Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1nccc(C2CC2)n1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
2,4-Dichloropyrimidine (15 g, 101 mmol), cyclopropylboronic acid (8.65 g, 101 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.22 g, 10.07 mmol), and potassium phosphate (53.4 g, 252 mmol) were combined in a 1 L round-bottom flask. THF (503 mL) was added and the suspension was heated to reflux with stifling overnight. The reaction was then cooled to room temperature, concentrated to ˜100 mL under reduced pressure, extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes to give 2-chloro-4-cyclopropylpyrimidine (10.124 g, 58.3 mmol, 57.9%) as an 89:11 mixture of regioisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:29])[C:27]#[CH:28]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:29][CH2:26][C:27]#[CH:28])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C#CCN
Solvent: c1ccccc1
Product: C#CCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), propargylamine (0.180 g, 3.27 mmol), and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from chloroform/hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propargyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.366 g, 31.8% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:28]([O-])([N+]([O-])=O)=[O:29]>>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CCCN1CCOCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CCCN1CCOCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 54.7 %

Procedure:
4.1 g of 1-(2-chloroethyl)-3-(3-morpholinopropyl)-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.4 g of 1-(2-chloroethyl)-1-nitroso-3-(3-morpholinopropyl)-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: ClCCl.[CH2:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][C@@H:20](O)[C@H:19]([O:23][CH2:24][O:25][CH3:26])[CH2:18]2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(S(F)(F)[F:33])CC)C>O>[CH2:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:21][C@H:20]([F:33])[C@H:19]([O:23][CH2:24][O:25][CH3:26])[CH2:18]2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COCO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@@H]1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 ml of a dichloromethane solution of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridine was added dropwise into a solution of 10 ml of dichloromethane containing 278 μl of diethylaminosulfur trifluoride at −78° C. over 10 minutes. After stirring at room temperature for one hour, it was heated under stirring at 40° C. for one hour. After cooling as it was, the reaction solution was poured into water. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (2:1), to give 56.7 mg of 2-benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]pyridine (1H-NMR (CDCl3) δ=3.38 (3H, s), 3.65-3.82 (4H, m), 3.97 (2H, s), 4.41-4.43 (1H, m), 4.69-4.75 (2H, m), 5.18 (1H, br.d, J=49 Hz), 6.18 (1H, d, J=8 Hz), 6.38 (1H, d, J=7 Hz), 7.01-7.36 (6H, m)) and 294 mg of a crude refined product of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine. This crude purified product was purified by a thin layer chromatography (developed three timed using hexane/ethyl acetate (5/1) and three times using hexane/ethyl acetate (4/1)), to give 47.8 g of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine (1H-NMR (CDCl3) δ=3.48 (3H, s), 3.54-3.73 (4H, m), 3.97 (2H, s), 4.00-4.04 (1H, m), 4.41-4.46 (1H, m), 5.41 (2H, d, J=56 Hz), 6.15 (1H, d, J=8 Hz), 6.37 (1H, d, J=7 Hz), 7.17-7.35 (6H, m)).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[OH-:32].[Na+].Cl>CN1CCN(C)C1=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1[OH:32])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(CO)nn(C)c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(CO)nn(C)c1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.58 g, 5.85 mmol) in 1,3-dimethylimidazolidinone (30 ml) was added 2N aqueous sodium hydroxide solution (15 ml), and stirred at 70° C. for 12 hours. After cooling to room temperature, 2N hydrochloric acid (25 ml) was added, and extracted with ethyl acetate 2 times. The combined organic layer was washed with water 2 times, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:2) to give 842 mg of Compound (I-24-1) (yield: 47%) as solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[C:24]([C:25]([N:27]3[C@H:36]([CH3:37])[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28]3)=[O:26])=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)=[CH:14][C:13]([C:38]([N:40]([C:47]2[CH:52]=[CH:51][C:50]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])=[CH:49][CH:48]=2)[C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)=[O:39])=[C:12]1[CH3:61])C1C=CC=CC=1>CO.[Pd]>[Si:54]([O:53][C:50]1[CH:49]=[CH:48][C:47]([N:40]([C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)[C:38]([C:13]2[CH:14]=[C:15]([C:16]3[C:24]([C:25]([N:27]4[C@H:36]([CH3:37])[CH2:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28]4)=[O:26])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[N:11]([CH2:10][CH2:9][OH:8])[C:12]=2[CH3:61])=[O:39])=[CH:52][CH:51]=1)([C:57]([CH3:58])([CH3:60])[CH3:59])([CH3:56])[CH3:55]
Reactant: Cc1c(C(=O)N(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2cnn(C)c2)cc(-c2cc3c(cc2C(=O)N2Cc4ccccc4C[C@H]2C)OCO3)n1CCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)N(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2cnn(C)c2)cc(-c2cc3c(cc2C(=O)N2Cc4ccccc4C[C@H]2C)OCO3)n1CCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6.86 g (8.19 mmol) of the compound of Step A in 70 mL of anhydrous methanol there are added 1.37 g of Pd/C 10%. The batch is degassed for 0.5 hours and then stirred at ambient temperature under dihydrogen pressure (1.5 bar) for 12 hours. The reaction mixture is then filtered and then concentrated to dryness. The expected product is obtained in the form of a solid.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:17][CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=O>>[CH3:29][O:28][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:9]1[CH2:10][CH2:5][CH:30]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:7][CH2:8]1)[N:9]=[CH:8][C:7]([C:12]#[N:13])=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1
Reactant: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)cc3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.37 mmol) of 7-fluoro-6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]-quinoline-3-carbonitrile, 287 mg (1.86 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 107 mg of 6-methoxy-4-[4-(pyridin-2-ylsulfanyl)-phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 182-184° C.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:24]([OH:26])=[O:25])[C:12](=[O:23])[C:13]3[CH:14]=[CH:15][C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:7]([C:8]=32)[O:6][CH2:5]1>O>[CH3:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:24]([O-:26])=[O:25])[C:12](=[O:23])[C:13]3[CH:14]=[CH:15][C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:7]([C:8]=32)[O:6][CH2:5]1.[Na+:2]
Reactant: CC1COc2c(-c3ccccc3)ccc3c(=O)c(C(=O)O)cn1c23
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1COc2c(-c3ccccc3)ccc3c(=O)c(C(=O)[O-])cn1c23

Procedure:
To a solution of 0.0997 g of sodium hydroxide in 40 ml of water was added 0.8 g of 2,3-dihydro-3-methyl-7-oxo-10-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. The mixture was heated briefly until the carboxylic acid dissolved. The solution was then filtered and the filtrate obtained was then evaporated to provide a residue. The residue was dissolved in 50 ml of water, the solution filtered and the filtrate was lyophilized to provide light tan solid, sodium 2,3-dihydro-3-methyl-7-oxo-10-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate, m.p. 236° C. (dec.). Analysis: Calculated for C19H14NNaO4.1.5H2O: %C, 61.6; %H, 4.6; %N, 3.8; Found: %C, 61.4; %H, 4.3; %N, 3.6. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.Cl[C:57]([O:59][CH:60]([CH3:62])[CH3:61])=[O:58].ClC([O-])=O>>[CH:60]([O:59][C:57]([N:26]1[C@H:25]([C:23](=[O:24])[NH:22][C@H:6]([C:5]([OH:4])=[O:55])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=3[CH3:21])=[CH:10][CH:9]=2)[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27]1)=[O:58])([CH3:62])[CH3:61]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Agent: O=C([O-])Cl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)OC(C)C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was reacted with isopropyl chloroformate according to General Procedure G (with excess of chloroformate). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (7 mg). LCMS (m/z): 825.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:35]=[N-:36]
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Methyl 3-amino-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)-isonicotinate (1.00 g, 2.44 mmol) was dissolved in trifluoroacetic acid (12 mL) and the yellow solution was cooled in an ice bath. Powdered sodium nitrite (0.336 gm, 4.87 mmol) was added with stirring to give a dark red mixture. After 30 min, powdered sodium azide (1.59 g, 24.4 mmol) was added followed by diethyl ether (12 mL). The light red mixture was stirred in the ice bath for 30 min. The reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was washed with brine, dried with sodium sulfate, and the solvent removed. Flash silica gel chromatography (elution with a 1:1 mixture of methylene chloride and EtOAc) afforded methyl 3-azido-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)isonicotinate (1.06 gm). 1H NMR (CDCl3) δ ppm 8.17 (2H, d, J=7.93 Hz), 8.01 (1H, s), 7.91 (2H, d, J=7.93 Hz), 7.82-7.88 (1H, m), 7.79 (1H, d, J=8.55 Hz), 7.04 (1H, t, J=8.55 Hz), 4.05 (3H, s), 3.96 (3H, s), 3.94 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH2:12][OH:13])=[CH:9][N:8]([C@@H:14]3[O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[C@@H:17]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[C@@:15]3([CH3:41])[OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:62]1[C:66](=[O:67])[C:65]2=[CH:68][CH:69]=[CH:70][CH:71]=[C:64]2[C:63]1=[O:72].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH2:12][O:13][N:62]3[C:63](=[O:72])[C:64]4=[CH:71][CH:70]=[CH:69][CH:68]=[C:65]4[C:66]3=[O:67])=[CH:9][N:8]([C@@H:14]3[O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[C@@H:17]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[C@@:15]3([CH3:41])[OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(CCO)c2c(Cl)ncnc21
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(CCON2C(=O)c3ccccc3C2=O)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of the compound 2.6 (359.0 mg, 0.54 mmol) in THF (10 mL) were added triphenylphosphine (215.0 mg, 0.82 mmol) and N-hydroxyphthalimide (132.0 mg, 0.0.81 mmol) followed by diethylazodicarboxylate (DEAD) (153 μL, 0.88 mmol), and the solution was stirred overnight at room temperature. The reaction mixture was diluted by adding 10 mL of CH2Cl2 and 10 mL of water. The aqueous layer was extracted three times with CH2Cl2, dried over Na2SO4, filtered and evaporated. The product was purified by flash column chromatography using 15-20% EtOAc in hexanes as eluent gave the desired compound 2.7 (369 mg, 85%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=1.FC(F)(F)C(=O)CC(C1C=CC=CC=1OC)=O.Cl.NO>C(O)C>[F:17][C:14]([F:15])([F:16])[C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[O:13][N:12]=1
Reactant: COc1ccccc1-c1cc(C(F)(F)F)no1
Agent: COc1ccccc1C(=O)CC(=O)C(F)(F)F
Agent: Cl
Agent: NO
Solvent: CCO
Product: Oc1ccccc1-c1cc(C(F)(F)F)no1
Temperature: 25 °C

Procedure:
Synthesis of 5-(2-methoxyphenyl)-3-(trifluoromethyl)-1,2-oxazole (C10) A mixture of 4,4,4-trifluoro-1-(2-methoxyphenyl)butane-1,3-dione (C9) (933 mg, 3.79 mmol) and hydroxylamine hydrochloride (798 mg, 11.4 mmol) in ethanol (10 mL) was refluxed under nitrogen for 3 hours, then cooled to room temperature. The reaction was concentrated in vacuo, treated with water (30 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptanes) afforded the title compound as a yellow oil. Yield: 502 mg, 2.06 mmol, 54%. GCMS m/z 243 (M+). 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 3H), 7.01 (s, 1H), 7.05 (dd, J=8.4, 0.9 Hz, 1H), 7.11 (ddd, J=7.8, 7.4, 1.1 Hz, 1H), 7.48 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.7 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:23])[O:4][C:5]1[CH:6]=[C:7]([OH:22])[CH:8]=[C:9]([C:11]2[NH:12][C:13]([C:16]3[O:17][C@@H:18]([CH3:21])[CH2:19][N:20]=3)=[CH:14][CH:15]=2)[CH:10]=1.F[C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][C@@H:18]1[O:17][C:16]([C:13]2[NH:12][C:11]([C:9]3[CH:10]=[C:5]([CH:6]=[C:7]([O:22][C:25]4[CH:30]=[CH:29][C:28]([S:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)(=[O:32])=[O:33])=[CH:27][CH:26]=4)[CH:8]=3)[O:4][C@@H:3]([CH3:23])[CH2:2][OH:1])=[CH:15][CH:14]=2)=[N:20][CH2:19]1
Reactant: C[C@H]1CN=C(c2ccc(-c3cc(O)cc(O[C@@H](C)CO)c3)[nH]2)O1
Reactant: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(S(=O)(=O)N5CCN(C)CC5)cc4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.13 mmol) synthesized in Example (117a) and 1-[(4-fluorophenyl)sulfonyl]-4-methylpiperazine (49 mg, 0.19 mmol) synthesized in Example (116a) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (52 mg, 0.38 mmol) was added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out twice with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (17 mg, yield 25%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:13])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=1
Reactant: BrBr
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a stirred solution of 3-tert-butylsalicylaldehyde (5.13 g, 28.8 mmol) in acetic acid (15 mL) was added a solution of bromine (1.65 mL, 32.25 mmol) in acetic acid (7.0 mL) dropwise within 20 min. The reaction mixture was stirred at room temperature for 3 h. Analytical HPLC analysis after 3 h shows the desired product ˜72% and the unreacted starting material ˜28%. A second batch of bromine (0.5 mL) in acetic acid (3 mL) was added and the reaction mixture was stirred at room temperature for another 3 h. Analytical HPLC analysis of the reaction mixture after 3 h (6 h total) shows the desired product ˜85% and still shows the starting material ˜15%. After 6 h of stifling, the reaction mixture was diluted with dichloromethane (50 mL) and the organic layer was washed with 39% sodium bisulfite solution (1×10 mL), water, saturated NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the desired product as a pale yellow crystalline solid (7.2421 g). Purification by silica-gel flash chromatography on silica gel column and elution with 0-5% ethyl acetate in n-heptane afforded the desired product as a pale yellow crystalline solid (4.792 g, 64% yield). LC-MS analysis of the product in negative mode shows the desired product's mass: m/z 255 (79BrM+−H) and m/z 257 (81BrM+−H). GC-MS analysis of the product in CI mode (Methane) shows the desired product's mass: m/z 256 (91BrM+) and m/z 258 (81BrM+), calc'd. for C11H13BrO2: 257.124. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H, t-Bu-), 7.50 (s, 1H, H-4), 7.56 (s, 1H, H-6), 9.79 (s, 1H, —CHO), 11.70 (s, 1H, —OH). 1H NMR of the isolated product was identical with that of a previously reported sample of the product (Girsch et al., 2007).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)([O-])=O.[H][H]>C(O)C.ClCCl.[Pd].CCCCCCC>[NH2:1][C:4]1[CH:5]=[C:6]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:7]([OH:14])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Yield: 50 %

Procedure:
In a 250 ml Parr flask, 3.6 g (14 mmoles) of 4-nitro-2,6-bis-(1,1-dimethylethyl)-phenol (J. Org; Chem. (1968), 33 (1), 223-226) is dissolved in 60 ml of a (2/1) mixture of ethanol and dichloromethane in the presence of a catalytic quantity of 10% Pd/C. The mixture is agitated for 2 hours, at 20° C., under 20 PSI of hydrogen. After filtration on celite, the filtrate is concentrated to dryness under reduced pressure. The reddish-brown powder obtained is suspended in heptane (30 ml), filtered and rinsed with the same volume of heptane. The expected product is obtained in the form of an salmon pink powder with a yield of 50% (1.56 g). Melting point: 123-124° C.