Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.O>[CH2:13]([C:9]1[CH:10]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(O)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
Separately, 60 g of 4-hydroxybenzoic acid was dissolved in 500 ml of ethanol, and a solution of 15 g of NaOH in 500 ml of water was added thereto. To the mixture was added 50 g of benzyl chloride, followed by stirring for 2 hours at room temperature and 2 hours of heat refluxing. After distilling off the solvent, the product was recrystallized from ethanol to obtain 40 g of benzyl-4-hydroxybenzoic acid. Then, 17 g of the benzyl-4-hydroxybenzoic acid was dissolved in 100 ml of pyridine, and 8 g of terephthaloyl chloride was added thereto, followed by stirring for 2 hours at room temperature and for 1 hour at 70° C. The reaction mixture was added to 500 ml of 2M-HCl to obtain 10 g of bis(4-benzyloxycarbonylphenyl)terephthalate, which was then added to 150 ml of trifluoroacetic acid, followed by addition of 10 ml of 33% HBr solution in acetic acid and reaction for 12 hours at room temperature. Acetone was added to the reaction mixture to result in a precipitate, which was then separated and washed with acetone to obtain 4 g of bis (4-carboxyphenyl)terephthalate. Then, 2 g of the diacid was mixed with 40 ml of SOCl2, followed by 2 hours of heat refluxing, reduced pressure distillation for removal of an excess of SOCl2, addition of 1,2-dichloroethane and addition of a solution of 1 g of the compound of the formula (IX) in 5 ml of pyridine. The mixture was subjected to reaction at 60° C. for 3 hours and at room temperature for 10 hours. The reaction product was re-precipitated from acetone and washed with water to obtain a polymer mesomorphic compound of the following formula (X) (ηinh =0.02 dl/g): ##STR38##
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1([CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B(O)O)[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][CH2:30][CH:27]3[CH2:28][CH2:29]3)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: OB(O)c1ccccc1OCC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccccc2OCC2CC2)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 51.4 %

Procedure:
To the stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.59 g, 1.6 mmol) and 2-(cyclopropylmethoxy)phenyl boronic acid (0.34 g, 1.9 mmol) in saturated sodium carbonate solution (5 ml) and 1,4-dioxane (5 ml) was added palladium(II) acetate (0.071 g, 0.32 mmol) followed by triphenylphosphine (0.083 g, 0.32 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 mL). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(2-cyclopropylmethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XV) (0.4 g, 35%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18]CC#N)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1.Cl.[C:26]([OH:32])([C:28](F)(F)F)=[O:27]>CO.[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:28][C:26]([OH:32])=[O:27])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:22]([CH3:24])[CH3:23])=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCC#N)CCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCC(=O)O)CCC2
Reaction time: 18 h

Procedure:
A solution of Intermediate 78 (128 mg, two batches) in Methanol (3.5 mL) and potassium hydroxide (10M aqueous soln) (0.749 mL) was heated to reflux overnight. LCMS after 18 h indicated approximately 20% conversion to the acid. Further potassium hydroxide (10M aqueous soln) (0.749 mL was added to the reaction mixture and it was left to heat for a further 36 h. LCMS after this time demonstrated full conversion to the acid product. Aqueous HCl (4.85 mL) was added to the reaction mixture to neutralise to the KOH. The product was extracted from the reaction mixture using EtOAc. The organic layer was washed with water, brine and then dried over MgSO4 and filtered, before being concentrated in vacuo to give the product, 88 mg. LC/MS MH+ 361, Rt 2.02 mins (5 min run, TFA modifier).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: COc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: CN1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1

Procedure:
Employing the procedure of Example XX, 7.7 g. of 4,6-dichloro-2-(4-methoxyphenyl)-pyrimidine is reacted with 6.0 g. of N-methylpiperazine in 45 ml. of absolute ethanol to afford 4-chloro-2-(4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-pyrimidine, m.p. 88°-90°C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH2:14][C:15]1[N:19]=[CH:18][O:17][N:16]=1.O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH2:14][C:15]1[N:19]=[CH:18][O:17][N:16]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1SCc1ncon1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1SCc1ncon1

Procedure:
Methanesulphonyl chloride (1.39 g) was added dropwise to a cooled solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (3.1 g) in pyridine (12 ml). The reaction mixture was then poured into water (75 ml) the so formed solid removed by filtration and crystallised from ethanol to give 3-(2-methylsulphonamidophenylthiomethyl)-1,2,4-oxadiazole, m.p. 106°.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13]>O1CCCC1.CO>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:13][CH:12]([CH3:14])[C:11]#[N:15])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: C=C(C)C#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C#N)CNc1ccccc1[N+](=O)[O-]

Procedure:
69 g (mol/2) of o-nitroaniline in solution in 270 ml of tetrahydrofuran are heated under reflux for 2 hours with 67 g (1 mol) of methacrylonitrile and 16 ml of a 40% solution of "Triton B" in methanol. After evaporation of the volatile substances under vacuum, washing the residue with water and then extraction with ethyl acetate, and after evaporation of the solvent, a yellow solid of melting point 44°-47° C. is obtained in a yield of 51.3 g = 50% (theoretical yield: 102.6 g). After recrystallisation from isopropanol and then from ethanol, there is obtained a yellow product of melting point 75°-76° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][CH2:9]C1C=C(S([O-])(=O)=O)C=CC=1C.[OH:21][C:22]1[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1>CC(N(C)C)=O>[Cl:7][CH2:8][CH2:9][O:21][C:22]1[C:23]([S:28]([NH2:31])(=[O:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: NS(=O)(=O)c1ncccc1O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ncccc1OCCCl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
First 17.9 g of potassium carbonate and then 28.14 g of 2-(2-chloroethyl)-toluene-4-sulfonate are added, with stirring, to a solution of 17.4 g of 3-hydroxy-pyrid-2-ylsulfonamide in 240 ml of dimethylacetamide. The reaction mixture is stirred for 1.5 hours at 80° C. and then cooled and filtered. The filtration residue is washed with acetonitrile. The filtrate and the washing liquid are adjusted to pH 5-6 with trifluoroacetic acid, filtered and concentrated using a rotary evaporator. For purification the residue is chromatographed on a silica gel column using ethyl acetate/n-hexane 4/1. Removal of the eluant by evaporation yields 14.42 g of the above sulfonamide in the form of colourless crystals which melt at 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)(=[O:20])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1ccc(Cl)c(Cl)c1
Yield: 21.4 %

Procedure:
3,4-Dichloro-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 1 g of 5-amino-1H-indazole, 20 ml of pyridine and 1.84 g of 3,4-dichlorobenzenesulfonyl chloride. 0.55 g of 3,4-dichloro-N-(1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a green solid melting at 209° C. (analysis C13H9Cl2N3O2S % calculated C, 45.63; H, 2.65; Cl, 20.72; N, 12.28; O, 9.35; S, 9.37. % found C, 45.87; H, 2.72; Cl, 21.10; N, 12.27; S, 9.21).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([N:21]1[CH2:22][CH2:23][N:18]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][N:12]=2)[CH2:19][CH2:20]1)=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: O=C(Nc1c(Cl)cccc1Cl)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 1.88 g. of 2,6-dichlorophenylisocyanate in 25 ml. of anhydrous ether was added dropwise to a stirred solution of 1.64 g. of 1-(2-pyrazinyl)piperazine in 250 ml. of anhydrous ether. The mixture was stirred for 30 minutes and the solid was collected and recrystallized from ethanol, giving 3.12 g. of the desired product, m.p. 177°-179° C.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:36]([CH2:38][NH2:39])[OH:37].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[OH:37][CH2:36][CH2:38][NH:39][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: NCCO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of quinaldic acid (5.0 g, 28.87 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g, 28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60 mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and 4-methylmorpholine (4.76 mL, 43.31 mmol). The reaction was stirred at 0° C. for an additional 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed 3 times with H2O, once with NaHCO3 (sat), once with brine, dried over MgSO4, and concentrated in vacuo to provide 1.5 g (24% yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]2([O:15][CH:14]2[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:25]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]([F:25])([CH:14]([OH:15])[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Reactant: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 0.247 g, (1 mmol) of 2-methyl-1-oxa-5-azaspiro[2,4]-heptane-5-carboxylic acid benzyl ester (Example A9) in dichloromethane (3 mL) is added to a polypropylene flask containing 0.5 mL of hydrogen fluoride-pyridine at −40° C. The reaction is allowed to come to room temperature and stirring is continued for 3 hours. The reaction mixture is poured into an aqueous ice-cold ammonium hydroxide solution (30 mL) and extracted with dichloromethane. The organic layer is dried, filtered and concentrated to afford the title compound (0.267 g). 1H NMR (200 MHz, CDCl3): δ 7.35 (s, 5H), 5.13 (s, 2H), 3.96-3.34 (m, 5H), 2.20-1.98 (m, 3H), 1.33-1.26 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH3:39])[C:36](O)=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:36](=[O:37])[CH:35]([C:30]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=2)[CH3:39])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Reactant: CC(C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (300 mg, 0.0008 mol), 2-(3,4-dichlorophenyl)propanoic acid (200 mg, 0.00092 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (600 mg, 0.002 mol), N,N-diisopropylethylamine (0.3 mL, 0.002 mol) and N,N-dimethylformamide (2 mL, 0.03 mol) and the reaction stirred at room temperature over night. The reaction did not go to completion. The solvent was removed and the residue was purified flash chromatography to obtain the product as a solid. MS m/z=578.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10]C)[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(Br)cc1O
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-benzonitrile (4.60 g, 21.7 mmol) in methylene chloride (20 mL) was added aluminum chloride (14.5 g, 108 mmol). After stirring under an argon atmosphere for 10 min, more methylene chloride (30 mL) was added, and the mixture left to reflux under argon overnight. The reaction was then diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure, providing (4.09 g, 95.2%) of 4-bromo-2-hydroxy-benzonitrile as a slightly gray-colored product. 1H-NMR (CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 7.19 (d, J=1.4 Hz, 1H), 7.14 (dd, J=8.4, 1,4 Hz, 1H), 6.15 (s, 1H); TLC Rf=0.78 (50% ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[NH:20][C:19](=[O:21])[CH2:18][C:16]=3[N:17]=2)[CH2:7][CH2:6]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)=O>CCO.N>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)=[C:18]1[C:16]2[N:17]=[C:12]([NH:11][CH:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]3)[N:13]=[CH:14][C:15]=2[NH:20][C:19]1=[O:21]
Reactant: COCCN1CCC(Nc2ncc3c(n2)CC(=O)N3)CC1
Reactant: O=C(c1cccc(Cl)c1)c1nc2ccccc2[nH]1
Agent: N
Solvent: CCO
Product: COCCN1CCC(Nc2ncc3c(n2)C(=C(c2cccc(Cl)c2)c2nc4ccccc4[nH]2)C(=O)N3)CC1
Reaction time: 8 h

Procedure:
A mixture of crude 2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-5,7-dihydro-pyrrolo[3,2-d]pyrimidin-6-one, TFA salts (8, 519 mgs, 0.71 mmol) and (1H-benzoimidazol-2-yl)-(3-chloro-phenyl)-methanone (9, 192 mgs, 0.75 mmol) was dissolved in EtOH saturated with ammonia (8.0 mls) and the mixture stirred at 90 C in a sealed reaction vessel overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 7-[(1H-Benzoimidazol-2-yl)-(3-chloro-phenyl)-methylene]-2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-5,7-dihydro-pyrrolo[3,2-d]pyrimidin-6-one (10). LC/MS Calcd for [M+H]+ 530, found 530.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][C:10]([I:13])=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1cnc(N2CCNCC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Ic1cnc(N2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)nc1

Procedure:
In 100 ml of methylene chloride was dissolved 13 g of 2-piperazin-1-yl-5-iodopyrimidine which was then reacted with 15 g of triphenylmethyl chloride at room temperature for 1 hour in the presence of 16 ml of triethylamine with stirring. The reaction mixture was added with methylene chloride, after which the organic layer was washed with water and brine, dehydrated, filtered and concentrated under vacuum. The residue was purified by use of ethyl acetate and a small quantity of methanol to obtain the title compound. 10 g.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Cc2ccc(O)cc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The solution of 3.26 of 6-methoxy-2-oxindole in 60 mL of dischloromethane was coold at -3° C. and 10 mL of 1 M boron tribromide solution in dichloromethane was added dropwise. The reaction mixture was stirred in ice-bath for 1 hour, room temperature for 1 hour, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and dried in a vacuum oven overnight to give 2.56 g of the 6-hydroxy-2-oxindole (86% yield),
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH2:20][C:21]([O:23]C)=O)=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH:9]2[NH:8][C:21](=[O:23])[CH2:20][NH:19][C:17]2=[O:18])[CH2:16][CH2:15]1
Reactant: COC(=O)CNC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC(=O)C(CC2CCOCC2)N1
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
A 250 mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-alanylglycinate (3.00 g, 8.71 mmol), 10 mL of CH2Cl2, and 5 mL of TFA. After 10 min, the mixture was concentrated then re-dissolved in MeOH (50 mL) and triethylamine (10 mL) and then heated at reflux for 18 h. After that time, the white precipitate formed was collected by filtration to give 3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:15]([O-])=O)[CH2:2][CH3:3]>[Pd].C(OCC)(=O)C>[CH2:1]([NH:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCNc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A mixture of 2.48 g of N-propyl-2-nitro-4-trifluoromethylaniline, 30 ml of ethyl acetate and 5% palladium charcoal was stirred for 1.5 hours at room temperature under a hydrogen atmosphere of about 1 atm. The reaction mixture was filtrated through Celite (registered trademark). The filtrate was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure, to obtain 1.91 g of N1-propyl-4-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28](O)=[O:29])=[CH:22][C:21]=1[Cl:31])([CH3:19])([CH3:18])[CH3:17].CN1CCOCC1>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[CH:22][C:21]=1[Cl:31])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ncc(OCC(=O)O)cc1Cl
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1ncc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1Cl
Yield: 30.6 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (192 mg, 0.751 mmol) was reacted with (6-tert-butyl-5-chloro-pyridin-3-yloxy)-acetic acid (183 mg) DMTMM (1.1 eq, 229 mg) and NMM (1.2 eq, 100 μl) in THF to give the title compound (102 mg, 30.6%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16]>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: Cc1ccccn1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(C=Cc2ccccn2)cc1
Yield: 45.6 %

Procedure:
A mixture of 20.4 g (0.2 mol) acetic acid anhydride, 18.6 g (0.2 mol) 2-methylpyridine and 26.2 g (0.2 mol) 4-cyanobenzaldehyde is heated to reflux for 24 h. One allows to cool, mixes with excess ether and filters. One isolates 18.8 g of title compound (46% of theory) of the m.p. 98°-98° C.