Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH2:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([CH2:11][NH:23][CH2:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Reactant: NCCc1ccccc1
Solvent: O
Product: OC1(CNCCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
18.2 g (95 mmol) of 5-benzyl-1-oxa-5-azaspiro[2,4]heptane are added dropwise to 15.6 ml (0.115 mol) of benzylmethylamine in 300 ml of water and the mixture is stirred for 15 hours at room temperature. The product is extracted using CH2Cl2, the extracts are dried using K2CO3 and concentrated, and incipient distillation is carried out up to 160° C. (oil bath temperature).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/B(O)O)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][N:15]=1.[OH-].[Tl+]>O1CCCC1.O.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14](/[CH:7]=[CH:6]/[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: Brc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [OH-]
Agent: [Tl+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(/C=C/c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (E)-4-fluorostyrylboronic acid (5 g, 30.1 mmol) and 2,4-dibromopyridine (6.49 g, 27.4 mmol) in tetrahydrofuran (150 mL) was purged with nitrogen for 20 min. To this was added Pd(Ph3P)4 (2.37 g, 2.05 mmol) and a 10% w/w solution of thallium(I) hydroxide (137 g, 62 mmol) in water. The reaction was stirred under nitrogen at room temperature. After 3 h, the gray suspension was diluted with dichloromethane and filtered through celite. The organics were washed with water, dried over magnesium sulfate, and concentrated. The resulting residue was purified by column chromatography (5%→13% EtOAc/Hex) to give 2.65 g (33%). 1H NMR (CDCl3) Shift: 8.43 (d, J=5.2 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.50-7.59 (m, 3H), 7.34 (dd, J=5.3, 1.7 Hz, 1H), 7.10 (t, J=8.7 Hz, 2H), 7.02 (d, J=16.2 Hz, 1H). 13C NMR (CDCl3) Shift: 163.1, 157.0, 150.4, 133.3, 133.2, 132.5, 129.0, 126.4, 125.3, 116.0. 19F NMR (CDCl3) Shift: −112.69 (bs, 1F). Mass spec.: 278.2 (MH)+.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1)[CH2:4][CH3:5].S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[CH2:29]=[C:30]([CH3:32])[CH3:31].C(=O)([O-])O.[Na+]>C(Cl)Cl>[ClH:1].[NH2:2][C@@H:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1)[CH2:4][CH3:5]
Reactant: CC[C@@H](N)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: C=C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixed solution of the compound S97 (703 mg), (R)-2,2′-bis(di-4-methylphenylphosphino)-1,1′-binaphthyl ruthenium (II) chloride complex (51 mg), ammonium formate (3.15 g), and 2M ammonia/methanol solution (20 ml) was stirred under a nitrogen atmosphere at 85° C. for 18 hours. Next, ethyl formate (4 ml) was added to the reaction solution and the mixture was stirred at 85° C. for 18 hours. The reaction solution was concentrated, saturated potassium hydrogensulfate aqueous solution and saturated saline were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate, then concentrated. Ethanol (10 ml), distilled water (2.5 ml), and concentrated hydrochloric acid (2.5 ml) were added to the residue, the mixture was stirred at 85° C. for 40 minutes, then the reaction solution was concentrated to obtain 4-[(1R)-1-aminopropyl]-2-nitrobenzoic acid hydrochloride (745 mg). To 500 mg of the obtained 4-[(1R)-1-aminopropyl]-2-nitrobenzoic acid hydrochloride, methylene chloride (20 ml) and anhydrous magnesium sulfate (3.5 g) were added and the mixture was stirred at room temperature for 15 minutes. Next, concentrated sulfuric acid (186 μl) was added to the reaction solution, the mixture was stirred at room temperature for 5 minutes, then isobutene (3.5 ml) was added and the mixture was stirred at room temperature for 24 hours. Saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The residue was diluted with ethyl acetate, then 4N hydrogen chloride/ethyl acetate solution (0.5 ml) was added dropwise in the obtained solution. The precipitate was collected by filtration to obtain the title compound (358 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[C:13](=[O:21])[N:12]3[CH2:22][CH2:23][CH2:24][C@H:11]3[C:10]=12)=[O:5])C.[OH-].[Na+]>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]2[N:9]3[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]3[C@@H:11]3[CH2:24][CH2:23][CH2:22][N:12]3[C:13](=[O:21])[C:14]=2[CH:19]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2

Procedure:
7 g (20.2 mmol) of (S)-(+)-ethyl-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 950 mg (23.8 mmol) of sodium hydroxide are heated to boiling under reflux for 30 minutes in 20 ml of alcohol and 4 ml of water. After evaporation of the ethanol, the residue is made acid with 23.7 ml of 1 N hydrochloric acid. The white material obtained is filtered off under suction, washed with a small amount of water and dried. There is obtained (S)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid of melting point 227°.
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N+]#N.[CH3:16][S-:17].[Na+].N#N>CC#N>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:17][CH3:16]
Reactant: C[S-]
Reactant: N#[N+]c1ccc(Cl)cc1Br
Agent: F[B-](F)(F)F
Agent: N#N
Agent: [Na+]
Solvent: CC#N
Product: CSc1ccc(Cl)cc1Br
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A cold (0° C.) solution of 2-bromo-4-chlorobenzenediazonium tetrafluoroborate (5.0 g, 16.3 mmol) in CH3CN (50 mL) was treated portion wise with sodium thiomethoxide (1.15 g, 16.4 mmol) and a strong evolution of gas (N2) was observed. The mixture was warmed up to 23° C., stirred for 0.25 hours and filtered. The filtrate was concentrated in vacuo; the residue was taken up in CH2Cl2, stirred and the solution was then filtered. The CH2Cl2 filtrate was concentrated in vacuo affording a brown syrup that was distilled under vacuum to provide the purified title compound; bp 125° C./0.4 mm, 1.4 g, 37%. 1H NMR (CDCl3) δ7.56 (d, J=2.5 Hz, H-3, 1H), 7.30 (dd, J=2.5 Hz, J=8.6 Hz, H-5, 1H), 7.07 (d, J=8.6 Hz, H-6, 1H), 2.49 (s, CH3, 3H). IR 1569, 1544, 1450, 1434, 1371,1248, 1105, 1024, 868, 803, 784 cm31 1. Anal. Calcd. for C7H6BrClS: C, 35.39; H, 2.55. Found: C, 34.89; H, 2.51.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:23]([C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1)[CH2:24][CH2:25][CH3:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][C:30]2[N:29]=[N:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:37][CH:38]=3)[CH:31]=2)([F:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a stirred solution of 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 mmol, 0.116.g) in THF (2 mL) at room temperature was added potassium tert-butoxide (0.5 mmol, 0.5 mL, 1M solution in THF) and continued stirring for 30 min. 3-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.5 mmol, 0.172 g) was taken THF (1 mL) and added to the reaction and stirred for 10 h at room temperature. The reaction was quenched with slow addition of water (2 mL) and the product was extracted with ethyl acetate (2×5 mL), Organic layer was washed with water (5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (90 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[OH:10]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a 0° C. mixture of 3-bromo-4-methyl aniline (5 g; 27 mmol) and H2SO4 (5.5 mL of a 16 M solution) in H2O (7.5 mL) was added dropwise a solution of aqueous NaNO2 (1.93 g; 28 mmol in 7.5 mL H2O). The reaction was stirred at 0° C. for 30 min, then was heated at 50° C. for 2 h, then was cooled to RT and extracted with EtOAc (2×). The combined organic extracts were washed with H2O, dried (Na2SO4) and concentrated in vacuo to give 3-bromo-4-methyl phenol (1.72 g; 34%) as an oil. This phenol was converted to 3-bromo-4-methyl phenyl chloroformate (1.9 g; 82%) using the same procedure (phosgene/dimethylaniline/heat) as for 3-fluoro-4-methyl phenyl chloroformate above.
Reaction SMILES: CS[C:3]1[N:8]2[C:9]([CH3:12])=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:13][CH3:14])[N:4]=1.C[O-].[Na+].Cl.C(=O)(O)[O-:20].[Na+]>O.CO>[CH3:12][CH:9]1[N:8]2[C:3](=[O:20])[N:4]=[C:5]([S:13][CH3:14])[CH:6]=[C:7]2[CH:11]=[N:10]1
Reactant: O=C([O-])O
Reactant: CSc1cc2cnc(C)n2c(SC)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1cc2n(c(=O)n1)C(C)N=C2
Temperature: 0 °C

Procedure:
To a solution of 4.8 g (21.3 mmole) of 5,7-bis(methylthio)-3-methylimidazo[1,5-c]pyrimidine in 10 ml of water and 90 ml of methanol was added 5.0 g (23.1 mmole) of 25% sodium methoxide in methanol. The mixture was heated at reflux for 16 hours, poured into 400 ml of an ice-water mixture, and acidified with 3 ml of concentrated hydrochloric acid. The mixture was basified with solid sodium bicarbonate, and the precipitate was separated by filtration. The solid was washed with water and dried to provide 3-methyl-7-methylthioimidazo[1,5-c]pyrimidin-5-one, m.p. 221°-222° C. Analysis: Calculated for C8H9N3OS; %C, 49.2; %H, 4.7; %N, 21.5; Found; %C, 48.9; %H, 4.6; %N, 21.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[C:44]([O:46][CH3:47])=[O:45]>>[CH3:47][O:46][C:44]([C:43]1[CH:42]=[CH:41][C:40]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:39][C:38]=1[F:37])=[O:45]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(F)c4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 64, step 7, trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 64, step 6) was reacted with 3-fluoro-4-(methoxycarbonyl)phenylboronic acid (70° C., 5.5 h) to give the title compound as a white solid. MS (m/e)=566.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH:26]1[CH2:28][C:27]1([F:30])[F:29]>O1CCOCC1>[F:29][C:27]1([F:30])[CH2:28][CH:26]1[CH2:25][N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:17]
Reactant: FC1(F)CC1CBr
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Temperature: 80 °C
Yield: 53.8 %

Procedure:
To a solution of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (1.19 g, 4.68 mmol) in anhydrous dioxane (50.0 mL) was added potassium carbonate (1.29 g, 9.36 mmol) and bromomethyl-2,2-difluorocyclopropane (1.00 g, 5.85 mmol). The reaction mixture was heated at 80° C. for 16 h, filtered and the solid was washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate in hexane to afford the title compound as a yellow solid (0.87 g, 54%): mp 146-148° C.; 1H NMR (300 MHz, CDCl3) δ 4.18 (q, J=7.1 Hz, 2H), 3.99 (t, J=8.4 Hz, 2H), 3.65-3.44 (m, 3H), 3.20-3.12 (m, 1H), 2.48 (s, 3H), 2.02-1.88 (m, 1H), 1.68-1.55 (m, 1H), 1.38-1.28 (m, 1H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 160.1, 156.8, 155.2, 114.9 (t), 113.8, 60.8, 42.4, 42.1, 41.1 (d), 20.3 (t, 2JC-F=43 Hz), 17.5, 14.9 (t, 2JC-F=43 Hz), 14.6; MS (ES+) m/z 399.0 (M+1).
Reaction SMILES: [I-:1].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]([CH2:18]Cl)=[CH2:17])=[C:10]([CH:13]=1)[CH:11]=[O:12])(=[O:5])[CH3:4].O>CC(C)=O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]([CH2:18][I:1])=[CH2:17])=[C:10]([CH:13]=1)[CH:11]=[O:12])(=[O:5])[CH3:4]
Reactant: C=C(CCl)COc1ccc(C(C)=O)cc1C=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(CI)COc1ccc(C(C)=O)cc1C=O
Reaction time: 5 h
Yield: 100.1 %

Procedure:
531 mg (3.54 mmol) of sodium iodide are added to 894 mg (3.54 mmol) of 5-acetyl-2-{[2-(chloromethyl)-2-propenyl]oxy}benzaldehyde in solution in 10 ml of distilled acetone. The medium is brought to reflux and is stirred for 5 hours. Water is added and then the solution is concentrated. After the addition of water and dichloromethane, the phases are separated by settling and then the aqueous phase is extracted with dichloromethane. The combined organic phases are washed, dried and then concentrated under vacuum to give 1.22 g (100%) of 5-acetyl-2-{[2-(iodomethyl)-2-propenyl]oxy}benzaldehyde in the form of a white solid which turns yellow in air; 1H NMR (300 MHz, CDCl3): 10.46 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.15 (dd, J=2.4 Hz and 8.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 5.52 and 5.32 (2s, 2H), 4.86 (s, 2H), 4.01 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:6][C:7](=[O:20])[CH2:8][NH:9]C(OCC1C=CC=CC=1)=O)[CH3:2].Br>CCOCC>[CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH:6][C:7](=[O:20])[CH2:8][NH2:9])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Reaction time: 0.5 h

Procedure:
The deposit was filtered off by a glass filter, and after the filtrate was washed with a 0.1% aqueous solution of NaHCO3 three times and then washed with a 0.1 N aqueous solution of HCl three times, it was dried over anhydrous magnesium sulfate and freed of dichloromethane under reduced pressure to obtain carbobenzoxyglycyl-L-phenylalanine ethyl ester, and to this ester was added 250 ml of HBr-saturated acetic acid, and after the mixture was stirred for 30 minutes, anhydrous ether was added to the mixture to produce a precipitate. The filtered off precipitate was washed with ether to obtain glycyl-L-phenylalanine ethyl ester.HBr.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=1.[CH2:29]1[O:31][CH2:30]1.Cl>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH:31][CH2:30][CH2:29][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: C1CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc(CCCO)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
1.7M n-butyllithium in hexane (19.4 ml, 33 mmole) was added dropwise to a chilled (-78° C.) and stirred solution of diisopropylamine (4.63 ml, 33 mmole) in 20 ml of dry tetrahydrofuran (hereinafter THF). After 20 minutes, a solution of p-toluic acid (2.042 g, 15 mmole) in 20 ml of dry THF was added dropwise. After stirring at -78° C. for another 1.5 hours, 4 ml of HMPA was added followed immediately by a solution of ethylene oxide (2.99 g, 67.9 mmole) in 10 ml of dry THF. The resulting solution was stirred at -78° C. for 2 hours, treated with 5% hydrochloric acid and warmed up to room temperature, the THF being removed in vacuo. The aqueous solution was saturated with sodium chloride and extracted three times with ethyl ether. The combined ether extracts were concentrated from 300 to 100 ml and extracted with a 0.5N sodium hydroxide solution. This extract was acidified with 10% hydrochloric acid and extracted three times with ethyl ether. The ether extracts were dried over anhydrous magnesium sulfate and evaporated to a residue. This residue was chromatographed on a silica gel column, eluting successively with dichloromethane-ethyl acetate (9:1 and 1:1), ethyl acetate and dichloromethane-methanol (9:1) to give 750 mg of the title A compound, with consistent spectral data.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:12]([O:10][C:9]([C@H:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([NH2:2])[CH2:4]1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: N[C@@H]1CCC[C@H](C(=O)OCc2ccccc2)C1

Procedure:
cis-3-Aminocyclohexanecarboxylic acid hydrochloride (8.78 g, 49 mmole) was refluxed for 24 hours with benzyl alcohol (26.4 g, 0.24 mole) and para-toluenesulphonic acid monohydrate (11.17 g, 0.59 mole) in toluene (150 ml) using a Dean-Stark trap. On cooling and addition of diethyl ether the required benzyl ester crystallised as a white solid (18.68 g, 94%), m.p. 148°-150° C. Found: C,62.21; H,6.75; N,3.34. C21H27NO5S requires C,62.20; H,6.71; N,3.45%.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:24])(=[NH:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([C:19]1[N:23]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:24]=1)[CH3:22]
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: CC(C)C(=N)N
Agent: Cl
Product: CC(C)c1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 87 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and isobutyramidine hydrochloride. Yield: 87%.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][NH2:18])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.FC(F)(F)C(O)=O.C(SCC(CCCN)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[NH2:18][CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CN)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-(3-acetylthio-2-aminomethylpropanoyl)-L-proline for the 1-(2-acetylthiomethyl-5-aminopentanoyl)-L-proline trifluoroacetate in the procedure of Example 15, 1-(2-aminomethyl-3-mercaptopropanoyl)-L-proline is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[O:19][C:20]1[N:25]=[CH:24][C:23]([C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]([NH2:33])[N:27]=2)=[CH:22][C:21]=1[CH3:34].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:33][C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([C:23]4[CH:22]=[C:21]([CH3:34])[C:20](=[O:19])[NH:25][CH:24]=4)[N:27]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: COc1ncc(-c2nc(N)ccc2C)cc1C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc(Cl)cc3)CC2)nc1-c1c[nH]c(=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (39.3 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionyl chloride (43.8 μL, 0.6 mmol) followed by DMF (1 drop) and the reaction was stirred at room temperature for 30 minutes and then the solvent was removed. Toluene (˜1 mL) was added, mixed with the residue and then removed by evaporation. The residue was then dissolved in dichloromethane (1 mL) and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (46 mg, 0.2 mmol) and triethyl amine (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) was added. The reaction was stirred at room temperature for 12 hors. The reaction was then concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC (10-99% acetonitrile/water) to yield 62 mg of the product. ESI-MS m/z calc. 407.1. found 408.2 (M+1)+. Retention time 2.07 minutes.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:6]=1>N1C=CC=CC=1>[C:13]1([C:8]2[CH:9]=[C:10]3[C:11]([NH2:12])=[N:3][NH:2][C:5]3=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: N#Cc1cc(-c2ccccc2)ncc1Cl
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2cnc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (0.3 mL, 5.9 mmol) was added to a stirred solution of 5-chloro-2-phenyl-isonicotinonitrile (420 mg, 1.9 mmol) in pyridine (5 mL). The reaction mixture was stirred at reflux for 3 hours, cooled and the resulting solid was filtered and dried in vacuo, affording a crude residue. Purification by column chromatography using a gradient elution of 0–5% methanol in dichloromethane as eluent afforded the title compound as a solid.