(2,4-difluorophenyl)propionyl chloride in dichloromethane (300 mL) was added dropwise to a mixture of aluminum chloride (23.4 g, 0.18 mol, Aldrich) in dichloromethane (300 mL) at ice bath temperature. After the addition was completed, the mixture was refluxed for 3.5 h and allowed to come to ambient temperature over-night. The reaction mixture was poured into ice water (I1500 mL), the two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed successively with 0.1N aqueous sodium hydroxide and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 21.7 g of crude 4,6-difluoro-1-indanone. Chromatography on silica gel with hexanes: dichloromethane (3:1) as eluent gave 10.1 g of a light yellow solid. Recrystallization of 0.5 g from acetone: water mixtures gave 0.2 g of 4,6-difluoro-1-indanone as a white solid: mp 97°-99° C.; NMR (CDCl3): d 7.02-7.27 (m, 2H), 3.12 (t, 2H), 2.76 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20](Cl)=[O:21]>>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]([O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:21]
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: O=C(OCCN1CCOCC1)c1ccc2ccccc2c1
Yield: 95 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-morpholinoethanol was used instead of the triethanolamine, and 2-naphthoyl chloride was used instead of the benzoyl chloride, to give 2-morpholinoethyl 2-naphthalenecarboxylate in a yield of 95%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][CH2:18][OH:19])[CH:14]=2)[CH:9]=[N:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH2:18][OH:19])[CH:14]=2)[CH:9]=[N:8]1
Reactant: OCCC(c1cccnc1)c1ccc2cn[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC=C(c1cccnc1)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of 3-(1H-Indazol-6-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CCXXXI (415 mg, 1.42 mmol) in THF (30 ml) was added 1 M solution of LiAlH4 (in THF, 2.81 ml) dropwise. The reaction mixture was stirred at room temperature for 1 hour and was quenched by addition of freshly ground Na2SO4.10H2O (2 g). After stirring for 30 minutes, the solid residue was filtered off and washed with EtOAc. The filtrate was dried over MgSO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH) affording 3-(1H-Indazol-6-yl)-3-pyridin-3-yl-prop-2-en-1-ol CCXXXII-A as a yellow oil (62 mg, 17% yield) in a first fraction, and 3-(1H-Indazol-6-yl)-3-pyridin-3-yl-propan-1-ol CCXXXII-B as a yellow foam (64 mg, 18% yield) in a second fraction.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:14]1[C:15]([CH3:29])=[CH:16][C:17]([N+:26]([O-:28])=[O:27])=[C:18]([CH:25]=1)[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:29][C:15]1[C:14]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:25][C:18]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)OC(C)C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 102.5 °C
Reaction time: 37 h
Yield: 97.9 %

Procedure:
Dimethylacetamide (716 ml), 170 g of 4-trifluoromethoxyphenol, 246 g of isopropyl 5-chloro-4-methyl-2-nitrobenzoate, and 263.9 g of potassium carbonate were added into a 2000-ml glass flask equipped with a stirring device, a thermometer, and a reflux condenser under a nitrogen atmosphere, and the temperature of the contents of the flask was raised to 100 to 105° C. with stirring. A reaction was allowed to proceed at the same temperature for 37 hr, and 360 ml of dimethylacetamide was then removed by evaporation under the reduced pressure. The reaction solution was poured into 2 L of ice-water, and 1.7 L of ethyl acetate was added thereto. The mixture was stirred and was allowed to stand, followed by separation. The ethyl acetate layer was washed with a 1.5% aqueous sodium hydroxide solution and brine and was concentrated under the reduced pressure to give isopropyl 4-methyl-2-nitro-5-(4-(trifluoromethoxy)phenoxy)benzoate (373.3 g, yield: 97.9%).