Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(O)C>[Br:21][C:22]1[CH:23]=[C:24]([N:25]=[CH:1][CH:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CC1(C)OC(=O)C(C=Nc2cccc(Br)c2)C(=O)O1
Temperature: 55 °C
Yield: 93.1 %

Procedure:
A mixture of triethyl orthoformate (154 g, 1.04 mol) and Meldrum's acid (142 g, 0.983 mol) was heated to 55° C. for 4 hours. After cooling to 50° C., a solution of 3-bromoaniline (162.6 g, 0.945 mol) in ethanol (300 mL) was added such that the temperature of the reaction was maintained between 50-55° C. After half of the 3-bromoaniline had been added, stirring became difficult due to the formation of solids, so more ethanol (1 L) was added to facilitate stirring. Upon complete addition, the reaction was cooled to room temperature, and the solids were collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless, and the product was dried at 65° C. under vacuum to afford 287 g of 5-[(3-bromophenylimino)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[O:19][N:18]=[C:17]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[S:23][CH:24]=3)[CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:38]>ClCCl.O1CCOCC1>[Cl-:38].[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[O:19][N:18]=[C:17]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:26][CH2:27][NH2+:28][CH2:29][CH2:30]4)[S:23][CH:24]=3)[CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OCC4CCCCC4)C3)cs2)CC1
Reactant: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: [Cl-]
Product: c1ccc(C2CC(c3csc(C4CC[NH2+]CC4)n3)=NO2)c(OCC2CCCCC2)c1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate (3.20 g) in dichloromethane was added dropwise, at 0° C., a 4 molar solution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reaction mixture was stirred at 0° C. and then gradually warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. This gave 4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidinium chloride (2.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[N:32]O)[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C1(C)C(S(Cl)(=O)=[O:41])=CC=CC=1>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@H:24]3[C@H:25]4[O:31][CH2:30][C:29](=[O:41])[NH:32][C@H:26]4[O:27][CH2:28]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1
Reactant: ON=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=C1CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,3aS,6aR)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one oxime (20 mg, 0.043 mmol) was dissolved in pyridine and was cooled in an ice bath. Toluene sulfonyl chloride (21.2 mg, 0.11 mmol) was added in one portion and the mixture was stirred in an ice bath for 1 hour. The mixture was warmed to room temperature and additional toluene sulfonyl chloride (17 mg, 0.09 mmol) was added. After 2 hours, the solution was placed in a 60 degree oil bath for 1.5 hours and then cooled to room temperature. The reaction mixture was evaporated to give a foam, which was dissolved in methanol (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water to give the title compound. LC-MS: calculated for C24H19ClN4O4 462.11 observed m/e: 463.95 (M+14)+ (Rt 1.25/2 min); 1H NMR δ (ppm) (CD3OD): 7.93 (s, 1H), 7.78 and 7.73 (ABq, 4H), 7.70 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 6.44 (d, 1H), 5.48 (t, 1H), 4.83 (t, 1H), 4.63 (ABq, 2H), 4.50 (dd, 2H) and 4.45 (dd, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][NH2:12])[N:8]=[N:7][C:6]=1[Cl:13])([CH3:4])([CH3:3])[CH3:2].[Cl:14][CH:15]([Cl:19])[C:16](O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6]([Cl:13])=[N:7][N:8]2[C:16]([CH:15]([Cl:19])[Cl:14])=[N:12][N:11]=[C:9]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(C)(C)c1cc(NN)nnc1Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2nnc(C(Cl)Cl)n2nc1Cl
Yield: 74 %

Procedure:
4-t-Butyl-3-chloro-6-hydrazinopyridazine (9.5 g, 48 mmol) and dichloroacetic acid (20 ml) were heated in toluene (130 ml) under Dean Stark conditions for 2.5 hours. The toluene was removed and the residue was poured into water to precipitate the product as a brown solid. The product was purified by chromotography on silica gel using 10% ethyl acetate/dichloromethane as eluant to yield a yellow solid (10.4 g, 74%), 1H NMR (250 MHz, CDCl3) δ 1.59 (9H, s, t-Bu), 6.01 (1H, s, CH), 8.37 (1H, s, ArH); MS (ES+) m/e 293 [MH]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[C:10]([O:13][CH2:14][CH3:15])(=[O:12])[CH3:11].CCCC[CH2:20][CH3:21]>>[CH2:14]([O:13][C:10](=[O:12])[CH2:11][C:7]([C:8]#[N:9])([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH2:11][C:10]([O:13][CH2:20][CH3:21])=[O:12])[CH3:15]
Reactant: CCCCCC
Reactant: N#CCc1ccncc1
Reactant: CCOC(C)=O
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccncc1

Procedure:
Prepare by the method of Example 49.1.2 using 4-pyridineacetonitrile to give, after chromatography on silica gel eluting with ethyl acetate/hexane 1/1, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1)=[CH:16][CH:15]=3.[N:30]#[C:31]Br.C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([C:31]#[N:30])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1ccc(-c2ccc3[nH]c4c(cc(-c5ccc(Cl)cc5Cl)c(=O)n4C)c3c2)n1
Reactant: N#CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C#N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
460 mg (1.09 mmol) of compound from Example 37 above, 3-(2,4-dichlorophenyl)-1-methyl-6-(1-methyl-1H-pyrazol-3-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one are dissolved in 50 ml of CH2Cl2. 576 mg (5.43 mmol) of CNBr, 44 mg (0.36 mmol) of DMAP and then 308 μl (2.17 mmol) of triethylamine are added. The mixture is stirred at ambient temperature for 18 h. H2O is added, the mixture is extracted with CH2Cl2, and the organic phase is dried over MgSO4, filtered and concentrated, and purification is carried out on a silica column, elution being carried out with EtOAc/50% cyclohexane.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH2:15][C:16]1[CH:17]=[C:18]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:52][C:53]([CH3:55])=[CH2:54]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH:15]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:54][C:53]([CH3:55])=[CH2:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one (6.0 g, 11.00 mmol) in dry THF (22 mL) at −78° C. was added sodium hexamethyl disilazide (NaHMDS) (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below −75° C. The resulting red solution was stirred at −78° C. for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature below −75° C. When the addition was at near completion, the system turned to green. At this point the dry-ice bath was quickly removed and replaced with wet-ice bath and completed the addition. The reaction mixture was stirred further at 0° C. for 30 min and quenched with saturated aqueous NH4Cl solution. The system was diluted with EtOAC (100 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.3 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)OC)c(OC)c1
Temperature: 50 °C
Yield: 496.4 %

Procedure:
To a solution of 4-hydroxy-2-methoxybenzoic acid methyl ester (4.17 g, 22 mmol) in DMF (50 ml) under argon was added potassium carbonate (6.33 g, 4.6 mmol) followed by iodoethane (7.15 g, 4.6 mmol). The mixture was then heated to 50° C. under argon for 12h. On cooling the mixture was poured into a large excess of water and extracted with ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown oil (4.8 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH2:17])[C:12]3[CH:18]=[CH:19][C:20]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:23])=[CH:21][C:11]=3[N:10]=2)=[CH:5][CH:4]=1>Br>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH2:17])[C:12]3[CH:18]=[CH:19][C:20]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:21][C:11]=3[N:10]=2)=[CH:7][CH:8]=1.[C:27]([OH:29])(=[O:28])[CH3:26]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(CN)cc1)n2CCCN
Agent: Br
Product: CC(=O)O
Product: NCCCn1c(-c2ccc(CN)cc2)nc2cc(C(=O)NCCC(=O)O)ccc21

Procedure:
0.8 g of 2-(4-aminomethyl-phenyl)-1-(3-amino-propyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-benzimidazole are left to stand for 20 hours at ambient temperature in 10 ml of 48% hydrobromic acid. The mixture is concentrated by evaporation in vacuo and the residue is purified by chromatography on silica gel (eluant:n-butanol/glacial acetic acid/water=4:1:1 to 4:2:2). Yield: 0.6 g (67% of theory), Rf value: 0.66 (Reversed Phase Plate RP18; methanol/5% sodium chloride solution/conc. hydrobromic acid=6:10:0.01)
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:25][CH2:26][OH:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][O:27][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OCCN1CCOCC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCN1CCOCC1

Procedure:
The title compound, white solid, m.p.=135-137° C. and MS: m/e=369.3 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2-morpholin-4-yl-ethanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:21](OCC)(=O)CCCCCCCCCCC.COCCNCCN>>[CH2:1]([O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:21]
Reactant: CCCCCCCCCCCC1=NCCN1CCOC
Reactant: CCCCCCCCCCCC(=O)OCC
Agent: COCCNCCN
Product: CCCCCCCCCCCC1=NCCN1CCOCC

Procedure:
1-(2-methoxyethyl)-2-undecyl-2-imidazoline was similarly prepared from 30.8 g of ethyl dodecanoate and 16 g of N-(2-methoxyethyl)ethylenediamine. Distillation of the crude product at 150° C./0.1 mm gave 9.3 g of pure product.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]1[O:17][CH2:16][C:15](C(O)=O)=[CH:14][C:13]2=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:34])C=CC=CC=1.Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]1[O:17][CH2:16][C:15](=[O:34])[CH2:14][C:13]2=1
Reactant: COc1ccc2ncc3c(c2c1)C=C(C(=O)O)CO3
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2c1)CC(=O)CO3
Temperature: 90 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Triethylamine (13 μL, 0.09 mmol, 1.2 eq) is added at room temperature to a stirred solution of 6-methoxy-2H-1-oxa-9-aza-phenanthrene-3-carboxylic acid (20 mg, 0.08 mmol, 1.0 eq) in dichloromethane (1 mL), followed by a solution of diphenylphosphoryl azide (23 mg, 0.08 mmol, 1.0 eq) in toluene (1.5 mL). After 1 h 30 stirring at 80° C., 6M hydrochloric acid aqueous solution (0.5 mL) is added and the resulting mixture is heated at 90° C. for 2 hours. The reaction mixture is then cooled down to room temperature and extracted with ethyl acetate (3×10 mL) and saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate) to afford 6-methoxy-4H-1-oxa-9-aza-phenanthrene-3-one as a yellow semisolid (5 mg, 28% yield).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:23])[CH2:6][CH:7]([N:16]1[C:20](=[O:21])[NH:19][NH:18][C:17]1=[O:22])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:24][C:25](N(C)C)=[O:26]>[OH-].C[N+](C)(C)CC1C=CC=CC=1>[OH:26][CH2:25][CH2:24][N:19]1[C:20](=[O:21])[N:16]([CH:7]([CH2:6][CH:5]([CH3:23])[CH3:4])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:22])[N:18]1[CH2:2][CH2:1][OH:3]
Reactant: CC(C)CC(CCc1ccccc1)n1c(=O)[nH][nH]c1=O
Reactant: CC(=O)N(C)C
Reactant: C1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CC(C)CC(CCc1ccccc1)n1c(=O)n(CCO)n(CCO)c1=O
Yield: 62.4 %

Procedure:
26.4 g of ethylene oxide are introduced into 82.5 g of 4-(5-methyl-1-phenyl-3-hexyl)-1,2,4-triazolidine-3,5-dione (starting material 9) and 0.3 g of trimethyl benzyl ammonium hydroxide in 150 g of dimethyl acetamide. The solvent is distilled off in vacuo, the residue is dissolved by heating in 150 ml of ethyl acetate, 10 g of powdered active carbon are added and the whole is filtered hot. A deposit crystallises out on cooling and is isolated by filtration under suction and dried, giving 68 g of 1,2-bis-(2-hydroxyethyl)-4-(5-methyl-1-phenyl-3-hexyl)-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 114° C. IR- and NMR-spectra together with elemental analysis confirm the assumed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Br:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=[O:25])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].N1CC[O:29][CH2:28]C1>>[Br:11][C:12]1[CH:13]=[C:14]([CH:22]2[C:3]3[C:2](=[C:10]4[NH:9][CH:8]=[CH:7][C:6]4=[CH:5][CH:4]=3)[O:1][CH:24]([OH:25])[CH2:23]2)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:28][OH:29]
Reactant: Oc1cccc2cc[nH]c12
Reactant: C1COCCN1
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Product: CO
Product: COc1cc(C2CC(O)Oc3c2ccc2cc[nH]c32)cc(Br)c1OC
Yield: 20 %

Procedure:
The title compound was prepared following the procedure as in Example 18 from 7-hydroxy-indole (0.200 g, 1.50 mmol) and 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (0.416 g, 1.50 mmol) using morpholine (0.143 mL, 1.65 mmol) as a base in refluxing methanol (7.5 mL) (yield: 20%). 1H NMR (CDCl3): 10.22 and 10.16 (s each, 1H); 7.27-7.24 (m, 1H); 7.03-6.94 (m, 3H); 6.42-6.36 (m, 2H); 6.21 (d, J=7.6 Hz) and 6.16 (dd, J=5.0, 1.0 Hz) (1H); 5.74-5.71 and 5.61-5.56 (m each, 1H); 4.42-4.36 (m, 1H); 3.83 (s, 3H); 3.79 (s, 3H); 2.85-2.48 and 2.28-2.09 (m each, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[C:9]([CH3:12])=[C:10](I)[C:3]=12.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[C:9]([CH3:12])=[C:10]([C:21]3[CH:22]=[C:23]4[C:18]([CH2:17][CH2:16][N:15]4[CH3:14])=[CH:19][CH:20]=3)[C:3]=12
Reactant: Cc1c(I)c2c(Br)ccnc2n1C
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc2n1C
Temperature: 65 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
To a solution of 4-bromo-3-iodo-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine (D27) (580 mg, 1.653 mmol) in ACN (9 mL) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (557 mg, 2.148 mmol), bis(triphenylphosphine)palladium(II) chloride (116 mg, 0.165 mmol) and 9 mL of sodium carbonate (2N aqueous solution). The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was diluted with water (30 mL), the aqueous layer was then extracted with ethyl acetate (50 mL×3). The organic layers were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give an impure material which was further purified by column chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane to afford the title compound (89 mg). LCMS (A): m/z (M+H)+ 356/358, C18H18BrN3 requires 355/357 (acidic).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH:11]([CH:15]([NH:23][C:24](=[O:42])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](O)=[O:13].Cl.[CH3:44][O:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[OH:10][CH:11]([C:12]([NH:46][O:45][CH3:44])=[O:13])[CH:15]([NH:23][C:24](=[O:42])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[N:32]=[C:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:34][CH:35]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Reactant: CON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
DIPEA (200 μl, 0.567 mmol) was added to a suspension of 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid (250 mg, 0.544 mmol) and O-methylhydroxylamine hydrochloride (90 mg, 1.078 mmol) in dichloromethane (50 ml) at 5° C. After about 5 min 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (665 mg, 1.748 mmol) was added, the pH adjusted to 8 via addition of further DIPEA, and the mixture then stirred for 1 h at 5° C. and then overnight at room temperature. Then dichloromethane (50 ml) was added, washed 2× with 10 ml of water and brine, dried, filtered and concentrated to give 430 mg of the crude product which was purified by chromatography on silica gel (dichloromethane+11-12% methanol. Concentration of the combined fractions and drying afforded 224 mg of a white amorphous solid;
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:17]1([C:23]2[S:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>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.O>[NH2:1][CH:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:26]3[S:27][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)[CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(Cc1c[nH]c2ccc(Br)cc12)C(=O)O
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(Cc1c[nH]c2ccc(-c3ccc(-c4ccccc4)s3)cc12)C(=O)O
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 19.4 %

Procedure:
2-Amino-3-(5-bromo-1H-indol-3-yl)-propionic acid (0.020 g, 0.071 mmol) was added to a 5 ml microwave vial, which contained 5-phenyl-thiophen-2-boronic acid (0.016 g, 0.078 mmol), Na2CO3 (0.015 g, 0.142 mmol), acetonitrile (1.5 ml)/water (1.5 ml) and dichlorobis(triphenylphosphine)-palladium (3 mg, 0.003 mmol). Microwave vial was capped and stirred at 150° C. for 5 min under microwave radiation. Reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100×30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give 5 mg of pure product, 2-amino-3-[5-(5-phenyl-thiophen-2-yl)-1H-indol-3-yl]-propionic acid. 1H-NMR (300 MHz, CD3OD): 3.21-3.26 (m, 2H), 4.25 (q, 1H), 7.15-7.35 (m, 8H), 7.58 (d, 2H), 7.82 (d, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]1[CH2:32][O:31][C:10]2([CH2:15][CH2:14][C@H:13]3[C@H:16]4[C@H:25]([CH2:26][CH2:27][C@:11]23[CH3:12])[C:24]2[CH:23]=[C:22]([O:28][CH3:29])C(O)=C[C:19]=2[CH2:18][CH2:17]4)[O:9]1.N1C=CC=CC=1>CO>[C:5]([O:4][C:1]1[C:22]([O:28][CH3:29])=[CH:23][C:24]2[C@@H:25]3[C@H:16]([C@H:13]4[C@@:11]([CH2:27][CH2:26]3)([CH3:12])[C:10]3([O:9][CH2:8][CH2:32][O:31]3)[CH2:15][CH2:14]4)[CH2:17][CH2:18][C:19]=2[CH:2]=1)(=[O:7])[CH3:6]
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Under nitrogen, acetic anhydride (25 mL, 265 mmol) was added to a solution of the ketal (11) (4.5 g, 13.06 mmol) in dry pyridine (25 mL, 310 mmol). The reaction was stirred overnight at room temperature in the dark. After that time, methanol (50 mL) was added and solvents removed in vacuo. The treatment with methanol was repeated and the residue obtained crystallized from methanol to give the pure 3-acetate (12) (4.85 g, 96%).