Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]#[C:50][CH2:51][OH:52])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]#[C:50][CH2:51][OH:52])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(CC#CCO)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC#CCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.2 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 241 mg, 0.73 mmol) was suspended in methylene chloride (3.6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (364 μL, 0.73 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (170 μL, 1.46 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 4-(3-Amino-pyrazol-1-yl)-but-2-yn-1-ol (110 mg, 0.73 mmol) was dissolved in methylene chloride (3.6 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 5% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-but-2-ynyl)-1H-pyrazol-3-yl]-propionamide (92 mg, 27%) as a white foam: ESI-LRMS m/e calcd for C22H26ClN3O4S [M+] 463.1, found 464.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.24 (m, 2H, CH2), 1.44-1.95 (m, 8H, 4×CH2), 2.10-2.37 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.56 (t, J=7.4 Hz, 1H, CH), 4.31 (t, J=1.7 Hz, 2H, OCH2), 4.82 (t, J=1.7 Hz, 2H, NCH2), 6.72 (d, Jo=2.3, 1H, Ar), 7.43 (d, Jo=2.3, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.4 Hz. 1H, Ar), 7.59 (d, Jm=1.4 Hz, 1H, Ar), 8.08 (brs, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (45 mg, 18%)
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[CH:5][N:4]=1.COC1N=CC(CN2C3C(=CC=CC=3)C3(C4C(=CC5OCCOC=5C=4)OC3)C2=O)=CC=1>>[OH:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[CH:7][N:8]=1
Reactant: COc1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1
Agent: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1
Product: O=C1N(Cc2cnc(O)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 35 and making non-critical variations using 1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (19%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ8.31 (s, 2H), 7.37-7.28 (m, 1H), 7.28-7.21 (m, 1H), 7.20-7.12 (m, 1H), 7.10-7.00 (m, 1H), 6.50 (s, 1H), 6.08 (s, 1H), 4.71 (s, 2H), 4.71 (ABq, J=47.0, 9.4 Hz, 2H), 4.23-4.04 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 176.9, 154.7, 144.2, 141.7, 137.8, 131.9, 128.8, 123.7, 123.2, 121.2, 112.1, 111.0, 109.3, 98.8, 79.4, 64.2, 63.6, 57.2, 37.6; MS (ES+) m/z 403.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10](Cl)(Cl)Cl)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=2[CH:20]=1.[CH3:21][CH:22]([CH3:42])[CH2:23][NH:24][C@@H:25]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][C@H:27]([C:38]([O:40][CH3:41])=[O:39])[CH2:26]1.C(=O)([O-])[O-:44].[Cs+].[Cs+].Cl>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:24]([CH2:23][CH:22]([CH3:42])[CH3:21])[C@@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:28][C@H:27]([C:38]([O:40][CH3:41])=[O:39])[CH2:26]3)=[O:44])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Reactant: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(F)cc21
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 28.5 %

Procedure:
6-Fluoro-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (3.40 g) and 1-tert-butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (3.14 g) were dissolved in acetonitrile (100 ml) and water (50 ml), cesium carbonate (32.6 g) was added, and the mixture was stirred at 60° C. for 17 hr. The reaction mixture was cooled to room temperature, adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl (3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.60 g), and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.36 g).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[Cl:27])[CH2:9]1)C1C=CC=CC=1.[Cl:28]C(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[ClH:27].[ClH:28].[Cl:27][C:15]1[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[N:19][C:14]=1[NH:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Product: Cl
Reaction time: 1 h
Yield: 299 %

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate (770 mg) in toluene (14 ml) was added 1-chloroethyl chloroformate (713 mg) at 23° C. and stirred at the same temperature for 1 hour. N,N-Diisopropylethylamine (0.348 ml) was added to the mixture, and the solution was stirred at 23° C. for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH (15 ml). The mixture was stirred at 65° C. for 30 minutes, and concentrated under reduced pressure. The residue was dissolved into EtOH (15 ml), and mixed with 2N-hydrogen chloride in EtOH solution (2 ml). The mixture was stirred at 86° C. for 5 hours. After it was concentrated under reduced pressure, the resulting residue was triturated with IPE (15 ml). Ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylate dihydrochloride (1.1 g) was obtained as brown syrup.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18]Cl)=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:21].[K+]>C(O)C>[C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:21])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Agent: [K+]
Solvent: CCO
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C
Yield: 87 %

Procedure:
N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-chloroacetamide (0.741 mole) and potassium iodide (1.62 mole) were refluxed in ethanol (3400 ml) for 5 hours with stirring. The reaction mixture was then cooled, the inorganic salts were filtered and the solvent was evaporated under vacuum. The obtained residue was purified by washing first with water and then with cold ethanol. M.p. 135°-137° C. Yield 87%.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)CCC>>[O:37]1[CH:38]=[CH:39][CH:40]=[C:36]1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccco1
Yield: 40 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and tributyl(furan-2-yl) stannane using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a yellow solid (40% yield); 1H-NMR (CDCl3) 1.26 (9H, s), 3.77 (2H, m), 4.16 (2H, m), 6.14 (1H, d), 6.33 (1H, m), 6.35 (1H, s), 7.35 (1H, d); 13C-NMR (d6-DMSO); 27.4, 41.1, 66.6, 104.0, 110.8, 132.2, 141.0; MS ES(+) 252.1 (M++1); HRMS m/z calcd for C13H17NO4+H+ 252.1236 [M+H+]. Found 252.1066. IR λmax=1693 cm−1.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14](C#C)([CH3:16])[CH3:15]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][Si:14]([CH3:16])([CH3:15])[CH:10]=[CH:9][O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C=COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
A solution of ethyl 4-iodo-benzoate (55.2 g, 0.2 mol) in triethylamine (800 mL) was purged with argon. Copper iodide (1.1 g) and bis(triphenylphosphine)palladium(II) dichloride (7.0 g) were then added and the mixture was purged again. Trimethylsilylacetylene (42 mL, 0.3 mol) was then added at 0° C. for 30 minutes and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated, triturated in hexane and filtered. The filtrate was concentrated to give ethyl 4-(2-trimethylsilylethen-1-yl-benzoate (51.5 g, 100% crude) as a black oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=4)[CH2:27][CH2:26]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Oc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
DIPEA (5.84 mL, 33.54 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.99 g, 13.41 mmol) and 4-(piperidin-4-yl)phenol hydrochloride (CAS 263139-27-1, 3.01 g, 14.08 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature, evaporated to dryness and re-dissolved in DCM (200 mL). The solution was washed with water (200 mL) and saturated brine (200 mL), dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 70% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (4.47 g, 92%) as a solid.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])C)([CH3:3])C.[CH2:8]([Li])CCC.[N+](C)([O-])=O.[CH:17]1[C:22]2C=C[CH2:25][CH2:26][CH2:27][C:21]=2[CH:20]=[CH:19][CH:18]=1>O1CCCC1.O>[CH3:8][N:4]1[CH2:1][C@H:3]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:22][C:21]=3[CH2:27][CH2:26][CH2:25][C@H:7]2[CH2:5]1
Reactant: CC(C)NC(C)C
Reactant: C1=Cc2ccccc2CCC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CN1C[C@@H]2CCCc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To diisopropylamine (808 mg, 8.0 mmol) in tetrahydrofuran (3 mL) was added n-butyllithium (4.0 mL, 2.0 N in hexanes, 8.0 mmol) at −78° C. followed by the addition of nitromethane (300 mg, 4.0 mmol). The mixture was stirred for 10 min and (Z)-6,7-dihydro-5H-benzo[7]annulene (288 mg, 2.0 mmol) in tetrahydrofuran (1 mL) was added. The mixture was warmed to room temperature for 10 minutes and stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The crude material was purified by silica gel column chromatography eluting with ethyl acetate to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.14 (m, 2H), 7.07 (m, 2H), 3.55 (dd, J=17.4, 10.0 Hz, 1H), 3.21 (t, J=8.1 Hz, 1H), 2.97 (t, J=8.3 Hz, 1H), 2.75 (td, J=12.7, 6.9 Hz, 1H), 2.56 (m, 1H), 2.38 (dt, J=11.1, 5.6 Hz, 1H), 2.36 (m, 1H), 2.26 (s, 3H), 1.66 (m, 2H), 1.44 (m, 1H), 1.33 (dd, J=13.7, 6.4 Hz, 1H), and 0.87 (m, 1H); MS (ESI+) m/z 202 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:19]([NH:20][C:21]([SH:23])=[NH:22])=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:19]([NH:20][C:21]3[S:23][CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=3)=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N#Cc1cc2c(NC(=N)S)n[nH]c2nc1-c1ccc(O)cc1F
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2n[nH]c3nc(-c4ccc(O)cc4F)c(C#N)cc23)n1
Yield: 44.8 %

Procedure:
To 66 mg (0.20 mmol) of N-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)carbamimidothioic acid diluted in 2 ml of ethanol are added 57 mg (0.20 mmol, 68%) of ethyl 3-bromo-2-oxopropanoate. The solution is refluxed for 2 h. The solid is filtered, washed with ethanol and dried to give 38 mg of ethyl 2-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-ylamino)thiazole-4-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([O:31][CH2:32][CH2:33][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)[CH3:29]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCOCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Compound A2 (0.13 mmol, 50 mg), and 1-bromo-2-ethoxy-ethane (0.65 mmol, 99 mg) were dissolved in DMF (1 mL) and triethylamine (0.91 mmol, 127 μL). The reaction was heated in a microwave at 80° C. for 20 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by prep-TLC provided Compound A12 as a yellow solid (20 mg, 33%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.06 (s, 1H), 8.29 (s, 1H), 7.84 (d, 2H), 7.74 (d, 2H), 5.39 (s broad, 1H), 3.53 (m, 2H), 3.39 (q, 2H), 2.86 (s, 3H), 2.77 (m, 2H), 2.65 (m, 3H), 2.04 (m, 2H), 1.92 (m, 3H), 1.09 (m, 3H). LCMS (ESI), m/z 466.3 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:14]([O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:14]([O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
N-t-butyloxycarbonylglycine (21.02 g, 120 mmole), L-proline benzylester hydrochloride (29.01 g, 120 mmole) and HOBt (1.62 g, 12 mmole) were dissolved in methylene chloride (400 ml), and triethylamine (12.14 g, 120 mmole) and WSC hydrochloride (23.00 g, 120 mmole) were added to the solution at -30° C. The mixture was stirred for 2 hours at less than 0° C., and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-t-butyloxycarbonylglycyl-l-proline benzylester(yield 42.50 g, 97.7%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][CH2:16][C@@H:17]([C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([C:75]2[CH:80]=[CH:79][C:78]([NH:81][C:82](=[O:107])[C@H:83]([CH2:98][CH2:99][C:100]([O:102]C(C)(C)C)=[O:101])[NH:84][C:85](=[O:97])[CH2:86][C:87]3[C:95]4[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=4)[NH:89][C:88]=3[CH3:96])=[CH:77][CH:76]=2)[C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:74])[C@H:50]([CH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68])[NH:51][C:52](=[O:64])[CH2:53][C:54]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]=3[CH3:63])=[CH:44][CH:43]=2)=[CH:37][CH:36]=1)=[O:33])[NH:18][C:19](=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]=1[CH3:30])=[O:14])(C)(C)C>CO>[CH3:96][C:88]1[NH:89][C:90]2[C:95]([C:87]=1[CH2:86][C:85]([NH:84][C@H:83]([C:82]([NH:81][C:78]1[CH:77]=[CH:76][C:75]([CH:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[C@H:17]([CH2:16][CH2:15][C:13](=[O:12])[OH:14])[NH:18][C:19](=[O:31])[CH2:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][C:22]=4[CH3:30])=[CH:40][CH:39]=3)[C:42]3[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:74])[C@H:50]([CH2:65][CH2:66][C:67](=[O:68])[OH:69])[NH:51][C:52](=[O:64])[CH2:53][C:54]4[C:62]5[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=5)[NH:56][C:55]=4[CH3:63])=[CH:44][CH:43]=3)=[CH:80][CH:79]=1)=[O:107])[CH2:98][CH2:99][C:100](=[O:101])[OH:102])=[O:97])=[CH:94][CH:93]=[CH:92][CH:91]=2
Reactant: Cc1[nH]c2ccccc2c1CC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1[nH]c2ccccc2c1CC(=O)N[C@@H](CCC(=O)O)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CCC(=O)O)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](CCC(=O)O)NC(=O)Cc3c(C)[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A methanol solution containing trifluoroacetic acid (40%, 6 ml) was added to the tris[4-[β-t-butoxycarbonylmethyl-N-[2-(2-methyl-1H-indol-3-yl)acetyl]-L-alanyl]aminophenyl]methane (50 mg) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, a portion of the residue was purified by preparative high performance liquid chromatography using methanol/trifluoroacetic acid (100/0.1) and water/trifluoroacetic acid (100/0.1) as a mixed eluent, to obtain 2.0 mg of the title compound.
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20](OC)[C:21](=C=O)[C:22]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([NH2:31])=[C:24]([CH3:32])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[NH:5]1.C1[CH2:45][O:44]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:45]([OH:44])=[O:2])[CH2:21][C:22]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([NH2:31])=[C:24]([CH3:32])[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[NH:5]1
Reactant: [OH-]
Reactant: CO[C@H](OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)C(=C=O)c1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 120 mg (5.0 mmol) LiOH in 5 mL water was metered into a solution of 1.0 g (1.8 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL THF, the reaction solution was stirred for 4 h at RT and then evaporated down i.vac. The residue was combined with 30 mL water, washed with 30 mL diethyl ether, acidified with 4 M HCl while cooling with an ice bath and stirred for 30 min at RT. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:3](=[O:5])[CH3:2])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 84.2 %

Procedure:
(3R)-1-(4-Nitrophenyl)pyrrolidin-3-amine trifluoroacetate salt (Method 41; 0.96 g, 3 mmol) and sodium acetate (0.245 g, 3 mmol) in acetic acid (10 ml) were reacted with acetic anhydride (0.57 ml, 6 mmol) for 18 hours at room temperature. After filtration and washing with ether gave the title compound as a yellow solid (0.63 g, 84%). NMR: 1.79 (s, 3H), 1.85-1.98 (m, 1H), 2.09-2.23 (m, 1H), 3.19-3.30 (m, 1H), 3.39-3.52 (m, 2H), 3.55-3.67 (m, 1H), 4.30-4.43 (m, 1H), 6.60 (d, 2H), 8.04 (d, 2H), 8.15 (d, 1H); m/z 250.