Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:48])[CH2:10][C:11]1[CH:47]=[CH:46][CH:45]=[CH:44][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:27]=[N:28][N:29]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[CH:30]=2)[N:16]=1>C(Cl)Cl>[NH:34]1[CH2:33][CH2:32][CH:31]([N:29]2[CH:30]=[C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:44]=[CH:45][CH:46]=[CH:47][C:11]=4[CH2:10][C:9]([NH2:8])=[O:48])[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][N:18]=3)[CH:27]=[N:28]2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A137) (171 mg, 0.298 mmol) in DCM (25 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resultant solid was dissolved in CHCl3 (1 mL). Cyclohexane (25 mL) was added and the resultant precipitate was removed by filtration, washed with cyclohexane (25 mL) and air dried to yield the title compound as a white solid (101 mg, 72%). LCMS-A: rt 4.717 min; m/z 474.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:32]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34][CH2:33]1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[N:32]1([S:36]([NH:39][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:4][C:5]=2[F:11])(=[O:38])=[O:37])[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1cc(Cl)c(COC2CCCCC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(COC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
To a solution of 5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoic acid (0.12 g, 0.42 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (0.088 g, 0.55 mmol). The reaction solution was heated to reflux under a nitrogen atmosphere for 15 minutes and cooled to ambient temperature. To this solution was added azetidine-1-sulfonamide (0.086 g, 63 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 g, 1.05 mmol). The mixture was stirred at ambient temperature for 16 hours, then diluted with ethyl acetate (15 mL) and washed with 1 M hydrochloric acid (2×10 mL) and brine (2×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by reverse-phase preparative HPLC to afford the title compound (0.005 g, 3%) as a colorless powder: MS (ES+) m/z 405.1, 407.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])[CH3:11].C[O-].[Na+].[C:16](OC)(=[O:21])[C:17]([O:19][CH3:20])=[O:18]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])/[CH:11]=[C:16](\[OH:21])/[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)c1c(F)ccc(C)c1Cl
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(O)=C/C(=O)c1c(F)ccc(C)c1Cl
Reaction time: 0.5 h

Procedure:
2′-chloro-6′-fluoro-3′-methylacetophenone (1.00 g, 5.36 mmol) was dissolved in 2.0 mL anhydrous methanol under N2 and subjected to the addition of 25% sodium methoxide in methanol (2.2 equiv, 11.8 mmol, 2.7 mL) via syringe. The nearly colorless solution was stirred for 30 min and then dimethyl oxalate (2.2 equiv, 11.8 mmol, 1.39 g) was added. The cloudy white mixture was stirred at 30° C. After 15 h, the cloudy white mixture was quenched with 2.0 mL 2 M HCl(aq) and extracted with 3×10 mL EtOAc. The light yellow organics were washed with 10 mL saturated brine solution, dried over anhydrous MgSO4 for 5 min, filtered, and concentrated in vacuo to afford a light yellow solid. Silica gel chromatography followed by recrystallization from hot hexanes/dichloromethane (ca. 5:1) afforded the desired product as analytically pure white needles (688 mg, 47% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].CCCC[Sn]([C:36]1[N:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(CCCC)CCCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][N:41]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccccn2)c2onc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 12 from 7-Bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 2-(1,1,1-tributylstannyl)pyridine; ESI MS (m/z): 362.31 (M+H+); 360.34 (M−H+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][C@@H:32]([OH:33])[C@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: COC[O:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]COC)=[CH:15][CH:14]=3)[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])[CH:24]=3)[CH:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2c2cccc(OCCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: Oc1ccc(C2COc3cc(O)ccc3C2c2cccc(OCCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-4-[3-(5-(4,4,5,5,5-pentafluoropentylthio)pentyloxy)phenyl]-2,3-dihydro-4H-benzopyran (290 mg, 0.4 mmol) and pyridinium p-toluenesulfonate (1.05 g, 4 mmol) were dissolved in methanol (6 ml) and then refluxed for 8 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=1:1) to obtain 177mg (yield: 74%) of the title compound as a colorless oil.
Reaction SMILES: C[C:2](CC(C)C)=[O:3].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:8]([CH:13]([CH2:12][CH2:11][CH2:10][CH3:9])[CH2:2][OH:3])[CH3:14]
Reactant: CC(=O)CC(C)C
Reactant: Cc1ccccc1
Product: CCCCC(CC)CO
Yield: 0 %

Procedure:
Subsequently, there were introduced into a four neck flask of the same type as used above 120 g of the aromatic polymer obtained above, 100 g of methylisobutyl ketone, 200 g of toluene, and 0.04 g of 2-ethylhexanol-modified chloroplatinic acid, followed by azeotropic dehydration for 1 hour. Thereafter, 80 g of organopolysiloxanes indicated in Table 1 were, respectively, dropped at a refluxing temperature in 30 minutes and agitated for reaction at the same temperature for 4 hours. The resulting product was washed with water and the solvent was distilled off under reduced pressure to obtain reaction products (copolymers I, II, and III).
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:32][CH2:33][CH3:34]>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH2:32][CH2:33][CH3:34])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCBr
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt in 250 parts of hexamethylphosphoramide are added 49.2 parts of 1-bromopropane and the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The viscous residue is filtered off over hyflo, yielding propyl p-(2-thenoyl)hydratropate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[ClH:34]>CCO>[ClH:34].[ClH:34].[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[N:20][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCc3cccc(F)c3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (160 mg) in EtOH (1.6 mL) was added 2N—HCl solution in EtOH (0.9 mL) and stirred for 3 hours at ambient temperature. The solvent was evaporated in vacuo. To the residue was added IPE. The resulting solid was collected by the filtration to give (2E)-3-[5-({(3R)-1-[2-(3-fluorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamide dihydrochloride (116 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]=NC1C=CC([N+]([O-])=O)=CC=1)([O-])=O.C1C(N)=CC=C(N)C=1>C(O)C>[NH2:13][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: Nc1ccc(N)cc1
Solvent: CCO
Product: Nc1ccc(N)c(N)c1
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A 500 ml autoclave equipped with a stirrer and a gas-introducing tube was charged with 9.5 g of 2,4,4'-trinitroazobenzene, 0.6 g of PtO and 100 ml of ethanol. The inside of the reactor was purged completely with hydrogen, and the reaction was performed at 80° C. for 6 hours with stirring while maintaining the pressure of hydrogen at 70 kg/cm2.G. The reaction mixture was filtered. The cake was washed with water. The wash liquid and the filtrate were combined, and distilled to afford 2.5 g of a fraction having a boiling point of 174° to 180° C./30 mmHg.ab. This fraction coincided with p-phenylenediamine as a standard product. The distillation residue was recrystallized from chloroform to afford 3.2 g of 1,2,4-triaminobenzene having a melting point of 93° to 96° C. This product corresponded in IR spectrum with a standard product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH2:10][CH:11]=[CH2:12])[CH2:6][C:7](C)=C)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH:7]=[C:11]([CH3:12])[CH2:10]1)=[O:13])[CH3:2]
Reactant: C=CCC(CC(=C)C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1CC=C(C)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 92.7 %

Procedure:
To a refluxing stirred solution of the 2-Allyl-4-methyl-pent-4-enoic acid ethyl ester (364 mg, 2.0 mmol) in CH2Cl2 (100 mL, 0.02 M solution) was added drop wise a solution of the tricyclohexylphosphine (1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(benzylidine)ruthenium (IV) dichloride (85 mg, 0.1 mmol) in CH2Cl2 (3.0 mL). After 50 min, the reaction mixture was cooled to room temperature, concentrated and purified on silica gel bond elute using EtOAc/hexane (1:20) as an eluent furnished the 3-Methyl-cyclopent-3-enecarboxylic acid ethyl ester (286 mg, 93% yield) as an oil. 1H NMR (CDCl3, 400 MHz), 5.25 (brs, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.2-3.1 (m, 1H), 2.65-2.46 (m, 4H), 1.74 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH3:12].[O:13]1[CH2:15][CH2:14]1>C1COCC1>[CH2:11]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:15][CH2:14][OH:13])[CH3:12]
Reactant: CCOc1ccccc1Br
Reactant: C1CO1
Agent: II
Solvent: C1CCOC1
Product: CCOc1ccccc1CCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, maintained with an inert atmosphere of nitrogen, was placed Mg (1.0 g, 41.67 mmol, 2.09 equiv) and I2 (10 mg). Then a solution of 1-bromo-2-ethoxybenzene (4.0 g, 19.89 mmol, 1.00 equiv) in 25 mL THF was added dropwise and the resulting mixture was heated to reflux for 0.5 hr. After the reaction was complete, the resulting mixture was cooled to 0° C. and then oxirane (50 mL) was added in one portion. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of NH4Cl (aq.) and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 2.14 g (65%) of 2-(2-ethoxyphenyl)ethan-1-ol as a yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=2)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[N:21][CH:22]=1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=2)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[CH:20]=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1

Procedure:
In a 100 mL round-bottom flask with magnetic stirrer and H2 balloon, tert-butyl [3-[5-[[1-(benzyloxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]benzyl]carbamate (91.2 mg, 181 μmol) in MeOH (3 mL) was stirred with 10% Pd/C (19 mg; Alfa Aesar #38305, water content 50%) at room temperature for 2.5 h. H2 was replaced with Ar, and the catalyst was filtered off over a cotton plug and rinsed with MeOH (1.5 mL). The solution was evaporated and dried (35° C., oil pump vacuum) to yield the free azetidine (67.3 mg, 101%, must contain a trace of solvent) as a colorless film. [α]D0, [α]5460 (c 6.4 g/L, MeOH). 1H NMR (CDCl3, 500 MHz) δ 8.46 (br s, 1H), 8.32 (br s, 1H, J=2.8 Hz), 7.51-7.34 (m, 5H), 4.98 (br, 1H), 4.42 (narrow m, 1H), 4.34 (m, 1H), 4.18-4.08 (m, 2H), 3.75 (q, 1H, J=7.9 Hz), 3.50 (m, 1H), 2.44 (m, 1H), 2.33 (m, 1H), 1.89 (br, 2H), 1.49 (s, 9H). MS (EI) m/z 369 (M+, 0.1%), 314 (15%), 313 (21%), 257 (23%), 214 (24%), 213 (11%), 70 (11%), 56 (100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)=[O:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C1COCC1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)CNCC(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 36.1 %

Procedure:
{[({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-carbamoyl)-methyl]-amino}-acetic acid methyl ester (44 mg, 88%) was prepared by treating 2-amino-N-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (104 mg, 0.25 mmol) with methyl bromoacetate (0.023 mL, 0.25 mmol) in THF (5 mL) at 60° C. for 2 h followed by column purification [silica, DCM:ethyl acetate (80:20 to 20:80)].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1N=C(Cl)C(C)=CN=1.OC1C=C(C=CC=1)N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([CH3:25])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Nc1cccc(O)c1
Product: Cc1cnc(Nc2cccc(O)c2)nc1Nc1cccc(O)c1

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with 3-hydroxyaniline gave N2,N4-bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS: ret. time: 16.76 min.; purity: 100%, MS (m/e): 309 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=O)[N:2]=1.ClC(OCC)=O.[CH3:23][NH2:24]>O1CCCC1.C(N(CC)CC)C>[CH3:23][NH:24][C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:16]
Reactant: CN
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5 g of β-carbolin-3-carboxylic acid in a mixture of 900 ml of tetrahydrofuran and 3.6 ml of triethylamine is boiled under reflux for 15 minutes and cooled to room temperature. Freshly distilled ethyl chloroformate (2.5 ml), dissolved in 100 ml of tetrahydrofuran, is added dropwise with stirring over a period of 11/2 hours. After the reaction mixture has been stirred for an additional 30 minutes, a large excess of methylamine is added. Stirring is continued for one hour, whereafter the mixture is filtered and concentrated to approximately 50 ml under reduced pressure. Addition of water (250 ml) causes the amide to precipitate. The mixture is left at 5° C. overnight, filtered and dried at 60° C. for 15 hours. β-carbolin-3-carboxylic acid methylamide thus formed (4.1 g; 77%) is recrystallized from toluene. The melting point is 275° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[CH3:15])[CH3:2].[Br:16]NC(=O)CCC(N)=O.C(OCC)(=O)C>C1COCC1>[Br:16][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]=1[CH3:15].[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[CH3:15])[CH3:2]
Reactant: NC(=O)CCC(=O)NBr
Agent: CCn1c(C)cc2ccc([N+](=O)[O-])cc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(C)c(Br)c2ccc([N+](=O)[O-])cc21

Procedure:
Stir a solution of 1-ethyl-2-methyl-6-nitro-1H-indole, 19 (0.36 g, 1.76 mmol) and N-bromosuccinamide (0.31 g, 1.76 mmol) in anhydrous THF (10 mL) under inert atmosphere at ambient temperature for 14 hours. Quench the reaction with saturated aqueous sodium bicarbonate, add ethyl acetate, and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. Chromatograph over silica gel using hexanes/ethyl acetate (9:1) to afford the title compound and unreacted 1-ethyl-2-methyl-6-nitro-1H-indole (0.37 g) in a 4:1 mixture which can be used in the subsequent step without further purification. LRMS (API ES+)=: 283, 285 (M, M+2M).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21].N1CCCCC1.C(OCC)(=O)C>CO>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3/[CH:18]=[CH:21]/[C:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CC(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1c[nH]c2ccc(OCc3ccccc3)cc12)c1ccncc1

Procedure:
In a dried, 25 mL round bottom flask under argon, 5-benzyloxyindole-3-carboxaldehyde (100 mg, 0.40 mmol) was dissolved in anhydrous methanol (3 mL). 4-Acetyl-pyridine (75 μL, 0.68 mmol) and piperidine (20 μL, 0.2 mmol) were added. The reaction was stirred under reflux, during which a crude yellow solid precipitated. The solid was filtered, rinsed with cold methanol and dried under vacuum. This crude product (107 mg) was purified from residual aldehyde by column chromatography in ethyl acetate:hexanes (1:1-3:1 gradient), yielding pure, yellow solid (70 mg, 49%). 1H NMR (600 MHz, d6-DMSO): δ 8.837-8.827 (dd, J1=4.5, J2=1.5, 2H, pyr-2,6H), 8.148-8.143 (d, J=3.0, 1H, indole-2H), 8.095-8.069 (d, J=15.6, 1H, C═CH), 7.932-7.922 (dd, J1=4.5, J2=1.5, 2H, pyr-3,5H), 7.556-7.553 (d, J=1.8, 1H, indole-4H), 7.523-7.511 (d, J=7.2, 2H, phenyl-2,6H), 7.460-7.434 (d, J=15.6, 1H, C═CH), 7.411-7.370 (m, 3H, phenyl-3,5H, indole-7H), 7.330-7.306 (t, J=7.2, 1H, phenyl-4H), 6.979-6.961 (dd, J1=8.4, J2=2.4, 1H, indole-6H), 5.252 (s, 2H, methylene). 13C NMR (150 MHz, d6-DMSO): 188.4, 154.1, 150.7, 144.9, 140.9, 137.7, 134.6, 132.5, 128.4, 127.7, 127.6, 125.8, 121.5, 114.2, 113.3, 113.1, 112.7, 104.1, 69.8. Melting point: 218-221° C. TLC (in 4:1 ethyl acetate:hexanes) Rf=0.26. Elemental analysis calculated (for C23H19N2O2.0.2C6H14.0.05H2O): C, 78.02; H, 5.93; N, 7.52. found: C, 77.69; H, 5.62; N, 7.24.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[N:5]=[N:4][N:3]=1>Cl>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[N:5]=[N:4][N:3]=1
Reactant: COC(=O)CCCn1nnnc1C
Agent: Cl
Product: Cc1nnnn1CCCC(=O)O
Yield: 92.5 %

Procedure:
20% Hydrochloric acid (30 ml) is added to methyl 4-(5-methyl-1,2,3,4-tetrazol-1-yl)butyrate (5.5 g) and the mixture is refluxed for 2 hour. The mixture is concentrated to dryness under reduced pressure. Acetone and benzene are added to the residue and water is removed by azeotropic distillation to obtain 4-(5-methyl-1,2,3,4-tetrazol-1-yl)butyric acid (4.7 g) as colorless liquid.