Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH3:2].[CH3:11][CH:12]1C(=O)CCCC1=O>>[OH:9][CH:8]([CH2:3][CH2:1][CH3:2])[CH2:7][CH2:6][CH2:5][C:4](=[O:10])[CH:11]=[CH2:12]
Reactant: CC1C(=O)CCCC1=O
Reactant: CCC1C(=O)CCCC1=O
Product: C=CC(=O)CCCC(O)CCC

Procedure:
Employing procedures similar to those described in Example 1, except that 2-ethylcyclohexane-1,3-dione is substituted for 2-methylcyclohexane-1,3-dione, 7-hydroxydec-1-en-3-one is produced.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.C(O)C.O.[NH2:18][NH2:19]>O>[CH3:2][O:3][C:4]([C:5]1[CH:10]=[N:18][NH:19][CH:6]=1)=[O:12]
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: NN
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cn[nH]c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
44.45 g of methyl 3,3-dimethoxypropionate and 45 ml of methyl formate was dissolved to 180 ml of dimethoxyethane. Under nitrogen atmosphere, 12.8 g of 60% sodium hydride was added to the solution keeping the temperature of the solution at 40 to 50° C. during addition. Then the mixture was stirred at room temperature for 18 hours. 180 ml of diethylether was added to the reaction mixture, as a result, a solid was formed. The solid was collected by filteration, followed by washing with 60 ml of diethylether. The obtained solid was dried under reduced pressure for overnight to obtain 49.41 g of methyl 2-(dimethoxymethyl)-3-hydroxy-acrylate sodium salt. 9.91 g of methyl 2-(dimethoxymethyl)-3-hydroxy-acrylate sodium salt was suspended to 100 ml of ethanol. 2.50 g of hydrazine hydrate was added to the suspension, followed by stirring at room temperature for 3 hours and at 80° C. for 1 hour. 100 ml of water was added to the reaction mixture which was cooled to room temperature. The mixture was concentrated under reduced pressure to about 100 ml. The concentrated solution was extracted by ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved to ethyl acetate, activated carbon was added to it, and stirred for overnight. The suspension was filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 1.40 g of 4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: O[C:2]1[CH:7]=CN=C[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:41][O:42][CH:43]([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]CCC)[CH2:44][OH:45]>C1COCC1.N1C=CC=CC=1>[CH3:41][O:42][CH:43]([CH:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:3][CH2:2][CH3:7])[CH2:44][OH:45]
Reactant: CCCCCCCCCCCCCCCCC(CO)OC
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCC)C(CO)OC
Reaction time: 8 h
Yield: 199.7 %

Procedure:
Preparation of pyridine terminated 4-hexadecylethylene glycol monomethylether (Ligand 2). 4-hydroxypyridine (2.0 g, 22 mmol), triphenylphosphine (6.3 g, 24 mmol), and diisopropyl azodicarboxylate (4.8 g, 24 mmol) in THF (250 mL) were stirred at room temperature under nitrogen for 30 min.; hexadecylethylene glycol monomethylether (14.3 g, 20 mmol) was added, and the mixture was stirred overnight. THF was removed under vacuum, and the residue was purified by column chromatography eluting with chloroform:acetone:methanol mixtures to yield 2 (12.0 g, 78%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, aromatic), 6.82 (d, aromatic), 4.15 (t, pyr-O—CH2—CH2), 3.86 (t, pyr-O—CH2—CH2), 3.66 (br, CH2, 3.37 (s, CH3) ppm; 13C NMR (75 MHz, CDCl3) δ 164.7, 150.9, 110.2, 72.6, 71.8, 70.8, 70.4, 70.1, 67.1, 69.2, 58.9 ppm; HRMS calcd. 769.4441; Found M−H 768.4385.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH2:17].Cl.[OH-].[Na+]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[NH:17][CH2:16][CH2:15]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)C(c1ccc(F)cc1)NCC2
Reaction time: 3 h

Procedure:
50 parts of p-fluorobenzaldehyde and 65 parts of 3,4-dimethoxyphenethylamine are combined and heated over a steam bath in a nitrogen atmosphere for 90 minutes. Then 800 parts by volume of 20% by weight hydrochloric acid is added and heating is continued for an additional 3 hours. The reaction mixture is cooled, made alkaline with sodium hydroxide and extracted with methylene chloride. The organic layer is dried over anhydrous calcium sulfate and stripped in vacuo to give 6,7-dimethoxy-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline. After crystallization from a mixture of ethyl ether and n-hexane, that product melts at about 145°-150°C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (113 mg, 156 μl, 1.12 mmol) and methanesulfonyl chloride (42.8 mg, 29 μl, 374 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (96 mg, 95%), MS (ISP) m/z=407.4 [(M+H)+], mp 152° C.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[N:20]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[O:25])=[N+]=[N-].C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:23][N:20]=1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1[N+](=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2ccccc2[N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphenylphosphine, polymer bound, (5.3 g, 3 mmol/g, Fluka Chimica, Buchs, Switzerland) was scurried in toluene (75 mL). A solution of 2-azido-2′-nitroacetophenone (2.18 g, 10.6 mmol) and acetyl chloride (0.848 g, 10.8 mmol) in toluene (25 mL) was added at room temperature, under a nitrogen atmosphere. The solution was stirred at room temperature for six hours, then filtered over celite. All volatiles were removed from the filtrate by evaporation under reduced pressure to yield 0.91 g of crude 2-methyl-5-(2-nitrophenyl)oxazole. Crude 2-methyl-5-(2-nitrophenyl)oxazole (0.905 g, 4.44 mmol) was reduced as in Example 64, and the product purified by silica chromatography to give 0.51 g of 5-(2-aminophenyl)-2-methyloxazole.
Reaction SMILES: Br[CH2:2]/[C:3](/[F:15])=[C:4](\[CH3:14])/[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]1([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2]/[C:3](/[F:15])=[C:4](\[CH3:14])/[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:26][CH:25]=2)=[O:31])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C/C(CNC(=O)OC(C)(C)C)=C(/F)CBr
Reactant: O=C(NC1CCCCC1)c1ccc(O)cc1
Product: C/C(CNC(=O)OC(C)(C)C)=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1

Procedure:
This compound was synthesized from tert-butyl [(2Z)-4-bromo-3-fluoro-2-methylbut-2-en-1-yl]carbamate and N-cyclohexyl-4-hydroxybenzamide following procedure F and was obtained as a colorless solid; 1H-NMR (400 MHz, CDCl3): δppm: 1.14-1.30 (3H, m), 1.35-1.49 (2H, m), 1.44 (9H, s), 1.60-1.70 (1H, m), 1.70-1.79 (2H, m), 1.76 (3H, d, J 3.2 Hz), 1.98-2.04 (2H, m), 3.90 (2H, d, J 5.3 Hz), 3.96 (1H, m), 4.59 (1H, br s), 4.63 (2H, d, J 21.2 Hz), 5.86 (1H, d, J 7.9 Hz), 6.93 (2H, d, J 8.7 Hz), 7.71 (2H, d, J 8.7 Hz).
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(NO)(C)(C)C.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:24]([C:28]1[S:32]/[C:31](=[N:33]\[C:34](=[O:46])[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2F)/[N:30]([CH2:47][C@H:48]2[CH2:52][CH2:51][CH2:50][O:49]2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([NH:5][O:6][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:42])([F:44])[F:43])=[CH:40][C:35]=1[C:34](/[N:33]=[C:31]1\[S:32][C:28]([C:24]([CH3:27])([CH3:25])[CH3:26])=[N:29][N:30]\1[CH2:47][C@H:48]1[CH2:52][CH2:51][CH2:50][O:49]1)=[O:46])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(C)(C)c1nn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butylhydroxylamine (145 mg, 1.62 mmol) (prepared from commercially available N-tert-butylhydroxylamine acetate (Aldrich) by adding saturated sodium bicarbonate solution and extracting the free base with ethyl ether) in anhydrous THF (10 mL) was added sodium hydride (58.4 mg, 1.46 mmol). The mixture was stirred at 0° C. for 20 minutes. A solution of Example 153A (350 mg, 0.81 mmol) in THF (4 mL) was added and the mixture was stirred at 0° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-50% gradient) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.42 (s, 9H), 1.74-1.89 (m, 1H), 1.88-2.08 (m, 3H), 3.74-3.84 (m, 1H), 3.89-4.00 (m, 1H), 4.29 (dd, J=12.0, 4.7 Hz, 1H), 4.45-4.63 (m, 2H), 5.73 (s, 1H), 7.59 (dd, J=8.8, 3.1 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H); MS (ESI) m/z 501 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:35])[C:19]([C:25]2[CH:34]=[CH:33][C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[CH:26]=2)=[CH:20][O:21][CH:22]([F:24])[F:23])=[CH:11][C:10]=1[O:36][CH3:37])C1C=CC=CC=1.Br.C(O)(=O)C>O>[F:23][CH:22]([F:24])[O:21][CH:20]=[C:19]([C:25]1[CH:34]=[CH:33][C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=1)[C:18]([NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:36][CH3:37])[CH:11]=1)=[O:35]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
2.40 g (4.73 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-difluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 1.20 g (7.09 mmol) of 48% hydrobromic acid and 30 ml of acetic acid were mixed and stirred at 80° C. for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to give 1.81 g of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1371).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Solvent: c1ccncc1
Product: O=C1Nc2cccc(-c3cccc(NS(=O)(=O)c4cccs4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (27 mg, 0.090 mmol) (from Example 4 supra) in 1.5 mL of pyridine (Fisher Scientific) was treated dropwise with 2-thiophenesulfonyl chloride (19 mg, 0.104) (Aldrich). The reaction mixture was stirred at room temperature for 30 min and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes then 40% ethyl acetate-hexanes elution) to provide a crude yellow solid. Recrystallization from chloroform-pentane provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]-2-thiophenesulfonamide (17 mg, 42%) as an orange solid (mp 218-220° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O.ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[N+:19]=[N-:20])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(N=[N+]=[N-])cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
3,4,5-Trimethoxyaniline (1.83 g; 10 mmol) is added to a 100 mL flask containing water (20 mL) and HCl (conc. aqueous solution, 5 mL). The solution is chilled to 0° C. and a solution of sodium nitrite (830 mg; 12 mmol) in water (5 mL) is added. The solution is stirred at 0° C. for 30 minutes, and then a solution of sodium azide (1.3 g; 20 mmol) in water (5 mL) is added. After another 30 minutes of stirring, dichloromethane is added (20 mL) and the organic phase was collected and filtered through a plug of silica, dried over magnesium sulfate and the solvent was evaporated to give approximately two grams of 3,4,5-trimethoxyphenyl azide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15].Cl.[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19].Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][C:6]2[C:7](=[O:14])[O:8][C:9]3[C:4]([C:5]=2[CH3:15])=[CH:3][C:2]([F:1])=[C:11]([OH:12])[C:10]=3[F:13])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(OC(=O)c2ccc(NC(=N)N)cc2)c(=O)oc2c(F)c(O)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a pale yellow solution of 6,8-difluoro-7-hydroxy-4-methylcoumarin (Compound 5, 0.13 g, 0.61 mmol) in THF (5 mL) under air at room temperature is added a solution of 4-guanidinobenzoic acid hydrochloride (132 mg, 0.61 mmol) in 4 mL water, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 125 mg, 0.65 mmol). The resulting solution is stirred at room temperature overnight, followed by the addition of more EDC (100 mg). After two hours, TLC analysis indicates the starting materials are consumed. Volatiles are removed in vacuo, and a portion of the residue (0.61 g of pale yellow powder) is purified by chromatography on SEPHADEX LH-20 resin using water:dioxane (1:1) as eluant to give nonfluorescent Compound 35 as a colorless powder: Rf =0.30 (MeCN:H2O:AcOH 90:5:5). Upon treatment with ammonia vapor, a TLC spot corresponding to Compound 35 becomes blue fluorescent.
Reaction SMILES: [CH3:1][O:2][C:3]([NH2:5])=[NH:4].C[O:7][C:8]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])=O>O1CCCC1>[NH2:4][C:3](=[N:5][C:8]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])=[O:7])[O:2][CH3:1]
Reactant: COC(=N)N
Reactant: COC(=O)P(=O)(OC)OC
Solvent: C1CCOC1
Product: COC(N)=NC(=O)P(=O)(OC)OC

Procedure:
a mixture of 23 parts of 0-methylisourea and 54 parts of dimethyl methoxycarbonylphosphonate in 1000 parts of anhydrous tetrahydrofuran was refluxed for one hour. The solvent was removed to give dimethyl 1-amino-1-methoxy-methyleneaminocarbonylphosphonate, nD27 = 1.4774.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].[NH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[N:14]=1.C(#N)C>C(Cl)Cl>[CH3:20][O:19][C:17]1[CH:16]=[C:15]([CH3:21])[N:14]=[C:13]([NH:12][C:10]([NH:9][S:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[O:11])[N:18]=1
Reactant: O=C=NS(=O)(=O)c1ccco1
Reactant: COc1cc(C)nc(N)n1
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccco2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.10 g of 2-furansulfonyl isocyanate in 40 ml of methylene chloride was added 1.60 g 2-amino-4-methoxy-6-methylpyrimidine. The resulting mixture was stirred for 1 hour at room temperature, then refluxed for 15 minutes, and the solvent was removed under vacuum. The solid obtained was allowed to stand under ethyl ether containing a trace of acetonitrile for one day, and was then filtered and dried to give the desired product melting at 185°-188° (dec).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:36]Br>C(Cl)Cl.O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[Br:36])[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: C[C@@H](O[C@H]1CN(C2=C(Br)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a round bottomed flask, 150 mg (0.299 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F) was dissolved in methylene chloride (5 mL) under nitrogen atmosphere and cooled to 0° C. To this solution was added a solution of 300 mg (1.877 mmol) bromine in methylene chloride (5 mL). The resulting solution was stirred for 0.25 hr at 0° C. then was quenched by the addition of sat. aq. Na2SO3 until a clear solution resulted. The mixture was diluted with 5 mL water then extracted with methylene chloride (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (95/5) to afford the title compound and a small amount of the less polar 2,2-dibromo compound. Monobromide, 1H-NMR (CD3OD): δ: 1.44 (d, 3H), 2.48 (br. s, 2H), 2.87 (m, 2H), 3.43 (m, 1H), 3.66 (m, 1H), 4.0-4.22 (m, 2H), 4.70-4.83 (m, 2H), 6.98 (t, 2H), 7.18 (dd, 2H), 7.70 (s, 2H), 7.83 (s, 1H)ppm. MS: 580.0 and 582 (MH+) observed. Dibromide, 1H-NMR (CD3OD): δ: 1.46 (d, 3H), 2.82 (d, 1H), 3.24 (dd, 1H), 3.38-4.85 (m, 7H), 5.35, 5.36 (2s, 1H), 7.00 (m, 2H), 7.20 (m, 2H), 7.67-7.87 (m, 3H)ppm. MS: 657.9, 659.9 and 661.9 (MH+) observed.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.C(Cl)Cl.CS(Cl)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:27][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: OCCCSc1ccncc1
Reactant: NCc1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CNCCCSc2ccncc2)nc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of 5.26 g (31.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.20 ml (37.3 mmol) of triethylamine in150 ml of methylene chloride, 2.90 ml (37.3 mmol) of methanesulfonyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. To 6.33 g of the residue was added 2.64 ml (25.6 mmol) of 2-aminomethylpyridine. The resulting mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 1.62 g of the desired compound (yield: 25.4%, yellow oil).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:28](=[O:29])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]=2[CH:8]=1)=[O:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CCNc1cc(C(=O)OC(C)(C)C)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CCn1c(=O)[nH]c2ccc(C(=O)OC(C)(C)C)cc21

Procedure:
To a solution of 4-Amino-3-(2-Ethoxycarbonyl-ethylamino)-benzoic acid tert-butyl ester (900 mg, 2.92 mmol) in THF (20 ml) was added CDI (997 mg, 6 mmol). The solution was heated at 90 degrees for 30 minutes. The reaction mixture was evaporated to dryness, and then taken up in Ethyl Acetate. The organic phase was washed with brine, dried over MgSO4, filtered, evaporated to dryness. The residue was purified by flash Chromatography eluded with 5% methanol in CH2Cl2. After evaporation of the desired fractions, 800 mg was obtained (82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:30][S:29][C:28](=[O:31])[NH:27][N:26]=2)=[CH:21][CH:20]=1.O>C(#N)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:30][S:29][C:28](=[O:31])[N:27]([CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CS1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1SCC(c2ccc(Cl)cc2)=NN1Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
4.19 g of 3-nitrobenzyl bromide and 9.95 g of potassium carbonate are added to a solution of 4.00 g of 5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one in 80 ml of acetonitrile, and the mixture is stirred at 80° for a further 2 h. The mixture is poured into water, extracted 2× with diethyl ether, dried, filtered and evaporated to dryness. A little diethyl ether is added to the residue, which is crystallised and dried in a vacuum drying cabinet at 50° C., giving 5.5 g (86%) of 5-(4-chlorophenyl)-3-(3-nitrobenzyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.