Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(C)=O>[C:35]([O:41][CH2:42][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)OCI
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To (+)-3-hydroxy-N-(benzyloxycarbonyl)morphinan (12.0 g, 31.8 mmol) from Example 1 and cesium carbonate (11.4 g, 35.0 mmol) in acetone (150 mL) was added iodomethyl pivalate (8.46 g, 35.0 mmol) (see Bristol-Myers Squibb Company, U.S. Pat. No. 5,470,845 A1 (1995/11/28), Appl.; US1994-266843 (1994 Jul. 5)) at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. The acetone was then removed by rotary evaporation under vacuum. To the residue was added saturated NaHCO3 solution. The mixture was extracted with EtOAc (150 mL×2). The combined organics were washed with 1N HCl solution (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide the crude product, which was further purified by prep reverse-phase HPLC to afford the title compound (13.2 g, 84%) as a yellow gum.
Reaction SMILES: CN(C)C=O.[C:6]([NH2:12])([NH2:11])=[N:7][C:8](N)=[NH:9].[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>O>[NH2:12][C:6]1[N:7]=[C:8]([NH2:9])[N:15]([CH2:13][CH3:14])[C:16](=[S:17])[N:11]=1
Reactant: CCN=C=S
Reactant: N=C(N)N=C(N)N
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(N)nc(N)nc1=S
Temperature: 100 °C
Yield: 104.9 %

Procedure:
To 15 ml of dry dimethylformamide were dissolved 1.52 g of diguanide and 1.31 g of ethylisothiocyanate, and the solution was heated at 100° C. for 4 hours. After cooling, the solution was added to 60 ml of water to produce white precipitates, which subsequently was dried to obtain 2.7 g of the title compound having the characteristics of:
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.ClCCl.[Cl:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([Cl:36])[C:30]=1[C:37](=[O:39])[CH3:38]>Cl.CO>[Cl:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([Cl:36])[C:30]=1[C@@H:37]([OH:39])[CH3:38]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C

Procedure:
To (R)-2-methyl-CBS-oxazaborolidine (Aldrich or Callery Chemical Co, 1M in toluene, 1 eq.) at −45° C. is added BH3. Me2S (1.06 eq.). To the previous solution is added at −30° C. a 1M dichloromethane solution of 1-(2,6-dichloro-3-fluorophenyl)ethanone. After completion of the reaction, excess MeOH is added followed by IN HCl. After warming up to room temperature, the resulting mixture is filtered through a pad of celite and silica gel and washed with 30% EtOAc in hexane. The solvent is removed under reduced pressure and the resulting oil is purified by flash chromatography (20% EtOAc in hexane) to afford (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (optically enriched).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:44](=[O:45])[CH2:43][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) in dry dimethylformamide (3 ml) containing dry pyridine (0.06 ml) was added a solution of 2-phenoxyacetyl chloride (0.12 g) in dry dimethylformamide (1 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. Additional pyridine (0.02 ml) and a solution of 2-phenoxyacetyl chloride (0.025 g) in dry dimethylformamide (0.3 ml) were added to the reaction mixture. After being stirred for 30 minutes, the mixture was poured into water (43 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a silica gel column chromatography. Elution with toluene-ethyl acetate afforded (2R)-2-benzyl-l-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-phenoxyacetyl)piperazine (0.34 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11])[C:5]#[N:6].P([O-])(O)(O)=[O:14].[K+].Cl([O-])=O.[Na+]>CS(C)=O.O>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([C:10]([OH:14])=[O:11])=[C:8]([F:12])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 3,5-difluoro-4-formylbenzonitrile (0.2 g, 1.1 mmol) in dimethylsulfoxide (10 mL), were added a aqueous solution of potassium dihydrogen phosphate (0.41 g, 2.9 mmol in 0.4 mL of water), sodium chlorite (0.216 g, 2.3 mmol in 4 mL of water) in one lot at an ambient temperature. The resulting reaction mixture was stirred for about 1 hour. The reaction mass was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-cyano-2,6-difluorobenzoic acid (200 mg, 91.32%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][CH:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].Br[CH2:35][C:36]1[O:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>CN(C)C=O>[O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][CH:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:35][C:36]1[O:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)OCC32C(=O)Nc3ccccc32)C1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)OCC32C(=O)N(Cc3ccc(C(F)(F)F)o3)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a stirred solution of tert-butyl 3-[(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.19 g, 0.45 mol) in N,N-dimethyl formamide (10 mL) was added sodium hydride (0.02 g, 0.54 mmol) slowly at 0° C. After 30 min, 2-(bromomethyl)-5-(trifluoromethyl)furan (0.12 g, 0.54 mmol) was added. The mixture was stirred at ambient temperature for 16 h, and then quenched with saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexanes, 1/2) to afford tert-butyl 3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate (0.14 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.29 (t, J=7.7 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.76-6.70 (m, 1H), 6.54 (d, J=8.2 Hz, 1H), 6.47 (s, 1H), 6.40-6.35 (m, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.86 (d, J=16.2 Hz, 1H), 4.80 (br s, 1H), 4.69 (d, J=9.0 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 593.2 (M+23).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].C(N(CC)CC)C.[C:31]([N:34]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:35]1=[O:61])(=[O:33])[NH2:32]>O1CCCC1>[OH:41][CH2:40][CH2:39][N:36]1[CH2:37][CH2:38][N:34]([C:31]([NH:32][S:18]([NH:21][C:22]([N:14]2[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]2=[O:16])=[O:23])(=[O:20])=[O:19])=[O:33])[C:35]1=[O:61]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: NC(=O)N1CCN(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(CCO)C2=O)C1=O)OCc1ccccc1
Temperature: -70 °C
Yield: 128 %

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (1.5 g) was suspended in 100 ml of dry tetrahydrofuran and cooled to -70° C. Chlorosulfonylisocyanate (1.1 g) dissolved in 10 ml of dry tetrahydrofuran was dropped in with stirring. The temperature was allowed to rise to 0° C. and maintained there for 20 minutes, followed by cooling to -40° C. Triethylamine (0.9 g) and 2.8 g of 1-carbamoyl-2-oxo-3-[2-[(triphenylmethyl)oxy]ethyl]imidazolidine were added and the mixture was stirred at room temperature for 14 hours. The solvent was removed in vacuo and the work-up procedure of example 34A was followed yielding 4.3 g of (S)-[1-[[[[[[3-(2-hydroxyethyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCN(C)CC3)nncc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCN(C)CC3)nncc2c1
Yield: 49.9 %

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide (20 mg, 50 μmol), 20 mg 10% palladium on activated carbon in 20 mL ethyl acetate was stirred under 50 psi hydrogen at 22° C. After 2 h reaction, the reaction was monitored for product (MS=401) and starting material (MS=399). The reaction mixture was stirred under 50 psi hydrogen at 22° C. for another 2 h, MS showed all starting material was converted to product. The mixture was filtered and washed with methanol 50 mL. After concentrating the filtrate, the residue was purified by PTLC to obtain the title compound (10 mg) as a pale yellow solid. Found MS (ES+): 401 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:22][C:23]=2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:15][CH:14]=1.O>C(OCC)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:22][C:23]=2[CH2:24][CH2:25][CH2:26][OH:27])=[CH:17][CH:18]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
Lithium aluminium hydride (185 mg) was gradually added to a tetrahydrofuran (20 ml) solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid (1.47 g) at room temperature. After the mixture was stirred for 1 hour, water (2 ml) was added to the reaction mixture with cooling with ice, and stirred for further 30 minutes. Diethyl ether (50 ml) was added to the reaction mixture, which was then dried (MgSO4), and the insoluble substances were removed by filtration. The resulting filtrate was concentrated, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (435 mg, 31%). This was recrystallized from dichloromethane-isopropyl ether to give colorless prisms. mp 128-129° C.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:24])=O.[NH:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CN1CCOCC1>ClCCl.CN(C)C=O>[ClH:24].[C:1]1([CH2:7][S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:18])=[CH:19][CH:20]=2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(NS(=O)(=O)Cc2ccccc2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(c1ccc(NS(=O)(=O)Cc2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1
Reaction time: 0.33 h

Procedure:
To a stirring solution of 4-phenylmethanesulfonylamino-benzoic acid (CAS 536-95-8, available from Aldrich) (0.300 g, 1.03 mmol), in dichloromethane (10 mL) is added oxalyl chloride (0.262 g, 2.06 mmol) and 1 drop of N,N-dimethylformamide and the mixture allowed to react at ambient temperature for 1 hour. The reaction is then concentrated to dryness. The residue is dissolved in toluene (10 mL) and concentrated again. The residue is dissolved in dichloromethane (6 mL) and added to a flask containing (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.154 g, 1.0 mmol) and N-methylmorpholine (0.111 g, 1.1 mmol) and stirred for 20 min. The reaction is diluted with dichloromethane and washed successively with a saturated solution of sodium bicarbonate and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid. The solid is dissolved in dichloromethane (1 mL) and 2:1 diethyl ether/hexane is added. The resultant solid is filtered and dried to give the pure free base of the title compound. The free base (0.021 g, 0.049 mmol) is dissolved in dichloromethane (1 ml) and 1M anhydrous HCl in diethyl ether (0.1 ml) is added to precipitate the desired title compound as a white solid. MS (ES+) m/e 428.2 (M+1)+ (free base).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)Nc2ccc(C(=O)O)cc2)cc1

Procedure:
In a mixture of 20 ml of dry chloroform and 10 ml of dry pyridine were dissolved 2.6 g of 4-aminobenzoic acid. To this mixture were added dropwise under cooling 20 ml of dry chloroform containing 3.2 g of 4-acetoxycinnamoyl chloride. The mixture was heated under reflux for 2 hours and the reaction mixture was concentrated under reduced pressure. The residue was poured into water and hydrochloric acid was then added to make the liquid weakly acidic. The precipitated crystals were collected by filtration and recrystallized from alcohol to yield 2.9 g of 4-(4'-acetoxycinnamoylamino)-benzoic acid. M.P.=305°-307°C (with decomposition).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:17]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
3-Bromomethylbenzonitrile (5.00 g, 25.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), phenol (2.40 g, 25.5 mmol) and potassium carbonate (10.6 g, 77 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (400 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (2×100 mL), dried (MgSO4) and evaporated in vacuo to afford 5.19 g (97%) 3-(phenoxymethyl)benzonitrile as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[C:15](=[O:18])([OH:17])[O-].[Na+].[I-].[K+].[CH3:22][N:23]([CH3:26])C=[O:25]>>[C:8]([OH:7])(=[O:25])[C:15]([OH:17])=[O:18].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:23]3[CH2:26][CH2:5][CH2:4][CH2:3][CH2:2][CH2:22]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: CN(C)C=O
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: Fc1ccc2c(CCCN3CCCCCC3)noc2c1
Product: O=C(O)C(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To 40 ml of dry dimethylformamide, was added 4.2 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 2.3 ml of hexamethyleneimine, 8.0 g of sodium bicarbonate, and a crystal of potassium iodide. After stirring at 80° C. for three hrs, the mixture was filtered and the filtrate was evaporated to an oil. The oil was stirred with 100 ml of water for five mins and then extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, the solvent was evaporated to an oil. The oil was treated with ethereal hydrogen chloride, and the resultant salt was recrystallized twice from ethylacetate/methanol/ether to give 2.4 g (33%) of product, mp 141°-142° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12](N)([CH3:15])([CH3:14])[CH3:13].C([N:19](CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([S:8]([NH2:19])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)N
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Brc1ccccc1
Product: CC(C)(C)S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Bromobenzenesulfonyl chloride (20 g) was dissolved in dichloromethane (100 mL) and cooled to 0° C. tert-Butylamine (8.2 mL) was added followed by triethylamine (16 mL). The reaction was stirred at room temperature until determined complete by analytical HPLC analysis. Water (100 mL) was added and the layers were separated. The aqueous layer was washed with dichloromethane (50 mL) and the combined organic layers were washed with brine (100 mL). Concentration of the organic phase gave 2-bromobenzene-tert-butylsulfonamide (20 g).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([S:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=3[CH3:32])(=[O:22])=[O:21])[CH2:17]2)=[CH:12][CH:11]=1)(=O)=O>CCO.O.C(OCC)(=O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH3:32])[C:23]([S:20]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][C:10]([CH2:9][C:1]#[N:2])=[CH:11][CH:12]=3)[CH2:17]2)(=[O:22])=[O:21])=[C:28]([CH3:29])[CH:27]=1
Reactant: [C-]#N
Reactant: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(COS(C)(=O)=O)cc3C2)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CC#N)cc3C2)c(C)c1
Yield: 71 %

Procedure:
KCN (2.73 mmol, 1.2 equiv.) was added to a solution of (2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl methanesulfonate (2.28 mmol, 1 equiv.) in EtOH/water (10 ml), and the mixture was refluxed for 24 h. The reaction mixture was then cooled and diluted with ethyl acetate. Extraction with sat. FeSO4 solution, water and sat. NaCl solution was carried out, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel). Yield: 71%
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:16]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([C:12]([F:15])([F:13])[F:14])=[N:10][N:11]=2)[CH2:16][NH:3]1
Reactant: C=O
Reactant: CN(N)C(=O)Nc1nnc(C(F)(F)F)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 35 °C

Procedure:
The 2-methyl-4-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)semicarbazide prepared in Example 2 was dissolved in methanol (100 ml) in a glass reaction flask equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (12 ml; 37% concentration) was then added to the flask with stirring. The reaction mixture warmed to a temperature of about 35°C. Sufficient aqueous potassium hydroxide was then added to adjust the pH of the reaction medium to from about 7 to 8. A solid precipitate was formed. The precipitate was then recovered by filtration, was recrystallized from an ethyl acetate-heptane mixture and was dried under vacuum to yield the desired product 2-methyl-4-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one having a melting point of 187° to 188°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:30]([C:33]4[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[CH:36]=[C:35]([O:42][CH3:43])[C:34]=4[Cl:44])=[CH:31][CH:32]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.C(Cl)Cl.O>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:30]([C:33]4[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[CH:36]=[C:35]([O:42][CH3:43])[C:34]=4[Cl:44])=[CH:31][CH:32]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c3nccnc23)c1Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(N4CCNCC4)cc3)c3nccnc23)c1Cl
Yield: 80.2 %

Procedure:
A mixture of 4-(4-{[8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonyl]-amino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Step 8.1) (137 mg, 0.22 mmol) and a 4 N solution of HCl in dioxane (5 mL) was stirred for 1 h at rt. The reaction mixture was diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in Et2O to afford 95 mg of the title compound as a red solid: ESI-MS: 537.9/539.9 [M+H]+; tR=4.01 min (System 1).
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>CO>[CH2:16]([NH:18][C:19](=[O:20])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CC[C@@H](C)Oc1ccc(OCCO)cc1
Reactant: CCN=C=O
Solvent: CO
Product: CCNC(=O)OCCOc1ccc(O[C@H](C)CC)cc1

Procedure:
Following the procedure of Example 9, the above alcohol (0.42 g, 2.0 mmol) is reacted with ethyl isocyanate (0.18 ml, 2.2 mmol) to give O-2-[(R)-4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate, specific rotation [α]D20 =-19.103° (c=10% in methanol).