Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:12]([O:10][C:9]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][NH:3]1)=[O:11])[CH3:13]
Reactant: O=C(O)C1CNCCN1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CNCCN1
Yield: 26 %

Procedure:
A mixture of 2-piperazinecarboxylic acid dihydrochloride (5.06 g, 0.025 mol), ethanol (100 ml) and concentrated sulphuric acid (6.0 ml) was heated at reflux temperature for 6 days. Toluene (10 ml) was added, and the resulting mixture was concentrated in vacuo to 2/3 of its original volume. Cold, saturated aqueous potassium carbonate (80 ml) was added and the mixture was extracted with toluene (3×100 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo, affording 1.0 g (26%) of 2-piperazinecarboxylic acid ethyl ester as an oil. The oil crystallised upon standing at room temperature.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(SCC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 83 %

Procedure:
0.4 g (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.26 g (1.0 mmol) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 0.35 g (0.83 mmol, 83%) of 6-ethylsulfanyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 421 (M+1)+.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH3:31][C:32]1[C:33]([CH:38]=O)=[N:34][CH:35]=[CH:36][CH:37]=1.[C:40]([BH3-])#[N:41].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:41]([CH2:40][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:38][C:33]3[C:32]([CH3:31])=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: Cc1cccnc1C=O
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with the compound (36.3 mg) obtained in Example 53-1 and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (91.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:25][O:24][C:16]1[C:15]2[C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(CCCCc2ccc3c(c2)OCO3)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1cc3c(cc1CCCC2)OCO3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
In 1 ml of dichloromethane, 73 mg (0.21 mmol) of 1-(3,4-methylenedioxyphenyl)-4-(3,4,5-trimethoxyphenyl)butane were dissolved. The solution was added with 0.1 ml of trifluoroacetic acid and 190 mg (0.41 mmol) of ferric perchlorate, followed by stirring at room temperature for 20 minutes. The reaction mixture was dissolved in 20 ml of ethyl acetate. After the resulting solution was washed with 2N-HCl and then with saturated NaCl, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by TLC (silica gel: "MERCK #5744", eluent: 1:5 mixed solvent of ethyl acetate and hexane), whereby 9 mg of the title compound were obtained as colorless oil (yield: 12%). In addition, the starting material were recovered as colorless oil (13 mg, recovery: 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CCN(C(C)C)C(C)C.CN(C(O[N:50]1N=[N:57][C:52]2C=CC=N[C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CN>CN(C=O)C>[NH2:50][CH2:51][CH2:52][NH:57][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:12]=2)=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)O)c(Cl)c4)ccc3=O)ccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: NCCN
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)NCCN)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzoic acid (494 mg, 1093 μmol), DIEA (191 μL, 1093 μmol), and HATU (416 mg, 1093 μmol) in DMF (5 mL) was stirred at 23° C. for 15 minutes. This dark solution was then added to a second solution of ethylenediamine (730 μL, 10933 μmol) in DMF (2 mL). The reaction was then stirred overnight at 23° C. followed by a partition between 9:1 CHCl3/IPA (75 mL) and NaOH (1 M, 25 mL). The organic was separated, dried over MgSO4, then concentrated onto dry silica (15 g). The product was purified on silica (40 g) eluting with 10% 2 M NH3 in MeOH/DCM, and isolated as a fluffy lyophilized solid from 1:1 ACN/water. MS (ESI pos. ion) m/z: 494 (MH+); calc'd for C25H24ClN5O4: 493. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (t, J=6.27 Hz, 2H) 3.26 (q, J=6.02 Hz, 2 H) 3.87 (s, 3 H) 4.68 (d, J=4.52 Hz, 4 H) 6.95 (d, J=5.52 Hz, 1 H) 7.05 (dd, J=9.29, 2.26 Hz, 1 H) 7.13 (d, J=10.04 Hz, 1 H) 7.28 (d, J=2.01 Hz, 1 H) 7.51-7.58 (m, 1 H) 7.82-7.97 (m, 3 H) 8.13 (d, J=10.04 Hz, 1 H) 8.50 (t, J=5.27 Hz, 1 H) 8.62 (d, J=5.52 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)=[O:43]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([O:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:53][CH:54]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 220 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.104 mL of triethylamine in 4.0 mL of THF was added 127 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 264 mg of 4-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidine-1-carboxylate in the form of a colorless amorphous substance as a crude product. ESI+: 623
Reaction SMILES: [NH2:1][C:2]1[C:10](C)=[C:9](OC)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14](N)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:23](Cl)(=[O:30])C1C=CC=CC=1>>[CH3:23][O:30][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:6]=[C:4]2[OH:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Product: COc1cccc2c(O)nc(-c3ccccc3)nc12
Yield: 80 %

Procedure:
The general procedure described in Example 8 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and benzoyl chloride as acid chloride [B], which gave the title compound (2.0 g, 80%), [M+H]=253.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8](=[S:10])=[S:9]>C(O)(C)C>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:8](=[S:9])[SH:10])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: S=C=S
Solvent: CC(C)O
Product: CC(C)N(C(=S)S)C(C)C
Reaction time: 1 h

Procedure:
5′-(Diisopropyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole (i.e., formula (I) where X is hydrogen and R1 and R2 are isopropyl radicals) was prepared in the following manner. In 100 grams of isopropyl alcohol 20.5 grams of diisopropylamine was combined with 16 grams of carbon disulfide (CS2) and held at a temperature of about 27° C. for about 1 hour to yield a diisopropyl dithiocarbamic acid intermediate. Subsequently, 30 g of a 2,5-dimercapto-1,3,4-thiadiazole was added to the mixture along of 20 g of 35 wt. % hydrogen peroxide. The mixture was reacted for about 1 hour at a temperature of about 28° C. to yield the solid end product 5′-(diisopropyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole. The isopropyl alcohol was filtered off and saved for recovery.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH2:51])[CH2:45][CH2:46][CH3:47]>C(Cl)(Cl)Cl.O>[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH:51][C:36]([NH:20][C:19]1[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:24])=[O:42])[CH2:45][CH2:46][CH3:47]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCCN(CCN)CCCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (81 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (82 mg, yield 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=1.[Br:22]Br>CC(O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:21])=[N:11][CH:12]=[C:13]([C:19]=2[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([Br:22])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cnc(C)c(Oc2ccnc(N)c2)c1C
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C)c(Oc2cc(N)ncc2Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Ethyl 5-(2-aminopyridin-4-yloxy)-4,6-dimethylnicotinate (2.5 g, 8.7 mmol) in AcOH (30 mL) was charged with dropwise addition of bromine (1M in AcOH, 8.7 ml, 8.7 mmol). The solution was stirred at ambient temperature for 30 minutes. The solution was then concentrated and neutralized with saturated NaHCO3 solution. The material was then extracted with EtOAc and the organic layer was dried, and concentrated. Flash chromatography gave the title compound (1.88 g, 59%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-])=O)[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2].NN>CO.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Agent: [Pd]
Agent: NN
Solvent: CO
Product: N#Cc1cc(N)cc2cc[nH]c12
Yield: 100.9 %

Procedure:
A solution of 7-cyano-5-nitroindole (1.5 g, 8.2 mmol), hydrazine (1.0 mL, 31.2 mmol) and 10% Pd/C (20 mg) in 30 mL of MeOH was stirred a: reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo to provide 1.3 g (>95%) of the amine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]CC(=O)C(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:34][C:35]1([CH3:42])[CH2:40][NH:39][C:38](=[S:41])[NH:37][CH2:36]1>CC(C)=O>[BrH:17].[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2([OH:10])[N:39]3[CH2:40][C:35]([CH3:42])([CH3:34])[CH2:36][N:37]=[C:38]3[S:41][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: CC1(C)CNC(=S)NC1
Solvent: CC(C)=O
Product: Br
Product: CC1(C)CN=C2SCC(O)(C(c3ccccc3)c3ccccc3)N2C1
Reaction time: 24 h

Procedure:
A 2.1 g. portion of 1,1-diphenyl-2-propanone is converted to 1-bromo-3,3-diphenyl-2-propanone as described in Example 22. This 1-bromo-3,3-diphenyl-2-propanone is dissolved in 15 ml. of acetone and added to a boiling mixture of 1.0 g. of tetrahydro-5,5-dimethyl-2(1H)-pyrimidinethione in 50 ml. of acetone. The mixture is allowed to stand at room temperature for 24 hours and the resulting solid is collected by filtration, giving the desired product, m.p. 259°-261° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[CH2:18]([CH2:22][C:23](=O)[CH3:24])[C:19]([CH3:21])=O>C(O)C>[CH:11]1([C:4]2[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]3[C:23]([CH3:24])=[CH:22][CH:18]=[C:19]3[CH3:21])[N:3]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)c1[nH]c(C2CC2)nc1N
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1[nH]c(C2CC2)nc1-n1c(C)ccc1C
Yield: 95.6 %

Procedure:
A suspension of methyl 4-amino-2-cyclopropylimidazole-5-carboxylate (Example 40, 5.72 g, 0.032 mol) in ethanol (40 mL) was treated with acetic acid (25 mL) and the mixture refluxed to effect solution. To the hot solution was added acetonylacetone (5.41 g, 0.047 mol) and the whole stirred and refluxed for 18 hours. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2 to afford 7.93 g of the title compound methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole-5-carboxylate. 1H-NMR (CDCl3) 5.85 (s, 2H), 3.68 (s, 3H), 2.0 (s, 6H), 1.80-2.0 (m, 1H), 1.0-1.18 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][CH2:22][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13]
Reactant: ClCCCI
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (1.21 g, 5.52 mmol) was added to a suspension of sodium amide (0.59 g, 14.4 mmol) in toluene (12 ml). The mixture was then heated to reflux for 2 hours before the addition of 1-chloro-3-iodopropane (0.9 ml, 8.3 mmol). The mixture was cooled to room temperature over 80 minutes, and worked up by addition of water. The product was extracted with methyl-t-butyl ether (MTBE). After usual work-up, including drying the organic extract using MgSO4 and concentrating under reduced pressure the product was purified on column chromatography eluting with (ethyl acetate: light petroleum (b.p. 40 -60° C.) =1:2), to give 1.4g (82% yield) of the required product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[OH:11]
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)cc1O

Procedure:
To a mixture of 4-chlorosalicylic acid (16 g, 92.6 mmol) in MeOH (210 mL) was added conc. HCl solution (5 mL). The resultant solution was refluxed for 23 h. After cooled, solid NaHCO3 was added to neutralize the mixture and then was concentrated. The slurry was suspended in EtOAc and filtered through a silica gel plug, washing with EtOAc. The filtrate was washed with ¼ saturated NaHCO3 solution (2×), brine, dried over Na2SO4, filtered and concentrated to provide the title compound (17.2 g). MS ESI(−) m/e: 185.0 (M−1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.C(Cl)Cl.C1N=CN([C:38](N2C=NC=C2)=[O:39])C=1.[NH:45]1[CH2:51][CH2:50][CH2:49][C@H:46]1[CH2:47][OH:48]>>[OH:48][CH2:47][C@@H:46]1[CH2:49][CH2:50][CH2:51][N:45]1[C:38]([O:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1)=[O:39]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H]1C[C@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCC[C@H]2CO)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (0.050 g, 0.00012 mol) in methylene chloride (1.00 mL, 0.0156 mol) was added N,N-carbonyldiimidazole (0.024 g, 0.0001480 mol). The reaction was stirred at rt for 2 h. To the resultant mixture was added L-prolinol (0.01704 mL, 0.0001726 mol) and the reaction was stirred at rt overnight. The mixture was concentrated to dry in vacuo and used directly in next step. MS (ESI): (M+H)+=533.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH:15]([C:21]([O-])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C=O.N1CCCCC1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH2:14][C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCS(=O)(=O)c1ccc(OC)cc1)C(=O)[O-]
Agent: C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: C=C(CCCS(=O)(=O)c1ccc(OC)cc1)C(=O)OCC

Procedure:
A mixture of 3-(4-methoxybenzenesulfonyl)-propylmalonic acid, monoethyl ester (1.1 g, 3.2 mmol), paraformaldehyde (0.11 g, 3.5 mmol), piperidine (0.03 mL, 0.32 mmol), and pyridine (20 mL) is refluxed for three hours. The mixture is transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine, and the organic phase is concentrated in vacuo to yield the title compound as a clear, colorless oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[N:42]=[CH:41][CH:40]=[CH:39][C:35]=3[C:36]([OH:38])=O)=[CH:32][C:27]=2[O:26][CH2:25]1.C(N(CC)C(C)C)(C)C.[CH3:52][O:53][C:54](=[O:64])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=1>ClCCl.O>[CH3:52][O:53][C:54](=[O:64])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:36]([C:35]2[C:34]([O:33][C:31]3[CH:30]=[CH:29][C:28]4[O:24][CH2:25][O:26][C:27]=4[CH:32]=3)=[N:42][CH:41]=[CH:40][CH:39]=2)=[O:38])=[CH:58][CH:57]=1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: COC(=O)Cc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.71 g), 1-hydoxybenzo-triazole hydrate (1.24 g), and 2-(benzo[1,3]dioxol-5-yloxy)-nicotinic acid were combined and suspended in anhydrous dichloromethane (40 mL). N,N-diisopropylethylamine (5.93 mL) was added to the suspension, which was stirred for 0.5 h. The suspension was added to (4-aminomethyl-phenyl)-acetic acid methyl ester (1.22 g) and the reaction mixture stirred at ambient temperature overnight. Water (approx. 15 mL) was then added to the reaction mixture, and it was extracted with dichloromethane (7×30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate:hexanes=3:2) to yield the title compound (1.41 g).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.Br[CH2:16][C:17]([NH2:19])=[O:18]>>[Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][N:13]([CH2:16][C:17]([NH2:19])=[O:18])[CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)CBr
Reactant: Brc1cccc2c1C[C@@H]1CNCCN21
Product: NC(=O)CN1CCN2c3cccc(Br)c3C[C@@H]2C1

Procedure:
The title compound, MS: m/e=310.1 (M+H+) was prepared in accordance with the general method of example 6 from (10aR)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and 2-bromoacetamide.