Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:20]2[C:19]3[C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)(=O)=O.[C-:36]#[N:37].[Na+]>CS(C)=O.C(Cl)Cl>[C:36]([CH2:6][CH2:7][C@H:8]1[C:20]2[C:19]3[C:18]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)#[N:37]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCOS(C)(=O)=O)CCC4)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC#N)CCC4)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-[2-(methanesulfonyloxy)ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (525 mg, 1.00 mmol, 1.00 equiv) in DMSO (20 mL) was added NaCN (294 mg, 6.00 mmol, 6.00 equiv) and the resulting solution was stirred for 2 h at 70° C. under nitrogen. After cooling, the mixture was diluted with DCM (80 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to yield 380 mg (83%) of tert-butyl N-(4-[[(13S)-13-(2-cyanoethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:24].Cl>C1COCC1.O>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH3:24])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: FC(F)(F)Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-trifluoromethoxyphenyl)-1H-indole (0.853, 3.08 mmoles) in dry THF (10 mL) was added sodium hydride (60% dispersion on mineral oil, 0.47 g, 12.3 mmol), portionwise. The reaction mixture was stirred under nitrogen for 30 minutes and, then cooled in ice bath. A solution of iodomethane (0.38 mL, 6.1 mmole) in dry THF (10 mL) was added and the reaction mixture was stirred for 1 hour at room temperature. The mixture was then poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 0.5% t-butyl methyl ether in hexane as an eluant. The title compound was obtained as a cream-colored solid that was vacuum dried at 66° C. (0.623 g, 70%). 1HNMR (300 MHz, DMSO-d6): δ 7.85 (d, 2H, J=8.3 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.3-7.4 (m, 2H), 6.45 (s, 1H), and 3.85 ppm (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:22](Br)[CH3:23].[OH-].[K+].CO>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([CH2:22][CH3:23])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1CCc2cc(OC)c(OC)cc2C(c2ccccc2)C1

Procedure:
A sample of 7,8-dimethoxy-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine weighing 4.32 g. (0.0154 mol), 2.18 g. (0.02 mol) of ethyl bromide and 1.12 g. (0.02 mol) of potassium hydroxide are dissolved in 120 ml. of dry methanol and the solution is refluxed overnight. Evaporation of the solution to dryness gives a mixture which is taken up in ethyl acetate and filtered to remove inorgaic salts. The filtrate is washed with water, dried and evaporated to give 7,8-dimethoxy-3-ethyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[C:12](N)(=N)[CH3:13].C([O-])(=O)C.[Na+]>[OH-].[Na+]>[CH3:12][C:13]1[NH:10][C:8](=[O:9])[C:7]2[NH:6][CH:5]=[N:4][C:3]=2[N:2]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 190 °C

Procedure:
A solid mix of 4-amino-5-imidazolecarboxamide hydrochloride (30.75 mmol, 5 g) and acetamidine hydrochloride (2 eq, 61.5 mmol, 5.8 g) and sodium acetate (3 eq, 92.25 mmol, 7.6 g) were heated at 190° C. for 1 h. To the resultant off-white solid, at RT, NaOH (100 ml) was added and a white ppt was filtered away. The filtrate was acidified to pH 6.0 with AcOH (5 ml) and the resultant ppt filtered away. Both precipitates were dried separately in a vacuum oven at 0° C. for 24 h. The combined weight of pure product was (4.16 g, 90%). The first precipitate (2.11 g) analyzed as follows: mp.>300° C. DCI/MS (M+1)=151. (300 MHz) 1H-nmr (DMSO-d6) δ: 8.0 (s, 1H), 2.3 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10](=[N:13][OH:14])[NH2:11]
Reactant: N#CCc1c(F)cccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Solvent: CCO
Solvent: O
Product: NC(Cc1c(F)cccc1Cl)=NO
Yield: 41 %

Procedure:
10.0 g (59 mmol) of (2-chloro-6-fluorophenyl)acetonitrile in 50 ml of ethanol were admixed with 7.0 g (101 mmol) of hydroxylamine hydrochloride and then with 7.5 g (71 mmol) of sodium carbonate dissolved in 30 ml of water. This mixture was refluxed for 4 h, poured into aqueous sodium dihydrogen phosphate buffer (pH 7.8) and extracted with methylene chloride, and the extract was dried over sodium sulfate. The solvent was removed under reduced pressure, and 4.9 g of product were obtained from the extract. A further 3.7 g precipitated from the aqueous phase. Overall yield: 8.6 g, which were directly reacted further.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7](=[C:10]=[N:11]O)[CH:6]([Cl:13])[CH2:5][CH2:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:3]1[CH2:9][CH2:8][C:7]([C:10]#[N:11])=[C:6]([Cl:13])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=C=NO)C(Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCC(Cl)=C(C#N)CC1

Procedure:
This compound was prepared from 1-ethyl-4-chloro-2,3,6,7-tetrahydro-5-oximinomethylene-1H-azepine and phosphorus oxychloride analogous to Example E.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:27])[N:14](COC(=O)C(C)(C)C)[CH:15]=[N:16]3)=[CH:11][C:10]=2[O:28][CH3:29])[CH:5]=[CH:4][N:3]=[CH:2]1>N>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:27])[NH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[O:28][CH3:29])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnc1
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCCn1ccnc1
Yield: 89.9 %

Procedure:
A solution of 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (640 mg, 1.6 mmol) in saturated methanolic ammonia (10 ml) was stirred for 15 hours at ambient temperature. The volatiles were removed by evaporation, the solid was triturated with ether, collected by filtration and dried under vacuum to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412 mg, 90%).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([O:27][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:15]([Cl:16])[C:10]=1[Cl:9])[CH3:8])[CH3:7]
Reactant: COc1ccc(C(=O)c2ccc(O)c(Cl)c2Cl)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(OC)cc2)c(Cl)c1Cl

Procedure:
A solution of 9.96 (0.055 mole) of ethyl 2-bromopropionate in 12 ml. of acetone was added over a period of 2 hours to a stirred, refluxing mixture of 14.85 g. (0.05 mole) of 2,3-dichloro-4-(4'-methoxybenzoyl)phenol and 7.60 g. (0.055 mole) of powdered anhydrous potassium carbonate in 200 ml. of acetone. After the addition, the mixture was refluxed for 20 hours and the hot mixture was filtered. The filtrate was evaporated in vacuo and the residue was taken up in 250 ml. of chloroform. The chloroform solution was washed with 10% aqueous potassium carbonate, water, dried over anhydrous sodium carbonate and evaporated in vacuo to give the product.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[C:9]([Cl:27])=[CH:10][C:11]4[N:15]=[C:14]([NH:16][C:17]5[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=5[Cl:25])[CH2:20][NH2:21])[NH:13][C:12]=4[CH:26]=3)[CH2:4]2)[CH2:2]1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH2:2]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[C:9]([Cl:27])=[CH:10][C:11]4[N:15]=[C:14]([NH:16][C:17]5[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=5[Cl:25])[CH2:20][NH:21][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[NH:13][C:12]=4[CH:26]=3)[CH2:4]2)[CH2:1]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1

Procedure:
The sub-title compound was prepared from 3-[6-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzylamine (60 mg, 0.1), pivaloyl chloride (20 μL, 0.1 mmol) and TEA (160 μL, 1.1 mmol) in THF (5 mL) in analogy to example 3, step (e).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:26]([OH:30])(=[O:29])[CH2:27][OH:28].C(O)(C(F)(F)F)=O>C1COCC1.C(OCC)(=O)C.O>[C:26]([CH2:27][O:28][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19])([OH:30])=[O:29]
Reactant: O=C(O)CO
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(=O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.7 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1h-pyrrol-2-yl)-meth-(z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indole-2-one (166 mg, 0.5 mmol), glycolic acid (163 mg, 1.5 mmol, 70% w/w in water) and (68 mg, 0.6 mmol) of TFA in 3 mL of THF was stirred at room temperature for 4 h and diluted with ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The precipitate was filtered, washed with small amount of ethyl acetate, and dried in a vacuum oven overnight to afford 42 mg (25%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid carboxymethyl ester. 1H NMR (400 MHz, DMSO-d6 and CDCl3) δ 12.63 (s, 1H, NH-1′), 7.92–7.94 (m, 1H), 7.52–7.55 (m, 1H), 7.44 (s, 1H, H-vinyl), 7.20–7.22 (m, 2H), 6.06 (s, br, 1H, H-4′), 4.94 (s, 2H, CH2), 2.39 (s, 3H, CH3), and 2.36 (s, 3H, CH3).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([OH:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[N:12]2)=[CH:7][CH:6]=1.Cl[C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28].CN(P(N(C)C)(N(C)C)=O)C>CN(C)C=O>[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([O:24][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Sodium hydride (50% dispersion in mineral oil) (0.8 g.) is added to a suspension of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (4.63 g.) in anhydrous dimethylformamide (45 cc.), whilst keeping the temperature between 18°-20° C. The reaction mixture is stirred for a further 4 hours 30 minutes. A solution of 1-chlorocarbonyl-4-methylpiperazine (2.7 g.) in anhydrous dimethylformamide (25 cc.) is then added over the course of 15 minutes and at a temperature of 20° C. The suspension is stirred for 17 hours at a temperature of about 20° C., and then anhydrous hexamethylphosphotriamide (7 cc.) is added. After 15 minutes, the reaction mixture is poured into ice-water (500 g.). The precipitate is filtered off and washed with water (45 cc.). A product (6.1 g.) is obtained and is recrystallised from diisopropyl ether (1,500 cc.). 2-(7-Methoxy-1,8 -naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (3 g.), melting at 191° C., is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:18])[CH2:14][CH2:15][S:16][CH3:17])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCC(=O)C1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: CSC
Solvent: C1CCOC1
Product: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.6 %

Procedure:
3-(3-Methylsulfanylpropionyl)-2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (188 mg, 654 μmol) was dissolved in THF (531 μL) under nitrogen. 2M BH3.Me2S in THF (981 μL) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 1 hours, then cooled to room temperature. The mixture was cooled on an ice bath and the reaction was slowly quenched with cold MeOH (100 mL). The mixture was stirred overnight and then diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg), which was used without further purification. LCMS m/z: [M+H]+ calcd for C13H25NO3S, 275.40; found 276.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]1=[O:27].C(N(C(C)C)CC)(C)C.O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 103.3 %

Procedure:
A mixture of 5.0 gm of 1-t-butoxycarbonyl piperazine, 6.26 gm of 1-(3-chloro propyl)-2,3-dihydro-1H-benzimidazol-2-one (available from Janssen) and 4.16 gm diisopropylethylamine in 150 ml ethanol is kept for 12 hours at 80° C. Upon cooling to ambient temperature, 100 ml water is added and the mixture is extracted with chloroform (CHCl3) and the extract is collected, washed with 20 ml water and dried over Na2SO4. After removing the solvents, 10 gm of a yellowish oil is obtained which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:27][CH2:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:3]=1
Reactant: COc1cccc(CCN)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1cccc(CCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(3-methoxyphenyl)ethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:31]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pt]>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Yield: 94 %

Procedure:
tert-Butyl[4-(6-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (17.62 g, 37.77 mmol) was dissolved in toluene (600 mL) with heating and added to a Parr vessel charged with 5% platinum on carbon (2.20 g). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 15.5 g of tert-butyl{4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate as a brown solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:26][C:27]([CH2:35][CH3:36])([CH2:33][CH3:34])[C:28]([O:30]CC)=[O:29])[C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.[OH-].[Na+].Cl.C(Cl)Cl.CO>C(O)C>[CH2:33]([C:27]([CH2:26][N:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:4][N:3]=[N:2][N:1]=2)=[CH:17][CH:16]=1)[C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])([CH2:35][CH3:36])[C:28]([OH:30])=[O:29])[CH3:34]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)CC(CC)(CC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)CC(CC)(CC)C(=O)O
Temperature: 25 °C

Procedure:
1.146 g of ethyl N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-2-aminomethyl-2-ethylbutyrate are dissolved in 10 ml of ethanol, treated with 4.66 ml of 2N NaOH solution and heated to reflux for 20 hours. After cooling to room temperature and addition of 4.66 ml of 2N hydrochloric acid, the mixture is evaporated. The product is isolated by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 --MeOH 80:20, Rf =0.38 (system N8). MS (FAB): m /e 486 (M+ +Na), 502 (M+ +K).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([O:29]C)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of methyl 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (1.91 g, 4 mmol) in tetrahydrofuran (10 ml)-methanol (10 ml) was added 1N sodium hydroxide (8 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-isopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.67 g, 90.3%) as crystals.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:33][NH:34][C:35]([NH2:37])=[O:36].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)[C:8]([NH:37][C:35]([NH:34][CH3:33])=[O:36])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: CNC(N)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Fc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (368 mg, 1.0 mmol) in fluorobenzene (1.5 mL) and NN-dimethylfornamide (6 μL) at 25° C. was treated dropwise with oxalyl chloride (107.7 μL, 1.21 mmol) over 2-3 min. The clear solution was stirred for 1 h at 25° C. and then treated with methyl urea (322 mg, 2.0 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (162 μL, 2.0 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 to 1/2 hexanes/ethyl acetate) afforded 1-{3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea (338 mg, 80%) as an amorphous white solid: EI-HRMS m/e calcd for C19H23F3N6O2 (M+) 424.1834, found 424.1833.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:19]=3)[C:14]2=[O:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:19]=3)[C:14]2=[O:35])[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:8]=1
Reactant: CCOC(=O)c1cc(N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2=O)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2=O)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
660 mg (1.20 mmol) of ethyl 3-{3-[3,5-bis(trifluoromethyl)phenyl]-2-oxoimidazolidin-1-yl}-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate were dissolved in 10 ml of ethanol, 72 mg (1.80 mmol) of 2N aqueous sodium hydroxide solution were added and the mixture was stirred at RT for 1 h. The solvent was distilled off under reduced pressure, the residue was taken up in water and the mixture was extracted once with methyl tert-butyl ether. The aqueous phase was then acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated.