Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.CC[O:16][C:17]([CH:19]1[C:24](=O)[CH2:23][CH2:22][CH2:21][CH2:20]1)=O.[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]2[C:17](=[O:16])[C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[NH:7][C:5]=2[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(-c2ccccn2)c2[nH]c3c(c(=O)c12)CCCC3
Temperature: 130 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
A mixture of polyphosphoric acid (4.02 g) and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (1.75 g, 10.0 mmol) was heated at 130° C. The mixture was stirred at the same temperature, while ethyl 2-cyclohexanone carboxylate(1.70 mL, 10.6 mmol) was added thereto gradually. The mixture was stirred at the same temperature further for 4 hours. The solution was allowed to cool to room temperature, and water was added to the mixture. The solution was neutralized by the addition of a sodium hydroxide solution and the organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=100:1 to 50:1 to 20:1), and recrystallized from ethyl acetate to give the title compound (0.39 g, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([NH:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=2)[CH2:34][CH2:35]1)=[O:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 25 °C

Procedure:
A 30 mL round-bottomed vial methyl 2,6-dichloropyrimidine-4-carboxylate (300 mg, 1 equiv.) was partially dissolved in anhydrous THF (5 mL). DIEA (278 μL, 1.1 equiv.) was added at once at 0° C. tert-Butyl(piperidin-4-ylmethyl)carbamate (311 mg, 1 equiv.) dissolved in THF (5 mL) was added at 0° C. in 5 min. The reaction mixture was warmed to RT in 3 h15. LC-MS showed mostly the desired product (2.77 min, M+1=385) and a small amount of the other regioisomer (3.28 min, M+1-isobutene=329). The solvent was evaporated and the residue was purified by biotage (SiO2, 10 g, Hex/EtOAc 9:1 to 1:1) to give the desired isomer (386.8 mg, 69.4%) as a white solid. LC-MS m/z 385 (M+1).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26].S(=O)(=O)(O)O>CC1C=CC=CC=1>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: CCO
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Yield: 91 %

Procedure:
To a flask was added 140 g of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid, obtained according to the Example 4, 70 g of ethanol, 1.8 g of a concentrated sulfuric acid and 500 g of methyl benzene. The mixture was refluxed for 15 hours to react. The excess ethanol was recovered by distillation. At room temperature the mixture was washed with 200 g of water, with 200 g of a 6% (wt/wt) aqueous solution of sodium carbonate and finally with water. The solvent was completely removed under reduced pressure to give carfentrazone-ethyl as a faint yellow transparent and viscous liquid in a yield of 91% with a purity of 98.2%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]12([C:15]3[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2>C(O)(=O)C.C(Cl)Cl>[N+:1]([C:26]1[CH:27]=[C:15]([C:5]23[CH2:6][CH:7]4[CH2:8][CH:9]([CH2:10][CH:11]([CH2:13]4)[CH2:12]2)[CH2:14]3)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([O-:4])=[O:2].[C:23]([OH:25])(=[O:24])[CH2:22][CH2:21][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(=O)O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
120 ml of fuming nitric acid in 40 ml of glacial acetic acid are added dropwise to a solution of 31.4 g of 4-[4-(1-adamantyl)-phenoxy]-butyric acid in 100 ml of glacial acetic acid and 30 ml of methylene chloride at -5°C, whilst stirring in an anhydrous atmosphere. After completion of the addition, the mixture is stirred for a further 15 minutes at -5°C and 30 minutes at -3°C. The reaction mixture is then poured onto 1 kg of ice and extracted with 3 times 200 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 1 kg of silica gel, with ethyl acetate as the eluant, gives 4-[2-nitro-4-(1-adamantyl)-phenoxy]-butyric acid of melting point 182°-185°C (from methylene chloride/petroleum ether) and 4-[2,6-dinitro-4-(1-adamantyl)-phenoxy[-butyric acid of melting point 170°-172°C (from ethanol-pentane).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>CCO.O>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[CH:27][C:28](/[CH:29]=[CH:13]/[C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)/C=C/c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)/C=C/c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
A solution of (E)-4-(4-(trifluoromethoxy)-phenyl)-but-3-en-2-one (623 mg, 2.7 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (748 mg, 5.4 mmol) in H2O (4 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (392 μl, 2.9 mmol), the mixture was continued to stir for 4 h at 0° C. and for 2 h at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW337 as a pale yellow solid (337 mg, 34%). mp: 97-99° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.76 (d, 3J=16.1 Hz, 1H, Hvin), 7.75 (d, 3J=15.7 Hz, 1H, Hvin), 7.74 (d, 3J=8.8 Hz, 2H, HAr), 7.69 (d, 3J=8.1 Hz, 2H, HAr), 7.67 (d, 3J=8.7 Hz, 2H, HAr), 7.29 (d, 3J=8.0 Hz, 2H, HAr), 7.15 (d, 3J=16.0 Hz, 1H, Hvin), 7.07 (d, 3J=16.0 Hz, 1H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.2 (C), 150.7 (C), 142.1 (CH), 141.6 (CH), 138.1 (q, 4J(C, F)=1.3 Hz, CH), 133.2 (C), 132.0 (q, 2J(C, F)=32.7 Hz, C), 129.9 (CH), 128.5 (CH), 127.3 (CH), 126.0 (q, 3J(C, F)=3.8 Hz, CH), 125.9 (CH), 122.1 (C), 122.0 (C), 121.2 (CH), 118.7 (C). MS (FAB) m/z: 387.1 (M+). Anal. calcd for C19H12F6O2.0.5H2O: C, 57.73; H, 3.31. Found: C, 57.75; H, 3.20%.
Reaction SMILES: [NH2:1][C:2]1[C:7](C=O)=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C1(P(=[CH:52][C:53]([O:55][CH3:56])=[O:54])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].[CH2:59](N(CC)CC)C>CS(C)=O>[CH3:56][O:55][C:53](=[O:54])/[CH:52]=[CH:59]/[C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[N:5][C:6]=1[N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[N:17]([CH3:32])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:29])[F:31])[CH:22]=3)[N:20]=2)[CH2:14][CH2:15]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbaldehyde (100 mg; 0.22 mmol; 1.0 eq.) in DMSO (2 mL), methyl (triphenylphosphoranylidene)acetate (82.0 mg; 0.25 mmol; 1.1 eq.), lithium chloride (19.1 mg; 0.45 mmol; 2.0 eq.) and triethylamine (0.04 ml; 0.27 mmol; 1.2 eq.) were added. The resulting suspension was stirred at 60° C. overnight. The crude was purified by pre-HPLC (Waters, basic condition) to afford the title compound in 72% yield. LC-MS: (M+1=505, obsd.=505).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C.CCCCCC>C1C=CC=CC=1.CO>[C:1]([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(C)=O
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2-acetylamino-4-nitrobenzoic acid (1.28 g, 5.71 mmol) in benzene-MeOH (4:1, v/v, 25 mL), was added trimethylsilyldiazomethane (2.0 M solution in n-hexane, 4.28 ml, 8.56 mmol) at 0° C. The stirring was continued for 18 hours at rt. The reaction was poured into hexane, and the resulting precipitate was collected by filtration to give methyl 2-acetylamino-4-nitrobenzoate (1.32 g, 97%) as a white solid; mp no data; 1H-NMR (400 MHz, CDCl3) δ 2.30 (s, 3 H), 4.00 (s, 3 H), 7.88 (m, 1 H), 8.18 (dd, J=2.0 Hz, 8.8 Hz, 1 H), 9.60 (t, J=2.2 Hz, 1 H), 11.10 (s, 1 H); MS (ESI) m/z 238 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Cl)=[N:6][CH:7]=1.[C:10]1([CH2:16][C:17](=O)[CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC1C=CC(CBr)=CC=1.[N:29]1C=CC=C(CC(=O)C)C=1>>[ClH:1].[NH2:29][CH:17]([CH:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH3:18]
Reactant: CC(=O)Cc1cccnc1
Reactant: CC(=O)Cc1ccccc1
Reactant: ClCc1ccc(Cl)cn1
Agent: Clc1ccc(CBr)cc1
Product: CC(N)C(Cc1ccc(Cl)cn1)c1ccccc1
Product: Cl

Procedure:
5-Chloro-2-choromethylpyridine (Weidmann, K. et al. J. Med. Chem. 1992, 35, 438) and phenylacetone were used in place of 4-chlorobenzyl bromide and 3-pyridylacetone in Step A of Reference Example 4. LC-MS: m/e 261 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10]1([C:13]2[N:18]=[C:17]([C:19](=N)OCC)[CH:16]=[CH:15][N:14]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C.C(O)(=O)C>C(O)C>[Br:1][C:2]1[N:3]=[C:4]2[NH:9][C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([CH:10]4[CH2:12][CH2:11]4)[N:18]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=N)c1ccnc(C2CC2)n1
Reactant: Nc1ncc(Br)nc1N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1cnc2nc(-c3ccnc(C4CC4)n3)[nH]c2n1
Temperature: 100 °C
Yield: 22.1 %

Procedure:
A mixture of 5-bromopyrazine-2,3-diamine (50 mg, 0.3 mmol) and ethyl 2-cyclopropylpyrimidine-4-carbimidate (Intermediate 19, 50.7 mg, 0.3 mmol), triethylamine (73.8 μL, 0.5 mmol), acetic acid (244 μL, 4.2 mmol) and ethanol (0.8 mL) was heated to 100° C. for 30 min. The mixture was concentrated and diluted with water. Then a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-5% methanol in dichloromethane) to afford 6-bromo-2-(2-cyclopropylpyrimidin-4-yl)-1H-imidazo[4,5-b]pyrazine (21 mg, 25%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-chloro-4-(trifluoromethyl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][C:10](=[O:12])[O:9][C:7](=[O:8])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[NH3:13]>>[C:7]([CH2:6][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:11][C:10]([OH:9])=[O:12])(=[O:8])[NH2:13]
Reactant: N
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Product: CC(C)CC(CC(N)=O)CC(=O)O

Procedure:
In another step of the method, 3-isobutylglutaric acid anhydride is reacted with ammonia to form (±)-3-(carbamoylmethyl)-5-methylhexanoic acid. In this step, the cyclic anhydride is opened and one of the carbonyl groups is converted to an amide. (±)-3-(carbamoyl methyl)-5-methylhexanoic acid can be recrystallized from a number of solvents including ethyl acetate, water, chloroform and 2-butanone.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)#[N:20].O>CN(C=O)C>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:8]2[C:7]3=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]3[N:5]=[C:4]2[S:3][CH2:1][CH3:2])=[CH:31][CH:32]=1)#[N:20]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (5.7 g) in DMF (30 ml) was added sodium hydride (60% oil, 0.98 g) under ice-cooling. After stirring the reaction mixture for 20 minutes, to the mixture was added dropwise a solution of (2'-cyanobiphenyl-4-yl)methyl bromide (7.25 g) in DMF (20 ml), followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow prisms (7.6 g, 77%), m.p. 149°-151° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1ccc(N)c(N)c1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a Parr hydrogenation bottle was added 3.5 g of 4-(2-(dimethylamino)ethoxy)-2-nitroaniline, 10% palladium in carbon (50% w/w water, 1.0 g) and methanol (100 mL). The atmosphere of the vessel was replaced by hydrogen gas. The reaction was carried out on the Parr shaker at 40 psi at room temperature for 1 hour. The reaction mixture was filtered through a plug of Celite. 2.0 g of sodium bicarbonate was subsequently added to the filtrate, which was stirred for 10 minutes. The filtrate was concentrated reduced pressure and the resulting residue was triturated with diethylether to give 4-(2-(dimethylamino)ethoxy)benzene-1,2-diamine (2.2 g, 73%). 1H-NMR (400 MHz, MeOH-d4): δ 6.67 (d, 1H), 6.44 (d, 1H), 6.27 (dd, 1H), 4.18 (t, 2H), 3.50 (t, 3H), 2.92 (s, 6H). MS (EI): 196 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.[K].C1(C(C2[C:27]([CH2:28][O:29][CH2:30][C:31]3[C:36](C4C(=CC=C(O)C=4)O)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=CC(=CC=1)O)O.[OH-:45].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[O:45][C:25]1[CH:24]=[CH:23][C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: [OH-]
Agent: [K+]
Agent: [K]
Solvent: CO
Product: FC(F)(F)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c(Cl)c1
Temperature: 120 °C
Yield: 70 %

Procedure:
To as flask equipped with a stirrer, thermometer, condenser and drying tube are charged 3,4-dichlorobenzotrifluoride (43 g., 0.20 mole), potassium 4-benzyloxyphenate (47.5 g., 0.20 mole-prepared from hydroquinone monobenzylether using potassium hydroxide pellets dissolved in methanol and removal of the solvent in vacuo and subsequent precipitation in ether) and dimethyl sulfoxide (400 ml.). The reaction mixture is then warmed to 120° C. and maintained at 135° C. for 3 hours, cooled, poured into water (3 liters) and extracted into hexane (500 ml., then 300 ml., then 200 ml.) and the combined hexane extracts washed again with water (200 ml.), dried with anhydrous magnesium sulfate, and the solvent removed in vacuo to give 52.6 g. (70% yield) of 4-benzyloxyphenyl 2-chloro-4-trifluoromethylphenyl ether, mp 63°-6° C., which is recrystallized from methanol to give white crystals, mp 69°-71° C.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][CH2:6][O:7][C:8]1[C:17]([C:18]#[N:19])=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:20])=[N:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=C(C)C=1>[CH:20]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:17]([C:18]#[N:19])[C:8]([O:7][CH2:6][O:5][CH3:4])=[CH:9][CH:10]=2)[N:15]=1)=[O:2]
Reactant: COCOc1ccc2ccc(C)nc2c1C#N
Reactant: O=[Se]=O
Solvent: Cc1cccc(C)c1
Product: COCOc1ccc2ccc(C=O)nc2c1C#N
Temperature: 74 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere selenium dioxide (0.0145 g, 0.131 mmol) was added to a solution of 8b (0.0300 g, 0.136 mmol) in m-xylene (5 mL). The mixture was stirred at 74° C. for 20 h then filtered. The filtrate was evaporated, and the residue was purified by column chromatography (3:7 EtOAc/hexane) to yield 9b (0.0100 g, 0.041 mmol, 30%) as a white solid: 1H NMR (CDCl3) δ 10.29 (1H, s), 8.34 (1H, d, J=8.0 Hz), 8.09 (1H, d, J=9.6 Hz), 8.04 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=9.2 Hz), 5.50 (2H, s), 3.61 (3H, s); 13C NMR (CDCl3) δ 193.7, 163.0, 154.2, 148.6, 137.9, 133.9, 125.4, 118.5, 117.3, 114.3, 95.4, 57.3; FTIR (neat) 2922, 2846, 2224, 1710, 1260, 1165, 1043, 922, 856, 775 cm−1; MS (ESI) m/z calculated for (C13H10N2O3+H)+ 243, found 243; HRMS (ESI) m/z calculated for (C13H10N2O3+H)+ 243.0769, found 243.0764.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH3:11].CS(O)(=O)=O.[CH2:23]([SH:26])[CH2:24][SH:25].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH3:11])[S:26][CH2:23][CH2:24][S:25]1
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)n1ccnc1
Reactant: SCCS
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(n1ccnc1)C1(c2ccc(Cl)cc2Cl)SCCS1

Procedure:
A mixture of 6 parts of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-1-propanone and 30 parts of methanesulfonic acid was stirred till all solid entered solution. After cooling, 5.5 parts of 1,2-ethanedithiol were added while nitrogen gas was introduced. The whole was stirred overnight at room temperature. The reaction mixture was diluted with trichloromethane till a volume of 150 parts. This solution was added dropwise to a vigorously stirred solution of potassium carbonate in water. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was converted into the nitrate salt in 2-propanol. 2,2'-Oxybispropane was added till turbid and the formed salt was allowed to crystallize. It was filtered off and dried, yielding 6 parts of 2-(2,4-dichlorophenyl)-2-[1-(1H-imidazol-1-yl)ethyl]-1,3-dithiolane; mp. 141.9° C. (compound 29).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:32])[C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:41])C=1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:32])[C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:24][C:18]=3[N:17]=2)=[O:41])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Yield: 51.5 %

Procedure:
The title compound (0.15 g, 51%) was prepared by the above general procedure using 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazole (0.28 g, 0.6 mmol) (obtained in example 20), m-chloroperbenzoic acid (50%, 0.25 g, 0.72 mmol) and chloroform (20 mL). mp 73-74° C.; IR (KBr) 3470, 1080 cm- 1; 1H NMR (CD3OD) δ 2.20 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.88 (t,J=4.6 Hz, 4H, N(CH2)2), 3.18 (t,J=4.8 Hz, 4H, N(CH2)2), 4.68 (q,J=8.2 Hz, 2H, OCH2CF3), 4.80 (s, 2H, SOCH2), 7.00 (d,J=5.8Hz, 1H), 7.24 (d,J=7.6Hz, 1H), 7.32 (d,J=12.2Hz, 1H), 8.18 (d,J=5.7Hz, 1H); Mass (m/z) 486 (M+ 1).
Reaction SMILES: [NH2:1][C@:2]1([CH2:23][OH:24])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][C@H:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:3]1.P(Cl)(Cl)([O:27][P:28](Cl)(Cl)=[O:29])=O.[OH2:34]>C(#N)C>[P:28]([OH:27])([OH:34])([O:24][CH2:23][C@@:2]1([NH2:1])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][C@H:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:3]1)=[O:29]
Reactant: CCCCCC[C@@H]1CCc2cc([C@@H]3CC[C@](N)(CO)C3)ccc2C1
Reactant: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Reactant: O
Solvent: CC#N
Product: CCCCCC[C@@H]1CCc2cc([C@@H]3CC[C@](N)(COP(=O)(O)O)C3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.68 %

Procedure:
To a stirred solution of ((1R,3R)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (Example 1, 10 mg, 0.030 mmol) in anhydrous acetonitrile (1 mL) at 0° C. was added pyrophosphoryl chloride (0.042 mL, 0.303 mmol). The clear solution obtained was stirred at the same temperature for 5 min and at RT overnight. After water (0.4 mL) was added, the mixture was stirred at RT for 1 h. Purification using reverse phase HPLC (Luna Axia 5μ c18 30×100 mm, 10 min. gradient from 40% to 100% of Solvent B, Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in MeCN), concentration and lyophilization gave ((1R,3R)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methyl dihydrogen phosphate (2 mg, 4.15 μmol, 13.68% yield) as a white solid. HPLC retention time=3.94 min (Condition C); LC/MS M+1=410; 1H NMR (500 MHz, methanol-d4+KOH) δ 6.97-6.87 (m, 3H), 3.77-3.71 (m, 1H), 3.71-3.66 (m, 1H), 2.83-2.70 (m, 3H), 2.32 (dd, J=16.2, 10.7 Hz, 1H), 2.14-1.98 (m, 2H), 1.96-1.83 (m, 2H), 1.74-1.60 (m, 3H), 1.59-1.49 (m, 1H), 1.45-1.26 (m, 11H), 0.94-0.87 (m, 3H), one proton under methanol solvent peak (˜3.3 ppm).