Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([NH:17]CC2C=CC(OC)=CC=2)=[C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:4]=1[CH3:33])#[N:2]>FC(F)(F)C(O)=O>[NH2:17][C:6]1[C:7]2[O:11][C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[N:9][C:8]=2[C:3]([C:1]#[N:2])=[C:4]([CH3:33])[C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccccc2)c(N)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 13 h
Yield: 95.3 %

Procedure:
4-Cyano-7-(4-methoxybenzylamino)-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-337) (2.10 g, 4.77 mmol) was dissolved in trifluoroacetic acid (22 ml), and stirred at room temperature for 13 hours. The solvent was evaporated away under reduced pressure, and the resulting residue was added to chloroform (25 ml) and an aqueous saturated sodium hydrogencarbonate solution (25 ml), followed by vigorously stirring for 15 minutes. The organic layer was separated, the aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:acetone=98:2, v/v) to obtain the entitled compound (1.456 g, 95%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]1.[H-].[Na+].CS([C:23]1[N:24]([CH3:34])[C:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH:14]([O:16][C:23]2[N:24]([CH3:34])[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[CH3:15])=[N:10]1
Reactant: Cc1ccc(F)c(-n2nnc(C(C)O)n2)c1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C)n2)c1

Procedure:
The title compound is prepared from 1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol), sodium hydride (1.5 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [NH2:1][C@H:2]([C:4](OC)=[O:5])[CH3:3].Cl.[NH:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12]>O>[NH2:1][C@H:2]([C:4]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:5])[CH3:3]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Solvent: O
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 37 °C
Reaction time: 72 h

Procedure:
L-Ala-OMe.HCl was added to the L-Pro-TBP prepared by the conversion of L-Pro into its ionic liquid form according to the method disclosed in Example 1 so as to control the concentration of the L-Ala-OMe.HCl to 1.000 mmol per unit mass (1 kg) of the L-Pro-TBP (the amount of water relative to the total mass of the reaction system: 2% by mass). The mixture was stirred enough to ensure the mixture uniform, and then, the reaction of these components was initiated while stirring the reaction system in a water bath and warming the same at 37° C. or 50° C. The reaction was finished 72 hours after the initiation of the reaction, and the samples, which were collected at appropriate intervals of time during the reaction, were analyzed according to the HPLC technique to confirm the formation of the desired dipeptide, i.e., L-Ala-Pro. The results are summarized in the following Table 1.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:8][C:7]=1C(=O)C.C1C=C(Cl)C=[C:24]([C:29]([O:31]O)=[O:30])C=1>C(Cl)(Cl)Cl>[C:29]([O:31][C:7]1[CH:8]=[C:9]([S:12]([C:15]([F:16])([F:17])[F:18])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@H:2]1[CH2:3][O:1]1)(=[O:30])[CH3:24]
Reactant: CC(=O)c1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 19 using 1-{2-[(2R)-oxiran-2-ylmethoxy]-5-[(trifluoromethyl)sulfonyl]phenyl}ethanone (1.2 g, 3.7 mmol) and m-CPBA (4.95 g, 22.5 mmol) in CHCl3 (50 ml). Crude yield 1.0 g. MS m/z (rel. intensity, 70 eV) 298 (34), 229 (77), 165 (bp), 107 (39), 79 (30).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:14]([N:17]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22](Br)=[C:21]([O:26][CH3:27])[CH:20]=1)([CH3:16])[CH3:15].Cl>N1C(C)=CC(C)=CC=1C>[CH:29]1([N:17]([CH:14]([CH3:16])[CH3:15])[C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:21]([O:26][CH3:27])[CH:20]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Br
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Oc1cc(OC)c(OC)c(OC)c1
Reaction time: 36 h

Procedure:
A slurry of cuprous oxide (1.00 g, 6.78 mmol) in a solution of 3,4,5-trimethoxyphenol (1.62 g, 8.53 mmol) and 4-bromo-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (2.42 g, 6.8I mmol) in 2,4,6-collidine (30 ml) was refluxed with stirring under a nitrogen atmosphere for 36 hr. Additional 3,4,5-trimethoxyphenol (0.32 g), and cuprous oxide (0.16 g) were added and reflux continued for 72 hrs. The reaction mixture was cooled, poured onto 6N HCl and extracted three times with ethyl acetate. The combined organic layers were washed twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4) The drying agent was filtered and the filtrate concentrated in vacuo to give 1.29 g of crude product. This material was chromatographed twice on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate hexane, m. pt. 126-128° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:6][C:5]=1[C:21]1[S:22][CH2:23][C@:24]([CH3:32])([C:26]([O:28]C(C)C)=[O:27])[N:25]=1>CO>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:6][C:5]=1[C:21]1[S:22][CH2:23][C@:24]([CH3:32])([C:26]([OH:28])=[O:27])[N:25]=1
Reactant: COCCOCCOCCOc1ccc(O)c(C2=N[C@@](C)(C(=O)OC(C)C)CS2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOCCOCCOc1ccc(O)c(C2=N[C@@](C)(C(=O)O)CS2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of 50% (w/w) NaOH (3.34 mL, 94 mmol) in CH3OH (34 mL) was added to 12 (2.14 g, 4.85 mmol) in CH3OH (70 mL) with ice bath cooling. The reaction mixture was stirred at room temperature for 18 h, and the bulk of the solvent was removed by rotary evaporation. The residue was treated with dilute NaCl (100 mL) and was extracted with ether (3×50 mL). The basic aqueous phase was cooled in ice, acidified with 2 N HCl to pH=2, and extracted with EtOAc (3×100 mL). After the EtOAc layers were washed with saturated NaCl (100 mL), glassware that was presoaked in 3 N HCl for 15 min was employed henceforth. After solvent removal by rotary evaporation, 1.88 g of 6 (97%) was obtained as an orange oil: [α]20+40.0% 1H NMR (D2O) δ 1.72 (s, 3H), 3.26 (d, 1H, J=11.2), 3.38 (s, 3H), 3.54-3.58 (m, 2H), 3.64-3.71 (m, 4H), 3.72-3.76 (m, 2H), 4.07-4.11 (m, 3H), 6.91-6.95 (m, 2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.[CH:16]1([N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH:16]1([N:19]2[CH:23]=[C:22]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]4)[CH:21]=[N:20]2)[CH2:18][CH2:17]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Temperature: 100 °C
Yield: 60.8 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.500 g, 1.858 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.457 g, 1.951 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (0.146 g, 0.186 mmol), and cesium carbonate (1.816 g, 5.57 mmol) in 1,4-dioxane (7.5 mL) and water (1.50 mL) was heated at 100° C. for 16 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.335 g, 61%) as an off-white solid. MS (ESI, pos. ion) m/z 297 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.Cl.[F:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:25][C:26](O)=[O:27].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[CH:16][C:15]([F:14])=[CH:24]3)[S:5][CH:6]=1
Reactant: O=C(O)Cc1cccc2cc(F)cnc12
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc2cc(F)cnc12)Nc1scc(Br)c1-c1nc[nH]n1
Reaction time: 1 h

Procedure:
4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (17 mg, 69.4 umol), 2-(3-fluoroquinolin-8-yl)acetic acid hydrogen chloride (22 mg, 91.0 umol), 2-chloro-1-methylpyridinium iodide (101 mg, 395 umol) and triethylamine (0.2 ml) in methylene chloride (1 ml) was heated to reflux. After stirring for 1 h, the solution was concentrated and the residue was purified by HPLC to yield N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-8-yl)acetamide. Method [7] retention time 5.67 min by HPLC (M+ 432 and 434) and (M+Na 454 and 456). 1H NMR (300 MHz, CDCl3) δ 12.25 (s, 1H), 8.83 (d, J=3.3 Hz, 1H), 7.87 (m, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.70 (broad s, 2H), 4.56 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(F)ccc1F
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Di-tert-butyl (2,5-difluorophenyl)imidodicarbonate (1.48 g, 4.49 mmol) was dissolved in DCM (15.0 mL) at rt. TFA (0.48 mL, 6.28 mmol) was added to the reaction and the contents were stirred for 1 h. LC/MS at this time shows that starting material has been consumed. The solution was then washed with saturated aqueous sodium bicarbonate. The organics were dried over MgSO4 filtered and concentrated. The crude product was purified on silica gel, eluting with 0-50% EtOAc in hexanes over 32 minutes to afford the title compound (758 mg, 2.88 mmol) as a pale yellow oil. MS (ESI): m/z=174.2 (M+H-[t-Bu]).
Reaction SMILES: Cl[C:2](=[CH2:11])[CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[K+].C(O)(=O)C>CN(C)C=O>[CH2:3]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:11]
Reactant: C=C(Cl)CC1(O)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C#CCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10.00 Grams of the 1-(2'-chloroallyl)-1-cyclohexanol obtained above were dissolved in 94 g of N,N-dimethylformamide, and 9.65 g of potassium hydroxide in a flake form were added. The mixture was stirred at room temperature for 6 hours, and neutralized with a 20% acetic acid aqueous solution. The resultant mixture was subjected to extraction with toluene. The toluene phase was washed with water and dried over magnesium sulfate. The desiccant was filtered off and the toluene was distilled off under reduced pressure to give 7.68 g of 1-propargyl-1-cyclohexanol; m.p.=53-54° C., FI-MS m/e 138(M+) (Propargyl compound/allene compound=100.0/0.0),
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:4]=1)[NH2:2].[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=O>C(O)(=O)C.C(O)C>[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[N:2][NH:1][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:4]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=NNc1cc(N3CCOCC3)nc(OCCN3CCOCC3)n1)C(=O)N2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (80 mg; ¼ mmol) was added to a flask along with 5-methylisatin (53 mg; ⅓ mmol) and ethanol (4 mL). One drop of acetic acid was added, and the reaction was stirred overnight at 60° C. The mixture was then filtered and the precipitate was washed with ethanol (1 mL) and dried to give 5-methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-1,3-dihydro-indol-2-one.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:18](=[O:34])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:19]2[C:18](=[O:34])[C:14]3([CH2:15][CH2:16][CH2:17]3)[N:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:12][CH:11]=3)[C:20]2=[S:21])=[CH:23][C:24]=1[C:30]([F:31])([F:32])[F:33])#[N:29]
Reactant: COC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
A mixture of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-phenyl}-butyric acid methyl ester (90) [ND-4] (0.501 g, 1 mmol) in methanol (10 ml) and solution of sodium hydroxide (10 ml, 2M) was stirred at room temperature for 5 hours. The methanol was evaporated. The residue was adjusted to pH=5 by HCl aq. (2M) and then, the medium was extracted with ethyl acetate (3×50 ml). The organic layer was dried over MgSO4 and concentrated to dryness to obtain 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-phenyl}-butyric acid (89) [ND-5] (0.482 g, 0.99 mmol, 99%), the structure of which is illustrated in Formula 89.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:20])[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[ClH:1].[CH3:2][O:3][C:4](=[O:20])[CH2:5][N:6]([C:21](=[O:23])[CH3:22])[CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CNC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COC(=O)CN(C(C)=O)C1CCN(Cc2ccccc2)CC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]glycine methyl ester hydrochloride and acetic anhydride.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCCCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Ammonium chloride (1.6 g) and iron powder (8.4 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-piperidinobenzonitrile (10 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (8.3 g), melting point: 148–149° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]([CH3:12])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O.C(O)(=O)C>[CH:10]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:12])[CH3:9]
Reactant: CC(C)=O
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CNC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a suspension of ethyl 2-aminoacetate hydrochloride (20 g, 143.28 mmol) in THF (400 mL) was added glacial acetic acid (20 mL) followed by acetone (11.59 mL, 151.62 mmol). The reaction was stirred 30 min at room temperature. Sodium triacetoxyborohydride (60.73 g, 286.56 mmol) was added over the course of one hour. The reaction was poured slowly into a vigorously stirred biphasic mixture of water (300 mL) and ethyl acetate (800 mL). The aqueous layer was adjusted to pH 13 using a solution of 50% (weight) NaOH. The mixture was stirred 30 min and poured into a separatory funnel. The organic layer was collected and the aqueous layer was back extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine (300 mL), dried with sodium sulfate, and concentrated to yield the title compound (17.6 g, 85%) as a translucent oil which was used in the next step without further purification. [M+H] calc'd for C7H15NO2, 146. found, 146.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:12]1)[C:8](=[O:42])[NH:7]2)=[O:5])C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:29]([O:28][C:26]([NH:25][CH:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:37])[CH3:36])[CH2:12]2)[C:8](=[O:42])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (1.5 g, 2.47 mmoL) in a mixed solvent system of THF (4 mL), methanol (1 mL), and water (2 mL), was added powdered lithium hydroxide monohydrate (1.0 g, 50 mmoL). The light yellow slurry was stirred at rt under N2 for 4 h. The mixture was then concentrated in vacuo, and the residue partioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1 N HCl until reaching pH 4. This acidic solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4), and concentrated in vacuo to give 1.2 g (84%) of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as an off-white solid. 1H NMR (300 MHz, CD3OD) 0.12 (s, 6H), 0.89 (s, 9H), 1.23-1.64 (m, 17H), 1.70-1.87 (m, 1H), 1.90-2.49 (m, 6H), 3.70-3.80 (m, 1H), 3.83-3.90 (m, 1H), 4.28-4.36 (m, 1H), 4.47-4.55 (m, 1H), 4.65 (s, 1H), 5.30-5.39 (m, 1H), 5.53-5.62 (m, 1H); MS m/z 580 (M++1).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][CH:9](O)[C:8]=2[N:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:2][CH:9]1[C:8]2[N:7]=[C:6]([CH3:5])[CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: BrP(Br)Br
Reactant: Cc1ccc2c(n1)C(O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)C(Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Phosphorus tribromide (0.0105 mol) was added dropwise at 0° C./5° C. under N2 flow to a mixture of (±)-5,6,7,8-tetrahydro-2-methyl-8-quinolinol (intermediate 17) (0.03 mol) in toluene (20 ml). The mixture was brought to room temperature and stirred at room temperature overnight. Ice water was added. The mixture was basified with a concentrated NaOH solution and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1; 20–45 μm). The pure fractions were collected and the solvent was evaporated, yielding 2 g (29%) of (±)-8-bromo-5,6,7,8-tetrahydro-2-methylquinoline (interm. 18).
Reaction SMILES: CO.[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:7]=[C:6]([CH2:19][C:20]2[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][N:24]3S(C2C=CC(C)=CC=2)(=O)=O)[N:5]=1.C([O-])([O-])=O.[K+].[K+]>O>[NH2:3][C:4]1[N:5]=[C:6]([CH2:19][C:20]2[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc(N)nc(Nc5ccc(C#N)cc5)n4)c(Cl)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)ccc4[nH]ccc34)n2)cc1
Yield: 45 %

Procedure:
Methanol (120 ml) was added to a mixture of intermediate (5) (2.35 g) and K2CO3 (9.19 g) in water (40 ml). The resulting reaction mixture was stirred and refluxed for 19 hours under argon. Water (120 ml) was added, the precipitate was filtered off and purified by column chromatography over silica gel (eluent: DCM/2-propanone 90/10). Two desired fractions were collected and their solvent was evaporated. The first fraction group was slurried in ACN, cooled, filtered off and dried, yielding 0.75 g (45%, white solid) of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 8, mp. 267-268° C.). The second column fraction group yielded 0.15 g of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzamide (compound 9). After 24 hours at RT the aqueous filtrate was filtered to give 0.25 g of compound (9). The two fractions of compound 9 were combined, dissolved in 500 ml of refluxing methanol, hot filtered, the filtrate concentrated to 50 ml, cooled and filtered, then dried, yielding 0.25 g (14%) of 4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzamide (compound 9, mp. 204-205° C.).