Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1.B(O)(O)O>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: Cc1ccccc1
Agent: OB(O)O
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 119 °C
Yield: 94 %

Procedure:
First, 9.00 g (107 mmol) of tiglic aldehyde and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.30 g (4.85 mmol) of boric acid was added. Then the mixture was heated under reflux for 4 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.1 g of 2-benzenesulfonyl-5-methylpyridine as colorless crystals (purity of 99%, yield of 94% based on benzenesulfonyl cyanide).
Reaction SMILES: [C:1]1([S:7]([O:10]C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[N:29]([C:30]([NH:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:31])[C:28](=[O:39])[N:27]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=4)[C:26]=3[CH3:50])=[CH:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1)#[N:13].O.CCOC(C)=O>C1COCC1>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[N:29]([C:30]([NH:32][CH2:33][CH2:34][CH2:35][N+:36]([CH3:1])([CH3:37])[CH3:38])=[O:31])[C:28](=[O:39])[N:27]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=4)[C:26]=3[CH3:50])=[CH:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1)#[N:13].[C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: COS(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(C(=O)NCCC[N+](C)(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: O=S(=O)([O-])c1ccccc1
Reaction time: 2 h
Yield: 140.9 %

Procedure:
Methyl benzenesulfonate (0.019 mL, 0.14 mmol) was added to a solution of 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[3-(dimethylamino)propyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazole-1-carboxamide (Example 9) (77 mg, 0.14 mmol) in THF (3.0 mL). The mixture was stirred for 2 hr then allowed to stand at RT for 2 days. Water (15 mL) and EtOAc (15 ml) were added with stirring. The phases were separated. The aqueous phase was washed with EtOAc (15 mL) then diluted with MeCN. The solvents were removed by lyophilisation to afford the title compound (70 mg) a white solid.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH2:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:12]([N:15]([CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH:13]=[CH2:14]
Reactant: O=C(CBr)c1cccnc1
Reactant: C=CCNCC=C
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CC=C)CC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
2-Bromo-1-(3-pyridyl)ethanone hydrobromide (10 g, 23.49 mmol) is added portion wise over 5 minutes to a stirred solution of diallylamine (5.2 mL, 42.29 mmol) and diisopropylethylamine (10.24 mL, 58.73 mmol) in tetrahydrofuran (150 mL) at 0° C. The resulting mixture is stirred at 0° C. for 1 hour. The reaction is quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL) and dichloromethane (300 mL). The layers are separated and the aqueous phase is re-extracted with dichloromethane (300 mL). The combined organic layers are dried over magnesium sulfate and the solvents are removed under reduced pressure to give a crude product which is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (4.75 g, 93%). ES/MS (m/e): 217 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[N:6]=[CH:5]2
Reactant: Fc1c(Br)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of 5-bromo-4-fluoro-1H-indazole (50 g, 0.23 mol) and DHP (23 g, 0.28 mol) in dry dichloromethane (1000 mL) was added PTSA (2.2 g, 11.5 mmol) at room temperature. The resulting mixture was stirred overnight at that temperature. Upon completion, saturated aqueous NaHCO3 (100 mL) was added slowly into the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜2% EtOAc in petroleum ether) and then re-crystallized from petroleum ether to afford the title compound (55 g). 1H NMR (300 MHz, DMSO-d6,): δ 8.28 (s, 1H), 7.58-7.66 (m, 2H), 5.89 (dd, 1H), 3.90-3.85 (m, 1H), 3.79-3.70 (m, 1H), 2.42-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.77-1.68 (m, 1H), 1.60-1.53 (m, 2H); LCMS: 299 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:36]=[N+:37]=[N-:38].[Na+]>C(Cl)(Cl)(Cl)Cl.CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([C:10]([F:13])([F:12])[F:11])=[N:38][N:37]=[N:36]1
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-n2nnnc2C(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
3-Bromo-4-(trifluoroacetamido)anisole (4.7 g, 0.16 mol) was suspended in carbon tetrachloride (60 ml) and triphenylphosphine (6.2 g, 0.024 mol) was added. The reaction was heated at reflux for 12 hours. The reaction was allowed to cool to ambient temperature, and filtered. The solid was washed thoroughly with ethyl acetate:diethyl ether (1:1, 200 ml:200 ml). The filtrate was concentrated in vacuo to afford a red solid. This solid was dissolved in N,N-dimethylformamide (10 ml) and this solution was added to sodium azide (1.55 g, 0.024 mol). The reaction was stirred at ambient temperature for 12 hours, and diluted with water (100 ml). The product was extracted into ethyl acetate (3×50 ml) and the combined organics were washed with brine (100 ml), dried over magnesium sulphate and the solvent removed in vacuo. Chromatography on silica eluting with 10% ethyl acetate in hexane afforded the title compound as a pale orange solid (4.2 g, 66%), m/z (ES+) 323 (M+ +H, 100%). 1H NMR (250 MHz, CDCl3) δ 3.92 (3H, s), 7.03 (1H, dd J 2.7 Hz, J 8.8 Hz), 7.30 (1H, d, J 2.7 Hz), 7.34 (1H, d, J 8.8 Hz).
Reaction SMILES: C([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:10]([CH3:22])[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[C].[Pd]>[CH3:22][C@H:10]1[CH2:9][NH:8][C@H:13]([CH3:14])[CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reaction time: 8 h
Yield: 101.1 %

Procedure:
(2S,5R)-tert-butyl 4-benzyl-2,5-dimethylpiperazine-1-carboxylate (3.11 g, 10.2 mmol) was dissolved in methanol (19 mL), added palladium carbon (156 mg) under an argon atmosphere, and added formic acid (2.4 g, 51.1 mmol) under ice-cold conditions. The solution was reverted to room temperature, and stirred overnight. Then, the reaction solution was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The obtained residue was added water and hexane, and extracted. An aqueous solution of sodium hydroxide was added to the aqueous layer, extracted with 2-methyltetrahydrofuran, dried over anhydrous sodium sulfate, concentrated in vacuo, and the title compound (2.21 g (yield >100%)) was obtained as a colorless oil.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:28][CH2:27][NH:26][C:25]2[N:24]=[C:23]([CH:29]=[O:30])[CH:22]=[CH:21][C:20]1=2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=C[CH:43]=1.[C:48]([O-:51])(O)=O.[Na+]>CO>[Si:1]([O:18][CH:19]1[C:20]2[C:25](=[N:24][C:23]([CH:29]([O:51][CH3:48])[O:30][CH3:43])=[CH:22][CH:21]=2)[NH:26][CH2:27][CH2:28]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1cc[nH+]cc1
Reactant: O=C([O-])O
Reactant: CC(C)(C)[Si](OC1CCNc2nc(C=O)ccc21)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc2c(n1)NCCC2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 5-((tert-butyldiphenylsilyl)oxy)-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carbaldehyde (intermediate 71, 300 mg, 0.720 mmol) in MeOH (10 ml) was treated with pyridinium p-toluenesulfonate (271 mg, 1.08 mmol) and heated to reflux for 16 h. The reaction mixture was allowed to cool to room temperature, treated with sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 40:60) to give the title compound as a colorless oil. (UPLC-MS 3) tR 1.42; ESI-MS 463.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:21])[CH:17]=[N:18][C:19]=1[CH3:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:21][C:16]2[CH:17]=[N:18][C:19]([CH3:20])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cnc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1C
Yield: 16.9 %

Procedure:
The title compound (117 mg, 0.372 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (469 mg, 2.2 mmol), 5-methoxy-6-methylpyridin-3-amine (336 mg, 2.4 mmol) and pyridine (0.54 mL, 7.5 mmol) in DCM (9 mL) at 0° C. to rt using the methods of (IntC1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])=[CH:34][CH:33]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C(Nc1ccc(F)cc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 4-Fluoro-phenylamine. MS (ESI): 452.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>CCCCCC.C(OCC)(=O)C>[C:10]([CH2:12][C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:9])=[O:14])#[N:11]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1NC(=O)CC#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
4-Fluoro-2-methylaniline (3.9 g, 31 mmol) was added to ethyl cyanoacetate (5.3 g, 46 mmol) and the mixture was stirred at 150° C. for 4 hr. After cooling to room temperature, hexane-ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (4.0 g, 67%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.O>C(Cl)(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(Cl)c1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Cc2ccc(Cl)cc2)cc(Cl)c1O

Procedure:
178.1 g (1.25 mol) 2-chloro-6-methylphenol and 80.5 g (0.5 mol) 4-chlorobenzyl chloride are dissolved in 300 ml dry chloroform. 40 g water-free, finely mortared ZnCl2 are subsequentlyadded.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:28])[NH:22][CH2:23][C:24](=[O:27])[NH:25][CH3:26])=[CH:17][C:16]=3[C:29]3[C:30]([C:36]([OH:38])=[O:37])=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:8][N:9]2CC)=[CH:5][CH:4]=1)#[N:2].[C:39]([C:42]1C=C2C(C(CC3C=CC(C(=O)NCC4C=NC=CC=4)=CC=3C3C(C(O)=O)=CC(C)=CC=3)=CN2CC)=CC=1)(=N)N.C[NH:81]C(=O)CN.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:14]([CH2:39][CH3:42])[C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:28])[NH:22][CH2:23][C:24](=[O:27])[NH:25][CH3:26])=[CH:17][C:16]=3[C:29]3[C:30]([C:36]([OH:38])=[O:37])=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1)(=[NH:2])[NH2:81]
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3cccnc3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Reactant: CNC(=O)CN
Reactant: CCn1cc(Cc2ccc(C(=O)NCC(=O)NC)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C#N)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(c1ccc(C(=O)NCC(=O)NC)cc1-c1ccc(C)cc1C(=O)O)c1c[nH]c2cc(C(=N)N)ccc12
Yield: 85 %

Procedure:
Part A. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methyl-5′-(methylcarbamoylmethyl-carbamoyl)-biphenyl-2-carboxylic acid: A solution of the compound of Example 37, Part D (0.1 g, 0.19 mmol), N-methylglycinamide (0.04 mg, 0.28 mmole), NMM (0.1 ml, 0.9 mmol) and BOP reagent (0.13 g, 0.28 mmol) in 1.5 ml DMF was stirred for 3 days at rt in a screw cap test tube. Reaction was diluted with water and extracted 3× with EtOAc. Combined extracts were washed with water and brine then dried over anh. Na2SO4, filtered and evaporated. Chromatography on silica gel provided the amide product (99 mg. 85%). 1H NMR (500 MHz, CDCl3) δ ppm 1.37 (t, J=7.15 Hz, 3H) 2.41 (s, 3H) 2.83 (d, J=4.40 Hz, 3H) 3.77 (s, 2H) 4.03 (m, 4H) 6.06 (s, 1H) 6.66 (s, 1H) 6.75 (t, J=5.22 Hz, 1H) 6.97 (d, J=7.70 Hz, 1H) 7.05 (m, 2H) 7.17 (dd, J=15.95, 8.25 Hz, 2H) 7.24 (m, 5H) 7.50 (s, 1H) 7.56 (s, 1H) 7.64 (d, J=6.05 Hz, 1H) 7.83 (s, 1H). LC/MS m/z 599.4)M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[H][H].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36][N:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9](=[O:12])[C:8]=2[CH:7]=1)[C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[O:15]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: [H][H]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N(COCC[Si](C)(C)C)c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reaction time: 16 h

Procedure:
A solution of 4-[[(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo-2-naphthalenyl)amino]carbonyl]benzoic acid, methyl ester (5.07 g, 14.4 mmol) in anhydrous N,N-dimethylformamide (75 mL) at 0° C. was treated with 80% sodium hydride (477 mg, 15.9 mmoles). When hydrogen evolution ceased 2-(trimethylsilyl)ethoxymethyl chloride (3.61 g, 21.7 mmol) was slowly added. After 16 h at room temperature, the mixture was diluted with a 10% sodium bicarbonate solution (100 mL) and extracted with diethyl ether. The organic phase was concentrated in vacuo and the residue chromatographed (eluted with 20% ethyl acetate in hexane) over silica to give 4.24 g (Y: 61%) of the title product; MS (DCI) m/e: 482 (MH+); 1H-NMR (CDCl3): δ 7.90 (d, J=7.5 Hz, 2H), 7.82 (s, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.25 (m, 2H), 5.22 (bs, 2H), 3.93 (s, 3H), 3.67 (t, J=8.0 Hz, 2H), 2.69 (t, J=7.0 Hz, 2H), 1.98 (t, J=7.0 Hz, 2H), 1.33 (s, 6H), 0.96 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1>>[OH:32][C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[N:20][C:12]=2[O:11][C:8]2[CH:9]=[CH:10][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: Cc1noc2ccc(Oc3ncccc3C(=O)O)cc12
Product: Cc1noc2ccc(Oc3ncccc3C(=O)NCc3ccc(C(C)(C)O)cc3)cc12

Procedure:
Prepared from 2-(3-Methyl-benzo-(d)isoxazol-5-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. mp 128-30° C. MS (m/e): 418 (M++1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:14][CH:12]([S:9]([NH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1])(=[O:11])=[O:10])[CH3:13]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCCC1=O
Temperature: -55 °C
Reaction time: 0.03 h
Yield: 82.2 %

Procedure:
Into a flame dried 250 mL 3 neck flask fitted with a thermometer and magnetic stirrer, DMSO (2.61 mL) in methylene chloride (10 mL) was added dropwise to oxalyl chloride (1.60 mL) in methylene chloride (50 mL) while stirring at −55° C. under a nitrogen atmosphere. After 2 minutes, (2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine (3.60 g, 16.3 mmol) in methylene chloride (10 mL) was added dropwise at this temperature and the reaction was stirred for an additional 15 minutes. Triethylamine (10.8 mL) was then added dropwise and the reaction was allowed to warm to room temperature. Water (76 mL) was added at room temperature and the layers were separated. The organic layer was washed once with water, dried over potassium carbonate filtered, and concentrated under reduced vacuum to yield 3.90 g as an orange solid. This material was purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with a solvent of methylene chloride/ethyl acetate 19:1 to yield the intermediate title compound (2.94 g, 82%) as a white solid. FD M.S. 219.2 (M*). Calculated for C9H17NO3S: Theory: C 49.29, H 7.81, N 6.39. Found: C 49.18, H 7.84, N 6.39.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]2[CH2:23][C:22](=[O:24])[NH:21][NH:20][C:19](=[O:25])[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:26]1([CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:17]2[CH2:23][C:22](=[O:24])[N:20]([N:21]=[CH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[C:19](=[O:25])[CH2:18]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)CC(=O)NN1
Reactant: Cc1cccc(C=O)n1
Solvent: c1ccccc1
Product: Cc1cccc(C=NN2C(=O)CN(C(c3ccccc3)c3ccccc3)CC2=O)n1

Procedure:
A mixture of 22.6 parts by weight of 6-methylpyridine-2-carboxaldehyde and 50 parts by weight of 5-diphenylmethyl-3,7-diketo-1,2-dihydro-1,2,5-triazepine in the presence of 800 parts by volume of benzene is heated at reflux temperature for 4 hrs. with continuous water separation. The mixture is first washed with 3N hydrochloric acid, then washed with water and evaporated to dryness to give a residue. Crystallization of this residue from ethanol affords 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine melting at 161°-163° C. This compound is represented by the following structural formula ##STR8##
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (1 g) and dichloromethane (5 mL), aq. HCl (20%) (5 mL) was added. The solution was stirred for 2 hours at room temperature for completion of reaction. The solution was concentrated under vacuum to remove dichloromethane and subsequently water was added. The aqueous layer was basified to pH 8-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine solution. Organic layer was concentrated under vacuum to obtain an oily residue 0.33 g of N-benzyl-O-benzyl-D-serinamide.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>CC#N.C(Cl)(Cl)Cl>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccc2ccccc2c1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccc4ccccc4c3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Yield: 84.4 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 2-{[(2-bromoethyl)oxy]methyl}naphthalene (38 mg, 0.143 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product was washed with EtOAc (3×1 mL). The product was dried under high vacuum to give the title compound (48.1 mg, 84%). LC/MS ESI RT 2.04 min M+ 478