Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[C:13]([Si:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(F)cc1F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenol (35, 5.00 g, 38.4 mmol) in N,N-dimethylformamide (100 mL) were added tert-butyldimethylsilyl chloride (7.00 g, 46.4 mmol) and imidazole (6.28 g, 92.2 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to provide the compound (36, 7.50 g, 80.0%). MS (ESI) [M+H+]+=245.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)C)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and isobutyryl chloride.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(Br)c1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 225 ml. of 40$ hydrobromic acid and cooled to 0°C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of cuprous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 3-bromo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C@:6]1([NH:24][C:25](=[O:28])[CH2:26]Cl)[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[P:29]([O:36]CC)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>>[C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C@:6]1([NH:24][C:25](=[O:28])[CH2:26][P:29]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:36])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](OC(C)=O)[C@@](NC(=O)CCl)(OCc2ccccc2)O[C@@H]1C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(=O)N[C@]1(OCc2ccccc2)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O)OCC

Procedure:
Benzyl 2,4-di-O-acetyl-3,6-dideoxychloroacetamido-alpha-D-mannopyranoside, 20, 0.65 g (0.00157 mole) and triethyl phosphite (5 mL) were heated at 110°-120° C. for 4.5 h with stirring under argon. The solvent was distilled at high vacuum, 50 mg of the residue was saved, and the rest carried on.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]=2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:21])[C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=S
Reaction time: 2 h
Yield: 173.5 %

Procedure:
To 2.0 g (0.007 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-one in 35 ml of acetonitrile was added 1.0 g (0.0023 mole) of phosphorus pentasulfide and the mixture heated to reflux for 2 hr. Another 0.4 g (0.001 mole) of phosphorus pentasulfide was added and heating continued for 2 hr. After cooling, the reaction mixture was diluted with 100 ml of toluene and filtered. The filtrate was washed with 3×50 ml of saturated sodium bicarbonate and 100 ml of water, dried over sodium sulfate, filtered, charcoaled, filtered, and concentrated by rotary evaporation. The crude oil was crystallized from isopropyl ether/toluene to give 1.2 g (57%) of yellow crystals, m.p. 153°-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([NH:24][CH3:25])=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:53])([F:52])[C:36]1[CH:37]=[C:38]([C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([N:24]([C:47](=[O:48])[C:46]([C:38]2[CH:37]=[C:36]([C:35]([F:34])([F:52])[F:53])[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:39]=2)([CH3:51])[CH3:50])[CH3:25])=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N(Cc2ccccc2)C(=O)OCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 1.075 g (2.5 mmol) benzyl-(5-methylamino-4-o-tolyl-pyridin-2-yl)-carbamic acid benzyl ester in 10 ml dichloromethane and 1 ml N-ethyldiisopropylamine was added dropwise at 0° C. a solution of 1.15 g (3.5 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid chloride in 2 ml dichloromethane and the mixture was stirred for 3 h at room temperature. The solution was washed with water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 1.15 g (62%) of the title compound as a yellow oil. MS m/e (%): 720 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide (Stage 32.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=4.18 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=451.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.89 (m, 2H) 2.94 (d, J=11.73 Hz, 1H) 3.18-3.33 (m, 2H) 3.36-3.49 (m, 1H) 4.18 (br. s, 1H) 4.81 (d, J=3.13 Hz, 1H) 6.38 (s, 1H) 7.68-7.85 (m, 2H) 8.02 (d, J=1.95 Hz, 1H) 8.32 (dd, J=8.60, 2.35 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 8.98 (d, J=2.35 Hz, 1H) 10.42 (s, 1H) 12.89-13.12 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=1.[Br:24]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:24][C:11]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][C:10]=1[CH:22]=[O:23]
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (330 mg) was dissolved in N,N-dimethylformamide (30 mL), N-bromosuccinimide (356 mg) was added and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 270 mg, 66%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3](/[C:7](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:8]\[OH:9])=[N:2]1.[C:17](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:17][O:9]/[N:8]=[C:7](/[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: O/N=C(\C1=NOCCO1)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Reaction time: 16 h
Yield: 62.7 %

Procedure:
1.2 g (0.0054 mol) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) in 5 ml of dimethylformamide are stirred at 20° C. together with 0.66 g (0.0062 mol) of sodium carbonate initially for 30 minutes. 0.83 g (0.00658 mol) of dimethyl sulphate is then added and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is adjusted to a slightly acidic pH using 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 0.8 g (50.35% of theory) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 80.3% (HPLC) is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH:8]3[C:13]4[C:18]([CH2:19][CH:7]3[C:6]=2[CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH3:3])[CH3:2].[CH2:20]([Li])CCC.IC>O1CCCC1>[CH3:20][C@@:8]12[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][C@@H:7]1[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][C:10]=1[NH:9]2
Reactant: CC(C)c1ccc2c(c1)C1Cc3ccccc3C1N2
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, a flame-dried flash was charged with 4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole (1.49 g 5.98 mmol) and dry tetrahydrofuran (THF, 20 cm3). The solution was cooled to -78° C., and a solution of n-butyllithium in hexanes (4.0 cm3 of 1.6M solution) added dropwise. The reaction was warmed to room temperature, and dry CO2 gas bubbled through until the colour of the anion had dispersed. The solvent and excess CO2 were carefully removed at a vacuum pump, the resulting solid re-dissolved in dry THF (20 cm3) and cooled to -78° C. A further equivalent of n-butyllithium was added, and the reaction stirred at -20° C. for 30 minutes. Iodomethane (0.4 cm3, 1 eq) was added at -78° C., and the reaction warmed to room temperature and stirred for 3 hours. The solvents were removed at the water pump, and 2N HCl solution (20 cm3) added. After 20 minutes, the solution was basified with solid sodium carbonate, and extracted into ethyl acetate. The organic extract was washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by flash chromatography as an unstable pale yellow oil. Yield: 1.01 g, 64%. 1H NMR (CDCl3) δ: 7.30-7.15 (4H, m), 7.00 (1H, s), 6.85 (1H, d, J=7.9 Hz), 6.49 (1H, d, J=7.9 Hz), 4.0 (1H, br), 3.73 (1H, d, J=8.1 Hz), 3.49 (1H, dd, J=16.1, 8.2 Hz), 3.16 (1H, d, J=16.1 Hz), 2.79 (1H, septet, J=6.8 Hz), 1.61 (3H, s), 1.19 (6H, d, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].C([Li])CCC.[C:20]([O:24][C:25](=[O:47])[NH:26][C@:27]([CH:45]=O)([CH3:44])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1)([CH3:23])([CH3:22])[CH3:21].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:45]/[C@@:27]([NH:26][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:47])([CH3:44])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1)[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCCCCOc1ccc(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@](C)(/C=C/C(=O)OCC)NC(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (diethoxy-phosphoryl)-acetic acid ethyl ester (429 mg, 1.92 mMol) in dry THF (7 ml) is added n-butyllithium (0.66 ml, 2.5M in hexane, 1.66 mMol) at −78° C. The mixture was stirred at −78° C. for 1 hour. After that time, a solution of [(R)-1-formyl-3-(4-heptyloxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (500 mg, 1.28 mMol) in THF (4 ml) is added and stirring is continued at −78° C. for 1.5 hours. The mixture is allowed to warm to RT and then stirred at RT for 2 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution) and the aqueous phase is extracted twice with AcOEt. The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 4% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Yield: 97.4 %

Procedure:
A mixture of 2-fluoro-4-nitrophenol (15 gr, 95.5 mmol) and benzyl bromide (18 g, 105 mmol) in acetone (125 ml) containing potassium carbonate (26.5 gr, 190 mmol) was heated at reflux for 2 hours. The volatiles were removed and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The solid was triturated with petroleum ether to give 2-fluoro-4-nitro-benzyloxybenzene (23 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[N:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:45](=[O:46])[O:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:7]=3)=[CH:10][CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.25 g, 0.6 mmol) in DCM (20 mL) was added pyridine (0.65 mL, 6 mmol). The suspension was cooled to 0° C., followed by slowly addition of a solution of phenylcarbonochloridate (98 mg, 0.63 mmol) in DCM (5 mL). The reaction was stirred at rt for 2 hours, diluted with DCM (20 mL), and then washed with water (25 mL×2), followed by washing with brine (25 mL). The organic solution was dried over anhydrous Na2SO4, then concentrated in vacuo, and the residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a white solid (134 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[N+:16]([O-])=O.CO.C([O-])=O.[NH4+]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]([F:13])([F:15])[F:14])=[CH:5][C:4]=1[NH2:16]
Reactant: COc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(N)cc(C(F)(F)F)cc1N
Yield: 92 %

Procedure:
2-Methoxy-1,3-dinitro-5-trifluoromethylbenzene (3.0 g, 11.3 mmol) was dissolved in 100 mL 50:50 EtOAc:MeOH. Ammonium formate (7.06 g, 112 mmol) was added followed by palladium-on-carbon catalyst (1.0 g). The reaction was heated to a gentle reflux for 45 min, then allowed to cool, and filtered through a plug of diatomaceous earth. The calalyst was washed with EtOAc repeatedly, and the filtrate was in vacuo. The residue was taken up in 500 ml 50% EtOAc in hexanes and filtered through a short plug of silica gel. The filtrate was concentrated in vacuo, providing 2.15 g (10.4 mmol, 95%) of 2-methoxy-5-trifluoromethyl-benzene-1,3-diamine as a brown oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](OB(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[F:22].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:17][C:16]=1[F:22]
Reactant: CCCc1ccc(OB(O)O)cc1
Reactant: Fc1cc(I)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CCCc1ccc(-c2ccc(Br)c(F)c2)cc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 16.5 g of 4-propylphenylboric acid as dissolved in 130 ml of ethanol was dropwise added to a mixture comprising 30 g of 1-bromo-2-fluoro-4-iodobenzene, 1.6 g of tetrakistriphenylphosphine palladium(O), 186 ml of benzene and 140 ml of 2M aqueous sodium carbonate solution, in nitrogen atmosphere at room temperature. The reaction solution was then refluxed for 5 hours, cooled to room temperature, extracted with chloroform and washed three times with water, and chloroform was removed by distillation. The residue formed was distilled under reduced pressure (b.p. 155° to 170° C./3 mmHg) to obtain 11.7 g of 4-bromo-3-fluoro-4'-propylbiphenyl.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
To a slurry of 215.1 g of 2.4-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 196.2 g of morpholine. Next 76.5 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and slowly poured into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and dried to yield 231.7 g of N-(2,4-dinitrobenzoyl)morpholine, mp 159°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]1.N1C=CC=CC=1.[C:30](Cl)(=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:22][C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]1
Reactant: CC(C)CC(=O)Cl
Reactant: COC1CN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CN(CCOc2ccc(NC(=O)CC(C)C)cc2-c2c(Br)cnn2C)C1
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine (40.3 mg, 0.107 mmol) and pyridine (35 μL) in CH2Cl2 (2 mL) was added isovaleryl chloride (15 μL, 0.122) and stirred for two hours. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a white solid (36.0 mg, 73%). LCMS m/z (%)=465 (M+H 79Br, 75), 467 (M+H 81Br, 90). 1H NMR (400 MHz, DMSO-d6) δ: 10.00 (bs, 1H), 7.69 (dd, J=8.99, 2.65 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J=2.63 Hz, 1H), 7.09 (d, J=9.06 Hz, 1H), 4.03-3.86 (m, 2H), 3.82 (quint, J=5.76 Hz, 1H), 3.65 (s, 3H), 3.35-3.28 (m, 1H), 3.24-3.17 (m, 1H), 3.08 (s, 3H), 2.73-2.55 (m, 41H), 2.16 (d, J=6.96 Hz, 2H), 2.12-2.00 (m, 1H), 0.92 (d, J=6.55 Hz, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)S(=O)(=O)c1ccccc1Cl
Yield: 35.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-chlorobenzene-1-sulfonyl chloride (79 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil (Yield: 35%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: Nc1ccccc1N1CCCCC1
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc([N+](=O)[O-])o1
Yield: 100 %

Procedure:
The compound was prepared according to the procedure described in Example 2 from 5-nitro-furan-2-carbonyl chloride and 2-piperidinoaniline. Yield: 100%. MS: 316 (M+1). LC/MS purity: 100%. 1HNMR (CDCl3, 300 MHz): δ 8.2 (d, 1H), 7.85 (d, 1H), 7.55 (m, 1H), 7.4 (m, 3H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 6H).