Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.[C:12]([O:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19][C:12](=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CCC(=O)OCC(=O)OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(NN=C(COC(=O)CCC(C)=O)OCc2ccccc2)cc1
Yield: 104.4 %

Procedure:
5.2 g of p-methoxyphenylhydrazine were suspended in 25 ml of glacial acetic acid and 90 ml of water and 10 g of benzyl levulinoyloxyacetate were slowly added at room temperature while stirring. After stirring for 1 hour, the mixture was extracted by shaking with toluene, the toluene solution was washed neutral with water, dried and concentrated. 15.1 g of benzyl levulinoyloxyacetate (p-methoxyphenyl)-hydrazone were obtained as a brownish oil, which was not purified but was dissolved in 25 ml of absolute pyridine, and then 100 ml of ether were added and mixed with a solution of 8.7 g of p-chlorobenzoyl chloride in 50 ml of ether at 0°C with the introduction of nitrogen. After boiling for 2 hours under nitrogen, the solution was cooled, washed neutral with water, dried and concentrated by evaporation. 19 g (crude yield) of N(2) -(p-chlorobenzoyl)-N(2) -(p-methoxyphenyl)-hydrazone of benzyl levulinoyloxyacetate were obtained. This product was further treated without purification, by taking it up in 75 ml of glacial acetic acid and heating for 5 hours at 80°C. After evaporating off the glacial acetic acid under vacuum, the further treatment was carried out as described in Example 1. The yield of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate amounted to 11% of the theoretical, based on the total amount of hydrazine.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.CN(C)C=O>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([S:7][CH2:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:6]=1
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CSc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 4-biphenylthiol (2.79 g., 0.015 mole) in dry tetrahydrofuran (30 ml) and dimethylformamide (6 ml) was added portionwise sodium hydride (0.37 g., 0.015 mole) with stirring under a nitrogen atmosphere. The resulting solution was added dropwise over 45 min. to ethyl bromopyruvate (3.0 g, 0.015 mole) in dry tetrahydrofuran (30 ml) with stirring under nitrogen at -7° to -10° C. After 1 hr. at 25° C. ice-water (250 ml) was added. Extraction with methylene chloride (3×50 ml) followed by evaporation of the extract, and recrystallization of the residue from carbon tetrachloride gave 1.56 g (35%) of ethyl 3-(4-biphenylylthio)-2-oxopropionate, m.p. 154.5°-156° C.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1>C(#N)C>[C:8]1([CH:2]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CSCCN1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 110.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml). DIPEA (0.26 ml, 1.481 mmol) and thiomorpholine (0.15 ml, 1.41 mmol) were sequentially added and the solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=95/5) to obtain ethyl 2-phenyl-2-thiomorpholinoacetate (362 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc([N+](=O)[O-])cc32)n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(N)cc32)n1
Yield: 18.1 %

Procedure:
10% Palladium-carbon (18 mg, manufactured by Merck Chemicals, Ltd.) was added to a solution of ethyl 2-(6-nitro-3-phenyl-1H-indazol-1-yl)thiazole-4-carboxylate (234 mg), which had been synthesized from the compound of Reference Example 24 according to the method of Example 3, in methanol (20 mL manufactured by Wako Pure Chemical Industries, Ltd.) at room temperature, and the mixture was stirred overnight in a hydrogen atmosphere. After completion of the reaction, the 10% palladium-carbon was removed by filtration, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:4), to give 39.1 mg of the title compound. LC-MS: HPLC retention time 1.95 minutes, m/z 365 (M+H), condition C-1.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.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(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](S)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 937 mg, 2.77 mmol), (R)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (prepared in STEP C of Example 18, c.a. 3.60 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (80.1 mg, 0.138 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.1 mg, 0.0690 mmol) and N,N-diisopropylethylamine (725 microL, 4.15 mmol) in 1,4-dioxane (15 mL) was stirred at 160° C. for 1 h under microwave. The mixture was concentrated in vacuo and the residue was purified by amine gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (802 mg, 63% mmol) as a pale orange gum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:32][C:33]([F:44])([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:34][C:33]([F:44])([F:43])[F:32])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N(CC(F)(F)F)c2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a suspension of 0.50 g (0.0017 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.50 g (0.0034 mole) of potassium carbonate and 10 mL of tetrahydrofuran was added 0.46 g (0.0020 mole) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester. After stirring at 75 degrees for four hours, the mixture was cooled and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with ethyl acetate-hexane (gradient, 100:0-30:70) gave 0.25 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-150)
Reaction SMILES: C[CH:2]([CH2:8][CH2:9][NH2:10])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].[C:11](#N)C(C)=C.C(#N)/C=C/C>>[CH3:11][CH:8]([CH2:9][NH2:10])[CH2:2][CH:3]([C:5]([OH:7])=[O:6])[NH2:4]
Reactant: C=C(C)C#N
Reactant: CC(CCN)C(N)C(=O)O
Agent: C/C=C/C#N
Product: CC(CN)CC(N)C(=O)O

Procedure:
γ-Methyl-DL-thiocitrulline (where R is H, R' is CH2 and R" is C(H)(CH3) and x is zero and Q is =S). This compound may be prepared by using y-methyl-DL-ornithine in place of L-ornithine in Example I. γ-Methyl-DL-ornithine is prepared as described above for β-methyl-DL-ornithine except methacrylonitrile is substituted for crotononitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: OCCC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCC1CCCCN1Cc1ccccc1
Yield: 100 %

Procedure:
2-Piperidineethanol (25.8 g, 0.2 mol), benzyl bromide (26.2 ml) and potassium carbonate (55.3 g) in acetonitrile (250 ml), as described above, gave 1-benzyl-2-piperidineethanol (43.8 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:20])[O:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:20])[CH3:14])[N:23]=1
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(N)nc(N)c1C#N
Temperature: 120 °C
Yield: 56.1 %

Procedure:
(1S)-1-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (106 mg, 0.393 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.179 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (89 mg, 56%). 1H NMR (500 MHz, CD3OD) δ ppm 1.36 (ddd, J=13.42, 6.59, 1.46 Hz, 3 H), 2.01 (d, J=1.46 Hz, 2 H), 2.15 (d, J=1.95 Hz, 1 H), 2.18-2.21 (m, 1 H), 2.32 (d, J=1.46 Hz, 2 H), 3.86 (d, J=1.46 Hz, 3 H), 5.38-5.49 (m, 1 H), 6.67 (dd, J=2.20, 1.22 Hz, 1H), 7.58 (dd, J=2.93, 1.46 Hz, 1 H), 7.69 (d, J=5.86 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H21N9O, 404; found 404.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:6][C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Temperature: 50 °C
Yield: 65 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (13.3 g, 39.3 mmol) from Step 1 was dissolved in anhydrous DMF (140 mL). Solid NaN3 (5.18 g, 79.7 mmol) was added and the reaction was warmed to 50° C. for 5 h. The reaction mixture was permitted to cool to rt and the solvent was removed under reduced pressure (150 Torr, 55° C.). This material was taken up into Et2O (150 mL), washed with water (3×10 mL) and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to give 13.9 g crude product. This was separated on a silica column using a gradient from 0-100% EtOAc in hexanes. Solvent was stripped from appropriate fractions to give (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (7.21 g, 65%) as a clear oil. 1H NMR (CDCl3) δ 0.60=1.80 (m 12H), 1.40 (s, 9H), 2.86 (d, 1H), 3.29 (d, 1H), 4.85 (d, 1H), 4.51 (m, 1H), 8.00 (s, 1H). MS ESI +ve m/z 183 (M(−BOC)+1).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[OH:9].[CH3:25]N(C)C=O.CI.[H-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[O:9][CH3:25]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)c(OCc2ccccc2C(O)c2ccccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC(c1ccccn1)c1ccccc1COc1cc(C)ccc1C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of 0.42 g (1.3 mmol) of 2-[2-(2,5-dimethylphenoxymethyl)-α-hydroxybenzyl]pyridine, 4 ml of N,N-dimethylformamide and 0.12 ml (2 mmol) of methyl iodide was added 0.07 g (1.7 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)-α-methoxybenzyl]pyridine (0.40 g, 92.3%) as colorless oil.
Reaction SMILES: [C:1]1([S:7]/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@@H]23)C=CC=CC=1.CSC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:1]1([S:7]/[CH:8]=[CH:9]/[C@H:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)/C=C/Sc1ccccc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CSC
Product: C[C@@H](O)/C=C/Sc1ccccc1
Reaction time: 2 h

Procedure:
(E)-4-phenylthio-3-buten-2-one (178 mg, 1.0 mmol), (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2] oxazaborol (28 mg, 0.1 mmol) and MS4A (Nacalai Tesque Inc., 500 mg) were dried by a vacuum pump, followed by substituting with an argon gas. Dry toluene (5 ml) and dimethylsulfide (3.0 mmol) were added thereto and, after ice cooling, a solution of borane dimethylsulfide complex in toluene (1.07M, 0.65 ml, 0.7 mmol) was dropwise added. After stirring for two hours, an aqueous saturated ammonium chloride solution was added, followed by filtering through a cotton plug. The filtrate was washed with ethyl acetate and, after separating an aqueous layer, the organic layer was washed with 2NHCl, water, an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous magnesium sulfate, the extract containing the titled compound as a main component was obtained by concentrating under a reduced pressure. The NMR chemical shifts of the titled compound are as follows.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.CO.[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:25][O+](C)C>ClCCl>[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:25][N+:1]1[N:2]=[CH:3][N:4]2[C:17]=1[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: c1ccc2c(c1)c1ccccc1n1cnnc21
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[n+]1ncn2c3ccccc3c3ccccc3c21
Temperature: 2 °C
Reaction time: 16 h

Procedure:
A solution of 1,2,4-triazolo[4,3-f]phenanthridine (A. G. Mikhailovskii, V. S. Shklyaev, Chem. Heterocycl. Comp. 1992, 445) (5.9 g, 27 mmol) in dichloromethane (200 ml) and methanol (20 ml) is admixed under argon at 2° C. with trimethyloxonium tetrafluoroborate (4.3 g, 29 mmol) and stirred at 2° C. for 1 h and at room temperature for 16 h. The resulting precipitate is filtered off and washed with dichloromethane, methanol and petroleum ether. Yield: 5.9 g (69%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:23]=[C:22]([NH2:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:6]=1[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:8].CO>[Ni].C1COCC1>[NH2:25][C:21]1[C:22]([NH2:24])=[N:23][C:5]([O:4][CH2:3][CH2:2][F:1])=[C:6]([CH:20]=1)[C:7]([NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([F:18])([F:17])[F:19])[CH2:14][CH2:15]1)=[O:8]
Reactant: Nc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCCF)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-fluoro-ethoxy)-6-amino-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (220 mg, 0.56 mmol), Ra—Ni (50 mg), MeOH (5 mL) and THF (15 mL) is stirred at rt for 2 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[C:23](Br)#[N:24].ClCCl.[OH-].[Na+]>C(O)C>[NH2:24][C:23]1[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH2:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]=1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: NC1=Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of 10.0 g (33.85 mmol) of N-[(2-aminophenyl)methyl]-1-(phenylmethyl)-4-piperidineamine in 150 ml of anhydrous ethanol was combined with 4.0 g (37.76 mmol) of bromocyanogen added batchwise. The mixture was left to stand overnight at ambient temperature, the ethanol was eliminated in vacuo and the residue was distributed between dichloromethane and 1N sodium hydroxide solution. After working up in the conventional way, 9.3 g (86% of theoretical) of colourless crystals were obtained, Rf 0.4 (El D), which were further processed without any additional purification.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([OH:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:6][C:7]=1[C:8](=[O:12])[CH2:9][CH2:10][CH3:11].O.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>O.O1CCCC1>[C:8]([CH:7]1[CH2:6][C:5]([OH:17])([C:13]([O:15][CH3:16])=[O:14])[CH:4]=[CH:3][C:2]1=[O:26])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)C1=C(N)C=CC(O)(C(=O)OC)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)C1CC(O)(C(=O)OC)C=CC1=O
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 4-amino-5-butyryl-1-hydroxycyclohexa-2,4-diene-1-carboxylate (1.25 g, 5.2 mmol) in a 1:1 mixture of water/tetrahydrofuran (10 mL) was added p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol). The reaction mixture was stirred for 18 h and then partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford methyl 5-butyryl-1-hydroxy-4-oxocyclohex-2-ene-1-carboxylate which was used without further purification or characterization.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](Cl)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:38]([N:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][CH:17]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
A mixture of 75 mg (0.166 mmole) of N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl chloride (from Step B), 46 mg (0.25 mmole) of N-phenylbenzylamine, 58 μL (43 mg, 0.33 mmole) of N,N-diisopropylethylamine, and 1 mL of dry toluene was stirred under N2 at 110° C. for 48 hours. The cooled reaction mixture was concentrated by rotary evaporation. Flash chromatography of the residual oil on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave 91 mg (92%) of the title compound as a tacky foam, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 599 (M+1)+.
Reaction SMILES: [C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18](O)=[CH:19][C:14]=2[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:10]1=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[CH:19][C:14]=2[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:10]1=[O:29])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cc3ccc(C#N)cc3)cc2C1=O
Temperature: 40 °C
Reaction time: 96 h
Yield: 85.3 %

Procedure:
1-(Carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-hydroxy-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (19.5 g, 48 mmol), α-bromo-p-tolunitrile (11.3 g, 58 mmol), and potassium carbonate (9.0 g, 65 mmol) were combined in a round bottom flask. Anhydrous DMF (300 mL) was added and the reaction mixture was stirred at 40° C. for 4 days. The reaction mixture was filtered and the filtrate was concentrated in vacuo on a rotary evaporator. The residue was partitioned between ethyl acetate (500 mL) and water (100 mL). The organics were washed with saturated NaCl (50 mL) and dried over Na2SO4. The volatiles were removed in vacuo on a rotary evaporator and the residue was chromatographed on silica gel, eluting the column with 5:6 ethyl acetate/hexanes. Fractions containing pure product (Rf=0.17, 5:6 ethyl acetate/hexanes) were combined and the solvents removed in vacuo on a rotary evaporator to yield 1-(carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-[(4-cyanophenyl)methyl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (20.7 g, 83% yield).