Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(I)C.C(O)C.[O-]CC.[Na+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([OH:8])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:9]2=[O:10])=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: CCOC(=O)CNCC(C)C
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ccc(F)cc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
A solution of 4-fluorophthalic anhydride (24.99 g, 150 mmol) and ethyl 2-(isobutylamino)acetate (23.88 g, 150 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (20.73 g, 150 mmol) and ethyl iodide (14.4 mL, 180 mmol) were added thereto. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (300 mL) and a solution of 20% sodium ethoxide ethanol solution (102 g, 300 mmol) was added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (300 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-fluoro-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (19.2 g, 41.7%) as crystals.
Reaction SMILES: [CH3:1][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][C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][OH:44])=[O:19].[C:45](O)(=[O:63])[CH2:46]CCCCCCCCCCCCCCCC>C1(C)C=CC=CC=1>[CH2:17]([C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:46][CH2:45][OH:63])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reaction time: 8 h

Procedure:
PEG400MS (polyethylene glycol 400 monostearate)—100 g (0.25 mol) of CARBOWAX™ 400 diol (commercially available from Union Carbide Corp., Danbury, Conn.) was combined with 71 g (0.25 mol) of stearic acid in 400 g of toluene in a 3-necked flask equipped with stirrer, heating mantle, thermometer and condenser. The contents were heated, azeotroped dry using a Dean Stark trap, and were allowed to cool. Next, 1.0 g (0 5% by weight of solids) of p-toluene sulfonic acid was added, and the mixture was refluxed with stirring overnight with the continuous removal of water. Infrared analysis indicated no acid carbonyl remained. A solution of 0.5 g of NaHCO3 in deionized water was then added. The resulting two-phase system was stirred and the water and toluene were removed at 80° C. using a ROTO-VAC™ evaporator to produce the desired monoester, C17H35C(O)O(C2H4O)8C2H4OH. This monostearate and its constituent reactants are presented as the first entry in TABLE 1.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1.Cl.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[CH2:29][CH2:28]2)=[CH:22][C:21]=1[C:43]([F:46])([F:45])[F:44])([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:28][CH2:29][CH:30]([O:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH2:2][C:3]4[O:4][C:5]5[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=5[N:7]=4)[CH2:39][CH2:38]3)=[O:36])[CH2:31][CH2:32]2)=[CH:22][C:21]=1[C:43]([F:46])([F:45])[F:44])([O-:19])=[O:18]
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Reactant: FC(F)(F)c1ccc2oc(CCl)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2nc3cc(C(F)(F)F)ccc3o2)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-chloromethyl-5-trifluoromethyl-benzoxazole (50 mg, 0.214 mmol), 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (100 mg, 0.214 mmol), potassium carbonate (60 mg, 0.428 mmol), and DMF (1 mL) was heated at 100° C. for two hours before the reaction mixture was cooled, diluted with EtOAc (60 mL), washed with water (2×40 mL), washed with brine (1×40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to an orange residue that was purified by silica gel chromatography, eluting with a gradient of 0 to 100% EtOAc in heptanes, to provide 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzooxazol-2-ylmethyl)-piperazin-1-yl]-ethanone as a stiff, orange solid (69 mg, 51%). (CI, m/z): [M+H]+ 360; 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 8.05 (d, J=9.23 Hz, 1H), 7.97 (d, J=8.54 Hz, 1H), 7.77 (dd, J=8.57, 1.44 Hz, 1H), 7.43 (d, J=7.71 Hz, 1H), 7.06 (s, 1H), 6.84 (dd, J=9.30, 2.51 Hz, 1H), 3.99 (s, 2H) 4.12 (s, 2H), 3.45 (br s, 5H), 2.52-2.64 (m, 4H), 1.95-2.04 (m, 2H), 1.92 (d, J=10.59 Hz, 2H), 1.28-1.40 (m, 2H), 1.19-1.27 (m, 2H); 19F NMR (376 MHz, DMSO-d6): δ ppm −59.45 (s, 3F)-59.17 (s, 3F).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:28][CH3:29])=[C:9]([C:26]#[N:27])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].I[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:28][CH3:29])=[C:9]([C:26]#[N:27])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: N#Cc1ccccc1I
Reactant: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C

Procedure:
Prepare a solution of 4-cyano-5-ethyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophene-2-carboxylic acid ethyl ester (0.26 mmol), 2-iodobenzonitrile (41 mg, 0.18 mmol), 2M aqueous Na2CO3 (0.6 mL, 1.2 mmol) and tetrakis(triphenylphosphine)-palladium(0) (20 mg, 0.02 mmol) in 3 mL of dioxane and heat to 80° C. under nitrogen. After 3 hours cool to room temperature, dilute with 50 mL of EtOAc and wash with water (2×10 mL) and brine (1×10 mL). Dry the organics over Na2SO4, filter and evaporate. Chromatograph on silica gel (100/0 to 3/1 toluene/EtOAc) to give the title compound as a yellow foam. Yield=61 mg (91%). HPLC=80%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from the intermediate obtained in Step A and 4-chloromethylbiphenyl by the procedure described in Example 1, Step K. FAB-MS: calculated for C33H39N3O4 541; found 542 (M+H,31%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.Cl>CO.[Pd]>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=3)[CH2:12]2)=[CH:25][CH:26]=1
Reactant: COc1cc2c(cc1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)CN(CCc1ccc(N)cc1)CC2
Reaction time: 8 h
Yield: 178.5 %

Procedure:
N-(4-Nitrophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (14.1 g, 0.037 m) was dissolved in methanol (500 ml) containing 10 ml of conc HCl and hydrogenated in a Parr apparatus over 5% Pd/C catalyst (1.5 g) at 40 psi for 1 hour. The catalyst was removed by filtration and the solvent volume reduced to ca 150 ml at an aspirator. Ethanol (100 ml) and ether (50 ml) were added and the mixture was hot filtered and allowed to stand overnight. The crystallized solid was collected by filtration and vacuum dried to give 12.8 g of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline dihydrochloride, m.p. 259°-261°.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)[N:5]=1)(=[O:3])[NH2:2].C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[C:1]([C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)CNc1cc(C(N)=O)nc2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(NCC(=O)O)c2cc(C(F)(F)F)ccc2n1
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 2-((2-carbamoyl-6-(trifluoromethyl)quinolin-4-yl)amino)acetate (200 mg, 0.54 mmol) above step B, in DCM (5 mL) was treated with thioanisole (0.05 mL) and stirred for 10 min and then treated with trifluoroacetic acid (5 mL) dropwise. The resulting opaque solution was stirred for 2.5 h at room temperature and diluted with Et2O (200 mL). Precipitate was formed. The solid was dried under high vacuum to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1.FC(F)(F)C(O)=O>ClCCl>[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)=[O:34]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and biphenyl-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C@:20]4([S:39][CH3:40])[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:38])[CH:27]5[CH2:32][CH2:31][N:30]([C:33]6[S:34][CH:35]=[CH:36][N:37]=6)[CH2:29][CH2:28]5)[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[OH:38][CH:26]([CH:27]1[CH2:28][CH2:29][N:30]([C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[CH2:31][CH2:32]1)[CH2:25][N:22]1[CH2:23][CH2:24][C@@:20]([S:39][CH3:40])([C:18]([NH:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:21]1
Reactant: CS[C@@]1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CCN(CC(=O)C2CCN(c3nccs3)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS[C@@]1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CCN(CC(O)C2CCN(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a solution of 7 (17 mg, 0.03 mmol) (Example 1) in MeOH (3 mL) was added NaBH4 (20 mg, 0.5 mmol). The mixture was stirred at room temperature for 3 hrs before it was concentrated to dryness. The residue was purified on a prep TLC plate eluting with 10% ammonia /MeOH (2 M) in CH2Cl2 to yield a yellow solid 31 (10 mg, 59%). LCMS M+1=578.3 retention time=1.70 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1>>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([CH2:24][CH2:23][N:13]2[C:12]([S:11][C:4]3[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: FC(F)(F)c1cc(CCBr)cc(C(F)(F)F)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-3,5-bis-trifluoromethyl-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 9-[2-(3,5-Bistrifluoromethyl-phenyl)-ethyl]-8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine: 1H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.86 (s, 1H), 7.54 (s, 2H), 7.01 (d, J=9.0 Hz, 1H), 6.83 (dd, J=11.0, 3.0 Hz, 1H), 6.40 (d, J=2.9 Hz, 1H), 4.50 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.59 (s, 3H), 3.24 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 544.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]1.BrC1C=CC(Cl)=CC=1N1C(C)=CC=N1.C([Mg]Cl)(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:34](=[O:36])[CH3:35])=[C:3]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:4]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2Br)n1
Reactant: CC(=O)Cl
Agent: CC(C)[Mg]Cl
Agent: Cc1ccnn1-c1cc(Cl)ccc1Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)cc1-n1ccc(C)n1
Temperature: 25 °C

Procedure:
1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) and cooled to 0° C. i-Propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and allowed to warm to RT over 30 min. The reaction was then cooled to −15° C. Acetyl chloride (481 μL, 5.5 mmol) was added and the reaction was warmed to RT for 3 h. The reaction was quenched with HCl (2 N, 4 mL), then extracted with water and EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethanone.
Reaction SMILES: Cl.C([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=3[Cl:30])[N:14]=2)=[CH:8][CH:7]=1)C>CCO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:15]2[N:14]=[C:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:31])=[O:4])=[CH:7][CH:8]=3)[O:17][N:16]=2)=[C:21]([Cl:30])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)cc1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1ccc(OCc2noc(Cc3ccc(C(=O)O)cc3)n2)c(Cl)c1O
Temperature: 150 °C
Yield: 32.5 %

Procedure:
Add 1 N hydrochloric acid (3.6 mL) to a solution of 4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester (55 mg, 0.13 mmol) in EtOH (1.2 mL) in a microwave tube. Seal the tube and heat in a microwave reactor at 150° C. for 30 min. Purify the reaction mixture by reverse phase HPLC using a gradient of 90:10 to 20:80 (H2O/0.1% TFA):CH3CN as eluent to give the title compound (17 mg, 33%). 1H NMR (DMSO-d6) δ 13.07 (s, 1H), 12.92 (s, 1H), 7.86-7.94 (m, 3H), 7.44 (d, 2H), 6.89 (d, 1H), 5.49 (s, 2H), 4.49 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).
Reaction SMILES: [OH:1][NH:2][C:3]([CH3:10])([C:5]([CH3:9])([NH:7][OH:8])[CH3:6])[CH3:4]>O.[O-2].[O-2].[Mn+4]>[OH:1][N:2]1[C:3]([CH3:10])([CH3:4])[C:5]([CH3:9])([CH3:6])[N:7]1[OH:8]
Reactant: CC(C)(NO)C(C)(C)NO
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Product: CC1(C)N(O)N(O)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of N,N'-dihydroxy 2,3-dimethyl-2,3-diaminobutane I (6 g.) in water (500 ml.) was added dropwise, over a period of 2 hours, to a suspension of manganese dioxide (45 g.) in water (150 ml.) at 75°-80° C. The reaction mixture was further stirred at 75°-80° for 6 hours and refluxed for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was saturated with solid ammonium chloride and extracted with chloroform. Removal of the solvent from the dried extract furnished the product, as white crystals (3.6 g., 60%), which was further purified by sublimation.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1.[ClH:18]>>[ClH:18].[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][CH:4]=1
Reactant: COc1cc2c(cc1OC)C(O)(CN)CCC2
Agent: Cl
Product: COc1cc2c(cc1OC)C(CN)=CCC2

Procedure:
10 g. of 1-aminomethyl-6,7-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene is treated with HCl as described in Example 3 to yield 1-aminomethyl-6,7-dimethoxy-3,4-dihydronaphthalene HCl; m.p. 197°-199° C.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[SH:22][CH2:23][C:24](O)=[O:25]>C(S(O)(=O)=O)(F)(F)F.C1(C)C=CC=CC=1>[C:1]([S:14]([N:17]([CH2:19][CH2:20][O:21][C:24]([CH2:23][SH:22])=[O:25])[CH3:18])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:12])[F:13])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=C(O)CS
Reactant: CN(CCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(CCOC(=O)CS)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 500 mL three-necked round bottom flask was charged with 16.86 g of C4F9SO2N(CH3)CH2CH2OH (MW=357; 47.22 mmol; Example 2, A from WO 01/30873), 4.35 g HSCH2CO2H (MW=92.12, 47.22 mmol; available from Sigma-Aldrich), 2 drops of CF3SO3H catalyst, and 120 mL toluene. The mixture was heated to reflux under nitrogen at 115–120° C. with a mechanical stirrer for 8 hours. Water was removed by azeotropic distillation. Fourier Transform Infrared Spectroscopy (FTIR) analysis indicated the formation of ester. Toluene was stripped using a rotary evaporator (21.35 g solid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:39][N:40]([CH:57]([C:65](=[O:68])[NH:66][CH3:67])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:41](=[O:56])[CH:42]([NH:54][CH3:55])[CH2:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10](/[CH:12]=[CH:13]/[C:14](=[O:16])[N:54]([CH3:55])[C@@H:42]([C:41](=[O:56])[N:40]([CH3:39])[C@@H:57]([C:65](=[O:68])[NH:66][CH3:67])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CC(/C=C/C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
3-((E)-2-Carboxyvinyl)azetidine-1-carboxylic acid tert-butyl ester (0.28 g; 1.24 mmol) was dissolved in methylene chloride (3 mL). 1-Hydroxy-7-azabenzotriazole (0.17 g; 1.24 mmol) and N-(3dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. N-Methyl-2-methylamino-N-(1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.50 g; 1.24 mmol) (prepared as in example 1) was dissolved in methylene chloride (3 mL) and added to the reaction mixture. Ethyldiisopropylamine (0.21 mL; 1.24 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (20 mL) was added and the reaction mixture was washed with water (10 mL), an aqueous solution of sodium hydrogen sulfate (10 mL; 10%), an aqueous solution of sodium hydrogen carbonate (10 mL; sat.) and water (10 mL). The organic phase was dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2,5×20 cm) using 2.5%(7% ammonia in ethanol) in methylene chloride as eluent to afford 0.49 g of 3-((E)-2-(methyl((1R)-1-(methyl((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([NH:14][CH3:15])=[O:13])[C:4]=2[O:3]1.[CH3:17][O:18][P:19]([O:22]C)[O:20][CH3:21]>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[C:8]([P:19]([O:20][CH3:21])([O:18][CH3:17])=[O:22])[CH:9]=[C:10]([O:11][C:12]([NH:14][CH3:15])=[O:13])[C:4]=2[O:3]1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: COP(OC)OC
Product: CNC(=O)Oc1cc(P(=O)(OC)OC)cc2c1OC(C)(C)C2
Yield: 26 %

Procedure:
0.1 mole of carbofuran (2,3-dihydro-2,2-dimethyl-7-methylaminocarbonyloxybenzofuran) were reacted with trimethylphosphite analogously to Example 1a. The product was obtained in the form of an oil in a yield of 26%.