Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 89 %

Procedure:
To 1.6 g (7.99 mmol) [1,4]diazepane-1-carboxylic acid tert-butyl ester was added 1.09 mL (1.64 g, 8.79 mmol) of 2-bromoanisole, 37 mg (0.04 mmol) of Pd2dba3, 75 mg (0.12 mmol) of (±)-BINAP, 1.08 g (11.19 mmol) of NaOt-Bu, 20 mL of toluene and resulting slurry was heated to 80° C. for 20 h. After cooling to 23° C., the reaction mixture was filtered through Celite and evaporated to leave a dark brown oil. Flash chromatography on silica gel, eluting with CH2Cl2/EtOAc (1/0 to 40/1 to 20/1) gave 2.17 g (7.08 mmol, an 89% yield) of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ1.45 and 1.47 (singlets, 9H—rotational isomers), 1.91-2.07 (m, 2H), 3.16-3.31 (m, 4H), 3.47-3.65 (m, 4H), 3.85 (s, 3H), 6.72-6.96 (m, 4H); IR (KBr, cm−1):1691s; MS (ES) m/z (relative intensity): 307 (M++H, 100). Anal. Calcd. for C17H26N2O3: C, 66.64; H, 8.55; N, 9.14. Found: C, 66.18; H 8.54; N, 8.80.
Reaction SMILES: [C@@H:1]([NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)([CH2:3][CH3:4])[CH3:2].[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[C@@H:1]([N:5]([CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=2)[CH2:26][CH2:27]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC[C@H](C)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (8.7 mg) from (S)-2-((sec-butylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H33FN4O4 484.6. found 485.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.87-8.08 (m, 2H) 7.09-7.25 (m, 2H) 4.41-4.57 (m, 2H) 4.20-4.40 (m, 3H) 4.16 (d, J=8.08 Hz, 1H) 3.83-3.97 (m, 2H) 3.19-3.42 (m, 3H) 3.11 (d, J=5.56 Hz, 1H) 2.93 (d, J=8.59 Hz, 1H) 2.43-2.71 (m, 3H) 2.17-2.36 (m, 2H) 2.00 (br. s., 1H) 1.68-1.92 (m, 3H) 1.22 (d, J=6.57 Hz, 2H) 1.09 (d, J=7.07 Hz, 1H) 0.66-0.83 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[N:14][OH:15])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(C=NO)c[nH]c2c1
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, Lit. 5) in ethanol (30 ml) was added at 22° C. hydroxylamine hydrochloride (0.46 g) and sodium acetate (0.54 g) and the mixture was stirred for 3 h. The mixture was evaporated and the residue triturated with water and dichloromethane/n-heptane (1:1) and dried to give 6-methyl-1H-indole-3-carbaldehyde oxime (0.96 g) as a pink solid. MS: 175.3 ([M+H]+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]([NH2:33])[CH2:29]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.CN(C)C=O>[CH3:24][N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH2:27][CH:28]([NH:33][C:10]([C:3]1[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=1)=[O:12])[CH2:29]2
Reactant: O=C(O)c1nsc2ccccc12
Reactant: CN1C2CCC1CC(N)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1CC(NC(=O)c1nsc3ccccc13)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of benzisothiazole-3-carboxylic acid (0.93 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (2.87 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride (0.99 mmol). The reaction mixture was maintained at room temperature for 30 min under nitrogen and then HATU (1.00 mmol) was added. After 18 h, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane/methanol (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using a mixture of [90/10/1 dichloromethane/methanol/ammonium hydroxide] as the eluent, thus providing the product in 20% yield. Alternatively, the residues were purified by preparative HPLC. 1H NMR (CD3OD) δ 8.79 (dd, J=8.3, 1.0, 1H), 8.10-8.06 (m, 1H), 7.63-7.49 (m, 2H), 4.39-4.32 (m, 0.5H), 4.17-4.15 (m, 0.5H), 3.33-3.27 (m, 2H), 2.35 (s, 1.5H), 2.34 (s, 1.5H), 2.31-1.75 (m, 8H); LC/MS (EI) tR 3.76 min, m/z 302 (M++1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(c1ccccc1F)C1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1F)C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 9.1 g of 3-(2-bromoethyl)indole in 100 ml of dimethylformamide is added to a stirring solution of 11.2 g of 4-(2-fluorobenzoyl)piperidine hydrochloride and 13 g of potassium carbonate in 400 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours, and then 800 ml of water are added dropwise, yielding a dark precipitate. This mixture is again stirred at ambient temperature for 24 hours and filtered to give a yellow crystalline material which is recrystallized thrice from an ethanol-water mixture to give an off-white crystalline material, mp 106°-108° C., 3-{2-[4-(2-fluorobenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH:32]([CH3:34])[CH3:33])[N:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:49]=[N+:50]=[N-:51])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH:32]([CH3:34])[CH3:33])[N:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:51][N:50]=[N:49][N:26]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
10.0 g of N-carboethoxy-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 9.2 g of tributyltin azide in 150 ml of xylene are heated to reflux for 18 hours. The reaction mixture is concentrated and the residue is stirred in 5M etherial hydrochloric acid for 15 minutes. The mixture is concentrated again, and the residue is dissolved in ether and extracted with cold 4M potassium hydroxide solution. The aqueous phase is rendered acidic and extracted with ethyl acetate. This ethyl acetate phase is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by means of flash chromatography (250 g of silica gel, eluent N6). Amorphous product, TLC (system N6) Rf : 0.22.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([NH2:30])=[CH:25][C:24]=2[CH3:31])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([N:30]=[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][NH:6]3)=[CH:25][C:24]=2[CH3:31])=[CH:21][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N
Reactant: O=C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N=C1CCCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 0.2 g (1.5 mmol) of phosphoric trichloride in 5 ml toluene was added to a mixture of 0.3 g (3.0 mmol) of piperidin-2-one, the exothermic reaction was stirred for 2 hrs at ambient temperature. Then a solution of 0.38 g (1.5 mmol) of 4′-tert-butyl-2,5-dimethylbiphenyl-4-amine in 5 ml of toluene was added and the reaction mixture was refluxed for 5 hrs. At ambient temperature 5 ml of a 10% aqueous solution of sodium hydroxide was added. Separation of the layers, extraction of the watery layer with 10 ml of toluene, drying over magnesium sulfate, concentration in vacuo and column chromatographic (gradient: cyclohexane->ethyl acetate) yielded 0.3 g (1.0 mmol) 63% of 4′-tert-butyl-2,5-dimethyl-N-[piperidin-2-ylidene]biphenyl-4-amine; log P (pH 2.3)=2.6.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]([C:13]2[S:17][C:16]([C:18]3[NH:22][C:21]([C@@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4C(OC(C)(C)C)=O)=[N:20][CH:19]=3)=[N:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[C:35]1[NH:39][C:38]([C@@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2C(OC(C)(C)C)=O)=[N:37][CH:36]=1>ClCCl>[NH:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:38]1[NH:39][C:35]([C:9]2[S:8][C:12]([C:13]3[S:17][C:16]([C:18]4[NH:22][C:21]([C@@H:23]5[CH2:27][CH2:26][CH2:25][NH:24]5)=[N:20][CH:19]=4)=[N:15][CH:14]=3)=[CH:11][N:10]=2)=[CH:36][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ncc(-c3cnc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)s3)s2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc([C@@H]2CCCN2)[nH]c1-c1ncc(-c2cnc(-c3cnc([C@@H]4CCCN4)[nH]3)s2)s1
Reaction time: 2 h
Yield: 58.6 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirred solution of di-tert-butyl (2S,2′S)-2,2′-(5,5′-bi-1,3-thiazole-2,2′-diylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate) (450 mg, 0.704 mmol) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred for 2 h, additional TFA (2 mL, 26.0 mmol) was added and the mixture was stirred for an additional 2 h. The reaction was concentrated in vacuo and the residue was dissolved in methanol and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and then the compound was released from the cartridge by washing with a solution of 2M ammonia in methanol. The filtrate was evaporated under reduced pressure to give 2,2′-bis(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-5,5′-bi-1,3-thiazole (181 mg) as an orange solid.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCCC1(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc(C2(c3ccccc3)CCCNC2)cc1
Temperature: 25 °C

Procedure:
In a 500 mL flask containing 3,3-diphenylpiperidin-2-one (3.77 g, 15 mmol; Example 68C) as a suspension in ether (300 mL) was added lithium aluminum hydride (2.0 Min tetrahydrofuran, 15 mL, 30 mmol) slowly via syringe under nitrogen. The reaction was refluxed overnight, cooled to room temperature, and then carefully quenched by the slow addition of 1 N NaOH (60 mL). The reaction was diluted with ethyl acetate (200 mL) and filtered through a pad or diatomaceous earth. The organic phase was separated, concentrated, and the residue was purified over silica gel eluting with 95:5 dichloromethane/methanol to give the title compound. MS (DCI+) m/z 238 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[Li].FC1C([O:15][S:16]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)(=O)=[O:17])=C(F)C(F)=C(F)C=1F.[OH-].[Na+]>C1COCC1.O>[S:6]1[C:2]([NH:1][S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)(=[O:17])=[O:15])=[N:3][CH:4]=[N:5]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: Nc1ncns1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-amino-1,2,4-thiadiazole (58 mg, 0.574 mmol, 1.1 eq) in THF (5 ml) was added, 1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 1.15 ml, 1.2 mmol, 2.2 eq) and the reaction mixture stirred at 50° C. for 5 minutes. Methyl 4-[(pentafluorophenoxy)sulfonyl]benzoate (Preparation 28, 196 mg, 0.513 mmol, 1 eq) was added and the reaction monitored. On the disappearance of the starting materials the reaction mixture was quenched with water (5 ml), diluted with ethyl acetate (10 ml), washed with saturated sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in dioxane (5 ml) and a solution of sodium hydroxide (100 mg, 2.5 mmol, 4.3 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml), the aqueous phase was acidified with concentrated HCl, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was triturated with DCM to yield the title compound as a pale yellow solid (64 mg, 0.22 mmol, 43%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[CH3:6][Si:7]([C:10]1([Na])[CH:14]=[CH:13][CH:12]=[CH:11]1)([CH3:9])[CH3:8]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:11]1[CH:12]=[CH:13][CH2:14][C:10]=1[Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)C1([Na])C=CC=C1
Reactant: COCCCl
Solvent: C1CCOC1
Product: COCCC1=C([Si](C)(C)C)CC=C1
Temperature: -78 °C
Yield: 84 %

Procedure:
A solution of 18.9 g (200 mmol) of chloroethyl methyl ether in 100 ml of THF was gradually dropwise added to a solution of 32 g (200 mmol) of trimethylsilyl-cyclopentadienylsodium in 400 ml of THF while being stirred in an argon atmosphere at −78° C. After completion of the addition, the reaction mixture was heated under reflux overnight. Then THF was distilled off under a reduced pressure, and the obtained solid was filtered off and subjected to vacuum distillation (80° C./1 mmHg) to give about 33 g of [(2-methoxy)ethyl]-trimethylsilylcyclopentadiene (TMSCpCH2CH2OMe). Yield: 85%. The chemical structure was confirmed by the following data obtained by 1H-NMR using CDCl3.
Reaction SMILES: Br.[NH2:2][C:3]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5](O)=[O:6].[Cl-].[NH4+].CC[N:17](CC)CC.C(P(C#N)(CC)=O)C>C(COC)OC>[NH2:2][C:3]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([NH2:17])=[O:6]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: Br
Agent: CCP(=O)(C#N)CC
Agent: [Cl-]
Solvent: COCCOC
Product: NC(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To an ice-cold suspension of 2-amino-5-bromo-nicotinic acid hydrobromide (5.11 g, 17.1 mmol) and ammonium chloride (9.15 g, 171 mmol) in dimethoxyethane (170 mL) was added Et3N (4.8 mL, 34.2 mmol). After 10 min, diethylphosphoryl cyanide was added dropwise and the cold bath removed. After 4 h, the solution was filtered and the filtrate concentrated. The resulting residue was partitioned between EtOAc and water. The organic layer was washed with satd NaHCO3 (2×) and satd NaCl, dried (Na2SO4) and concentrated under reduced pressure. The yellow solid was dissolved in EtOAc and then hexanes were added until precipitation occurred. The solid was collected by filtration and then triturated with EtOAc to give the title compound (1.62 g, 44%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 2H), 8.04 (bs, 1H), 7.46 (bs, 1H), 7.37 (bs, 2H).
Reaction SMILES: S([O-])(=O)(=O)C.CS(O[CH2:11][C:12]([O:24][CH:25]([CH3:27])[CH3:26])([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:13][CH2:14][CH3:15])(=O)=O.[Na].[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>CS(C)=O>[N:29]1([CH2:11][C:12]([O:24][CH:25]([CH3:27])[CH3:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:13][CH2:14][CH3:15])[CH:33]=[N:32][CH:31]=[N:30]1
Reactant: CCCC(COS(C)(=O)=O)(OC(C)C)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CS(C)=O
Product: CCCC(Cn1cncn1)(OC(C)C)c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The mesylate prepared in accordance with (a) is dissolved in 100 ml of absolute dimethyl sulfoxide, and 3.2 g (35 mmoles) of the sodium salt of 1,2,4-triazole are added. The reaction mixture is stirred for 8 hours at a bath temperature of 120° C. and is then cooled to room temperature and poured into ice water, and the mixture is extracted twice with ethyl acetate. The combined extracts are washed 4 times with half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography (silica gel; 1:1 ethyl acetate/petroleum ether) and affords a colourless oil. n50D =1.5299. 100 MHz -1H-NMR (CDCl3): δ=7.75 and 7.65 ppm (s, 2H of triazole); 7.1-7.6 ppm (m, 2H, aromatic); 4.85 ppm (dd, 2H, CH2 -N); 4.0 ppm (m, 1H, --CH(CH3)2); 0.8-2.6 ppm (m, 14H, --CH(CH3)2, --CH2 --CH2 --CH3);
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:21]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:30])[C:8]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccn1)CC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.3 %

Procedure:
261 mg of 6-acetyl-3,4-dihydro-2,2 -dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of dichloromethane at room temperature and 250 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days the mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 2%-5% (v/v) methanol/chloroform for the elution. The resulting foam was triturated with methylcyclohexane and the solid obtained was recrystallized from t-butyl methyl ether to give 20 mg of 2-(6-acetyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 132-133° C.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].[Cl-].C([N+](C)(C)C)C.Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].Cl>C(Cl)Cl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.3 %

Procedure:
To a solution of Boc-D-Trp-OBzl (3.0 g) in methylene chloride (60 ml) were added powdered sodium hydroxide (1.52 g), ethyltrimethylammonium chloride (150 mg) and ethyl bromoacetate (2.54 g). The mixture was stirred overnight at room temperature, then powdered sodium hydroxide (0.61 g) and ethyl bromoacetate (0.63 g) were added. The mixture was stirred further for four and half an hour at room temperature and for two hours under reflux. After cooling, 1N-hydrochloric acid (53 ml) was added to the mixture, and the organic layer was washed with sodium chloride solution and dried with magnesium sulfate. After evaporation, the residue (4.87 g) was chromatographed on a silica gel column (60 g) eluting successively with chloroform and chloroform-ethyl acetate (4:1) to give a purified Boc-D-Trp(CH2CO2Et)-OBzl (4.14 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH:23]1[CH2:24][NH:25][CH2:26]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH:23]2[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:26][N:25]([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=1)[CH2:24]2)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2

Procedure:
Is prepared according to method A from 2-chloro-6-nitroquinoline and 3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester.
Reaction SMILES: CO[CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.[NH2:10][CH:11]([CH2:17][SH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(#N)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>[NH2:10][CH:11]([CH2:17][S:18][C:5]1[O:4][CH:3]=[CH:7][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC1C=CC(OC)O1
Reactant: CCOC(=O)C(N)CS
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C(N)CSc1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To 16.25 g (125 mmol) of 2,5-dimethoxy-2,5-dihydrofuran and 23.20 g (125 mmol) of ethyl 2-amino-3-mercaptopropanoate in 100 ml dry acetonitrile was added approximately 0.15 g of tosyl chloride. The mixture was stirred 1 hour at room temperature under nitrogen during which time complete solution was attained which became very dark. The mixture was concentrated in vacuo, taken up in ethyl acetate, then extracted with aqueous NaHCO3 solution followed by saturated NaCl solution. The organic portion was dried over MgSO4, filtered then concentrated to 50 ml. The concentrate was then chromotographed to give 8.35 g (31.0%) of the title compound as a dark oil.