Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1>C(O)(C)C>[CH:18]([C:15]1[S:16][CH:17]=[C:13]([CH2:12][NH:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[N:14]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)c1nc(CNNC(=O)OC(C)(C)C)cs1

Procedure:
A solution of 7.5 g (57 mmol) to t-butylcarbazate in 200 ml of isopropyl alcohol was treated with a solution of 1.0 g (57 mmol) of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of isopropyl alcohol. The resulting solution was heated at reflux for 16 h, allowed to cool, and concentrated in vacuo. The residue was diluted with 1N HCl, washed with three portions of ethyl acetate, basified to pH 12 with aqueous NaOH, and extracted with three portion of ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography using 20% ethyl acetate in hexane provided 0.32 g (21%) of the desired compound (Rf 0.4, 5% methanol in chloroform). 1H NMR (CDCl3) δ1.40 (d, J=7 Hz, 6H), 1.47 (s, 9H), 2.53 (br, 1H), 3.33 (heptet, J=7 Hz, 1H), 4.11 (s, 2H), 6.22 (br, 1H), 7.01 (s, 1H). Mass spectrum: (M+H)+ =272.
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>ClCCl>[F:25][CH:2]([F:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:35])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: COCCc1noc(C2CNCC(c3ccc(CC(F)F)cc3)C2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 36.3 mg (0.061 mmol, purity 70%) of the compound from Example 61A in dichloromethane (2.0 ml) was admixed with 0.03 ml (21.6 mg, 0.21 mmol) of triethylamine and then 12.3 mg (0.061 mmol) of 4-nitrophenyl chloroformate were added at RT. The mixture was stirred at RT for 2 h and then the reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 56.2 mg (91% of theory, purity 60%)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCSCCCN(C)C)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1

Procedure:
A mixture of 7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-[9-(3-dimethylaminopropylthio)nonyl]thiochroman (50 mg, 0.09 mmol), hydrobromic acid (0.13 ml, 48% aqueous solution) and acetic acid (0.15 ml) was heated for 8 hours. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to give the title compound (60 ml, crude product) as a colorless oil. This compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[C:30]([CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)#[N:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][C:30]#[N:31])[CH2:35][CH2:36]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: N#CCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCC#N)CC3)ccc21
Yield: 99.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (40.8 mg, 0.0993 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 1-(2-cyanoethyl)piperazine (59.8 mg, 0.430 mmol), acetic acid (0.115 mL, 2.01 mmol) and sodium triacetoxyborohydride (74.3 mg, 0.351 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-cyanoethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (53.0 mg, yield 100%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[O:13]1[C:17]2[CH:18]=[C:19]([CH2:22][NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14]1>>[O:13]1[C:17]2[CH:18]=[C:19]([CH2:22][N:23]([C:2]3[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=3)[S:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3ccoc3c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3ccoc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-(benzofuran-6-ylmethyl)sulfamoyl)benzoate (step-1 of Example 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=S)[N:19]([CH:24]([C:26]([O:28]CC)=O)[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:33][NH2:34]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:12])([O:13][C:14]2[CH:31]=[C:18]3[C:17](=[CH:16][CH:15]=2)[O:22][CH2:21][C:20]2[N:19]3[CH:24]([CH3:25])[C:26](=[O:28])[NH:33][N:34]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.095 g, 0.211 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.105 g, 2.109 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.064 g, 75%) as a white solid. LC/MS (Table 1, Method 2) Rt=1.143 min.; MS m/z: 403 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)N.N[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CN1CCN(CCCN)CC1
Agent: NS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Temperature: 150 °C

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (3.0 g) from Example 1, sulfamic acid (1.9 g), and 1-(3-aminopropyl)-4-methylpiperazine (15 mL) was heated to approximately 150° C. for 24 hours. After cooling, the residue was dissolved in water. The aqueous solution was made alkaline with a solution of saturated sodium bicarbonate and extracted with dichloromethane several times. The dichloromethane layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give 2.0 g of 6-(2,6-dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 474=M+ +C2H5, 446=M+ +H (Base); mp 208°-211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: BrCc1ccccc1Br
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(NCc2ccccc2Br)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-2-nitrobenzenamine (16.8 g, 0.1 mol) and 1-bromo-2-(bromomethyl)benzene (30 g, 0.12 mol) in CH3CN (700 mL) was added K2CO3 (27.6 g, 0.2 mol). The mixture was heated to reflux for 60 h then cooled to RT filtered and concentrated to dryness. The resulting residue was purified by FCC to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[S:13][C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]2[C:14](=[O:23])[C:15]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17].C(N(CC)CC)C.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CO>[CH:31]1([NH:37][C:20]([CH2:19][NH:18][C:16]([C:15]2[C:14](=[O:23])[N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]=4[S:13][C:4]3=[N:3][C:2]=2[OH:1])=[O:17])=[O:22])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)CNC(=O)c1c(O)nc2sc3c(n2c1=O)CCCCC3
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1c(O)nc2sc3c(n2c1=O)CCCCC3)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To the stirred suspension of [(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid (0.70 gm, 0.0020 mole) in dichloromethane (20 ml), triethylamine (0.85 ml, 0.0062 mole) and cyclohexylamine (0.29 ml, 0.0025 mole) were added. To the reaction mixture, hydroxybenzotriazole (0.28 gm, 0.0020 mole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.60 gm, 0.0031 mole) were added and stirred at room temperature for 12 hrs. Dichloromethane was distilled off and 1N hydrochloric acid (50 ml) was added to the residue, the separated solid was collected by filtration. The solid thus obtained was stirred in methanol (20 ml) at 60° C. for 0.5 hr, filtered and suck dried to give 0.60 gm title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: Cc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(CC(=O)N2CC3C(=O)CCC(c4ccccc4)(c4ccccc4)C3C2)c1
Reaction time: 0.58 h
Yield: 46.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(3-methylphenyl)acetic acid (1.05 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 35 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized by dissolving in boiling ethyl acetate (10 cc). The crystals are drained, dried and recrystallized from a mixture of acetonitrile (8 cc) and isopropyl ether (7.5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(3-methylphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.37 g) melting at 184° C. is obtained.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[C:14]3[N:15]=[C:16]([NH:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[N:36]=1.O>CN1CCCC1=O>[CH3:41][C:37]1[N:38]=[C:39]([N:22]2[CH2:21][CH2:20][CH:19]([NH:18][C:16]3[S:17][C:13]4[CH2:12][CH2:11][CH2:10][CH:9]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[C:14]=4[N:15]=3)[CH2:24][CH2:23]2)[CH:40]=[CH:35][N:36]=1
Reactant: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Reactant: Cc1nccc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nccc(N2CCC(Nc3nc4c(s3)CCCC4c3ccccc3)CC2)n1
Temperature: 200 °C

Procedure:
(4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidin-4-yl-amine dihydrochloride (115.9 mg, 0.3 mmol) was dissolved in N-methylpyrrolidone (3 mL). N,N-diisopropylethylamine (165 1, 0.96 mmol) and 4-chloro-2-methylpyrimidine (44.7 mg, 0.33 mmol) were added at room temperature under nitrogen and stirring. The reaction was heated in a microwave oven to 200° C. for 30 minutes. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from EtOAc to EtOAc/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a light yellow viscous oil (34 mg, 28%).
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.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=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:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: NCCc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(phenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-aminoethylbenzene, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: S([O-])(=O)(=O)C.[CH3:6][O:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][OH:15].[CH3:19][O:20][C:21]([CH3:31])([CH3:30])[CH2:22][CH2:23][CH2:24][C:25]([CH3:29])=[CH:26][CH2:27][OH:28].COC(C)(C)CCCC(O)C.[CH2:43]([C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1)[CH3:44]>>[CH2:26]([C:25]1[CH:31]=[CH:21][C:22]([O:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH2:11][CH2:10][CH2:9][C:8]([O:7][CH3:6])([CH3:17])[CH3:18])=[CH:23][CH:24]=1)[CH3:27].[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([O:28][CH2:27][CH:26]=[C:25]([CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([O:20][CH3:19])([CH3:31])[CH3:30])=[CH:47][CH:46]=1)[CH3:44]
Reactant: CCc1ccc(O)cc1
Reactant: COC(C)(C)CCCC(C)CCO
Reactant: COC(C)(C)CCCC(C)=CCO
Agent: COC(C)(C)CCCC(C)O
Agent: CS(=O)(=O)[O-]
Product: CCc1ccc(OCC=C(C)CCCC(C)(C)OC)cc1
Product: CCc1ccc(OCCC(C)CCCC(C)(C)OC)cc1

Procedure:
The mesylate of each of 7-methoxy-3,7-dimethyloctan-1-ol, 7-methoxy-3,7-dimethyloct-2-en-1-ol and 6-methoxy-6-methylheptan-2-ol is reacted with p-ethylphenol using the process of Example 10(D) to yield 7-methoxy-3,7-dimethyloctyl p-ethylphenyl ether, 7-methoxy-3,7-dimethyloct-2-enyl p-ethylphenyl ether and 6-methoxy-6-methylhept-2-yl p-phenyl ether (5-methoxy-1,5-dimethylhexyl p-ethylphenyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9](=[O:31])[C@H:10]2[CH2:14][C@H:13]([O:15]C=O)[CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:31])[C@H:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:32][CH:33]=1
Reactant: COc1ccc(COC(=O)[C@H]2C[C@H](OC=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)[C@H]2C[C@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
215 mg of trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-proline p-methoxybenzyl ester was dissolved in 1.1 ml of tetrahydrofuran, and 0.93 ml of a 1N aqueous solution of sodium hydroxide was added to the resulting solution. After stirring for 10 minutes, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and distilled off to remove the solvent. The resulting residue was purified by silica gel thin layer chromatography to obtain trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline p-methoxybenzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Zn]I)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>C1COCC1.Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1([C:17]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc([Zn]I)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC2)cc1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
(4-Ethoxycarbonylphenyl)-iodo-zinc (20 mL of 0.5 M in THF, 10.0 mmol) was added over 10 min to dichloro-bis(triphenylphosphoranyl)palladium (211 mg, 0.3 mmol) in THF (20 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes, cyclopropanecarbonyl chloride (941 mg, 817 μL, 9.0 mmol) was added dropwise at 0° C. and stirred for 2 hours. The reaction mixture was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×50 mL). The organic layer was washed sequentially with sat. aq. NaHCO3 (5 mL) and brine solution (50 mL), dried over MgSO4 and purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give ethyl 4-(cyclopropanecarbonyl)benzoate (1.54 g, 71%) as a pale yellow oil. ESI-MS m/z calc. 218.0. Found 219.3 (M+1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:15]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[NH2:15][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:13]
Reactant: CN1CCOCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (1 g, 0.005 mol) in THF at 0° C. was added 4-methylmorpholine (0.588 g, 0.00581 mol) followed by dropwise addition of isobutyl chloroformate (0.794 g, 0.00581 mol) over 2 min. The reaction was stirred at 0° C. for 30 min. after which a solution of 30 wt. % ammonium hydroxide (12.0 mL, 0.0925 mol) was quickly poured into the reaction. The reaction was warmed to room temperature and stirred for 5 h. The reaction mixture was concentrated. Water was added and the mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford the crude product which was directly used in the next step reaction without further purification (800 mg, 80%). 1H-NMR (300 MHz, DMSO-d6): 12.40 (s, 1H), 7.10 (d, J=7.0 Hz, 1H), 3.88 (m, 1H), 1.35 (s, 9H), 1.20 (d, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[C:30]([CH3:37])[CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[CH3:37][C:30]1[CH:29]=[C:28]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]4[CH:10]=[C:11]5[C:6]([CH:5]=[CH:4][N:3]5[CH2:1][CH3:2])=[CH:7][CH:8]=4)=[CH:15][N:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)c(C)c5)CC4)nc3)cc21

Procedure:
2-methyl-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-2-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H29N5O3 (m/e) 483, obsd 484 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:3])=[O:14])=[O:8]
Reactant: O=C(CCl)Nc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Yield: 80 %

Procedure:
To a warm (55°-60° C.) solution of 250 ml. of thionyl chloride and 50 ml. of chloroform and 6 drops of pyridine is added 3-(chloroacetylamino)benzoic acid (150 g., 0.702 mole) in 3 equal portions at 0.5 hr. intervals. After the addition is complete, the reaction mixture is warmed to a temperature of 55°-65° C. for 2 hrs., cooled and diluted with 500 ml. of petroleum ether (b.p. 30°-60° C.). The precipitate which forms is collected, washed with petroleum ether (b.p. 30°-60° C.) and dried under vacuum over potassium hydroxide at room temperature to afford 143 g. (80% yield) of 3-(chloroacetylamino)benzoyl chloride, m.p. 106°-108° C.