Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:10]1[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
To a solution of (S)-methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)-methyl)phenoxy)methyl)-2-methoxybenzoate (0.90 g, 1.89 mmol) in a mixture of THF (9 mL) and methanol (9 mL) was added aqueous 2 M sodium hydroxide (9 mL). The reaction mixture was stirred at RT for 18 hours. 10% aqueous citric acid was added to the reaction mixture to pH 3. The mixture was extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (0.82 g, 87%).
Reaction SMILES: FC1C([O:8][C:9](=O)[CH2:10][NH:11]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C.[NH2:43][CH2:44][C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46]>CN(C=O)C>[NH2:11][CH2:10][C:9]([NH:43][CH2:44][C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[CH2:60][CH:61]([CH3:62])[CH3:63])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])=[O:8]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN)C(=O)O
Reaction time: 3 h

Procedure:
Fmoc-glycine pentafluorophenyl ester (46 mg, 0.1 mmol) is dissolved in anhydrous DMF (1 mL) containing DIEA (17 μL, 0.1 mmol). About 0.5-1.0 mL of this solution is added to Gly-L-Phe-L-Leu ELAMS™ in a test tube and the tube vortexed for about 3 hours. The ELAMS™ are pelleted and washed with DMF (4×) and methylene chloride (2×). Deprotection can be effected by treatment with a solution of 20% piperidine in DMF for 30 min. The ELAMS™ are then washed with DMF (2×), ethanol (2×) and methylene chloride (2×) and dried at 60° C. for 4 hours. The identifier tag for each ELAMS™ is detected and recorded.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[NH:29])[NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:16]([NH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[NH:29])=[O:17])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
750 mg of 4-t-butoxycarbonyl-1-(4-nitrobenzyloxycarbonylamidino)piperazine [prepared as described in step (b) above] were dissolved in 10 ml of trifluoroacetic acid, and the resulting solution was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was dissolved in a mixture of ethyl acetate and water, and an aqueous solution of sodium hydrogencarbonate was added thereto to make the mixture alkaline. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate three times. The ethyl acetate layer and all of the ethyl acetate washings were combined and concentrated by evaporation under reduced pressure, to obtain 530 mg of the title compound, as a powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[N:23]1C=CC=C[CH:24]=1.Cl>C(Cl)(Cl)Cl>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:23]
Reactant: c1ccncc1
Reactant: CCOC(=O)Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc2occ(-c3ccc(C#N)cc3)c2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 99 g. (0.29 mole) of the known (Belgian Pat. No. 846,502, Example 22) compound ethyl 3-(4-bromophenyl)benzofuran-5-acetate in 40 g. of cuprous cyanide in 30 ml. of pyridine is heated at 160°-175 C. with stirring under a nitrogen atmosphere for 20 hours. To this solution is added 200 g. of ferric chloride, 100 ml. of concentrated hydrochloric acid, and 200 ml. of ice water with rapid stirring. Next, 300 ml. of chloroform is added, and the mixture is stirred for one hour, then filtered, and the insoluble material is extracted several times with chloroform. The combined chloroform extracts are dried and evaporated to provide a residue. The residue is recrystallized from a N,N-dimethyl formamide-water mixture to provide ethyl 3-(4-cyanophenyl)benzofuran-5-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=O.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]1[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[N:6]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(F)cc1Cl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(F)cc2Cl)=N1

Procedure:
Reaction of 2-chloro-4-fluoro-N-(1-hydroxy-2-methyl-2-propyl)benzamide and thionyl chloride by the method described in Example 1b provides 2(2-chloro-4-fluorophenyl)-4,4-dimethyl-2-oxazoline as a liquid; hydrochloride salt, m.p. 138°-139°.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[C:9]([CH3:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd]>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[C:9]([CH3:27])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: [Pd]
Product: Cc1cc(C2CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Yield: 55.5 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)C12-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Reactant: CNc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3Cl)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-chloroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 168bp. 1H (500 MHz, CDCl3) δ 7.53 (d, J=7.7 Hz, 1H), 7.35-7.41 (m, 3H), 6.97 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 6.56 (s, 1H), 5.00 (s, 2H), 3.39 (s, 3H), 2.26 (s, 3H). LCMS (ESI) m/z: 370.1
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:33]=[CH:32][C:31]([C:34]([O:36]CC)=[O:35])=[N:30][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][C:22](=[O:29])[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:41]>O1CCCC1.CO>[ClH:41].[ClH:41].[CH:1]1([C:7]2[C:8]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[N:30][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][C:22](=[O:29])[N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCN(CC(=O)N1CCOCC1)c1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCN(CC(=O)N1CCOCC1)c1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of ethyl 12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (62 mg, 0.12 mmol) in tetrahydrofuran (3 ml) and methanol (3 ml) was added 4N aqueous sodium hydroxide solution (1.5 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. 2N Hydrochloric acid (3 ml) was added to the reaction mixture to adjust to pH 7, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (chloroform:methanol=8:1) and the solvent was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (1 ml) was added 4N HCl-ethyl acetate solution (1 ml) and the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the precipitated solid was collected by filtration, washed with hexane and dried in vacuo to give 12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride (20 mg, yield 30%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH:23]([C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)[OH:24]>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:21][CH2:22][CH:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[OH:24])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Reactant: NCC(O)c1ccco1
Product: CC(C)(C(=O)NCC(O)c1ccco1)c1ccc(-c2cncc(C#N)c2)cc1
Yield: 75 %

Procedure:
Prepared in a similar manner to Example 3 starting from 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid (example 21a) and 2-amino-1-(furan-2-yl)ethanol. Yield: 75%. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 6H), 3.26 (m, 1H), 3.41 (m, 1H), 4.63 (t, 1H), 5.45 (br-s, 1H), 6.21-6.22 (d, 1H), 6.35 (t, 1H), 7.34 (t, 3H), 7.35-7.37 (dd, 2H), 7.54-7.55 (d, 1H), 7.71-7.73 (dd, 2H), 8.61 (t, 1H), 8.97-8.98 (d, 1H), 9.15-9.16 (d, 1H). MS (M+H, 358).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=O.Cl.[NH2:25]/[C:26](/[NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=[N:27]/[H].[O-]CC.[Na+]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:27]=[C:26]([NH:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)[N:25]=2)[CH:13]=[CH:12][S:11]3)[CH:20]=[CH:19][CH:18]=1
Reactant: [H]/N=C(/N)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COc1cccc(-c2nc3sccn3c2C(=O)C=CN(C)C)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)c1
Yield: 92.9 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (5.0 g, 15.3 mmol) and tert-butyl (3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (5.28 g, 18.95 mmol) is diluted with 60 ml of absolute ethanol and treated with 1.15 eq. of a 21% w/w solution of sodium ethoxide in ethanol (6.56 ml) to form a reaction mixture. The reaction mixture is heated to reflux for 24 hours. Volatiles are removed in vacuo and the residue is taken up in 250 ml of ethyl acetate and 250 ml of water. The phases are separated and the aqueous phase is extracted with 250 ml of ethyl acetate. The combined organic extracts are washed with 250 ml each of water, and then with a saturated sodium chloride solution (250 ml). The organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo, to give a yellow oil. The product is purified by flash chromatography on silica gel (ethyl acetate/hexanes, 50%) to yield 7.2 g of a pale yellow solid (93%). 300 MHz 1H NMR (DMSO-d6 at 80° C.) δ: 8.69 (d, J=3.5 Hz, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.32-7.41 (m, 2H), 7.12-7.18 (m, 2H), 6.91-7.02 (m, 2H) 6.41 (d, J=5.3 Hz, 1H), 3.94 (br. d, J=7.0, 1H), 3.74-3.88 (m, 1H), 3.78 (s, 3H), 3.67 (br. d, J=13.2, 1H), 2.86-3.02 (m, 2H), 1.90-2.06 (m, 1H), 1.70-1.84 (m, 1H), 1.38-1.64 (m, 2H), 1.34 (s, 9H). LCMS: 507 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:17])[C:8]2=[CH:18][CH:19]=[CH:20][N:7]2[N:6]=1.[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:29]([S:36][CH2:2][CH2:3][C@H:4]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:17])[C:8]2=[CH:18][CH:19]=[CH:20][N:7]2[N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCBr)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](CCSCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 81.5 %

Procedure:
(S)-tert-Butyl (3-bromo-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (45 mg, 0.03 mmol) was treated with benzyl hydrosulfide (7 μl, 0.06 mmol) and potassium carbonate (6 mg, 0.05 mmol) according to the method described in Preparation 31. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 12 mg (81% yield) of the title compound. Purity 70%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([NH2:16])(=[O:15])[CH3:14]>>[C:13]([NH:16][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: COC(=O)c1cc(C)nc(NC(C)=O)n1
Yield: 68 %

Procedure:
The title compound is prepared in 68% yield (0.76 g, a yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol) and acetamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Yield: 5.1 %

Procedure:
10 g of 2,6-diacetylpyridine (0.0613 mol), 9.54 g of 2-chloro-4,6-dimethylaniline (0.0613 mol) and 0.6 g of p-toluenesulfonic acid were heated under reflux on a water separator in 400 ml of methanol for 90 min. The solvent was distilled off completely and the residue was recrystallized twice from 50 ml of isopropanol. 0.92 g (0.0031 mol) of 1-{6-[1-(2-chloro-4,6-dimethyl-phenylimino)ethyl]pyridin-2-yl}ethanone was obtained in a yield of 5%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][O:21][CH2:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH2:22][O:21][CH3:20])[CH2:28]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: COCC1CNCCN1
Solvent: c1ccncc1
Product: COCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 46.3 %

Procedure:
A mixture of 0.6 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.4 g of 2-(methoxymethyl)piperazine in 4 ml of pyridine was heated at 120°-130° C. under argon in a pressure bottle for 18 hours. The solvent was removed and the residue was chromatographed and the crude product triturated with methanol and ether, giving 370 mg of the desired product as white crystals, mp 215°-216° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.O.NN>CO>[NH2:3][CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)n1C
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CN)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
650 mg of methyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]-1-methyl-1H-pyrrole-2-carboxylate was dissolved in 20.0 mL of methanol, and 109 mg of hydrazine monohydrate was added thereto, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, to the obtained residue was added chloroform, and the insolubles were filtered off. Then, the filtrate was concentrated under reduced pressure to obtain 294 mg of methyl 5-(aminomethyl)-1-methyl-1H-pyrrole-2-carboxylate.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:21])[CH2:7][C@H:8]([CH3:20])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)=[O:10].C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.[NH4+]>C1COCC1>[NH2:17][C:13]1[CH:12]=[C:11]([C@@:9]([OH:10])([CH2:1][CH3:2])[C@@H:8]([CH3:20])[CH2:7][N:6]([CH3:21])[CH3:5])[CH:16]=[CH:15][CH:14]=1
Reactant: CC[Mg]Br
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)([O-])O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@](O)(c1cccc(N)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
726 ml of ethylmagnesium bromide (1M in THF; 0.726 mol) are added under a nitrogen flow into a 2-liter four-neck flask, provided with mechanical stirrer, thermometer and dropping funnel. A solution of (S)-3-(dimethylamino)-2-methyl-1-(3-nitro-phenyl)-propan-1-one (50 g, 0.242 mol) in 50 ml of THF are dripped maintaining the temperature between 15-30° C. The reaction is stirred at room temperature for 3 hours. It is cooled to about 10° C. and toluene (200 ml) and slowly a 20% ammonium hydrogen sulphate solution (200 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The organic phase is concentrated under vacuum almost to oily residue. Then toluene (200 ml), 30% sodium metabisulfite solution (300 ml) are added. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is washed 2 times with 200 ml of toluene. The organic phases are eliminated while Cert-butylmethylether (200 ml) is added to the aqueous phase. The pH of the mixture is brought to 11-12 with 28% sodium hydroxide. The mixture is stirred for 30 minutes and the phases are separated after about 15 minutes of rest. The aqueous phase is eliminated while the organic phase is concentrated under vacuum to oily residue which solidifies by cooling. 35 g of a yellowish solid with a 95% HPLC purity are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[O:4].[CH:6]1[CH:7]=[CH:8][C:9]2N[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:13]=[CH:12][C:10]=2[CH:11]=1>C(O)(=O)C>[CH:6]1[CH:7]=[CH:8][C:9]2[N:2]([C:3]([NH2:5])=[O:4])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:10]=2[CH:11]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: NC(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea hydrochloride (100 g, 1.036 mols) in acetic acid (125 ml), iminostilbene (25 g, 0.129 mols) was added under stirring at 25-30° C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.