Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:11]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:24]([O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)=[C:4]([CH3:9])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COC2CCCCO2)c1
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
A solution of 2,6-dimethyl-3′-[(tetrahydro-2H-pyran-2-yloxy)methyl]biphenyl-4-ol (1.78 g, 5.70 mmol), benzyl alcohol (0.885 mL, 8.55 mmol) and tributylphosphine (2.13 mL, 8.55 mmol) in toluene (80 mL) was stirred under ice-cooling, and 1,1′-(azodicarbonyl)dipiperidine (2.16 g, 8.55 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 24 hrs. Hexane (40 mL) was added to the reaction mixture and the precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound as a colorless oil (1.71 g, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](N(OC)C)=[O:9])=[CH:4][CH:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[CH3:14])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nn1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)nn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 6-chloro-N-methoxy-N-methylpyridazine-3-carboxamide (13.5 g, 0.0659 mol) in THF (600 mL) was added CH3MgBr (43.2 ml, 0.13 mol) at −78° C. under N2. The reaction mixture was stirred at −78° C. for 2 h, quenched by addition of aq NH4Cl and filtered. The filtrate was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under vacuum, and the residue was purified by column chromatography to afford 1-(6-chloropyridazin-3-yl)ethanone. (9.3 g, 90% yield). 1H NMR (CDCl3, 400 MHz): δ 8.03 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:13]=2[N:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)(Cl)Cl>[C:22]([N:10]1[CH2:11][CH2:12][C:13]2[N:14]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=2[CH2:9]1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)c1nc2c(s1)CNCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2c(s1)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-tert-butyl 2-ethyl 6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate obtained in step V of example 1 was deprotected to get the 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester. To a solution of 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester (1 eq) and triethyl amine (1 eq) in chloroform, acetic anhydride was added and the reaction mixture was stirred for 1 h at room temperature. Reaction mixture was then diluted with chloroform and washed with water. Organic layer was then separated, dried and concentrated under reduced pressure to afford the desired ethyl 5-acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O)=[CH:9][CH:8]=[C:7]([C:19]#[N:20])[C:4]=2[S:5][CH:6]=1.[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([NH:30][NH:29][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:32][CH:31]=3)=[O:15])=[CH:9][CH:8]=[C:7]([C:19]#[N:20])[C:4]=2[S:5][CH:6]=1
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a mixture of (2R,3S)-2-(3-chloro-7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (0.77 g, 2.48 mmol), 4-cyanobenzhydrazide (440 mg, 2.73 mmol), HOBt (369 mg, 2.73 mmol) in THF:DMF (1:1) (40 mL) was added EDC (712 mg, 3.71 mmol) and Et3N (0.53 mL, 3.80 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc (300 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent and purification of the residue gave the title compound N′-((2R,3S)-2-(3-chloro-7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.83 g, 74%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.82 (b, 2H), 8.10 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 7.53 (d, J=6.8 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 4.49 (m, 1H), 4.22 (dd, J=2.9, 6.8 Hz, 1H), 1.41 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14](=O)[CH3:15].[BH4-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:14][CH3:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1 eq, 5.37 mmol) in methanol (20 mL) was added acetaldehyde (0.95 eq) and the resulting mixture was heated to 80° C. and stirred for 2 h., then stirred at room temperature overnight. Sodium borohydride (0.95 eq, 5.1 mmol) was added and reaction mixture was stirred for an additional 2 h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.05 (3H, t), 1.45 (9H, s), 1.60–1.75 (1H, m), 2.00–2.10 (1H, m), 2.68 (4H, q), 2.90–3.15 (1H, m), 3.25–3.65 (4H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.CO.[OH-].[Na+]>O>[CH3:1][N:2]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(CN(C)C2CCC(Nc3ncnc4sc5c(c34)CCC5)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(C(=O)O)cc1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 206.4 %

Procedure:
A mixture of methyl 4-([methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino)cyclohexyl]amino]methyl)benzoate (500 mg, 1.11 mmol, 1.00 equiv), methanol (20 mL), sodium hydroxide (89 mg, 2.23 mmol, 2.00 equiv) and water (2 mL) was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 1 with hydrogen chloride (12 mol/L). The resulting mixture was concentrated under vacuum to yield 1 g of crude 4-([methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino)cyclohexyl]amino]methyl)benzoic acid as a yellow solid. The crude product was used in the next step without further purification. MS: m/z 437 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][C:25]1(C)[C:29](C)(C)OB(C(C)=C)O1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:25]([CH3:29])=[CH2:24])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cccc(F)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.953 g, 4.33 mmol) in a 100 mL round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet were added dioxane (17.3 mL), sodium carbonate (0.551 g, 5.20 mmol), water (4.33 mL), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.977 mL, 5.20 mmol). To this mixture was added bis(triphenyl-phosphine)palladium(II)chloride (0.243 g, 0.347 mmol). The flask was evacuated and purged with nitrogen (3×) and then heated to 80° C. and stirred overnight. The reaction was cooled to room temperature, filtered through Celite®, and the pad was washed with ethyl acetate. The phases were separated and the organic phase was concentrated. Purification by flash column chromatography provided the title compound (0.590 g, 3.26 mmol, 75% yield) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.48-7.36 (m, 1H), 7.21-7.06 (m, 2H), 5.23 (p, J=1.5 Hz, 1H), 5.05 (q, J=1.1 Hz, 1H), 2.09 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 153.56 (d, JCF=257.5 Hz), 139.62, 139.60, 138.83, 131.48 (d, JCF=8.6 Hz), 124.47 (d, JCF=3.6 Hz), 117.60, 115.51 (d, JCF=19.1 Hz), 23.18.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.IC>C1COCC1>[CH2:16]([C:11]1[S:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1sc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At −78° C., a solution of 4-phenylthiophene-2-carboxylic acid (800 mg, 3.92 mmol) in THF (10 mL) is treated with tert.-BuLi (8 mL, 1.6 M in pentane). The mixture is stirred at −70° C. for 40 min before iodomethane (1 mL) is added. Stirring is continued for 5 h at −78° C., then the reaction mixture is allowed to warm to rt overnight. The reaction is quenched with sat. aq. NH4Cl and extracted with EA. The organic extract is dried over MgSO4, the solvent is removed and the crude product is purified by CC on silica gel eluting with DCM containing 3% of methanol to give 5-ethyl-4-phenyl-thiophene-2-carboxylic acid (340 mg) as a red solid; LC-MS: tR=0.95 min, [M+1+MeCN]+=274.15; 1H NMR (CDCl3): δ 7.79 (s, 1H), 7.46-7.31 (m, 5), 2.92 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: CSC.B(F)(F)F.CCOCC.[CH3:13][O:14][C:15](=[O:38])[CH:16]([O:35][CH2:36][CH3:37])[CH2:17][C:18]1[C:26]2[O:25][CH:24]=[CH:23][C:22]=2[C:21]([O:27]CC2C=CC=CC=2)=[CH:20][CH:19]=1>ClCCl>[CH3:13][O:14][C:15](=[O:38])[CH:16]([O:35][CH2:36][CH3:37])[CH2:17][C:18]1[C:26]2[O:25][CH:24]=[CH:23][C:22]=2[C:21]([OH:27])=[CH:20][CH:19]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)c2ccoc12)C(=O)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CSC
Product: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
Dimethyl sulfide (4.4 ml, 60 mmol) and boron trifluoride diethyl etherate (46% purity, 3.3 ml, 12 mmol) were added to a ice cold solution of [rac]-3-(4-benzyloxy-benzofuran-7-yl)-2-ethoxy-propionic acid methyl ester (0.85 g, 2.4 mmol) in dichloromethane (25 ml) under an argon atmosphere. The mixture was stirred for 6 h at ambient temperature, poured into ice water and extracted three times with dichloromethane. The combined extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=4/1) to give 0.45 g (1.7 mmol, 71%) of the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[N:21][CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1ccc(C(=O)O)cn1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C)nc3)CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound (3 mg, 8%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 6-methylnicotinic acid. MS: 388.4 (MH+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(C(F)(F)F)ccc1C#N
Temperature: 50 °C
Yield: 82 %

Procedure:
The 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq) in isopropanol (20 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give e as a yellow solid (0.45 g, 82% Yield, 1.96 mmol). 1HNMR (DMSO, 200 MHz) δ 1.35 (s, 3H), 1.38 (s, 3H), 5.33 (m, 1H), 7.55 (d, 1H, J=6), 8.26 (d, 1H, J=6).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[CH3:22][C:23]1([CH3:38])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[C:29]2[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][C:24]1=2.Cl>>[CH3:33][C:30]1([CH3:34])[CH2:31][CH2:32][C:23]([CH3:38])([CH3:22])[C:24]2[CH:25]=[C:26]([C:16]3[N:15]=[C:14]([N:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)[CH:19]=[CH:18][CH:17]=3)[CH:27]=[CH:28][C:29]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc(Br)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS 102 starting from (6′-bromo-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl)carbamic acid tert-butyl ester (preparation analogous to WO2005/26149) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid. The protecting group is subsequently cleaved off in a corresponding manner to FS201. The product is in the form of the hydrochloride.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:18][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(O)n2nc(C)nc2n1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Temperature: 0 °C
Yield: 33.7 %

Procedure:
To an ice-cooled mixture of 30.5 g (0.15 mole) of 7-hydroxy-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and 300 ml of phosphorus oxychloride, 18.6 ml (0.15 ml) of N,N-dimethylaniline was added dropwise over 5 minutes and the mixture was stirred under reflux for 1 hour, followed by concentration. The residue obtained was dissolved in 300 ml of chloroform and washed with water, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated and n-hexane was added to the set residue. The crystals were collected by filtration and dried to obtain 11.19 g of the title compound (Yield: 33.7%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1)[C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:9]([C:10]2[O:15][C:14](=[O:16])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)[C:21]2[O:26][C:25](=[O:27])[C:24]3[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1oc(Cc2nc3ccccc3c(=O)o2)nc2ccccc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12

Procedure:
Benzaldehyde (259 mg, 2.45 mmol), Compound (2,2'-methylenebis(3,1-benzoxazine-4-one) (500 mg, 1.63 mmol), and BF3.(C2H5)2O (0.045 ml, 0.163 mmol) were heated under reflux in dry toluene (20 ml) for 20 hours. After the reaction, the solvent was removed under reduced pressure from the reaction mixture, the residue was treated with water, extracted with benzene, and the organic layer was separated, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in the developing solvent and adsorbed on silica gel, and was purified by column chromatography to give the desired compound 52. The obtained product was crystallized from isopropylether to give the desired compound 52 in white solid in a good yield. m.p., IR, and NMR spectra of the product fully agreed with those of the one obtained in Example 19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH:14][NH2:15])=[O:13])=[N:7]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][CH:23]=1>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:13][C:26]([C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)=[N:15][N:14]=2)=[N:7]1
Reactant: Cc1nc(C(=O)NN)nn1Cc1cccc(Br)c1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2nnc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1cccc(Br)c1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
To a solution of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide (682 mg, 2.19 mmol), dissolved in POCl3 (6 mL), 4-(trifluoromethoxy)benzoic acid (453 mg, 2.19 mmol) was added. The reaction was heated to 100° C. for 2.5 h. The solvent was removed under reduced pressure and the crude material was taken up in EtOAc. The organic layer was then washed with NaHCO3 (3×40 mL) and brine (1×40 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified on a Biotage pre-packed silica gel column (MeOH:DCM 2% to 40% MeOH) to afford 2-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole (443 mg, 42%). MS (ES+) C19H13BrF3N5O2 requires: 479, 481 found: 480, 482 [M+H]+(1:1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:12][C:11]([C:17]([O:19]C)=[O:18])=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([CH:8]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:12][C:11]([C:17]([OH:19])=[O:18])=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCCC2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)CCCC2Cc1ccccc1
Yield: 93 %

Procedure:
The title compound was synthesized from methyl 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (20 mg, 0.08 mmol) and aqueous NaOH (1M in H2O, 0.8 mL, 0.8 mmol) according to General Procedure 7. The solid was filtered off, washed with water and dried under vacuum for about 12 h to give 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (32) (19 mg). 1H NMR (CHLOROFORM-d 400 MHz) δ ppm 8.8 (1H, br s), 7.3-7.33 (2H, m), 7.2-7.26 (3H, m), 6.81 (1H, s), 3.09 (1H, dd), 2.9 (1H, m), 2.55-2.65 (3H, m), 1.9-2.0 (1H, m), 1.6-1.8 (2H, m), 1.3-1.4 (1H, m); LC/MS: 89%, m/z=255
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:40][CH3:41].O>CN(C=O)C>[CH2:40]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:10])[CH3:41]
Reactant: CCI
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.6 mmol, 300 mg) and sodium bicarbonate (3.6 mmol, 302 mg) in DMF (4 mL) was added iodoethane (3.6 mmol, 0.29 mL) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into water (50 mL) and was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 155 mg (50% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl ester as a crystalline white solid: mp 262-265° C. ES-HRMS m/e calcd for C25H25Cl2N3O5 (M+Na) 540.1062, found 540.1049.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH2:15].C[Si]([N:30]=[C:31]=[O:32])(C)C>C(O)(C)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH:15][C:31]([NH2:30])=[O:32]
Reactant: C[Si](C)(C)N=C=O
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Solvent: CC(C)O
Product: NC(=O)NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 20 h

Procedure:
A solution of N-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-propane-1,3-diamine (0.14 g, 0.42 mmol—see preparation of N-{3-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-propyl}-guanidine) in isopropanol (2.8 mL) was treated with trimethylsilylisocyanate (80 μL, 0.58 mmol) at room temperature. The reaction was stirred 20 hours and concentrated under reduced pressure. This afforded, after column chromatography with silica gel (5:1:94 MeOH:NH4OH:CH2Cl2), the desired urea (37 mg, 23%). 1H NMR (CDCl3) δ 1.57 (m, 1H), 1.70-1.85 (m, 3H), 2.06 (br, 1H), 2.26 (br, 1H), 2.62 (m, 1H), 2.70-3.00 (m, 4H), 3.38 (br, 1H), 3.87 (m, 2H), 4.18 (m, 1H), 4.50 (br, 2H, NH2), 6.95 (br, 1H, NH), 7.18 (m, 3H), 7.46 (d, 1H, J=7.0 Hz), 7.45-7.70 (br, 2H), 8.55 (d, 1H, J=4.0 Hz).