Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:18][CH2:19][C:20]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=2[C:22](Cl)=[O:23])[CH:17]=1>[OH-].[Na+].C(OCC)C.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:18][CH2:19][C:20]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([NH:10][C:8](=[NH:9])[S:7][CH3:6])=[O:23])[CH:17]=1
Reactant: CSC(=N)N
Reactant: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)NC(=N)SC
Reaction time: 3.5 h

Procedure:
A solution of 2-methyl-2-thiopseudourea sulfate (1.6 g, 5.75 mmol, 2.5 equiv) in 1N NaOH (10 mL) was cooled to 0° C. To this solution was added dropwise a solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluoro-benzoyl chloride (2.3 mmol, 1 equiv) in diethyl ether (4 mL). The solution-was allowed to stir for 3.5 hr and then diluted with H2O. The aqueous solution was extracted with dichloromethane and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give 1-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoyl}-2-methylisothiourea in quantitative yield. The crude product was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.2 Hz, 1H), 7.07-7.30 (m, 4H), 6.68 (d, J=8.1 Hz, 1H), 3.73 (s, 3H), 3.27-3.33 (m, 2H), 2.84-2.90 (m, 2H), and 2.52 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:3]([F:24])=[C:4]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(N)c1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(NC(C)=O)c1F

Procedure:
In analogy to example 87.2 (RS)-2-(3-amino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 30.5) was reacted with acetyl chloride to give (RS)-2-(3-acetylamino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide as white foam.
Reaction SMILES: N.[Li].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15]CC2C=CC=CC=2)[CH2:12][C@H:11]1[CH2:23][O:24][CH3:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(C)(C)C>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]1[CH2:23][O:24][CH3:25])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
In a flask purged with ammonia gas, about 40 mL of liquid ammonia is collected with ammonia condenser at −78° C. To the liquid ammonia is added portionwise lithium metal (46 mmol; 320 mg) at the same temperature. To the deep blue solution is added a solution of (2S,4R)-4-benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (9.2 mmol; 3.1 g) and tert-butanol (18.4 mmol; 1.36 g) in THF (15 mL). After stirring for 2 hours, the reaction mixture is quenched with MeOH, and then warmed to ambient temperature. The mixture is diluted with water, and then aqueous 1M HCl is added to reach pH 8-9. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give (2S,4R)-4-hydroxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:9])=[CH:6][C:5]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:4][N:3]=1.O.[NH3:28]>C(O)(C)C>[NH2:28][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[O:9])=[CH:6][C:5]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:4][N:3]=1
Reactant: COc1cc(C(=O)c2cc(-c3nccs3)cnc2Cl)cc(OC)c1OC
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)c2cc(-c3nccs3)cnc2N)cc(OC)c1OC
Yield: 38.84 %

Procedure:
(2-Chloro-5-(thiazol-2-yl)pyridin-3-yl)(3,4,5-trimethoxyphenyl)methanone (65 mg, 0.16 mmol) as a starting material was dissolved in isopropyl alcohol (3 ml), and ammonia water (10 ml) was added thereto. The mixture was heated for 3 hours in a Steel Bomb. After completion of the reaction, the reaction mixture was vacuum concentrated, and extracted with dichloromethane (30 ml) and water (10 ml). The organic layer was washed with brine, and dried over anhydrous MgSO4. The solid substance filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/1) to obtain a desired yellow solid compound (24.0 mg, 38.84%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:2]1.[CH3:15][C:16]1([CH3:33])[O:20][CH:19]([CH2:21]OS(C2C=CC(Cl)=CC=2)(=O)=O)[CH2:18][O:17]1.CC(C)([O-])C.[Na+].O>O1CCOCC1>[CH3:15][C:16]1([CH3:33])[O:20][C@H:19]([CH2:21][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:2]2)[CH2:18][O:17]1
Reactant: CC1(C)OCC(COS(=O)(=O)c2ccc(Cl)cc2)O1
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)c3ccccc3)n2)O1
Temperature: 10 °C
Yield: 49.8 %

Procedure:
N-(1H-Pyrazol-3-yl)-benzamide (2.5 g, 20 mmol) and 4-Chloro-benzenesulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (6.75 g, 22 mmol) were dissolved in anhydrous 1,4-dioxane (30 ml). Sodium tert-butoxide (2.28 g, 23.8 mmol) was added in one portion at room temperature. The yellow suspension was heated to reflux with agitation for 23 hrs. The mixture was cooled to 10° C., water (80 ml) was added. The mixture was extracted with ethyl acetate (30 ml*2), the organic layer was washed with 1N NaOH (20 ml), 10% aqueous NaCl (40 ml*2). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give the crude product as oil. Purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (3 g), yield: 50%. 1H-NMR (400 MHz, d6-DMSO): δ 10.86 (s, 1H), 7.99-8.01 (d, 2H), 7.67 (s, 1H), 7.47-7.58 (m, 3H), 6.63 (s, 1H), 4.4-4.42 (m, 1H), 4.16-4.38 (m, 2H), 4.01-4.05 (m, 1H), 3.75-3.78 (m, 1H), 1.33 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH:7]=[CH:8]/[C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][CH:14]([OH:17])[CH2:15]3)[CH2:11][C@H:10]2[OH:18])=[CH:4][C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]1=2.[H][H]>C(OCC)(=O)C.[Pd]>[S:1]1[C:5]([C@H:6]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:7][CH2:8][C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][CH:14]([OH:17])[CH2:15]3)[CH2:11][C@H:10]2[OH:18])=[CH:4][C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]1=2
Reactant: [H][H]
Reactant: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@H](CC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(3aR,4R,5R,6aS)-4-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol (Example 2, Step E, 1 mol equivalent) is dissolved in ethyl acetate (0.05 M) under a nitrogen atmosphere. 10% Pd/C (10 mol %) is added and hydrogen gas is introduced. After stirring for several hours at room temperature the reaction mixture is filtered over Celite. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes (+0.4% acetic acid) to afford the title intermediate.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:30])([F:31])[F:17])=[CH:24][CH:23]=3)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=426.04.
Reaction SMILES: N1CCC([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)CC1.[OH-].[Na+].C(O[CH2:24][CH3:25])(=O)C>O>[CH2:8]([N:12]([CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[CH2:11][CH2:24][CH3:25])[CH3:7]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1csc(CC2CCNCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CC)Cc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-(4-piperidinylmethyl)-1,3-thiazole-4-carboxylate (19 g, 74 mmol) was added a solution of sodium hydroxide (3.6 g, 88.8 mmol) in water (250 ml). The resulting mixture was stirred at room temperature for 18 h, then ethyl acetate was added and the layers were separated. The aqueous phase was acidified with conc. H2SO4 and concentrated to give a brown solid. The solid was recrystallised from methanol/ethyl acetate, then again from DCM/methanol to give the title compound as a light brown solid (16 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[N:4]=1.[C-:41]#[N:42].[K+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=1)[N:4]=[C:3]2[CH2:2][C:41]#[N:42]
Reactant: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(CC#N)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Temperature: 25 °C
Yield: 67 %

Procedure:
In 1200 ml of dimethyl sulfoxide was suspended 165.0 g of 3-chloromethyl-5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazole, followed by stirring at room temperature. To the suspension was added 43.6 g of potassium cyanide, having been ground to powder in a mortar, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into 15000 ml of water with vigorous stirring, followed by stirring for 1 hour. A precipitated solid was collected, washed with three 1000 ml portions of water, and dissolved in 5000 ml of chloroform. The solution was dried over sodium sulfate, filtered, and the solvent was evaporated. Silica gel column chromatography (ethyl acetate) of the residue yielded 108.7 g of a pale brown solid, which was used in the next reaction as such.
Reaction SMILES: C1(OC)C=CC=CC=1.[F:9][C:10]1[CH:15]=[C:14]([S:16]CC2C=CC(OC)=CC=2)[CH:13]=[C:12]([O:26][CH3:27])[CH:11]=1>C(O)(C(F)(F)F)=O>[F:9][C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([O:26][CH3:27])[CH:11]=1
Reactant: COc1ccc(CSc2cc(F)cc(OC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc(F)cc(S)c1
Yield: 65.3 %

Procedure:
A mixture of anisole (12.04 g), 1-fluoro-3-methoxy-5-((4-methoxybenzyl)sulfanyl)benzene (6.2 g) and TFA (20 mL) was refluxed for 1 h, then concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and extracted with 2N NaOH (100 mL×3). The water layer was acidified with 6N HCl and extracted with EtOAc. The EtOAc extract was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound (2.30 g).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=O)OCC)C.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.O>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
2.63 g of sodium hydride are added to 50 ml of dimethylformamide. The mixture is cooled to 0° C. and 16 g (58.6 mmol) of (4-nitro-benzyl)-phosphonic acid diethyl ester is added portionwise. The solution is stirred at room temperature for 1.5 h, then cooled to −10°. A solution of 6.09 g (50 mmol)4-fluoro-benzaldehyde in 10 ml dimethylformamide is slowly added to the mixture at −10°. Stirring at room temperature for 45 min followed by additon of 250 ml water yields a precipitate which is filtered and recrystallised from ethanol/water 85:15 to yield 10.81 g (91%) of a yellow solid. MS: m/e=243.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: [H][H]
Reactant: Cc1nc2c(N)nc3cnccc3c2n1CC(C)C
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated, and the aqueous layer was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 226-230° C. Analysis: Calculated for C14H21N5+1.75H2O: % C, 57.81; % H, 8.49; % N, 24.07; Found: % C, 57.89; % H, 8.04; % N, 23.45.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:14]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc([N+](=O)[O-])c1OC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
A mixture of 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (1.0 g, 5.5 mmol), nicotinic acid 4 (0.8 g, 5.8 mmol), DCC (2.4 g, 11.6 mmol) and DMAP (0.7 g, 5.8 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 12 hours. After cooling to 0° C., the precipitated dicyclohexyl urea was removed by filtration and the filtrate concentrated. The crude residue was purified by flash chromatography eluting with Pentane/EtOAc (10:1) to give 5 (1.3 g, 81% yield).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=2)[CH2:4][CH2:3]1.[I:15]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[CH2:13]([O:12][C:10]([C:7]1[C:6]([I:15])=[C:5]([C:2]2([CH3:1])[CH2:3][CH2:4]2)[O:9][N:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc(C2(C)CC2)on1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(C2(C)CC2)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A mixture of ethyl 5-(1-methylcyclopropyl)isoxazole-3-carboxylate (Preparation 4C, 1.5 g, 7.68 mmol) and 1-iodopyrrolidine-2,5-dione (2.07 g, 9.22 mmol) in TFA (25 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed sequentially with water (50 mL), 1N aqueous sodium hydroxide (50 mL), 2.5 M aqueous sodium bisulfate (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl-4-iodo-5-(1-methylcyclopropyl)isoxazole-3-carboxylate (1.93 g, 75% yield) as a yellow liquid. The product had an HPLC ret. time=2.49 min. (condition B); LC/MS M+1=321.9; 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (m, 2H), 1.12 (m, 2H), 1.40 (t, J=7.15 Hz, 3H), 1.42 (s, 3H), and 4.41 (q, J=7.15 Hz, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:18]([O-])=O)=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH2:18])=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-n2ccnc2)cc1N1CCCCC1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To 1-(5-imidazol-1-yl-2-nitro-phenyl)-piperidine (117 mg, 0.430 mmol, as prepared in the previous step) in 3 mL of THF was added 6.5 mL of 10% TiCl3 in H2O dropwise over 3 min. After 10 min, the reaction was extracted with 20 mL of EtOAc, and the organic layer was discarded. The aqueous layer was basified with 10M NaOH to pH>9, then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo to afford 74 mg (66%) of the title compound as a light brown solid. Mass spectrum (ESI, m/z): Calcd. for C14H18N4, 243.1 (M+H), found 243.2;
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].C(O)(=O)C.[N+:31]([O-:34])(O)=[O:32].OO>O>[Cl:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[CH:13]=[CH:14][C:2]([N+:31]([O-:34])=[O:32])=[C:3]([CH:11]=1)[C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1N
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A stirred solution is prepared containing 39.5 g of 2-amino-5-(2-chloro-4-trifluoromethylphenoxy)-N-methanesulphonyl benzamide of the formula (V), R1 =methyl, 1380 ml of glacial acetic acid and 1.0 g of concentrated nitric acid at about 40° C. To the solution is added 138 g of a 30% by weight hydrogen peroxide in water solution and the reaction mixture is raised to and maintained at about 70° C. for 20 hours. The solution is then poured slowly into about 3 liters of ice water with precipitation of crude product. After filtration, the product is isolated as a solid, m.p. 175°-183° C., containing 68% of the compound of formula (I), R1 =methyl, as determined by high pressure liquid chromatography, thin layer chromatography and its mass spectrum. Recrystallization from aqueous methanol yields the product 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro-N-methanesulphonyl benzamide, m.p. 216°-218° C.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:38]=[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:40]=1)[CH2:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+].Cl>C1COCC1.CCO>[CH2:42]([O:41][C:39]1[CH:38]=[C:26]([CH:25]=[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:40]=1)[CH2:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][OH:31])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(Cc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(Cc2cc(OC)ccc2CO)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Reaction time: 3.5 h
Yield: 94 %

Procedure:
2-(3′,5′-Di(docosyloxy)benzyl)-4-methoxybenzaldehyde (450 mg, 0.50 mmol) was dissolved in THF-EtOH (4 ml+0.5 ml), sodium borohydride (34 mg, 0.90 mmol) was added, and the mixture was stirred for 3.5 hr. 1N Hydrochloric acid was added dropwise to the reaction mixture to quench the reaction, and the mixture was extracted with chloroform (15 ml), washed once with 1N hydrochloric acid (10 ml), and 3 times with water (5 ml). The solvent was evaporated, and the obtained residue was precipitated with methanol (5 ml) to give 2-(3′,5′-di(docosyloxy)benzyl)-4-methoxybenzyl alcohol (424 mg, 0.47 mmol, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[F:10])#[N:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:11])=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-cyano-3-fluorotoluene, as described above in Step C, (5.0 g, 37.0 mmol) in carbon tetrachloride (300 mL) was added N-bromosuccinimide (7.57 g, 42.6 mmol) and 2,2′-azobisisobutyronitrile (610 mg, 3.7 mmol). The reaction mixture was heated to reflux under argon for 24 hrs, then cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexane −4% to 7% EtOAc, to yield the titled product as a yellow solid.
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:21][CH2:22][CH2:23]O)[CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:17]1[C:12]([Cl:11])=[CH:13][C:14]([CH2:21][CH2:22][CH2:23][Br:2])=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: COc1cc(CCCO)cc(Cl)c1Cl
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(CCCBr)cc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
In a four-necked flask fitted with a stirrer, internal thermometer, dropping funnel and calcium chloride tube is placed freshly distilled phosphorus tribromide (9.6 g., 0.036 mole) and dry toluene (50 ml.). To this is added dry pyridine (1.5 g.). The mixture is stirred for 15 minutes and then cooled to -5° C. A mixture of the product of Step 2 (23.5 g., 0.1 mole) and pyridine (0.5 g.) in toluene (50 ml.) is added dropwise with stirring at -5° C. to -3° C. over a one hour period. The reaction mixture is stirred at -5° C. to -3° C. for an additional hour and then allowed to warm up to 20°-25° C. The mixture is kept for 48 hours and then added to ice water (ca. 500 ml.). The toluene layer is separated and washed with water, dilute hydrochloric acid, sodium bicarbonate solution and again with water. After drying over Na2SO4 and evaporation of the toluene under reduced pressure there is obtained 2,3-dichloro-5-(3-bromopropyl)anisole.