Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:26]([CH3:28])[CH3:27]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:26]([CH3:28])[CH3:27])[CH2:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:17][C:18]([C:33]([F:36])([F:35])[F:34])([OH:32])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO.O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([C:33]([F:34])([F:35])[F:36])([OH:32])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(COC(C)=O)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(COC(C)=O)ccc12)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution that consists of 170 mg (0.34 mmol) of 1-(2-(acetoxymethyl)quinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 1.5 ml of methanol and 0.8 ml of tetrahydrofuran is mixed with 53 mg (1.38 mmol) of sodium borohydride. After 3 hours at room temperature, the reaction is halted by adding water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried on sodium sulfate. After removal of the solvent and chromatography on silica gel with hexane-ethyl acetate (0-100%), 94 mg (55% of theory) of the product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH2:21][O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:30][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 7.88 g (0.025 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml toluene was heated under nitrogen until a solution resulted. Then there was added 39.6 g (0.250 mole) of ethyl N-piperazinocarboxylate followed by 14.2g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was taken up in 25 ml of hot methanol from which 8.5 g (75%) of product crystallized. Recrystallization from ethyl acetate gave the analytical sample, mp 128°-131° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:4].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34].C(N(CC)CC)C>COC(O)C>[CH3:30][O:31][C:32]([CH2:33][NH:34][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:4])=[O:35]
Reactant: CCOC(=O)c1cc2c(NC(=O)CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CN
Agent: COC(C)O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(NC(=O)CNCC(=O)OC)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
Ethyl 4-chloroacetamido-N-(3,4-dichlorobenzyl)indole-2-carboxylate (0.4 g), glycine methyl ester hydrochloride (0.57 g) and triethylamine (1.25 ml) were dissolved in methoxyethanol (4.0 ml) and the reaction heated at 100° C. for 6 hours. The reaction was cooled and partitioned between water and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated and the residue purified by chromatography using toluene:ethyl acetate (1:1) as eluent to give the product, ethyl 4-[(N-(methoxycarbonylmethyl)glycyl)amino]-N-(3,4-dichlorobenzyl)indole-2-carboxylate, as a pale yellow solid (0.17 g, 38%); NMR d (CD3SOCD3) 1.28 (t, 3H), 3.44 (s, 2H), 3.50 (s, 2H), 3.63 (s, 3H), 4.28 (q, 2H), 5.82 (s, 2H), 6.88 (dd, 1H), 7.10-7.30 (m, 4H), 7.50 (d, 1H), 7.69 (s, 1H), 7.80 (dd, 1H), 10.00 (brs, 1H); M/z (+) 494, 492 (M+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([O-:29])=[CH:27][CH:26]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([O:29][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[O:6][CH2:7][C:8]#[N:9])=[CH:27][CH:26]=1
Reactant: N#CCOc1cccc(CCl)c1
Reactant: [O-]c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCOc1cccc(COc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of α-(3-chloromethylphenoxy)acetonitrile (0.025 mol), sodium 4-(2-quinolinylmethyloxy)phenoxide (0.025 mol) and anhydrous potassium carbonate (0.125 mol) in dimethylsulfoxide (50 ml) is stirred at ambient temperature for 18 hrs. The reaction is diluted with water (600 ml) and extracted with ethylacetate (3×150 ml). The ethyl acetate solution is washed with water (3×100 ml) and brine (100 ml) then dried and evaporated to give α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile. (M.P. 110°-114° C.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13](I)[CH:14]=[CH:15][CH:16]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:19])([F:18])[F:9])[CH:16]=2)[CH:7]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: Cc1ccc(=O)n(-c2cccc(C(F)(F)F)c2)c1
Yield: 78 %

Procedure:
The reaction of 5-methyl-2-(1H)-pyridone with -3-trifluoromethyl-iodobenzene by the procedure of Example 1, gives a 78% yield of 5-methyl-1-(3'-trifluoromethylphenyl)-2-(1H)-pyridone.
Reaction SMILES: [C:1]([OH:13])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([NH:36][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(O)c(O)c1)NCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 5 ml of tetrahydrofuran containing 180 mg of caffeic acid were added 206 mg of dicyclohexyl carbodiimide and 107 mg of benzylamine. The mixture was stirred at 50° C. for 6 hours and then filtrated. The filtrate was concentrated and the residue obtained was recrystallized from ethyl acetate/hexane to give 100 mg of granular crystals.
Reaction SMILES: C(O)[C:2](N)([CH2:5][OH:6])CO.Cl.C(S)[C@@H](O)[C@H]([OH:15])CS.[CH2:18]([N:29]([CH2:34]C(O)=O)CC(O)=O)[CH2:19][N:20](CC(O)=O)CC(O)=O>>[CH:19]1[N:20]=[CH:34][NH:29][C:18]=1[CH2:2][C:5]([OH:6])=[O:15]
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: NC(CO)(CO)CO
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: Cl
Product: O=C(O)Cc1cnc[nH]1

Procedure:
The cell pellet was homogenized in 6 volumes 0.1 M Tris-HCl pH 8, 0.2 M NaCl, 5 mM DTT, 1 mM EDTA, and Apo-2L was isolated from the soluble fraction by IMAC on a chelating hiTRAP column (Pharmacia) charged with nickel. The Apo-2L had a weak affinity for immobilized metal and could be eluted with low concentrations of imidazole. A final purification was obtained by cation exchange chromatography on a SP hiTRAP column (Pharmacia). Concentrations of purified Apo-2L variants were determined by absorbance measurements using an e280 of 1.4 mg−1 ml cm−1.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 100 °C

Procedure:
After weighing 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde to 50 ml of the mixture of formic acid and triethylamine prepared according to Example 1, the reaction mixture was heated to 100° C. during 1 hour and maintained at the same temperature for further 1 hour. Then the excess of formic acid and triethylamine was distilled off under reduced pressure of 2 kPa to give a distillate of 40 ml volume. The distillation residue was dissolved in 100 ml of chloroform and extracted with 50 ml of 1N sodium hydroxide solution. The chloroform phase was extracted with 2×100 ml of 1N sodium hydroxide solution. Thereafter Example 1 was followed to give a yield of 8.6 g (81.8%), m.p.: 96°-97° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][S:42](Cl)(=[O:44])=[O:43])([O-:34])=[O:33].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N+:32]([O-:34])=[O:33])(=[O:43])=[O:44]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. (2-nitrophenyl)methansulfonyl chloride (12 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-(2-nitrophenyl)methansulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.OC(C(F)(F)F)=O.[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57](OC(C)(C)C)=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:47]5[CH2:48][CH2:49][CH:43]4[CH2:44][N:45]([CH3:50])[CH2:46]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:64][CH:65]([S:67]([NH2:70])(=[O:69])=[O:68])[CH3:66].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57]([NH:70][S:67]([CH:65]([CH3:66])[CH3:64])(=[O:69])=[O:68])=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:43]5[CH2:49][CH2:48][CH:47]4[CH2:46][N:45]([CH3:50])[CH2:44]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: CC(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Temperature: 60 °C
Yield: 14.7 %

Procedure:
CDI (80 mg, 0.49 mmol) was added to a solution of tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate TFA (200 mg, 0.30 mmol) in THF (1.5 mL) and the reaction mixture was heated at 60° C. for 2 h. The reaction was cooled to rt and then ⅓ (˜0.55 mL) of the reaction solution was added to a stirring solution of propane-2-sulfonamide (40 mg, 0.33 mmol) in DBU (0.20 mL, 1.3 mmol) and THF (0.20 mL). The reaction was stirred at rt ON (complete by LCMS), concentrated to an oil, quenched with 1N HCl (˜1 mL) (prec. formed) and extracted with EtOAc (2×1 mL). The combined organics wee concentrated to dryness, dissolved into MeOH (1.5 mL) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (28.5 mg, 0.044 mmol, 43% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ ppm 1.13-2.77 (m, 28H), 2.80-2.93 (m, 1H), 3.93 (s, 3H), 3.90-4.02 (m, 1H), 4.27-4.65 (m, 2H), 5.11-5.31 (m, 1H), 7.04 (s, 1H), 7.11 (d, J=2.6 Hz, 1H), 7.16 (dd, J=8.4, 2.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.67 (dd, J=8.4, 1.5 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 8.18 (br s, 1H). LC-MS retention time: 2.55 min; m/z 643 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[CH:9]1([NH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CCCCCl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCl)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 5-chlorovaleryl chloride (50.0 g, 0.322 mol) in dichloromethane (300 ml) at 0° C. was treated dropwise with a solution containing cyclohexylamine (31.68 g, 0.320 mol), triethylamine (32.32 g, 0.320 mol) and dimethylaminopyridine (0.02 g) in dichloromethane (300 ml). The resulting solution was stirred for 2 hours at 0° C. and then for an additional 16 hours at room temperature. The solution was diluted with dichloromethane (400 ml), washed with water (3×200ml), saturated aqueous sodium hydrogen carbonate (3×100 ml), saturated aqueous ammonium chloride (3×100 ml), and brine (2×100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to yield a crude product. The crude product was recrystallized from ethyl acetate-hexane to yield N-cyclohexyl-5-chloropentanamide as a colorless crystalline solid, having a melting point of 70°-71° C. and the following physical characteristics:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)(=[O:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[C:1]([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NCC1CNCCO1

Procedure:
2-Acetylaminomethyl-4-benzylmorpholine (120 g) is dissolved in a mixture of ethanol (1000 ml) and acetic acid (30 ml) and hydrogenated over 10% palladium on carbon (5 g) at about 60° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][C:13]1[O:14][CH:15]=[C:16]([CH3:18])[N:17]=1.C(Cl)Cl.CO>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][C:13]2[O:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: Cc1coc(N)n1
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: Cc1coc(NC(=S)Nc2ccc(Cl)cc2C)n1

Procedure:
Prepared using Method A from 4.04 g (22 mmol) of 4-chloro-2-methyl-phenyl isothiocyanate and 2.16 g (22 mmol) of 2-amino-4-methyloxazole to give 4.5 g of crude title compound. Pure title compound was obtained by flash chromatography (silica Merck 60, CH2Cl2—CH3OH, 19:1) and crystallization from CH3CN to give 2.12 g of the title compound as a yellow solid (72.5% yield, m.p. 214° C. with decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(C)=O.O>[CH3:1][N:2]([CH3:14])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1CCCNc2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Yield: 97.1 %

Procedure:
To a solution of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine (50 g) in a mixture of acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g), and thereto is added p-nitrobenzoyl chloride (40 g) with stirring under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction mixture is added an appropriate amount of water, and the precipitated crystals are collected by filtration and dried to give 5-dimethylamino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (71 g) as pale yellow powder, mp. 139°-142° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.N1CCNCC1.C(N)C1C=CC2OCOC=2C=1.[CH:28]1[CH:29]=[N:30][C:31]([NH:34][S:35]([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[CH:42][CH:43]=2)(=[O:37])=[O:36])=[N:32][CH:33]=1.[C:45](Cl)([Cl:47])=[S:46]>N1C=CC=CC=1.O1CCOCC1.ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[Cl-:47].[N:30]1[CH:29]=[CH:28][CH:33]=[N:32][C:31]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][CH:45]=[S:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Reactant: S=C(Cl)Cl
Agent: C1CNCCN1
Agent: NCc1ccc2c(c1)OCO2
Agent: c1ccc2ncncc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The synthesis of 4-piperazinylpyrimido[4,5-b]indoles (1b), benzofuranopyrimidines (2b), benzothieno[3,2-d]pyrimidines (3b), and quinazoline (4b) derivatives is depicted in FIG. 20. 4-Chloro-tricyclic and quinazoline building blocks (1a-4a) were synthesized using literature methods. (Pandey, A., et al., J. Med. Chem. 2002, 45:3772-93; Matsuno, K., et al., J. Med. Chem. 2002, 45:3057-66; Matsuno, K., et al., J. Med. Chem. 2002, 45:4513-23; and Venugopalan, B., et al., J. Heterocycl. Chem. 1988, 25:1633-39.) These were converted to the corresponding 4-piperazine derivatives by refluxing with piperazine in pyridine or dioxane. Piperonylamine or sulfadiazine were slowly added to a solution of thiophosgene in dichloromethane while cooling with an ice bath. The resulting mixture was stirred for four hours at room temperature, which gave 1c or 1d, as shown in FIG. 21. Compounds 1c or 1d were further reacted with 4-piperazine-substituted tricyclic or quinazoline derivatives in dichloromethane and stirred overnight at room temperature. To quench excess isothiocyanate, methanol was added, and after removal of solvent, the residue was purified by silica gel chromatography to give compounds 1-7 of FIG. 17 in approximately 20-40% yields.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O:21]C)=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1.[OH-].[Li+]>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([OH:21])=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1
Reactant: COC(=O)c1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nonc1-c1nc2cnc(Oc3cccc(C(=O)O)c3)cc2n1-c1ccccc1
Temperature: 65 °C
Yield: 93.9 %

Procedure:
The product from Step 8 (0.22 g, 0.514 mmol) in THF (10 mL) was treated with a solution of 1N lithium hydroxide in water (1.5 mL) and heated to 65° C. for 10 h. The reaction mixture was cooled and concentrated and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the organic layers were combined, washed with brine and dried over Na2SO4 and concentrated to give the title compound (0.20 g, 94%). MS (ES+) m/e 415 [M+H]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18].O>C(O)(C)(C)C>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Phosphorus oxychloride (363 g, 221 mL, 2.37 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (169 g, 0.79 mol) were added to a 1-L flask and heated at 90° C. for 5 h. The reaction mixture was cooled to 30° C. and added over 60 minutes into a 2-L jacketed reactor containing a well-stirred mixture of t-butanol (280 mL) and water (750 mL) while maintaining the temperature at 5-10° C. After the addition of the reaction mixture was about 70% complete, the aqueous t-butanol mixture was seeded to initiate crystallization, and the addition of the reaction mixture was continued. At the end of the addition, water (750 mL) was added gradually at 10-15° C., and the mixture was stirred for an additional 1 h. The resulting mixture was cooled to 5° C., filtered, and the collected solid was washed with water (3×50 mL). The resulting wet cake was dried in a vacuum-oven at 60° C. to give 156 g (85% yield) of the title compound as a solid melting at 126-127° C.