Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16](O)[C@@H:15]([CH3:27])[O:14][C@@H:10]1[S:11][CH2:12][CH3:13])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[N-:57]=[N+:58]=[N-:59].[Na+]>C(Cl)Cl.CN(C=O)C>[N:57]([C@@H:16]1[C@@H:15]([CH3:27])[O:14][C@H:10]([S:11][CH2:12][CH3:13])[C@H:9]([O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5])[C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:58]=[N-:59]
Reactant: CCS[C@H]1O[C@H](C)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OC(=O)CCC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCS[C@H]1O[C@H](C)[C@@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OC(=O)CCC(C)=O
Yield: 79.1 %

Procedure:
Treatment of 12 (0.50 g, 1.26 mmol) in pyridine (1.02 mL, 12.61 mmol) and DCM (6.5 mL) with trifluoromethanesulfonic anhydride (0.32 mL, 1.90 mmol) followed by treatment of triflate residue in DMF (16 mL) with sodium azide (0.41 g, 6.31 mmol) according to the general procedure for introduction of the C-4 azide group gave compound 13 as colorless oil (0.42 g, 79%). Rf=0.32 (Hexane/EtOAc, 4:1, v:v). [α]27D=+13.1 (CHCl3, c=5.1 mg/mL). 1H NMR (300 MHz, CDCl3): δ 1.67 (t, 3H, J=7.5 Hz, SCH2CH3), 1.30 (d, 3H, J5,6=5.7 Hz, H-6), 2.10 (s, 3H, CH3C(O)CH2CH2C(O)O), 2.44-2.49 (m, 2H, CH3C(O)CH2CH2C(O)O), 2.57-2.67 (m, 4H, SCH2CH3, CH3C(O)CH2CH2C(O)O), 3.11-3.24 (m, 2H, H-4, H-5), 3.48 (t, J3,4=9.0, J2,3=9.0 Hz, H-3), 4.27 (d, 1H, J1,2=9.9 Hz, H-1), 4.68 (d, 1H, J=11.1 Hz, PhCH2), 4.71 (d, 1H, J=11.1 Hz, PhCH′2), 4.94 (dd, 1H, J1,2=9.9, J2,3=9.0 Hz, H-2), 7.22-7.29 (m, 5H, Harom); 13C NMR (75 MHz, CDCl3): δ 14.8 (SCH2CH3), 18.7 (C-6), 23.9 (SCH2CH3), 28.0 (CH3C(O)CH2CH2C(O)O), 29.8 (CH3C(O)CH2CH2C(O)O), 37.8 (CH3C(O)CH2CH2C(O)O), 67.7 (C-4), 72.2 (C-2), 74.9 (PhCH2), 75.1 (C-5), 82.3 (C-3), 83.2 (C-1), [127.9, 128.0, 128.2, 128.4, 137.5 (Carom)], 171.5 (CH3C(O)CH2CH2C(O)O), 206.1 (CH3C(O)CH2CH2C(O)O); MALDI-TOF/MS: m/z: found [M+Na]+ 444.1, C20H27N3O5S calcd for [M+Na]+ 444.15.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:5]/[CH:4]=[C:2](\[CH3:3])/[C:1]([O:7][CH3:8])=[O:6]
Reactant: C/C=C(\C)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(C)=C/CBr

Procedure:
To a solution of methyl tiglate (2.00 g, 17.5 mmol) in CCl4 (8.76 mL) was added NBS (3.43 g, 19.3 mmol) and benzoyl peroxide (212 mg, 0.876 mmol). The reaction was heated to reflux for 3 hours, cooled and filtered through Celite using DCM to wash the filtrate. The reaction was concentrated in vacuo and then purified by silica chromatography using 1-15% EtOAc/hexane. The product was collected and concentrated in vacuo to afford the desired product as a colorless oil that was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2nccs2)cc1

Procedure:
Using 2-bromothiazole (0.5 g, 3.05 mmol) and (4-chlorophenyl)boronic acid (0.57 g, 3.65 mmol) and following the procedure described in Example 7, Step 1, the title compound was obtained after purification by column chromatography (15% ethyl acetate in hexane) as colorless viscous liquid (0.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, 2H), 7.92 (d, 1H), 7.80 (d, 1H), 7.55 (d, 2H); LC-MS m/z calculated for [M+H]+ 195.99, found 195.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2cccnc2c1OCc1ccccc1
Yield: 77 %

Procedure:
7-Methyloxy-8-hydroxyquinoline (1.10 g; 6.29 mmol) and K2CO3 (1.30 g; 9.43 mmol) in 30 ml of dry acetonitrile are stirred for 10 minutes under argon. Benzyl chloride (0.87 ml, 7.54 mmol) is then added and the reaction medium is heated under reflux overnight. After returning to ambient temperature, the precipitate is filtered, washed with CH2Cl2 and the filtrate is concentrated under reduced pressure. The oil obtained is dissolved again in CH2Cl2 (50 ml) and washed in succession with an aqueous solution of NaOH 2 N (4×50 ml) and water (1×50 ml). The organic phase is dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure to yield 7-methyloxy-8-[(phenylmethyl)oxy]quinoline in the form of a brown oil (1.28 g; 4.84 mmol, yield=77%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.94 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.06 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.59-7.51 (m, 3H); 7.36-7.24 (m, 5H); 5.40 (s, 2H); 3.92 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 151.3 (CH); 149.5 (Cq); 142.9 (Cq); 141.2 (Cq); 137.4 (Cq); 135.3 (CH); 127.9 (CH); 127.4 (CH); 127.1 (CH); 123.6 (Cq); 122.9 (CH); 118.5 (CH) 114.8 (CH); 75.2 (CH2); 56.1 (CH3). MS (CID, NH3): m/z=266 (MH+). Analysis (%) for C17H15NO2.0.05 CHCl3: calculated C, 75.49; H, 5.59; N, 5.16. found C, 75.74; H, 5.40; N, 5.33.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][NH:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]4[CH2:49][CH2:50][C:51]5[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=5)[CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCc3ccccc3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 1,2,3,4-tetrahydroisoquinoline (Aldrich) to give the title product. LC-MS (ES+) 780 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:22][N:23](C=O)C.CN>C(Cl)Cl>[CH3:22][NH:23][C:13]([C:8]12[CH2:11][CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:10][CH2:9]1)[CH2:6][CH2:7]2)=[O:15]
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)C12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 1-A (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (4.0 g, 18.9 mmol) was dissolved in 12 mL of anhydrous methylene chloride under a nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 28 mL, 56 mmol) and subsequently with 0.5 ml of DMF. The reaction was stirred at room temperature under a nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The reaction was concentrated and stripped from toluene 3 times. The acid chloride was dissolved in anhydrous methylene chloride (75 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 57 mL, 113 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 1000 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. Product was purified by flash silica gel chromatography, eluting with a 0-5% MeOH/CH2Cl2 gradient to yield 1-B as a white solid. MS (ESI+)=226.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].[CH2:19](C1CCC(=O)CC1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:5][C:6]2[CH2:2][CH:1]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:4][CH2:8][C:7]=2[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: N#CCC(=O)c1cccs1
Reactant: CC(=O)c1cccs1
Agent: [S]
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1cccs1)CCC(Cc1ccccc1)C2
Yield: 72 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophen-2-carbonyl)acetonitrile (Steps A and B). 4-Benzyl-cyclohexanone (Rosowsky et al., (1999) J. Med. Chem. 42: 1007–1017), 2-(thiophen-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 72%; IR (KBr) cm−1: 3465, 2925, 1554, 1425, 1270, 1041, 768, 730, 702; 1H NMR (CDCl3): 0.88 (m, 1H), 1.27 (m, 2H, 1.56 (m, 1H), 2.23 (m, 3H), 2.66 (dd, 2H, J=7.2 and 3 Hz), 6.11 (bs, 2H), 7.04 (t,1H, J=4.4 Hz), 7.23 (m, 6H), 7.52 (d, 1H, J=4.8 Hz); mp: 116–118° C. (petroleum ether).
Reaction SMILES: [C:1]1(OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[C:17]1=O)[CH2:23]2.FC(F)(F)CO[C:31](=O)[C:32]1[CH:37]=CC(Cl)=C(OC)[CH:33]=1>C1COCC1.[Cl-].[Cl-].[Cl-].[Ti+3].[Zn]>[CH:1]12[CH2:6][CH:5]3[CH2:31][CH:32]([CH2:37][CH:3]([CH2:4]3)[C:2]1=[C:17]1[CH:18]3[CH2:24][CH:22]4[CH2:21][CH:20]([CH2:25][CH:16]1[CH2:23]4)[CH2:19]3)[CH2:33]2
Reactant: COc1ccccc1
Reactant: COc1cc(C(=O)OCC(F)(F)F)ccc1Cl
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Reaction time: 0.25 h

Procedure:
2-Chloro-5-(2,2,2-trifluoroethoxy-tricyclo[3.3.1.13,7 ]de-2-ylidenemethyl) anisole. Titanium trichloride, 7.9 g (51.3 mmol), was weighed into a round-bottomed flask in a glove bag under an argon atmosphere. Freshly distilled tetrahydrofuran (from LAH), 60 mL, was added quickly under argon flow. Care should be taken, as this addition can be exothermic. The purple suspension was stirred vigorously so as to break up the solid adhering to the walls of the flask. After 15 minutes, zinc dust, 5.2 g, was added all at once under argon with continued stirring. A moderate exotherm resulted in a reddish-brown mixture which did not contain black suspended solids. After 15 minutes stirring, the triethylamine, 11 mL, was added with exclusion of air. The mixture was then refluxed for 2 hours. A solution of 2-adamantanone, 3.0 g (20 mmol), and 2,2,2-trifluoroethyl-4-chloro-3-methoxybenzoate, 2.6 g (10 mmol) in dry THF, 30 mL, was added dropwise to the refluxing brown mixture over approximately 65 minutes. Reflux was continued overnight for 16 hours. The solvents were rotary evaporated from the cooled reaction mixture to yield a brown-black gum. This gum was triturated with hexanes, 100 mL, and ethyl acetate, 20 mL. The yellow-orange supernate was decanted and the trituration procedure was repeated. After 10 minutes of agitation, triethylamine and methanol, 5 mL each, were added. The gum began to stiffen and eventually became a lumpy solid. The solid was broken up and the supernate decanted. One final trituration was accomplished with 20% ethyl acetate-hexanes. The combined decanted supernates were rotary evaporated to a light yellow, semisolid pasta. The mixture was treated with hot hexanes, 50 mL, and filtered warm to remove some insolubles. The residue obtained after rotary evaporation of the filtrate was applied to a 2.1×20 cm column of activity I aluminum oxide as a slurry in a small amount of warm hexanes. The column was eluted with hexanes to obtain adamantylidene adamantane. The elution was continued with 10% dichloromethane-hexanes to obtain an oil which contained two major mid Rf, UV-active components. The oil was taken up in a small amount of hot hexanes. A crystalline, colorless solid, weighing 0.71 g and having a melting point of 108-124° C., precipitated out upon cooling.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:9]1[CH:14]=[C:13]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
1-methylpiperazine (298.5 mg, 330.6 μL, 2.980 mmol) in THF (5 mL) was added to a stirred solution of 2,4-dichloro-5-nitro-pyridine (500 mg, 2.591 mmol) and DIPEA (401.8 mg, 541.5 μL, 3.109 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to stir at ambient temperature for 1 hour then the solvent removed in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM solutions) to give 1-(2-chloro-5-nitropyridin-4-yl)-4-methylpiperazine as a yellow solid (638 mg, 96% Yield). MS (ES+) 257.1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl>O1CCCC1.O>[CH2:34]([O:33][C:31]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.6 %

Procedure:
A solution of (2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid trifluoroacetate (45 mg, 109 μmol), sodium hydroxide (26.2 mg, 655 μmol), water (100 μL) and tetrahydrofuran (2 mL) was cooled to 0° C. and then benzyl chloroformate (18.7 μL, 131 μmol) was added. The reaction was warmed to 25° C. and stirred for 20 h. The solution was acidified with 1 N aq. HCl solution (1.00 mL) and the crude residue was purified by preparative LCMS to yield the desired product (13 mg, 28%). MF=C20H20N2O7S; LCMS found for C20H21N2O7S (M+H)+: m/z=433.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)=[N:10]1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)cc1OC
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 43.5 %

Procedure:
The title compound was prepared by following the procedure as described for step-6 of Intermediate-26 by using methyl 4-(1-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-methoxybenzoate (Intermediate-46, 0.070 g, 0.17 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.048 g, 0.26 mmol), trimethyl aluminum (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.040 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.49-7.64 (m, 4H), 7.72-7.76 (m, 3H), 7.99 (m, 1H), 8.25 (m, 1H), 10.52 (s, 1H), 12.86 (s, 1H); MS (m/z): 541.05 (M+).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[C:10](=[O:16])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:38])(C2C=CC=CC=2)=O)C=CC=CC=1.CN(C=O)C>C1COCC1.CCOC(C)=O>[NH2:38][N:9]1[C:10](=[O:16])[C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc(-c2ccccc2)c2sccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nn1nc(-c2ccccc2)c2sccc2c1=O
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A mixture of Example 9A (69.1 mg, 0.303 mmol) and KOtBu (1 M in THF, 0.35 mL, 0.35 mmol) in THF (1.5 mL) was stirred for 60 min, and O-(diphenylphosphoryl)hydroxylamine (81.0 mg, 0.348 mmol) and DMF (1.5 mL) were added and stirred 1 hour. The mixture was diluted with EtOAc, washed with 1 N NaOH and water, dried (Na2SO4), filtered, and concentrated to give the title compound as a white solid (62.6 mg), which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, 1H), 7.89-7.82 (m, 2H), 7.75 (d, 1H), 7.64-7.51 (m, 3H), 6.65 (s, 2H); LC/MS (APCI) M/Z 244.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[NH:7].C(N(CC)CC)C.[C:28]([Cl:45])(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[ClH:45].[C:28]([O:1][CH:2]([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[NH:7])(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: N=C(NOCC(O)CN1CCCCC1)c1cccnc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OC(CONC(=N)c1cccnc1)CN1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.7 g (52.8 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide [Hung. Pat. 177.578 (1976)] was dissolved in 160 ml of chloroform. 7.7 ml (55 mmol) of triethylamine was added, followed by dropwise addition of a solution of palmitoyl chloride (14.7 g; 56.5 mmol) in 85 ml of chloroform. The mixture was stirred overnight at room temperature. Next day further amount of 3.8 ml of triethylamine and 7.4 g of palmitoylchloride was added, and the stirring was continued for one more day. The solution was extracted then with water, 5% acetic acid and water, successively, dried over anh. sodium sulfate, and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]1>>[CH2:23]([CH:21]1[CH2:20][O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1)[CH3:24]
Reactant: CCC1COC(CBr)O1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1COC(CNc2ccccc2OC)O1

Procedure:
2-Methoxyaniline (0.5 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-ethyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4-ethyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N:20]1([C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
To 0.200 g (0.77 mmol) of 2-bromo-7-nitro-1,3-benzothiazole in 2 mL of DMF was added 0.21 g (1.5 mmol) of potassium carbonate and 81 μL (0.93 mmol) of morpholine. The mixture was stirred at room temperature for 72 h and diluted with water. The precipitate that formed was collected by filtration and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.075 g (37%) of the title compound as a cream colored powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:11]([O-:14])(=[O:13])[CH3:12].[NH4+:15].C(O)(=O)CC(O)=O>>[NH2:15][CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][C:11]([OH:14])=[O:13]
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Reactant: COc1cccc(C=O)c1
Agent: O=C(O)CC(=O)O
Product: COc1cccc(C(N)CC(=O)O)c1

Procedure:
Corresponding to Example 1a, 200 g of 3-methoxybenzaldehyde were reacted with ammonium acetate and malonic acid. A white solid was obtained (yield: 135.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:14])([CH:12]=[CH2:13])[CH:10]=[CH2:11])=[CH:5][CH:4]=1.[CH3:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([P:9]2(=[O:14])[CH2:12][CH2:13][N:16]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CN
Reactant: C=CP(=O)(C=C)c1ccc(OC)cc1
Product: COc1ccc(P2(=O)CCN(C)CC2)cc1
Temperature: 25 °C

Procedure:
(4-Methoxyphenyl)(divinyl) phosphine oxide (1.22 g, 5.88 mmol) and methylamine (0.53 mL, 6.18 mmol, 40% in water) was heated to 90° C. for 2 h. The reaction mixture was cooled to ambient temperature then extracted with DCM (3×). The combined organic extracts were dried (MgSO4) then concentrated in vacuo to afford the requisite product. MS: cal'd 240 (MH+), exp 240 (MH+)