Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[CH2:50]([NH:57][C:47]([C:3]1[C:4]([CH3:46])=[CH:5][C:6]2[CH2:23][C@@H:22]([OH:24])[C@:21]3([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]4[C:19]([C:20]3=[O:27])=[C:18]([OH:28])[C:17]3[C:16](=[O:29])[CH:15]=[C:14]([NH:30][CH:31]5[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]5)[C:13](=[O:43])[C:12]=3[CH:11]=4)[C:7]=2[C:2]=1[OH:1])=[O:48])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)NCc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.7 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (50 mg, 0.073 mmol) in THF (5 mL) was added benzyl amine (15 μL, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction was quenched by adding 1N HCl solution (5 mL) and brine (25 mL). The aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) and lyophilized to afford (6R,6aS,14aR)—N-benzyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (19 mg, 33%) as a red-brown powder and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 8.12 (s, 1H), 7.32-7.21 (m, 5H), 6.61 (s, 1H), 5.99 (s, 1H), 4.96-4.87 (m, 2H), 4.53-4.33 (m, 2H), 3.75 (s, 3H), 3.75-3.72 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H), 3.47-3.38 (m, 4H), 3.25 (d, J=18.7 Hz, 1H), 3.06 (t, J=9.5 Hz, 1H), 2.19 (s, 3H), 1.27 (d, J=6.5 Hz, 3H); MS (ESI−) m/z 771 (M−H); HPLC >99% (AUC), tR 13.83 min.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[CH2:2].[CH2:13]([SH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[C:3]1([CH2:1][CH2:2][S:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCS
Reactant: C=Cc1cccc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCCCSCCc1cccc2ccccc12
Temperature: 110 °C
Reaction time: 68 h

Procedure:
5.0 grams (32.4 mmol, MW: 154.21) 1-vinylnaphthalene, 7.1 grams (48.6 mmol, MW: 146.29) octanethiol and 0.266 grams (1.62 mmol, MW: 164.21) 2,2′-azobis(2-methylpropionitrile) (AIBN) were charged in a 25 milliliter thick sealed glass reactor. After addition, the reaction mixture was stirred for 68 hours at 110° C. The reaction was then stopped and cooled down to room temperature. The excess of unreacted octanethiol was removed by air bath oven at 200° C. under vacuum for 1 hour. The final product was determined by IR, 1HNMR. Yield: 8.8 grams (90%). IR: (cm−1) 30045, 2924, 2853, 1596, 1510, 1459, 1394, 1377, 1261, 1219, 1165, 1016, 779, 730. 1H NMR (CDCl3): 8.03-7.33 (7H, m), 3.32 (2H, t), 2.91 (2H, t), 2.55 (2H, t), 1.57 (2H, m) 1.46-1.27 (10H, m), 0.87 (3H, t).
Reaction SMILES: Cl[CH2:2][CH:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4].[I-].[Na+].[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4]
Reactant: CN
Reactant: OC(CCl)c1ncccn1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CNCC(O)c1ncccn1
Yield: 47.7 %

Procedure:
In a pressure bottle was placed 2-chloro-1-pyrimidin-2-ylethanol (3.525 g, 22.24 mmol), sodium iodide (0.344 g, 2.29 mmol) and a 2M. methylamine solution (160 ml, 320 mmol) in methanol. The bottle was sealed and heated at 62° for 17 hr. The solvent was evaporated and the residue stirred with 10% MeOH—CHCl3. Filtration and evaporation gave a dark oil that was chromatographed over silica gel (90 g) eluting with 5-10% MeOH—CH2Cl2 containing 1% triethylamine The product was obtained as an amber oil (1.625 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)[CH3:2].Br[CH:22]([CH2:39]Br)[C:23]([N:25]([CH2:35][CH2:36][O:37][CH3:38])[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]([C:23]([N:25]([CH2:35][CH2:36][O:37][CH3:38])[C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:24])[CH2:39]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COCCN(C(=O)C(Br)CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CCOc1ccc(NCCNCc2ccccc2)cc1
Product: CCOc1ccc(N2CCN(Cc3ccccc3)C(C(=O)N(CCOC)c3ccc([N+](=O)[O-])cc3)C2)cc1

Procedure:
In a manner similar to Preparation 23, react N-(4-ethoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine with 2,3-dibromo-N-(2-methoxyethyl)-N-(4-nitrophenyl)propanamide to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH2:4][N:5]([CH3:9])[CH2:6][CH2:7][CH:8]=1)#[N:2].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:9][N:5]1[CH2:6][CH2:7][CH:8]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]([C:1]#[N:2])[CH2:4]1
Reactant: CN1CCC=C(C#N)C1
Reactant: Sc1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CN1CCC(Sc2ccccc2)C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-cyano-1-methyl-1,2,5,6-tetrahydropyridine (6.1 g 0.05 m.) thiophenol (5.50 g., 0.05 m.) and pyridine (1 ml.) was stirred at room temperature for 1 hour, diluted with dioxan (7 ml.) and heated at 110° with stirring for 24 hours. The solvent was removed in vacuo and the residual brown oil diluted with benzene (100 ml.) washed with N/1 hydrochloric acid (3 × 25 ml.) and the combined washings made basic, with 2N sodium hydroxide and extracted into benzene (3 × 25 ml). The combined extracts were washed with saturated brine, dried (MgSO4) and evaporated to give a residual solid. Recrystallisation from benzene - 60°/80° petroleum ether gave the title compound as colourless plates (8 g., 75%) m.p. 114°C. Found: C, 67.42; H, 6.97; N, 11.99. C13H16N2S requires: C, 67.21; H, 6.94; N, 12.06%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][C:20](Cl)=[O:21]>O1CCOCC1>[OH:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:2]2[NH:1][C:20](=[O:21])[CH3:19]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c(O)cccc12
Temperature: 80 °C
Yield: 75.9 %

Procedure:
To a solution of 5-amino-1-naphthol (17.6 g; 0.11 mol) in 500 ml of dioxane, there were added 11 g of calcium carbonate (0.11 mol) and, dropwise, 8 ml of chloroacetyl chloride (0.112 mol), with stirring and under an inert atmosphere. The reaction medium was heated at 80° C. for 2 hours 30 minutes. The suspension was cooled to room temperature, filtered on sintered glass and the inorganic salts were rinsed twice with dioxane. The mixture of the organic solutions was concentrated until an insoluble product appeared, and then poured over 400 ml of ice-cold water. The precipitate formed was drained, washed once with water and once with pentane. The brown powder obtained was dried under vacuum to a constant weight to give 16.8 g of N-(5-hydroxynaphthalen-1-yl)acetamide with a yield of 76%.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C@H:8]2[O:12][CH:11]([OH:13])[C@H:10]([OH:14])[C@@H:9]2[OH:15])[CH:4]=1)[CH3:2].C(O[C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1>[C:3]([O:15][C@H:9]1[C@@H:10]([O:14][C:11](=[O:12])[CH3:10])[CH:11]([O:13][C:20](=[O:22])[CH3:21])[O:12][C@@H:8]1[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[O:7][N:6]=1)(=[O:7])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc([C@H]2OC(O)[C@H](O)[C@@H]2O)no1
Solvent: c1ccncc1
Product: CCc1cc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
(3R,4S,5R)-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-2,3,4-triol isomer 1 (150 mg) was dissolved in pyridine (4 ml) and the mixture treated with acetic anhydride (0.983 ml). The resulting solution was stirred at 22° C. for 18 h. The mixture was concentrated in vacuo to afford a brown oil. Purification by chromatography on silica gel (Varian Bondelut SiO2 cartridge), eluting with (i) dichloromethane, (ii) ether (iii) ethyl acetate, afforded the title compound as a pale yellow solid (142 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([O:12][CH3:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSc1ccccn1)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSc1ccccn1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid (0.75 g, 2.40 mmol) in methanol (16 mL) and toluene (50 mL) was added a 2.0M solution of (trimethylsilyl)diazomethane (3.12 mmol) dropwise. After 3 h, the reaction mixture was concentrated to give methyl 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyrate as an oily residue which was used without further purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]1([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]([OH:31])([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:22]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCC[Mg]Br
Reactant: CCCCCC(=O)CCN1CCC(CCCc2ccccc2)CC1
Solvent: C1CCOC1
Product: CCCCCC(O)(CCCCC)CCN1CCC(CCCc2ccccc2)CC1

Procedure:
1 equivalent of pentylmagnesium bromide was reacted with 1 equivalent of the compound obtained in Example 2, in anhydrous THF, under nitrogen, at room temperature. The product thus obtained was worked up and purified on a column of silica. The results of the NMR and mass spectrometry analyses were in accordance with the expected structure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH2:6]([O:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[S:28](=[O:33])(=[O:32])[N:29]([CH3:31])[CH3:30])[NH:17][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C(C(C)=O)C>[CH2:6]([O:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[S:28](=[O:33])(=[O:32])[N:29]([CH3:31])[CH3:30])[N:17]([CH2:2][CH2:3][CH2:4][Cl:5])[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCBr
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OCc3ccccc3)cc1N2
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OCc3ccccc3)cc1N2CCCCl
Yield: 108.8 %

Procedure:
2-Benzyloxy-6-dimethylsulphamoyl-10-(3-chloro-propyl)phenothiazine (m.p. 124°-126°C.; 89.0 g.) is prepared by reacting 1-bromo-3-chloropropane (92 g.) with 2-benzyloxy-6-dimethylsulphamoylphenothiazine (69.0 g.) in the presence of powdered potassium hydroxide (16.4 g.) in methyl ethyl ketone (230 cc.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23](=[O:25])[CH3:24])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (950 mg, 4.94 mmol) and potassium carbonate (4.10 g, 29.64 mmol) in 12 mL DMF was treated with chloroacetone (787 μL, 9.89 mmol) and stirred at room temperature overnight. After this time, the mixture was cooled to 0° C. and treated with 50 mL H2O under rapid stirring. A precipitate formed and it was filtered then washed with 50 mL H2O. The solid was collected and dried under reduced pressure overnight (1.01 g, 82.1%). 1H-NMR (DMSO-d6) δ: 8.17 (d, J=2.4 Hz, 1H), 8.05 (dd, J=2.4, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.33 (s, 2H), 3.05 (t, J=7.8 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 2.24 (s, 3H). MS (EI): 248 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:5][N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[Br:28][C:29]1C(Cl)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1>C(Cl)Cl>[Br:28][C:29]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH2:13][CH2:12]2)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Cn1cncc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reaction time: 1 h
Yield: 36.1 %

Procedure:
tert-Butyl 4-((1-methyl-1H-imidazol-5-yl)methyl)piperazine-1-carboxylate (0.150 g, 0.54 mmol, 1.1 eq) was dissolved in DCM (1.7 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (1.7 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 1-((1-methyl-1H-imidazol-5-yl)methyl)piperazine (supposedly 0.097 g, 0.54 mmol, 1 eq) was suspended in iPrOH (1.6 mL) and DIPEA (0.42 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.120 g, 0.49 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.070 g, 33%); 1H-NMR (500 MHz, DMSO-d6): δ 3.03 (br s, 4H, piperazine N(CH2)2), 3.49 (s, 2H, NCH2), 3.62 (s, 3H, imidazole Me), 6.76 (s, 1H, imidazole H-4), 6.96 (s, 2H, NH2), 7.54 (s, 1H, imidazole H-2), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=1.56 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[C:22]=1[CH3:29])=[O:17])C>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]3[CH2:20][CH:18]3[C:16]([OH:17])=[O:15])=[C:22]([CH3:29])[C:23]=2[CH3:28])[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Reactant: CC(C)Sc1cccc(CCl)n1
Product: Cc1c(OCc2cccc(SC(C)C)n2)ccc(C2CC2C(=O)O)c1C
Yield: 83.1 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.030 g, 0.149 mmol) obtained in Step C of Preparation Example 16 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.046 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].C(NCC)C.[O-]CC.[Na+]>C(O)C>[C:13]([C:15](=[CH:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[C:16]([NH2:18])=[O:17])#[N:14]
Reactant: N#CCC(N)=O
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CCO
Product: N#CC(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(N)=O
Reaction time: 2.5 h

Procedure:
A mixture of 5-chloro-2-nitrobenzaldehyde (47.0 g., 0.25 mole), 2-cyanoacetamide (21.0 g., 0.25 mole), diethylamine (0.5 ml.) and ethanol (500 ml is heated at reflux for 1 hour. Sodium ethoxide (10 mg.) is added to the clear mixture and refluxing continued for an additional 2.5 hours. It is then cooled and the crystalline product which precipitates recovered by filtration. Yield = 52.3 g. (88%); m.p. of crude = 183°-185° C. It is used without purification in step B.
Reaction SMILES: [Si:1]([O:8][CH2:9]C1C=CN=C(C#N)C=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:18]([C:21]1[CH:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:26]=[C:25]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:24]=[CH:23][N:22]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Reactant: CC(=O)c1cc(Cl)ccn1
Product: CC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
The title compound was prepared from 4-(tert-butyldimethylsilyloxymethyl)pyridinecarbonitrile (A. Hadri et al., J. Heterocycl. Chem., 1993, 30, 631) according to the procedure for preparing 2-acetyl-4-chloropyridine described in Example 33.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[C:24]([F:23])([F:33])[F:34])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccccc1C(F)(F)F
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C(F)(F)F)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-trifluoromethylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.23,(1H, t), 8.04,(2H, d), 7.91,(1H, dd), 7.78,(1H, d), 7.75,(1H, d), 7.67,(1H, t), 7.56,(4H, m), 7.49,(1H, t), 4.70,(2H, d), 2.57,(3H, s),2.33,(3H, s). LCMS; retention time 3.58 min, MH+ 452.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][S:10][CH3:11])(=O)=O.[S:20]([O-:23])([O-:22])=[O:21].[Na+:24].[Na+]>CCO.O>[C:16]([O:15][C:13]([NH:12][C@@H:7]([CH2:8][CH2:9][S:10][CH3:11])[CH2:6][S:20]([O-:23])(=[O:22])=[O:21])=[O:14])([CH3:17])([CH3:18])[CH3:19].[Na+:24]
Reactant: O=S([O-])[O-]
Reactant: CSCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCC[C@@H](CS(=O)(=O)[O-])NC(=O)OC(C)(C)C
Yield: 33.3 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butyl methanesulfonate (1.1 g, 3.51 mmol, 1.0 eq) was dissolved in EtOH (10 mL) and water (8.0 mL). Sodium sulfite (2.21 g, 5.0 eq) was added. The mixture was heated to reflux for 16 hours, and concentrated. The residue was purified by reversed phase column (Diaion HP-20) using distilled water (200 ml) first, then 10% CH3CN in water and finally 20% CH3CN in water to give sodium (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butane-1-sulfonate (376 mg, 37%). 1H NMR (DMSO-d6, 300 MHz) d 6.75 (d, 1H, NH), 3.50 (br s, 1H, BocNHCH), 2.3-2.5 (m, 4H, SCH2 and OSCH2, overlapped with DMSO solvent peak), 2.0 (s, 3H, SCH3), 1.8 (m, 1H, NHCHCH2CH2S), 1.6 (m, 1H, NHCHCH2CH2S), 1.35 (s, 9H, OC(CH3)3). LC-MS: 2.03 min; MS (ESI−) m/z 298 (M-Na)+, 198 (M-Na-Boc)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9]>>[OH:4][CH2:3][CH:2]([NH:1][C:8](=[O:9])[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)NC(CO)CO

Procedure:
Isobutyl 1,3-dihydroxypropan-2-yl-carbamate (iBuDHPC) was prepared using serinol and isobutyl chloroformate according to the general procedure described in Example 2.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C(B(CC)[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:3]=3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CCB(CC)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccnc4)ncnc32)cc1
Yield: 54.9 %

Procedure:
A solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [4 g, Reference Example 3] and diethyl-3-pyridyl-borane (2.1 g) in tetrahydrofuran (180 mL) was treated with palladium tetrakis triphenylphosphine (0.65 g) and potassium carbonate (3.59 g). The solution was stirred at reflux for 24 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected twice to flash column chromatography on silica eluting with a mixture of ethyl acetate and methanol (90:10, v/v) and a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (2.5 g) as an amorphous solid. MS: 351 [MH]+. LCMS (Method B) RT=3.05 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.C(OC(=O)C)(=O)C>>[CH3:20][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([N:35]([C:36]3[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:40][CH:41]=3)[C:32]3[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])=[CH:34][CH:33]=3)[C:9]3=[N:14][CH:13]=[CH:12][N:11]=[C:10]3[C:15](=[O:17])[O:8]2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)c2nccnc2C(=O)O)cc1
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3nccnc32)cc1

Procedure:
A mixture containing 0.7 g. of 3-[4-(dimethylamino)benzoyl]-2-pyrazinecarboxylic acid, 1.0 g. of 4,4'-dioctyldiphenylamine and 7 ml. of acetic anhydride was stirred and gently heated in a warm bath for one hour. The product, 7-[4-(dimethylamino)phenyl]-7-[bis(4-octylphenyl)amino]furo[3,4-b]pyrazine-5(7H)-one was isolated by column chromatography as a rust-colored solid, m.p. 158°-168° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a reddish-brown image.