Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]C(CC)C.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1.C(=O)=O>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([OH:35])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of tert-butyl (4-chlorophenyl)carbamate (3.0 g, 13.2 mmol) in 100 ml of THF was added TMEDA (1.53 g, 13.2 mmol) followed by sec-BuLi (21 ml, 32.9 mmol) slowly and dropwise via syringe. The reaction mixture turns bright yellow after about half the s-BuLi was added. The reaction mixture was allowed to stir for 15 min at −78° C. then allowed to warm to about −20° C. (tip of flask in dry-ice bath) for 1 hr, then the reaction mixture was cooled to −78° C. again. The reaction mixture was in now a dull yellow/orange, slightly heterogeneous and 4-bromobenzaldehyde was added dropwise, and stirred for 30 min at −78° C. The reaction mixture was quenched with 100 mL sat NH4Cl (pink fades to yellow), extracted with 150 ml of ether, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 5-30% EtOAc/hex as the eluent to provide tert-butyl {2-[(4-bromophenyl)(hydroxy)methyl]-4-chlorophenyl}carbamate as a yellow solid. 1HNMR: (400 MHz, CDCl3) δ 7.72 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4, 1H), 7.40˜7.50 (m, 1H), 7.27 (s, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.81 (s, 1H), 4.70˜4.90 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@H:5]([CH:7]([CH2:17][O:18][CH3:19])[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[CH2:21]=O.O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[CH:21][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]=1[CH2:17][O:18][CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:20])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)C(COC)c1c[nH]c2ccccc12
Reactant: C=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Yield: 30.6 %

Procedure:
20.3 g of beta-methoxymethyl-tryptophane-ethylester is dissolved in 350 ml of benzene, mixed with 2.48 g of paraformaldehyde and heated for 3.5 h in the water separator. After cooling, the benzene is distilled off, the residue is absorbed in 350 ml of toluene, and after adding 4.5 g of 10% palladium carbon, the mixture is heated with reflux for 20 h. The cooled solution is filtered and concentrated. The residue is chromatographed on silica gel with hexane/ethyl-acetate. The crystallization of the main fraction out of ethylacetate/diisopropylether yields 6.4 g of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester with a m.p. 118°-119° C.
Reaction SMILES: [CH3:1][C:2]([NH:13][C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16](=[C:17]([C:25]3[NH:33][C:32]4[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=4[CH:26]=3)[CH:18]=[CH:19][CH:20]=2)[N:15]=1)([CH3:12])[CH2:3][NH:4]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:4][CH2:3][C:2]([NH:13][C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16]([N:15]=1)=[C:17]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=1)[CH:18]=[CH:19][CH:20]=2)([CH3:12])[CH3:1]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of tert-butyl (2-methyl-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propyl)carbamate (339) (0.13 g, 0.28 mmol) in DCM (2.80 mL) and TFA (1.0 mL, 13.99 mmol) was stirred at 0° C. for 20 min before it was warmed to RT and stir for 1 h. The reaction mixture was concentrated and the residue was diluted with CHCl3/IPA(3:2) (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (65 mg, 0.17 mmol, 63% yield) which was impure by NMR. This material was dissolved in MeOH (˜20 mg/mL) and injected (2×1.0 mL) onto the Shimadzu preparatory LC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA); the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with CHCl3/IPA(3:2), separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (341) (19 mg, 0.05 mmol, 18% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 6H) 2.59 (s, 3H) 2.95 (s, 2H) 2.99 (t, J=6.85 Hz, 2H) 3.65 (td, J=6.85, 2.54 Hz, 2H) 5.33 (br. s., 1H) 6.19 (s, 1H) 7.10 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.65 (dd, J=8.02, 1.37 Hz, 1H) 7.92 (dd, J=7.63, 1.37 Hz, 1H) 12.64 (br. s., 1H). MS (ESI, pos. ion) m/z: 365.3 (M+1).
Reaction SMILES: CC1C=C(C2C=CC(C3CCNCC3)=NC=2)C=CN=1.O.[NH2:21][NH2:22].[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=O)[CH2:33][CH:34](N2CCOCC2)[C:35]([OH:37])=O)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>CC(O)CC>[CH:23]([N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[CH:33]=[CH:34][C:35](=[O:37])[NH:21][N:22]=2)[CH2:30][CH2:31]1)([CH3:24])[CH3:25]
Reactant: NN
Reactant: CC(C)N1CCC(C(=O)CC(C(=O)O)N2CCOCC2)CC1
Agent: Cc1cc(-c2ccc(C3CCNCC3)nc2)ccn1
Solvent: O
Solvent: CCC(C)O
Product: CC(C)N1CCC(c2ccc(=O)[nH]n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In analogy to Wermuth et al. in J. Med. Chem. 1987, 30 (2), 246, hydrazine hydrate (10 mL) was added to a solution of 4-(1-isopropylpiperidin-4-yl)-2-morpholin-4-yl-4-oxo-butyric acid (99.9 g, 0.25 mol) in 2-butanol (500 mL). The reaction mixture was stirred at room temperature for 1 h followed by reflux overnight. After cooling to room temperature the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (SiO2, dichloromethane with 3% methanol followed by 5% and 7%.). Evaporation of the fractions containing the desired product yielded a yellow solid, which was used as such.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].B(O)(O)O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc[nH]1
Agent: OB(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: c1c[nH]c(-c2nc3ccccc3s2)c1
Yield: 14 %

Procedure:
A mixture of 5.55 g (50 mmol) of pyrrole-2-carboxylic acid, 6.26 g (50 mmol) of 2-aminothiophenol and 3.09 g (50 mmol) of boric acid in 250 mL of xylene was heated under reflux for 3 days while removing water which was generated from reaction using a Dean-Stark trap. the cooled reaction mixture was diluted with 200 mL of ethyl acetate, washed with 200 mL of 5% sodium hydroxide solution and then with 200 mL of water. The separated organic layer was dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography on silica gel with 10% ethyl acetate in hexane as eluant. The desired product, 2-(pyrrol-2-yl)benzothiazole (1.40 g, 14%) was obtained as a pale yellow solid. m.p. 150°-151° C.; 1H-NMR (CDCl3) 6.32-6.35 (m, 1H, ArH), 6.87-6.89 (m, 1H, ArH), 6.94-6.96 (m, 1H, ArH), 6.33 (t, 1H, ArH), 6.43 (t, 1H, ArH), 7.84 (d, 1H, ArH), 7.90 (d, 1H, ArH).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[C:13]=3[CH2:12][C:11]2=[O:21])=[CH:7][CH:6]=1.Br[CH:25](Br)[CH3:26]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[C:13]=3[C:12]3([CH2:26][CH2:25]3)[C:11]2=[O:21])=[CH:22][CH:23]=1
Reactant: CC(Br)Br
Reactant: COc1ccc(CN2C(=O)Cc3c(C#N)cccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C3(CC3)c3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
NaH (0.457 g, 19.0 mmol) was added to a solution of 1-(4-methoxybenzyl)-2-oxoindoline-4-carbonitrile (5.30 g, 19.0 mmol) in DMF (38 mL), and the resulting slurry was stirred at ambient temperature for 1 hour. Dibromoethane (3.94 g, 21.0 mmol) was then added to this mixture, and the mixture was stirred at room temperature for 1 hour. An additional equivalent of NaH (0.457 g, 19.0 mmol) was then added to the reaction mixture, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was concentrated and purified by column chromatography with a hexanes/ethyl acetate gradient +15% DCM. The mixed product fractions were recrystallized with DCM/hexanes to give 1′-(4-methoxybenzyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-4′-carbonitrile (5.00 g, 16.4 mmol, 86%). LCMS (APCI+) M+H+ 305 (100%); Rt=3.65 min.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH:18]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)c(C(F)(F)F)c1

Procedure:
2 mmol of methyl 4-fluoro-3-trifluoromethylbenzoate, 2 mmol of 3-hydroxypyridine and 4 mmol of K2CO3 were stirred at 110° C. for 1.5 h in 15 ml of DMF (anhydrous). The mixture was then poured onto 100 ml of water and extracted 3 times using 50 ml of EA each time. It was dried over Na2SO4, the solvent was removed in vacuo and the product was reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][C:9]=2[F:11])[NH:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]=[C:17](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:12][C:7]1[CH:8]=[C:9]([F:11])[C:10]2[C:2]3[NH:1][C:17](=[O:16])[NH:15][C:13](=[O:14])[C:3]=3[NH:4][C:5]=2[CH:6]=1
Reactant: NC(=O)c1[nH]c2cc(Br)cc(F)c2c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2[nH]c3cc(Br)cc(F)c3c2[nH]1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
15.4 g (56.6 mmol) 3-amino-6-bromo-4-fluoro-1H-indole-2-carboxylic acid amide was suspended in 300 ml dioxan and after the addition of 7.5 ml (61.8 mmol) diphosgene the suspension was refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 12.5 g (74%) 7-bromo-9-fluoro-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 296, 298 [M−H]−
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:12]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr
Yield: 79.9 %

Procedure:
A solution of 1-bromo-2-methyl-3-nitro-benzene (16.095 g, 74.5 mmol), 1-Bromo-pyrrolidine-2,5-dione (13.26 g, 74.5 mmol), benzoyl peroxide (180 mg, 0.74 mmol) in CCl4(100 ml) was heated under reflux overnight. After removing the solvent by using rotary evaporator, the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 1-bromo-2-bromomethyl-3-nitro-benzene as a yellow solid (17.55 g, 80%). 1H NMR (CDCl3, 300 MHz) δ: 4.89(s, 2H), 7.35(dd, 1H, J1=J2=8.1 Hz), 7.88(dd, 2H, J1=1.6 Hz, J2=8.1 Hz).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[O:21]=[C:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>CCO>[CH3:18][O:17][C:14]1[N:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:26]1[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:22](=[O:21])[CH2:27]1
Reactant: O=C1CNCCN1CCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Solvent: CCO
Product: COc1ccc2nccc(N3CCN(CCN4C(=O)c5ccccc5C4=O)C(=O)C3)c2n1
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A solution of 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (169 mg, 0.55 mmol) and 2-[2-(2-oxo-1-piperazinyl)ethyl]-1H-isoindole-1,3(2H)-dione (150 mg, 0.55 mmol) in EtOH (2 mL) were stirred at 85° C. After 12 h, the solution was concentrated and the residue purified via column chromatography (silica, 0-8% MeOH in DCM (1% NH4OH)) yielding the title compound (100 mg, 42%) as a light yellow solid: LCMS (ES) m/e 432 (M+H)+.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:11][N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](C=O)[C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO.C(OCC)C>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:21]1[C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:11])[C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CN1c2ccccc2Sc2c(C=O)cccc21
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
15.0 ml of triethyl orthoformate were added at room temperature to a solution of 4.90 g (20.3 mmol) of 10-methylphenothiazine-4-carbaldehyde and 50 mg of p-toluenesulphonic acid×1H2O in 15 ml of methanol. The reaction mixture was boiled at reflux for 45 minutes, cooled and poured into 30 g of ice, 30 ml of saturated aqueous sodium hydrogen carbonate solution and 100 ml of diethyl ether. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on 300 g of silica gel with diethyl ether/hexane (1:4), whereupon, after crystallization from diethyl ether/hexane in a refrigerator, 6.16 g (96.2%) of 4-diethoxymethyl-10-methyl-phenothiazine were obtained as a white solid of m.p. 44.6°-46.2°.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])=[CH:11][CH:10]=1)#[N:8].C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[OH:17][C:16]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)=[C:21]([OH:22])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: N#Cc1ccc(-c2c(O)nc3ncnn3c2O)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
A mixture of 14 g of 3-amino-1,2,4-triazole, 0.17 mol of the ester from example 1 and 50 ml of tributylamine (50 ml) was stirred at 180° C. for approximately 6 hours. A solution of 21 g of NaOH in 200 ml of water was added at approximately 700 and the mixture was stirred for a further 30 min. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The product precipitated from the aqueous phase after acidification with concentrated hydrochloric acid. 28 g of the title compound were obtained by filtration.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O>C(#N)C>[Cl:12][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(O)c(C(=O)O)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1ncc(C(=O)O)c(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Commercially available 4-hydroxy-6-methyl-nicotinic acid (300 mg) was suspended in 3 ml of acetonitrile, and N-chlorosuccinimide (380 mg) was then added to the suspension. The resulting mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was heated under reflux for 45 minutes. After the disappearance of the materials had been confirmed, the reaction solution was cooled on ice, and the precipitate was then collected by filtration, so as to obtain the title compound (324 mg) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:30]=[CH:31][C:32]=1[NH2:33].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:28][C:27]=2[Cl:26])=[O:19])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(NC(=O)c2cn(Cc3ccccc3)c3ccccc23)c(Cl)c1
Temperature: -15 °C
Yield: 98.4 %

Procedure:
To a solution of 1-benzylindole-3-carboxylic acid (201.3 mg, 0.801 mmol) in methylene chloride (4.0 ml) was added oxalyl chloride (103.1 μl, 1.202 mmol) under stirring at −15° C. The reaction mixture was stirred at room temperature for 2.5 hours and then, distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (4.0 ml) and to the resulting solution were added a solution of methyl 3-chloro-4-aminophenylacetate (167.9 mg, 0.841 mmol) in methylene chloride (4.0 ml) and triethylamine (0.35 ml, 2.523 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with chloroform, washed with 1N HCl, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 4-((1-benzyl-3-indolylcarbonyl)amino)-3-chlorophenylacetate (341.3 mg, 98%) was obtained. The compound was provided for the subsequent reaction without further purification.
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)([S:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1)[CH2:37][CH2:36]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(Cc2cccc(CCl)c2)Sc2ccc(C)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(Cc2cccc(N3CCc4cc(OC)c(OC)cc4C3)c2)Sc2ccc(C)cc2)cc1OC
Temperature: 85 °C
Yield: 65.8 %

Procedure:
A mixture of 0.21 g of 3-(chloromethyl)-α-(3,4-dimethoxyphenyl)-α-[(4-methylphenyl)thio]benzene propane nitrile, 0.091 g of 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline and 0.3 g of anhydrous potassium carbonate in 2.0 mL of N,N-dimethylformamide is heated at 85° C. for 4 hours, cooled, poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated in vacuo to yield an oil. This oil is purified by flash chromatography with 1.5% methyl alcohol in chloroform to yield 0.18 g of the desired product as a yellow glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: Cc1cccc(C=O)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(C)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 3-methylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)#[N:18].C1C(O)=CC=CC=1C>>[O:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[NH:18])[CH2:12][CH2:11]1
Reactant: N#CN1CCOCC1
Reactant: Nc1ccccc1CN1CCOCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: N=C(Nc1ccccc1CN1CCOCC1)N1CCOCC1

Procedure:
A mixture of 4(2-aminobenzyl)morpholine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heated at 90°-95° C. for 12 hours to yield N-(2-morpholinomethylphenyl)morpholine-4-carboxamidine (m.p. 118°-119° C.) which was recrystallised from hexane and then converted into its difumarate salt (m.p. 166°-167° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C@H:18]([OH:23])[CH2:19][C:20](=[O:22])[CH3:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:35]2[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=2)[N:29]=[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])[N:27]=1.C(N(CC)CC)C>[Pd].CO>[OH:23][C@H:18]([CH2:19][C:20](=[O:22])[CH3:21])[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:35]3[C:30](=[CH:31][C:32]([CH3:36])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[N:27]=2)[CH2:16][CH2:15]1)=[O:24]
Reactant: CC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of 4-((R)-2-hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylic acid benzyl ester (0.13 g, 0.39 mmol) and MeOH (4 mL) was stirred with 10 mg of Pd/C (10% wt Pd on carbon) under H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent, the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.11 g, 0.39 mmol) and triethylamine (0.11 mL, 0.78 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentane-1,4-dione as a yellow solid (91 mg, 54%). LC/MS: m/z 435.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).