Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NCCCN(C)C)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH2:20][CH:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)[C:22](O)=[O:23]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([CH:21]2[C:22](=[O:23])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19][CH2:20]2)=[CH:26][CH:27]=1
Reactant: Nc1ccccc1SCC(C(=O)O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C1Nc2ccccc2SCC1c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
1.74 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide were added to 1.55 g of the product of Step A suspended in 25 ml of methylene chloride and the mixture was stirred for 30 minutes. 50 ml of methylene chloride were added, followed by washing with water, and extraction with methylene chloride. The organic phase was dried and concentrated to dryness under reduced pressure to obtain 1.25 g of expected product which after crystallization from isopropanol melted at 195° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].Cl>C(Cl)Cl.CCOC(C)=O.O>[C:29]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=2)[C:20]([OH:21])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C@@H:2]([NH:1][C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[C:3]([OH:5])=[O:4])=[O:10])[N:12]=1)#[N:30]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1nc(C(=O)NCC[C@@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-2-Amino-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (16 mg, 0.03 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. To the solution were added triethylamine (0.05 mL, 0.31 mmol) and dimethylcarbamoyl chloride (4 μL, 0.05 mmol). After stirring for 16 hours at room temperature, H2O (10 mL) and EtOAc (10 mL) were added. To the stirred mixture was added 1 N hydrochloric acid (1 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 9 mg. MS: (−) m/z 476.25 (M−1).
Reaction SMILES: [CH:1]([C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].O.CC(C)(O)[C:19]#[N:20].[C-]#N.[K+]>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:19]([CH:1]([OH:2])[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][CH2:6][CH3:7])#[N:20]
Reactant: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(O)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl (1S)-1-formylpentylcarbamate in toluene was added water (50 mL), acetone cyanohydrin (16.4 mL, 180.0 mmol), potassium cyanide (250 mg) and tetrabutylammonium iodide (300 mg). The mixture was stirred at ambient temperature for 20 h, and then the layers were separated. The organic layer was washed with water (5×60 mL), dried with magnesium sulfate and concentrated in vacuo to afford the title compound (26.7 g, 92%) as a thick oil. The 1H NMR spectrum showed an approximately equal mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6): δ 6.91,6.83 (2d, J=8 Hz, J=9 Hz, 1H), 6.54, 6.47 (2d, J=7 Hz, J=6 Hz, 1H), 4.44, 4.17 (2t, J=5 Hz, J=8 Hz, 1H), 3.60-3.50 (m, 1H), 1.65-1.10 (m, 6H), 1.34 (s, 9H), 0.80 (t, J=6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Nc1cc(Cl)ncn1
Product: Nc1cc(Nc2ccc(OCCN3CCCC3)cc2)ncn1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 152A but using 6-chloro-pyrimidin-4-ylamine, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Example 148B), and stirring the reaction mixture for 2 h at 150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([OH:12])=[O:11])([O-:3])=[O:2].Br[CH2:14]C(O)=O.[OH-].[Na+]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH3:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)O
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 91 %

Procedure:
This is contradicted by investigations by A. Courtin, H. -R. von Tobel and G. Auerbach, Helv. Chim. Acta 63, 1412 (1980), according to which, on heating of 1 mol of 2-nitrobenzenesulfinic acid, 2 mol of bromoacetic acid and 2 mol of sodium hydroxide solution under reflux conditions for 24 hours, only methyl 2-nitrophenyl sulfone is obtained in 91% yield. Evidently, the carboxymethyl aryl sulfone forming is immediately decarboxylated to the methyl aryl sulfone under the acidic reaction conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][C:19]1[C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[O:21][N:20]=1.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][CH2:18][C:19]3[C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[O:21][N:20]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To 30 ml of dry dimethylformamide was added 3.0 g of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.99 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 8.0 g of sodium bicarbonate, and a crystal of potassium iodide. After stirring at 90° C. for one hr, the mixture was evaporated to an oil. The oil was stirred with 100 ml of water for five mins, and then extracted with ether. The ether solution was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent was evaporated. Recrystallization of the residue from ethyl ether gave 3.6 g of product, mp 142°-145° C. The analytical sample was obtained by recrystallization from ethyl and had mp 148°-150° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[N:10]1[C:3]2[C:2]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1ncnc2scnc12
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(CCNc2ncnc3scnc23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
7-Chlorothiazolo[5,4-d]pyrimidine (2.71 grams (g), 15.7 millimoles (mmol)) and tyramine (2.16 g, 15.7 mmol) were dissolved with magnetic stirring in N,N-dimethylformamide (DMF; 20 milliliters (mL)) in a 100 mL round bottom flask equipped with a reflux condenser and a dry nitrogen line at 25° C. To the solution was added potassium carbonate (K2CO3; 6.0 g, 43.4 mmol), and the mixture was heated at 100° C., then cooled to 25° C., and stirred overnight. The reaction was diluted with water (H2O; 150 mL), and then treated with 2 N hydrochloric acid (HCl) to adjust the pH to 6. The aqueous layer was washed repeatedly with EtOAc, and the pooled organic fractions were filtered and concentrated in vacuo to provide 4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethyl]-phenol (Compound 3; 1.0 g) as an amber powder: mp 161-168° C.; 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 9.18 (s, 1H), 8.42 (s, 1H), 8.29 (br s, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.67 (d, J=8.3 Hz, 2H), 3.65 (m, 2H), 2.81 (m, 2H); ESIMS m/z 273.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(O)(=O)C(O)=O.CS(O[CH:39]1[CH2:42][N:41]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:40]1)(=O)=O>>[CH:43]1([N:41]2[CH2:42][CH:39]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([N:11]5[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]6[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=6)[C:12]5=[O:26])[CH:6]=4)[C:2]([CH3:27])([CH3:1])[CH2:3]3)[CH2:40]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21
Reactant: CS(=O)(=O)OC1CN(C2CCCCC2)C1
Agent: O=C(O)C(=O)O
Product: CC1(C)CN(C2CN(C3CCCCC3)C2)c2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21

Procedure:
prepared as described for example 96 by reaction of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione with 1-cyclohexylazetidin-3-yl methanesulphonate oxalate
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:2]=[CH:3][C:4]([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([O:26][C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccc4)cc3)cc2)C(=O)O)cc1
Yield: 85.3 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-(4-isopropylphenoxy)propionate (630 mg), which is the product of Example 86, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (510 mg) as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:11].CN>[Ni]>[CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:10][NH2:11])[CH:13]=1
Reactant: N#Cc1cccnc1
Agent: [Ni]
Agent: CN
Agent: CNCc1cccnc1
Product: NCc1cccnc1

Procedure:
For example, in U.S. Pat. No. 2,798,077, "Preparation of Methyl-(beta-picolyl)-Amine," issued to R. Schlapfer et al. in 1957, it is disclosed that 3-cyanopyridine can be hydrogenated in the presence of excess methylamine and a Raney nickel catalyst to yield N-methyl-3-picolylamine and beta-picolylamine. Separation of the beta-picolylamine is then required.
Reaction SMILES: Br[C:2]1[C:3]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH:15]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:13][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=4)[C:20](=[O:21])[CH:15]4[CH2:16][O:17][CH2:18][CH2:19][N:14]4[C:3]=3[N:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1nccn1-c1ncc(Br)c(N2CCOCC2C(=O)NCc2ccc(S(C)(=O)=O)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Cc1nccn1-c1ncc2c(n1)N1CCOCC1C(=O)N2Cc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A mixture of 4-(5-bromo-2-(2-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-N-(4-(methylsulfonyl)benzyl)morpholine-3-carboxamide (100 mg, 0.187 mmol), palladium(II) acetate (4.19 mg, 0.019 mmol), Xantphos (21.61 mg, 0.037 mmol), and potassium phosphate, tribasic (79 mg, 0.374 mmol) in 1,4-dioxane (1 mL) and tert-butanol 0.25 mL was heated to 100° C. in a microwave for 1 hour and then heated again to 100° C. in the microwave for 10 hours. Water was subsequently added to the reaction mixture, which formed a precipitate that was collected by filtration. The solids were washed with water and EtOAc to afford the title compound as an off-white solid (54.2 mg, 63.8%). 1H NMR (400 MHz, DMSO-d6) δ 2.63 (s, 3 H), 3.02-3.13 (m, 1 H), 3.21 (s, 3 H), 3.53-3.64 (m, 1 H), 3.71 (t, J=10.99 Hz, 1 H), 3.98-4.06 (m, 1 H), 4.26 (dd, J=11.24, 3.92 Hz, 1 H), 4.37-4.45 (m, 1 H), 4.65 (dd, J=10.61, 3.79 Hz, 1 H), 5.17-5.37 (m, 2 H), 6.83 (d, J=1.52 Hz, 1 H), 7.59 (d, J=8.34 Hz, 2 H), 7.73 (d, J=1.52 Hz, 1 H), 7.84-7.94 (m, 3 H). ESI-MS m/z [M+H]+ calc'd for C21H22N6O4S, 455.14; found 455.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][C:10]=1[C:11]([NH:42][C:41]1[CH:43]=[CH:44][CH:45]=[C:39]([Cl:38])[CH:40]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-(benzyloxy)-4-(morpholinomethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in description 50, 270 mg, 0.683 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added DIPEA (0.239 mL, 1.366 mmol), 3-chloroaniline (72.0 μl, 0.683 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.819 mmol) and EDC (262 mg, 1.366 mmol). The solution was stirred for 3 hours then partitioned between EtOAc (20 ml) and water (15 ml). The organic layer was separated, washed further with water (2×20 ml), dried (MgSO4) and the solvent removed. Purification by column (SiO2, Isolute, 3:1-1:1 Cyclohexane/EtOAc) gave the product as a white solid. 205 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](=O)O[C:7]2=[CH:11][CH:12]=[CH:13][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:6]=12)=[O:4].[CH2:19](NCC)C>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([CH:11]=[CH:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[CH:19][CH:9]=1)=[O:4]
Reactant: COC(=O)c1c2cc(C(C)C)cccc-2oc1=O
Reactant: CCNCC
Product: COC(=O)c1ccc2cccc(C(C)C)cc1-2

Procedure:
To a diethylamine (120 ml) suspension of 3-methoxycarbonyl-5-isopropyl-2H-cyclohepta[b]furan-2-one (16) (5.0 g) acetaldehyde (5.7 ml) was added.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][N:6]=[CH:7][C:8]=1[CH3:9])#[N:2].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:1]([C:3]1[C:4](=[O:10])[N:5]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:6]=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cn[nH]c(=O)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc(C)c(C#N)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A mixture of 4-cyano-5-methyl-3-pyridazinone (P. Schmidt and J. Drucy, Helvetica Chemica Acta, 37, 1467 (1954)) (0.93 g, 6.9 mmol) and NaH (50% in oil, 0.344 g, 8.6 mmol) in DMF (15 mL) was stirred at rt for 1 hour. 4-Methoxybenzyl chloride (1.34 g, 8.6 mmol) was added, and the mixture was stirred for 16 hours. The mixture was diluted with water. and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated. Trituration of the residue with ethyl acetate gave 4-cyano-2-(4-methoxybenzyl)-5-methyl-3-pyridazinone (0.83 , 3.2 mmol, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=O.[Na+].[NH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O.ClCCl.CO.[Os](=O)(=O)(=O)=O.ClCCl.O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:23]2[CH2:24][CH2:25][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:27][CH2:28]2)=[CH:5][CH:4]=1
Reactant: C=CCn1c(=O)ccc2ccc(OC)nc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1

Procedure:
A solution of 7-(methyloxy)-1-(2-propen-1-yl)-1,8-naphthyridin-2(1H)-one (240 mg, 1.1 mmol) in 1,4-dioxane/water (12 ml/20 ml) was treated with osmium tetroxide solution (4% in water, 1 ml) followed by sodium periodate (2.1 g, 10 mmol). After 30 minutes more water (15 ml) was added. After a further 1 hour the mixture was diluted with an equal mixture of brine and extracted twice with ethyl acetate. The dried extracts were evaporated to give a yellow oil. This was dissolved in dichloromethane/methanol (6 ml/0.6 ml) and treated with 1,1-dimethylethyl 4-piperidinylcarbamate (240 mg, 1.2 mmol) then sodium triacetoxyborohydride (626 mg, 3 mmol). After 2 hours the mixture was treated with saturated aqueous sodium bicarbonate and dichloromethane. The organic extract was added to a silica column, eluting with 0-100% ethyl acetate in hexane then 0-20% methanol in ethyl acetate, affording a brown foam (320 mg, 72% over 2 steps).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.25 mmol) in THF (4.5 mL) was cooled to 0° C. t-BuOK (1M in THF, 3.75 mL) was added dropwise and the reaction mixture was stirred at room temperature for 1 h then cooled to 0° C. 1-Iodopentane (816 μL, 6.25 mmol) was added and the solution was stirred at room temperature for 18 h. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified on column chromatography (eluent: pentane/EtOAc, 95/5) to give the title compound (267 mg, 69%) as a clear oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CSCCC1N=CNC=1)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)([O-:23])=[O:22]
Reactant: NCCSCCc1c[nH]cn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCCc1c[nH]cn1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCCc1c[nH]cn1

Procedure:
4-[2-(2-Aminoethylthio)ethyl]imidazole (from the dihydrobromide (4.0 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[2-(2-(4-imidazolyl)ethylthio)ethylamino]ethylene is treated with methylamine according to the procedure of Example 8(ii) to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31](O)=[O:32])[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([CH:78]2[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]2)[CH2:72][CH2:71][CH:70]([C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:69][CH2:68]1>C1COCC1.CCOC(C)=O>[CH3:30][C:28]1[C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=[C:20]([CH2:19][C@@H:18]([O:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([N:8]3[CH2:7][CH2:6][C:5]4[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=4[NH:3][C:2]3=[O:1])[CH2:14][CH2:13]2)=[O:16])[C:31]([N:81]2[CH2:82][CH2:83][CH:78]([N:67]3[CH2:68][CH2:69][CH:70]([C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:71][CH2:72]3)[CH2:79][CH2:80]2)=[O:32])[CH:29]=1
Reactant: CCOC(=O)C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 300 mg (0.59 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 210 mg (0.65 mmol) TBTU and 100 μL (0.72 mmol) triethylamine in 20 mL THF was stirred for 1 h at RT. Then 220 mg (0.70 mmol) ethyl [1,4′]bipiperidinyl-4-carboxylate (used as the bis-hydrochloride salt) and 400 μL (2.87 mmol) triethylamine were added. The reaction mixture was stirred for 24 h at RT. The mixture was diluted with EtOAc, the organic phase was washed with saturated NaHCO3 solution and dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (Alox, activity grade II-III, gradient DCM/EtOH 20:1 to DCM/EtOH 10:1). The fractions containing the product were combined, evaporated down i. vac., the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.Cl.[NH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35].Cl>C(#N)C>[C:34]([CH2:33][CH2:32][NH:31][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])(=[O:35])[NH2:36]
Reactant: CN(C(=O)c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCC(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C(=O)c1ccccc1)c1ccc(NCCC(N)=O)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
N-(4-fluoro-3-nitro-phenyl)-N-methyl-benzamide (1.47 g, 5.37 mmol) was taken up in dry acetonitrile under argon, DIEA (2.08 g, 16.11 mmol, 2.80 ml) and β-alanine amide hydrochloride (1.00 g, 8.06 mmol) were added. The reaction mixture was heated to 80° C. for 48 h. The reaction was poured into 1N HCl and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The residue was triturated twice with cold hexane and dried to give N-[4-(2-carbamoyl-ethylamino)-3-nitro-phenyl]-N-methyl-benzamide. (1.75 g, 95%)