Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([N:20]([C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])[CH3:19]
Reactant: C=C(C)CNCC
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C)CN(CC)c1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 41.3 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.29 mmol), N-ethyl-2-methylallylamine (Aldrich Chemical Company) (0.19 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by preparative TLC on silica gel with 1:1 EtOAc:hexanes as eluant to give 36.7 mg (42%) of the title compound as off-white solid. An analytical sample was obtained by recrystallization from EtOAc. Mp: 148-150° C. 1H NMR (CDCl3; 500 MHz): δ 1.32 (t, 3, J=7.1), 1.95 (s, 3), 2.59 (s, 3), 3.78 (q, 2, J=7.1), 4.20 (s, 2), 5.18 (s, 1), 5.24 (s, 1), 6.74 (s, 1), 7.35-7.48 (m, 3), 7.55 (d, 2, J=7.4), 8.47 (br s, 1). MS m/z: 307 (M+1), 305 (M−1). Anal. Calcd for C19H22N4: C, 74.48; H, 7.24; N, 18.28. Found: C, 74.36; H, 7.27; N, 18.19.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19](OC)=O)[CH:14]=2)[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>CO>[C:19]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:16]2=[O:18])#[N:23]
Reactant: N
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(Cc1ccccc1)O2
Solvent: CO
Product: N#Cc1ccc2c(c1)C(=O)CC(Cc1ccccc1)O2

Procedure:
Methyl 2-benzylchroman-4-one-6-carboxylate, the product of Preparation A33, is converted to the corresponding amide by the action of a molar excess of ammonia in aqueous methanol, recovered by simple stripping of the solvent and excess ammonia. In turn, the amide is converted to the title nitrile by the action of p-toluenesulfonyl chloride on a pyridine solution of the amide, according to the conditions of Stephens et al., J. Am. Chem. Soc., Vol. 77, pp 1701-1702 (1955). This product is well suited for the preparation of 6-cyano-c-4-hydroxy-r-2-benzylchroman-4-acetic acid by the methods of Examples above.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCO
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CN(C)CCOB(c1ccccc1)C(OC(B(OCCN(C)C)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (10 mg) was obtained by allowing 25 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 12 mg of N,N-dimethylethanolamine to act in 0.4 mL of ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO.C(O)(=O)C.[Br:19]Br>>[Br:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]=[CH:8][NH:7][C:6]2=[O:12]
Reactant: BrBr
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
7-methylquinazolin-4(3H)-one (14.56 g, 91 mmol) was added to methanol (70 ml, 91 mmol) and glacial acetic acid (70 ml, 1212 mmol). The mixture was stirred at RT for 5 min followed by the slow addition of bromine (9.3 mL, 182 mmol). The reaction was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure and the resulting crude residue washed with aqueous sodium thiosulfate to remove excess bromine and HBr, then oven dried to give 6-bromo-7-methylquinazolin-4(3H)-one (18.35 g, 84% yield) as light yellow amorphous solid. MS (ESI, pos. ion) m/z: 239 [M+H]+
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
3-Formylindol (10 g, 69 mmol) was dissolved in N,N-dimethylformamide (100 mL) and under an atmosphere of nitrogen and with external cooling, keeping the temperature below 15° C., sodium hydride (60% in mineral oil, 3.0 g, 76 mmol) was added in portions. Then a solution of ethyl bromoacetate (8.4 mL, 76 mmol) in N,N-dimethylformamide (15 mL) was added dropwise over 30 minutes and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between water (300 mL) and ethyl acetate (2×150 mL). The combined organic extracts were washed with a saturated aqueous solution of ammonium chloride (100 mL), dried (MgSO4) and concentrated in vacuo to afford 15.9 g (quant.) of (3-formylindol-1-yl)acetic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=[O:13]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([O:14][CH3:1])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 87 %

Procedure:
A solution of trimethylsilyldiazomethane (2M in hexane, 50 ml, 4 eq) is slowly added to a solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 1 eq) in methanol (70 ml) until the gas evolution ceases. The excess trimethylsilyldiazomethane is consumed by the dropwise addition of acetic acid until the solution becomes discoloured. The mixture is then concentrated under reduced pressure at a temperature of approximately 40° C. Water (200 ml) and dichloromethane (300 ml) are added to the residue. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is washed with petroleum ether and dried (4.4 g; 87% yield).
Reaction SMILES: N[C:2]1C=CC(CC(N)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.[S:23](=[O:27])(=[O:26])([OH:25])[OH:24]>CO>[S:23]([OH:27])([OH:26])(=[O:25])=[O:24].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH3:2])=[O:21])=[CH:17][CH:18]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The 4-aminophenylacetamide used in this example was obtained according to patent literature WO 02/08247 A2 or WO 03/051909 A2. Procedure was as follows: Methanol (200 mL) was charged to 4-aminophenylacetic acid (Aldrich) (25 g, 0.165 mol). Sulfuric acid (18 mL concentrated, 0.648 mol) was added maintaining the temperature <20° C. The mixture was then refluxed for one hour and concentrated by distillation at atmospheric pressure until the volume of 140 mL. The mixture was then cooled to 50° C. and tert-buthyl methyl ether (300 mL) was added maintaining the temperature above 45° C. The mixture was gradually cooled to 0-5° C. and held at this temperature for 1 hour. The resultant crystalline product was isolated by filtration and washed with cold methanol: tert-butyl methyl ether (20 mL: 55 mL) and cold tert-butyl methyl ether and then dried under vacuum to give methyl 4-aminophenylacetate hydrogensulfate (35.3 g, 80% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([C:22](OC)=[O:23])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10].O>O1CCCC1>[CH2:7]([C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][C:16]([CH2:22][OH:23])=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(=O)c2cc(C(=O)OC)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
To a suspension of 0.013 g of lithium aluminum hydride in 5.0 ml of tetrahydrofuran is added 0.100 g of methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate followed by stirring at room temperature for 5 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for 18 hours. An additional 20 mg of lithium aluminum hydride is added and stirring continued for an additional 8 hours. The reaction mixture is poured into 75 ml of water and extracted with ethyl acetate. The extract is evaporated in vacuo to a residue which is stirred with acetone and filtered to give 0.040 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:20][C@H:21]([CH3:24])[CH2:22][OH:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:12]([Cl:25])=[C:11]([NH:20][C@H:21]([CH3:24])[CH2:22][OH:23])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CO)Nc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc(NS(C)(=O)=O)c1Cl

Procedure:
The title compound of Example 3 (0.4 g) was dissolved in DCM (20 ml) and treated with N-chlorosuccinimide (0.14 g) for 2 h. The volatiles were removed in vacuo and the residue purified by reverse phase HPLC ((gradient 95% to 20% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound as a white solid. Yield: 0.25 g.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:33](=[O:34])[O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (400 mg, 874 μmol) was initially charged in abs. pyridine (15 ml). At 0° C., benzyl chloroformate was added in a plurality of portions (3×460 mg, 3×2621 μmol; 9 eq.), and the mixture was then stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (500 mg, quant.).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:10](#[N:13])[CH:11]=[CH2:12]>ClCCl>[C:10]([CH2:11][CH2:12][O:9][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][CH2:11][C:10]#[N:13])#[N:13]
Reactant: OCCOCCO
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCCOCCOCCOCCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2% (w/v) sodium hydroxide (5 mL) and diethylene glycol (5.3 g, 50 mmol) was added acrylonitrile (7.95 g, 150 mmol). The mixture was stirred at room temperature overnight and additioned with 50 mL dichloromethane. The organic layer was washed 2× with brine and dried (MgSO4). The solvent was removed by rotary evaporation. The oily residue was treated with 200 proof ethanol, and the solvent was removed by rotary evaporation. This was repeated 2× to remove excess unreacted acrylonitrile. The product was used without further purification
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:8]1[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2[nH]c(=O)c(C(F)(F)F)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)c(C(F)(F)F)cc2c1
Yield: 94 %

Procedure:
A solution of 6-methoxy-3-(trifluoromethyl)quinolin-2(1H)-one (4.60 g, 18.9 mmol) in POCl3 (30 mL) was refluxed for 2.5 hours. The solvent was removed under reduced pressure and the residue was neutralized by 2M NaOH to pH 7. An EtOAc workup was followed by removal of volatiles under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EtOAc=15/1) to give the product (4.60 g, yield 94%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccncc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccncc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (29 mg, 0.075 mmol), β-alanine (868 mg, 9.7 mmol) and NaOMe solution (15 mL, 7.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 1 M HCl, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound as a bright yellow solid. MS: (+) m/z 445.26 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:34](=[O:36])[CH3:35])[CH:7]=[CH:6][CH:5]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: CC(=O)Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and acetyl chloride as starting materials, 75 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 2.10 (s, 3 H); ES-MS m/z 474.41 [M+H]+, HPLC RT (min) 3.04.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8](=[O:9])[CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:6](=[O:17])[N:5]1[CH3:18]>C(Cl)(Cl)Cl>[Br:1][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:8](=[O:9])[N:4]([CH3:3])[N:5]([CH3:18])[C:6]1=[O:17]
Reactant: CN1C(=O)C(c2ccccc2Cl)C(=O)N1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C(Br)(c2ccccc2Cl)C(=O)N1C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A chloroform solution (5 ml) of 0.33 g (2.1 mmols) of bromine was added dropwise to a solution of 0.50 g (2.1 mmols) of 1,2-dimethyl-4-(2-chlorophenyl)pyrazolidine-3,5-dione in 10 ml of chloroform with ice cooling. The obtained mixture was stirred with ice cooling for 30 minutes. The reaction mixture was washed successively with water, an aqueous solution of saturated sodium hydrogencarbonate and a saturated solution of sodium chloride and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was washed with hexane, thereby obtaining 0.50 g (yield 75%) of 4-bromo-4-(2-chlorophenyl)-1,2-dimethylpyrazoline-3,5-dione in the form of yellow crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>C(O)C.O>[Br:14][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([Cl:13])[CH:10]=1)[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(Br)cc(Cl)c21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cc(Br)cc2c1NCC2
Yield: 87.8 %

Procedure:
Part B: 1-acetyl-5-bromo-7-chloroindoline (1.17 g) was dissolved in a mixture of ethanol (15 mL) and water (8 mL) containing KOH (0.5 g) and heated to reflux for 2 h. The reaction was partitioned between EtOAc (100 mL) and water (20 mL). The organic extract was washed with brine (20 mL), dried and stripped in vacuo to give 5-bromo-7-chloroindoline (0.87 g).
Reaction SMILES: C(O)(=O)C.C[O:6][C:7](=[O:35])[C@@H:8]([NH:15][C:16](=[O:34])[CH:17]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:36]>O.C(O)(=O)C>[ClH:36].[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:17]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]([NH:15][C@@H:8]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:7]([OH:35])=[O:6])=[O:34])=[CH:24][CH:23]=1)(=[NH:26])[NH2:27]
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)O)C2CCCCC2)C2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
[3-(4-Carbamimidoyl-phenyl)-2-(R,S)-cyclohexyl-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester acetic acid salt was dissolved in a mixture of hydrochloric acid (100 ml), water (100 ml) and acetic acid (50 ml) within 1 hour. After 15 hours stirring at room temperature and 8 hours at 50° C., the mixture was evaporated and after addition of water lyophilized to yield a diastereomeric mixture (2.7 g, 72% step g and h) of the desired product. MS m/z: 414.3 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:24][CH2:25][CH2:26][CH3:27])=[O:10])=[CH:7][CH:6]=1.[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2([C:11]3[C:15]4[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=4[O:13][C:12]=3[CH2:24][CH2:25][CH2:26][CH3:27])[O:32][CH2:31][CH2:30][O:10]2)=[CH:28][CH:29]=1
Reactant: OCCO
Reactant: CCCCc1oc2ccc(C(=O)OC)cc2c1C(=O)c1ccc(OCCBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1oc2ccc(C(=O)OC)cc2c1C1(c2ccc(OCCBr)cc2)OCCO1
Yield: 45.1 %

Procedure:
10.0 g (0.022 mol) of methyl 3-[4-(2-bromoethoxy)benzoyl]-2-butylbenzofuran-5-carboxylate, 3.39 g (0.055 mol) of ethylene glycol, 890 mg of para-toluenesulfonic acid (pTsA) and 100 ml of benzene are brought to reflux for 3 days, eliminating the water formed using a Dean-Stark apparatus. The mixture is evaporated to dryness and the residue is chromatographed on a column of silica, eluting with DCM (dichloromethane) and then a DCM/ethyl acetate (99/1) mixture. 5 g of the pure desired compound are thus isolated.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:6]1([O:5][CH2:4][CH:3]([OH:1])[CH2:2][N:25]2[CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CCO
Product: OC(COc1cccc2ccccc12)CN1CCC(c2ccccc2)CC1

Procedure:
To a solution of 5.0 parts of 1,2-epoxy-3-(1-naphthoxy)propane in 79 parts of ethanol is added 5.0 parts of 4-phenylpiperidine. The resulting mixture is then refluxed for 24 hours. Evaporation of the solvent from the reaction mixture under reduced pressure affords 1-(1-naphthoxy)-3-(4-phenylpiperidino)-2-propanol. This free amine is then dissolved in isopropanol and treated with a solution of hydrochloric acid in isopropanol. The resulting salt is separated by filtration and recrystallized from a mixture of ethanol and ethyl ether to give 1-(1-naphthoxy)-3-(4-phenylpiperidino)-2-propanol hydrochloride. This compound melts at 195°-197° C. and is represented by the following structural formula ##STR6##
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[C:8]2[N:7]=1)=[O:5])C.CO.[OH-].[Na+].Cl>O1CCCC1>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[N:12][N:9]3[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a mixture of 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester (18.00 g), 120 ml of methanol, and 120 ml of tetrahydrofuran, 60 ml of a 2N aqueous sodium hydroxide solution was added, and stirred at room temperature over 2 hours. To the reactant, 60 ml of 2N hydrochloride was added dropwise, and the precipitated crystal was filtered to yield 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid (14.02 g, 86%) as a yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Na+].[Cl-].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccnc2ccccc12
Temperature: 160 °C
Yield: 47.7 %

Procedure:
4-(Bis-ethoxycarbonyl methyl)-quinoline (5.05 g, 17.6 mmol), NaCl (2.06 g, 35.2 mmol), and H2O (0.63 mL, 35 mmol) were combined with DMSO (22 mL) in a round-bottom flask fitted with a reflux condenser. The heterogeneous mixture was stirred and heated to 160° C. for 90 minutes. TLC analysis (silca, 20% EtOAc-hexanes) indicated complete consumption of the starting material. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. Purification by gradient elution chromatography (SiO2, 20% EtOAc-hexanes to 30% EtOAc-hexanes) gave 4-(ethoxycarbonyl methyl)-quinoline (1.81 g, 8.40 mmol) in 48% yield. MS (APCI) m/z 216.1 (M+H). 1H NMR (300 MHz) CDCl3 δ 8.87 (d, J=4.4 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.73 (m, 1H), 7.60 (m, 1H), 7.34 (d, J=4.5 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.07 (s, 2H), 1.23 (t, J=7.2 Hz, 3H).