Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: Br
Solvent: O
Product: O=C1CCCc2cc(O)c(O)cc21
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 6,7-dimethoxy-3,4-dihydro-2H-naphthalene-1-one (15.0 g) and 48% aqueous hydrobromic acid (60 cm3) was heated under reflux for 18 h. Upon cooling to room temperature, water (100 cm3) was added and the resulting aqueous mass was extracted with ethyl acetate (3×100 cm3). The combined extracts were dried (Na2SO4), filtered and evaporated to dryness to leave a brown powder. This was recrystallised from acetonitrile to afford the title compound (9.4 g) as a red powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)/[CH:6]=[CH:7]/[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[N:9]=1.Br.[OH-].[Na+].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>C(OCC)(=O)C.C(O)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[OH:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)/[CH:6]=[CH:7]/[C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[N:9]=1
Reactant: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1
Agent: Br
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Oc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
According to the literature procedure (Kawasaki, I.; Matsuda, K.; Kaneko, T. Bull. Chem. Soc. Jpn. 1971, 44, 1986.), a solution of (E)-2-(3-methoxystyryl)-1-(2-pyridyl)-1H-benzimidazole (76 mg, 0.23 mmol), glacial acetic acid (10 ml) and 48% aqueous solution of hydrogen bromide (5 ml) was heated under reflux condition for 4 h. The resulting solution was neutralized by sodium hydroxide pellet and this mixture was extracted with dichloromethane (3×15 ml). Combined organic layer was dried (magnesium sulfate) and filtered. The filtrate was concentrated then the residue (39 mg, 54%) and oxalic acid (12 mg, 0.12 mmol) were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([OH:12])[CH:11]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CC#N>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([O:12][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cc(OCc2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A suspension of (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (70 mg, 0.22 mmol), K2CO3 (60 mg, 2.0 equivalents), 4-chlorobenzyl bromide (50 mg, 1.1 equivalents) in MeCN (2 mL) was heated at 80° C. for 2 hours. The resultant suspension was filtered and evaporated to dryness. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 85 mg (83%) [5-(4-chloro-benzoxy)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:14]([O-])=O)[CH:4]=1>CO.[Pd]>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(N)=O)cc1OC
Reaction time: 20 h
Yield: 100.2 %

Procedure:
A solution of 4,5-dimethoxy-2-nitrobenzamide (10 g, 44.24 mmol) in MeOH (260 mL) was mixed with palladium/carbon (2 g) and subjected to hydrogenation (50 psi) for 20 h. The reaction mixture was filtered through a Celite pad, concentrated to yield 8.7 g of 2-amino-4,5-dimethoxybenzamide (100%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[C:32]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:33][C:34]([CH3:36])=[O:35].COC1C=CC(C=O)=CC=1>C(O)C>[OH:35][C@H:34]([CH3:36])[CH2:33][C:32]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)CC(C)=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)C[C@@H](C)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
Geotrichum candidum (ATCC 34614) was cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H20 (0.5 gram), NaNO3 (2 grams), FeSO4.7H20 (0.02 gram), and KC1(0.5 gram) with rotary shaking at 25° C. Two grams of ethyl acetoacetate was dissolved in 2 ml of 95% ethanol, the resulting solution was added to the culture, and shaking was resumed. The reaction was followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction was judged complete, and the reaction was terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension was suction filtered through a pad of Celite and the clear yellow filtrate was extracted with ethyl acetate (4×200 ml). The extracts were combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.4 grams of (R)-ethyl 3-hydroxybutyrate as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]=2[CH:4]=1.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O>C(OCC)C>[C:37]1([PH+:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]=2[CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCC1c2cc(CBr)ccc2-c2ccc(CBr)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1

Procedure:
In a 1 L three-neck flask equipped with a stirrer, a thermometer and a reflux condenser, 43.6 g (0.1 mol) of 2,7-bis(bromomethyl)-9-normal-hexylfluorene, 78.7 g (0.3 mol) of triphenylphosphine, and 500 ml of dimethylformamide were introduced and reacted for 12 hours at reflux temperature. When the temperature was decreased to room temperature after reaction, and the reaction solution was dropped down slowly into a 3 L ethylether solvent being thoroughly stirred, to obtain a white solid. After filtering, this solid was washed several times with ethylether, and then dried sufficiently in a vacuum oven at a temperature of 40° C. As a result, 92.2 g (yield: 96%) of a white solid was obtained. [1H-NMR (CDCl3), δ 0.25(br, 3H, CH3), 1.60-1.24(m, 10H, CH2), 2.83(t, 1H, CH), 5.66-5.76(d, 4H, CH2Br), 6.76-7.11(m, 6H, aromatic fluorenyl), 7.49-7.81(m, 30H, aromatic)].
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[CH:37][CH:36]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CCC3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(CC2CCC2)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(cyclobutylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.046 g, 0.12 mmol) and EtOH (1.5 mL), was added 4-(morpholinomethyl)benzaldehyde (0.028 g, 0.14 mmol) in EtOH (1.3 mL) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.37 mL, 0.37 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether and (0.011 g, 17%); 1H-NMR (500 Mz, DMSO-d6): δ 1.61-1.74 (m, 2H), 1.76-1.94 (m, 3H), 2.00-2.10 (m, 2H), 2.33-2.45 (m, 6H), 2.52-2.61 (m, 4H, piperazine N(CH2)2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64 (m, 4H), 7.48 (d, J=8.5 Hz, 2H, ArH), 8.14 (d, J=8.5 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.67 min—525/527 [(M+H)+, Br isotopic pattern]; ESI-HRMS: Found: 525.1972, calculated for C28H31BrFN6O (M+H)+: 525.1977.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(OC)c(Br)c1

Procedure:
3-Bromo-4-methoxy-benzoic acid (2.5 g, 11.6 mmol) was dissolved in EtOH (20 mL) and conc. H2SO4 (1 mL) was added. The reaction was heated to reflux overnight then submitted to standard aqueous workup. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23](O)=[O:24])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:39][NH:40][O:41][CH3:42]>N1C=CC=CC=1>[CH3:42][O:41][N:40]([CH3:39])[C:23]([C:11]1[C:10]2[C:15](=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)[CH:14]=[CH:13][CH:12]=1)=[O:24]
Reactant: O=C(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyl-3-phenyl-7-trifluoromethyl-2H-indazole (353 mg, 1 mmol), prepared similarly to that of Example 1, was treated with 3 ml of 70% aq H2SO4 at 90° C. for 4 hours. After cooling, 10 volumes of water were added and the product was extracted with dichloromethane. Flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid in 60% yleld. The 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid (1.64 g, 5 mmol) was dissolved in 20 ml of pyridine followed by addition of 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) and N,O-dimethyhydroxylamine hydrochloride (585 mg, 6 mmol). The reaction mixture was stirred at room temperature overnight. Pyridine was evaporated and the residue was shaken with 0.5M aq HCl and dichloromethane. The product was extracted with dichloromethane, and flash column chromatography (SiO2, dichloromethane as an eluant) afforded 2-benzyl-3-phenyl-2H-indazole-7-carboxylic acid methoxy-methyl-amide in 79% yleld.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>C1(C)C=CC=CC=1>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:25]([NH:24][CH2:22][CH3:23])=[O:26])[CH:16]=2)=[CH:13][N:12]=1
Reactant: CCN=C=O
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Yield: 83.2 %

Procedure:
A solution of 5-(5-amino-2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.117 g, 0.4 mmol) and ethyl isocyanate (0.034 g, 0.5 mmol) in 4 mL of toluene was heated to 100° C. in a sealed tube. After 5 h the solution was cooled and concentrated in vacuo gave a brown solid. Purification via flash chromatography (CH2Cl2/MeOH 97:3) afforded 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-3-ethyl-urea (0.120 g, 83%) as a white solid; (M+H)=361.
Reaction SMILES: COC(C1C=C(C2C=CC(C(C3C=CC=CC=3C)CC(C3C=CN=C(C)C=3)=O)=CC=2)C=CC=1F)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH:49]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:50][C:51]([C:53]3[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[CH:54]=3)=O)=[CH:45][CH:44]=2)=[CH:39][C:38]=1[C:67]([OH:69])=[O:68].Cl.[NH2:71][OH:72].C([O-])(O)=O.[Na+]>>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([CH:49]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:50][C:51](=[N:71][OH:72])[C:53]3[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[CH:54]=3)=[CH:47][CH:48]=2)=[CH:39][C:38]=1[C:67]([OH:69])=[O:68]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(F)c(C(=O)O)c3)cc2)c2ccccc2C)ccn1
Agent: COC(=O)c1cc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)ccc1F
Agent: Cl
Agent: O=C([O-])O
Product: Cc1cc(C(CC(c2ccc(-c3ccc(F)c(C(=O)O)c3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 75, from 4-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid methyl ester was prepared 4-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid, which was directly subjected to the next step. In analogy to example 74, step 7, from 4-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a colorless oil, MS (ESI+): m/z=469.1910 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([S:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1)=[O:5].[CH3:26][PH:27](=[O:32])[O:28][CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.C([SiH](CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:29]([O:28][P:27]([C:10]1[CH:9]=[N:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[C:15]([S:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)[C:16]([F:18])=[CH:17][C:2]=2[NH2:1])=[CH:12][CH:11]=1)([CH3:26])=[O:32])([CH3:31])[CH3:30]
Reactant: Cn1ccnc1Sc1cc(C(=O)Nc2ccc(Br)cn2)c(N)cc1F
Reactant: CC(C)O[PH](C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)OP(C)(=O)c1ccc(NC(=O)c2cc(Sc3nccn3C)c(F)cc2N)nc1
Temperature: 150 °C
Yield: 15.8 %

Procedure:
A mixture of 2-amino-N-(5-bromo-pyridin-2-yl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide (346 mg, 0.82 mmol), isopropyl methylphosphinate (0.256 mL, 2.05 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (60 mg, 0.082 mmol) and 8 mL of toluene was degassed by bubbling N2 through it for 2 min, then triethylamine (0.285 mL, 2.05 mmol) and triethylsilane (0.033 mL, 0.205 mmol) were added and the mixture microwave heated at 150° C. for 10 min. The solvent was evaporated and the residue dissolved in CH2Cl2, washed with brine, dried (MgSO4) and evaporated. The residue was adsorbed to SiO2 and subjected to MPLC on a 12 g SiO2 column eluting with % EtOAc in hexanes (time): 75 (8 min), 85 (10 min), 90 (10 min), 100 (20 min), then % MeOH in EtOAc (time): 1 (10 min), 2 (10 min) to provide 60 mg (16%) of the title compound. 1H NMR (500 MHz, DMSO-do): δ 1.11 (d, 3H, J=6 Hz), 1.29 (d, 3H, J=6 Hz), 1.69 (d, 3H, J=15 Hz), 3.68 (s, 3H), 4.40 (septet, 1H, J=6 Hz), 6.60 (d, 1H, J=12 Hz), 6.90 (d, 1H, J=1 Hz), 6.98 (s, 2H), 7.27 (d, 1H, J=1 Hz), 8.02 (d, 1H, J=8 Hz), 8.12 (td, 1H, J=7, 3 Hz), 8.17 (dd, 1H, J=7, 2 Hz), 8.67 (dt, 1H, J=5, 1 Hz), 11.02 (s, 1H); LCMS (m/z): 464.1 [C20H23FN5O3PS+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]1[CH2:15][CH2:16][CH3:17])=[O:7])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I:28]I.C(OCC)(=O)C>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][N:9]1[C:13]([I:28])=[C:12]([CH3:14])[N:11]=[C:10]1[CH2:15][CH2:16][CH3:17])=[O:7])[CH3:2]
Reactant: II
Reactant: CCCc1nc(C)cn1NC(=O)c1ccccc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(I)n1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Ethoxy-N-(4-methyl-2-propylimidazol-1-yl)benzamide from Example D (3.5 g, 12.2 mmol) is dissolved in 480 ml of a dioxane/water mixture, and sodium carbonate (3.9 g, 36.6 mmol) and iodine (6.8 g, 26.8 mmol) are added. The mixture is stirred with exclusion of light at room temperature for 24 hours. 50 ml of ethyl acetate are added to the reaction mixture and washed twice with 50 ml of saturated sodium sulphite solution each time. The combined aqueous phases are re-extracted twice with 50 ml of ethyl acetate each time, and the combined organic phase is dried with sodium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][P:13](=[O:52])([O:47]C(C)(C)C)[O:14][CH2:15][C:16]([NH:43]C(=O)C)([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=2)[CH2:27]1)[CH2:17][O:18][Si](C(C)(C)C)(C)C)(C)(C)C>C(Cl)Cl>[NH2:43][C:16]([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=2)[CH2:27]1)([CH2:17][OH:18])[CH2:15][O:14][P:13](=[O:12])([OH:47])[OH:52]
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(CO[Si](C)(C)C(C)(C)C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(C)=O)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc2c(c1)CC(C(N)(CO)COP(=O)(O)O)C2
Reaction time: 3 h

Procedure:
To 1-1 solution of trifluoro acetic acid and CH2Cl2 was added 14 (10 mg, 0.015 mmol). The reaction was left to stir for 3 hours. When reaction complete, product was concentrated and repeatedly co-evaporated with diethyl ether (5×10 mL) to remove TFA. The product could not be purified by column chromatography. Diethyl ether was added to bring the product into solution, followed by the addition of hexanes to precipitate out product 15. The precipitate was then washed with water to remove ionic impurities and then concentrated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[CH:19]=3)[N:14](C3CCCCO3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[CH:19]=3)[NH:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCNc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1
Solvent: Cc1ccccc1
Product: COCCNc1cccc(-c2n[nH]c3ccc(C(N)=O)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a suspension of 3-{3-[(2-methoxyethyl)amino]phenyl}-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide in 20 mL of toluene was bubbled HCl gas for 20 min. The reaction was then stirred at room temperature overnight. The mixture was neutralized with an aqueous saturated solution of NaHCO3 and was concentrated to dryness under reduced pressure. After 2 preparatory HPLC purifications, a small amount of pure material was isolated. (0.015 g, 8% over 2 steps): 1H NMR (CD3OD) δ 8.59 (dd, 1H), 7.91 (d, 1H), 7.56 (ds, 1H), 7.29–7.20 (m, 3H), 6.73 (dt, 1H), 3.61 (t, 2H), 3.36 (s, 3H), 3.334 (t, 2H); ES-MS (m/z) 311 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([C@@H:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[NH2:35])[CH:26]=[CH:27][C:28]=1[O:29][C:30]([F:33])([F:32])[F:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([NH:35][C@@H:34]([C:25]2[CH:26]=[CH:27][C:28]([O:29][C:30]([F:33])([F:31])[F:32])=[C:23]([F:22])[CH:24]=2)[C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[O:17])[CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 6-(benzyloxy)-5-nitropicolinic acid (500 mg, 0.0018 mol) in DMF (10 mL), were added (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (620 mg, 0.0018 mol, Intermediate 6), HATU (1 g, 0.0029 mol) and DIPEA (700 mg, 0.0054 mol). The reaction mixture was then stirred for 12 h at room temperature. Progress was monitored by TLC (100% EtOAc). After completion of reaction, water (100 mL) was added and product was extracted with EtOAc (50 mL×3) and concentrated to obtain the product which was purified by column chromatography, silica gel (100-200 mesh), using 80-100% EtOAc in petroleum ether as the eluent to afford the title compound 1H NMR (400 MHz, DMSO-d6) δ: 9.75 (d, J=7.6 Hz, 1H), 8.61-8.56 (m, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.59-7.54 (m, 5H), 7.35-7.32 (m, 4H), 6.60 (d, 1H), 5.77 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16])[CH2:2][CH3:3].[CH2:18]([C:21]1C([N+]([O-])=O)=CC2NC(=O)COC=2C=1)[CH2:19]C.C([Mg]Br)CC>>[CH2:1]([C:4]1[C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=[C:6]([CH2:19][CH2:18][CH3:21])[C:5]=1[N+:15]([O-:17])=[O:16])[CH2:2][CH3:3]
Reactant: CCCc1c([N+](=O)[O-])ccc2c1NC(=O)CO2
Reactant: CCCc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Agent: CCC[Mg]Br
Product: CCCc1cc2c(c(CCC)c1[N+](=O)[O-])NC(=O)CO2

Procedure:
The title compound is synthesized from either 5-propyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine or 7-propyl-6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine and propyl magnesium bromide using the method illustrated in Example 37.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:8][Cl:9])([C:5](=[O:7])[CH3:6])[CH3:4].[Br:10]Br>>[Br:10][CH2:6][C:5](=[O:7])[C:3]([CH2:8][Cl:9])([CH2:2][Cl:1])[CH3:4]
Reactant: CC(=O)C(C)(CCl)CCl
Reactant: BrBr
Product: CC(CCl)(CCl)C(=O)CBr

Procedure:
Finally, the 2,2-bis-chloromethyl-butan-3-one was then reacted with bromine to give 1-bromo-3,3-bis-chloromethylbutan-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].O>C(Cl)(Cl)Cl>[C:27]([O:13][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:12]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1

Procedure:
3-(4-bromophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol (3 mmol, 1 equivalent) was dissolved in 10 mL of CHCl3 and 1.2 equivalents of triethylamine were added thereto at 0° C. Then, 1 equivalent of acetyl chloride was added thereto, followed by refluxing for 10 minutes. After the reaction was completed, H2O (10 mL) was added to the solution which was then extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered, concentrated, and then separated by column chromatography (n-hexane:EA=5:1 (v/v)) to afford the title compound.