Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(N(C)C)=O.O.C([SiH](CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C#Cc2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 70 °C
Yield: 88.1 %

Procedure:
To a vessel N-(4-((3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)ethynyl)phenyl)methanesulfonamide (6) (5.00 g; 10.69 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.375 g; 5.35 mmol) are charged and the vessel is purged with nitrogen. Nitrogen purged dimethylacetamide (20 ml) and water (0.578 g, 32.1 mmol) are charged to the vessel and the mixture was heated to 70° C. Triethylsilane (2.49 g, 21.4 mmol) was charged over 2 hours at a temperature of 70° C. The mixture was heated at 70° C. for approximately 5 hours and cooled to ambient temperature. The mixture was diluted with tetrahydrofuran (40 g) and extracted with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution. The solids which formed were removed by filtration and washed with tetrahydrofuran (18 g). The aqueous layer was extracted with tetrahydrofuran (18 g). The combined tetrahydrofuran extracts were washed successively with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution and a 2.5% NaHCO3/7% NaCl solution. Methanol (28 g) was charged and the solution concentrated to 28 g. Methanol (28 g) was charged and the product was allowed to crystallize. Methanol (28 g) was charged and the slurry was concentrated to 45 g. Methanol (60 g) was charged and the mixture concentrated to 75 g. The slurry was heated to 60° C. for 30 minutes and then cooled to ambient temperature. The solids were isolated by filtration, washed with methanol (2×8 gm) and vacuum dried at 50° C. to provide 4.42 g of the titled compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (s, 9 H) 2.99 (s, 3 H) 3.76 (s, 3 H) 5.62 (d, J=7.82 Hz, 1 H) 7.12-7.29 (m, 5 H) 7.51-7.65 (m, 3 H) 7.72 (d, J=7.82 Hz, 1 H) 9.83 (s, 1 H) 11.39 (s, 1 H). MS (APCI) m/e 470.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Li+].CC([N-]C(C)C)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH:6]1[CH2:5][CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1=[O:1])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-oxopyrrolidine-1-carboxylate (10 g, 54.0 mmol) was dissolved in THF (75 mL) and cooled to −78° C. LDA (1.8 M in THF/heptane, 30.0 mL, 54.0 mmol) was added and the solution was stirred for 1 h. Ethyl 2-bromoacetate (9.02 g, 54.0 mmol) was added and the mixture was stirred for 1 h and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted two times with EtOAc and the combined extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide partially purified tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate (4.72 g, 17.40 mmol) was dissolved in EtOH (30 mL) and TFA (10 mL). The reaction was stirred at room temperature for 2 h and 20 mL of TFA was added. After stirring for an additional 2 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to provide the title compound (1.77 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.2 Hz, 3H), 1.81-1.93 (m, 1H), 2.35-2.49 (m, 2H), 2.75-2.85 (m, 1H), 2.88 (dd, J=16.4, 3.9 Hz, 1H), 3.31-3.40 (m, 2H), 4.09-4.21 (m, 2H), 5.96 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[OH:25]CCNN>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][OH:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NNCCO
Product: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 0.5 h

Procedure:
Compound 7 was synthesised following similar procedures outlined in Example 31 (Compound 18), using 2-hydroxyethyl hydrazine instead of ethyl hydrazine in Step 3. As a slightly modified procedure, Step 3 was performed at 90° C. for 30 min in the microwave. The crude residue was purified by column chromatography (silica gel, gradient 10 to 50% ethyl acetate/isohexane), yielding Compound 7 as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(C(=O)O)c1
Yield: 102.3 %

Procedure:
111 g of 2-fluoro-5-nitrobenzoic acid was dissolved in 1 liter of ethyl acetate. To this solution was added 5 g of 5 percent palladium on charcoal. The mixture was hydrogenated on a Parr apparatus for 24 hours at 20° C. at 50 psi of hydrogen. The theoretical amount of hydrogen was absorbed. The solution was filtered, then evaporated to dryness to provide a tan residue of 95.2 g of 5-amino-2-fluorobenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:25][O:24]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>C(O)C>[CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][NH2:27])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCc1ccc(OCC2CO2)cc1)OCc1ccccc1
Reactant: N
Solvent: CCO
Product: NCC(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
An ethanol solution of 39 (9.86 g, 2.42 mmol) was saturated with ammonia and stirred overnight at room temperature. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 40 (0.75 g, 87%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.40 (m, 2H), 1.51 (m, 2H), 2.50 (m, 2H), 2.58 (m, 1H), 2.68 (m, 1H), 3.00 (m, 2H), 3.69 (m, 1H), 3.80 (m, 1H), 3.90 (m, 1H), 5.08 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.35 (br s, 5H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.C(#[N+][O-])C1C=CC=NC=1.[CH3:19][Si:20]([CH3:28])([CH3:27])[C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:19][Si:20]([CH3:28])([CH3:27])[C:21]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][O:9][C:22]=1[Si:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: ON=Cc1cccnc1
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: [O-][N+]#Cc1cccnc1
Product: C[Si](C)(C)c1onc(-c2cccnc2)c1[Si](C)(C)C

Procedure:
Commercially available 3-pyridinealdoxime (61) is converted to its chlorohydroxyimino derivative (US 2004/0157900) which is converted to nicotinonitrile oxide (Tetrahedron, 61, 2005, 4363-4371) “in situ” and reacted with 1,2-bis-trimethylsilanyl-ethyne (Chem. Ber., 107, 1974, 3717-3722) to afford the 1,3-dipolar cycloaddition product 3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62). Halogen-induced ipso desilylation resulted in the 4-bromo-5-trimethylsilanyl derivative (63). Subsequent desilylation with NH4OH (Chem. Ber., 112, 1979, 2829-2836) generates 3-(4-bromo-isoxazol-3-yl)-pyridine (64).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8]CC(N(C)C)=O)=[O:7])=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:3]=1.CO.O[Li].O.Cl>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:3]=1
Reactant: CN(C)C(=O)COC(=O)c1ccc(Cl)cc1OCC(=O)N(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Yield: 159.6 %

Procedure:
The product from step (v) (1.0 g) was dissolved in a 2:1 water: methanol mixture (15 ml) and LiOH.H2O added. After 2 hours 2M aqueous HCl solution and ethyl acetate were added, the organic phase separated, dried and concentrated to give the sub-titled product as a solid (1.2 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N+:18]([O-])([OH:20])=[O:19]>ClCCl.C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:8]([CH:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
The aforementioned J. Med. Chem., 44, 3965 (2001) further describes a process for preparing a 4-alkoxy-5-halogenoalkoxy-2-nitrobenzoic acid compound from a 4-alkoxy-3-hydroxybenzoic acid compound. For example, methyl 3-hydroxy-4-methoxybenzoate is reacted with 3-chloropropyl p-toluenesulfonate in an aqueous potassium carbonate solution in the presence of tricaprylmethyl ammonium chloride to produce methyl 3-(3-chloropropoxy)-4-methoxybenzoate, and the methyl 3-(3-chloropropoxy)-4-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate in 61% yield (based on the amount of methyl 3-hydroxy-4-methoxybenzoate).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][CH:39]([S:48][C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][C:41]1[O:42][CH2:43][C:44]([CH3:47])([CH3:46])[N:45]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.O>[OH:36][CH2:37][CH2:38][CH:39]([S:48][C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][C:41]1[O:42][CH2:43][C:44]([CH3:47])([CH3:46])[N:45]=1
Reactant: CC1(C)COC(CC(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Sc2cc3ccccc3[nH]2)=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(CC(CCO)Sc2cc3ccccc3[nH]2)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
1 ml of a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran was added to a solution of 460 mg of 2-[4-tert-butyldiphenylsilyloxy-2-(indol-2-ylthio)butyl]-4,4-dimethyl-2-oxazoline [prepared as described in Example 78b)] in 20 ml of tetrahydrofuran, with stirring, at room temperature, and stirring was continued at this temperature for 30 minutes. After this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a mixture of 60% v/v ethyl acetate in hexane as the eluent, to afford 165 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.C([O:40][C:41]([N:43]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=O)(C)(C)C.[C:50](Cl)(=O)C>>[C:41]([N:43]1[CH2:49][CH2:48][CH2:47][N:46]([C:17]2[CH:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]4[CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=[C:3]([C:2]([F:35])([F:1])[F:34])[CH:4]=4)[CH2:8][CH2:9][O:10][C:11]=3[N:18]=2)[CH2:45][CH2:44]1)(=[O:40])[CH3:50]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCCN(c2cc(-c3ccccc3C)c3c(n2)OCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 11 %

Procedure:
In a similar manner to Example 6, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (compound of Reference Erxample 17; 51.5 mg) was reacted with 1-(t-butoxycarbonyl)homopiperazine (50.1 mg) and acetyl chloride (0.1 mL) to obtain 8-(4-acetylhomopiperazine-1-yl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.7 mg, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)=[CH:34][N:33]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)=[CH:34][N:33]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2csc(C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.48 g), tetrahydrofuran (12 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.44 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 181-182° C.
Reaction SMILES: [CH3:1][Mg]Cl.[NH2:4][C:5]1[C:14](C)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](OC)=O.CC[O:18][CH2:19][CH3:20]>C1COCC1>[NH2:4][C:5]1[C:6]([CH3:7])=[CH:11][CH:12]=[CH:13][C:14]=1[C:19]([CH3:20])([CH3:1])[OH:18]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: CCOCC
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(C)(C)O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 ml of a 3 M solution of methyl magnesium chloride in 130 ml of THF was added drop-by-drop to a stirred solution of 11 g of 49A in 70 ml of dry ether at 0°-5° C. in a nitrogen atmosphere. The resulting mixture was allowed to warm to room temperature and stirred at reflux (40° C.) for 5 hours and held overnight at room temperature. The mixture then was quenched in a mixture of 48 g of ammonium chloride and 350 g of ice. 30 ml of 3 N hydrochloric acid was added, the solvents were evaporated, and the residue was extracted with ether. The extract phase was washed with water, then brine, dried (K2CO3), filtered and stripped of solvent. The residue was recrystallized from hexane to give (2-amino-3-methylphenyl)dimethylcarbinol (49B), as colorless needles, m.p.: 78°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[Br:12][C:13]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Br:33])[C:14]=1[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:12][C:13]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([Br:33])[C:14]=1[CH2:15][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:11]
Reactant: COc1ccc(CNCc2c(Br)cc([N+](=O)[O-])cc2Br)cc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: COc1ccc(CN(Cc2c(Br)cc([N+](=O)[O-])cc2Br)C(=O)Nc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-dichlorophenylisocyanate (1.54 g, 8.18 mmol) was added under nitrogen to a solution of N-(2,6-dibromo-4-nitrobenzyl)-N-(-4-methoxybenzyl)amine (3.35 g, 7.79 mmol) in CH2Cl2 (95 mL). The resulting mixture was stirred at rt for ca. 3 h. The reaction mixture was then concentrated under reduced pressure to yield N-(2,6-dibromo-4-nitrobenzyl)-N′-(2,6-dichlorophenyl)-N-(4-methoxybenzyl)urea as a yellow solid. Mass spectrum (ESI) 616 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[CH3:16][S:17]SC>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([S:17][CH3:16])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CSSC
Reactant: COc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-2-fluoroanisole (5.0 g, 24.4 mmol) in THF (100 mL) was added n-butyllithium (23 mL, 1.6M in hexanes, 36.8 mmol) at −78° C. After stirring at −78° C. for 1 h, dimethyl disulfide (11 mL, 12.2 mmol) was added and the reaction was then allowed to warm to room temperature slowly. After stirring at room temperature for 12 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. The residue was used directly in next step.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12](Br)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1C2C(=CC=CC=2)C=C[CH:16]=1>>[C:1]([C:9]1[S:13][C:12]([C:16]#[N:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2ncccc2c1
Reactant: O=C(c1ccccc1)c1ccc(Br)s1
Product: N#Cc1ccc(C(=O)c2ccccc2)s1
Temperature: 25 °C

Procedure:
5-Benzoyl-2-bromothiophene (8 g., 30 mmoles) and cuprous cyanide (3.2 g., 36 mmoles) were combined in 75 ml. of quinoline and refluxed for 3 hours. The reaction mixture was cooled to room temperature and solids removed by filtration with 15 ml. of quinoline and 15 ml. of water wash. The combined filtrate and washings were poured into approximately 300 g. of ice, acidified with conc. hydrochloric acid and product extracted into 300 ml. of ether. The ether extract was back-washed with 150 ml. of water, filtered from insolubles and concentrated to yield solid 5-benzoyl-2-cyanothiophene (5.7 g., m.p. 85°-89° C., m/e 213).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].[O-:14][Mn](=O)(=O)=O.[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:14])=[O:6]
Reactant: CCCOc1ccc(C=O)cc1Br
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCOc1ccc(C(=O)O)cc1Br

Procedure:
3-Bromo-4-propoxybenzaldehyde was oxidized by KMnO4, according to the procedure as described in Example 47, Step A, to give the title compound in 96%, as white solid. 1H-NMR (DMSO-d6) 0.98 (t, 3H, J=7.32 Hz); 1.68-1.79 (m, 2H); 4.06 (t, 2H, J=6.39 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.87 (dd, 1H, J=2.07, 8.61 Hz); 8.01 (d, 1H, J=2.04 Hz); 11.2 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.C(O)=[O:28]>>[NH2:1][C:2]1[C:7]([CH:8]=[O:28])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C#N
Reactant: O=CO
Product: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C=O
Temperature: 25 °C
Yield: 36 %

Procedure:
To a suspension of Example 176 (73 mg, 0.2 mmol) in HCOOH (5 ml, 98%) was added AlNi3 (84 mg, 0.6 mmol). The mixture was refluxed for overnight and filtered after cooled down to r.t. The filtrate was concentrated and the remainder was purified on HPLC (10 mM ammonium acetate, 5% acetonitrile in H2O/CH3CN) to yield the titled compound (25 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.20 (t, J=6.44 Hz, 1H) 8.46 (s, 1H), 7.95 (s, 1H), 7.88 (d, J=8.48 Hz, 1H), 7.55 (d, J=8.48 Hz, 2H), 7.08 (s, 1H) 4.57 (d, J=8.48 Hz, 2H), 4.54 (d, J=6.44 Hz, 2H), 3.18 (s, 3H), 1.35 (q, J=6.44 Hz, 3H); MS (APCI) m/z 378 [M+H]+, 376 [M−H]−.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOC(C)=O.O>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)NCCCCCl
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCN(C(=O)OC(C)(C)C)C(C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.9 %

Procedure:
Metallic sodium (0.28 g, 0.012 mol) is dissolved in absolute ethyl alcohol (EtOH) (9 ml) under nitrogen atmosphere. The mixture is heated to 60° C. and diethyl malonate (3.8 g, 0.024 mol) is then dripped therein. N-tert-butoxycarbonyl-4-chloro-butylamine (2.5 g, 0.012 mol) is then gradually added, at room temperature, to the resulting solution. The reaction mixture is stirred at room temperature for 2 hours and at the reflux temperature for 6 hours, and then poured into a mixture AcOEt/water (100 ml 1/1 v/v). The organic phase which is separated is then washed repeatedly with water and dried over MgSO4The solvent is removed under vacuum at 100° C. affording a crude oily product which is purified by reverse-phase HPLC on an RP-18 column eluting with an aqueous phase modified with CH3CN (45% by volume). The desired compound (1.31 g) is thus obtained as a pure product.