Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][C@@H:10]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][N:8]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:24]([O:23][C:21]([N:8]1[CH2:9][C@H:10]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@H:7]1[C:6]([OH:28])=[O:5])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: COC(=O)[C@@H]1C[C@@H](CNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Lithium hydroxide monohydrate (29 mg) was added to a stirred solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline methyl ester (C, 204 mg) in tetrahydrofuran (1 mL)-methanol (1 mL)-water (1 mL) at 0° C. The mixture was stirred at room temperature for 4 hr. The reaction mixture was acidified with 10% citric acid and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (167 mg).
Reaction SMILES: [ClH:1].C[N+:3]1(C2N=C(OC)N=C(OC)N=2)[CH2:8][CH2:7][O:6]CC1.[Cl-].[N+]([O-])([O-])=[O:21].[Na+:24].C(O)(C)C.[CH3:29][S:30]([CH3:32])=[O:31]>O>[C:7]([OH:21])(=[O:6])[CH3:8].[NH3:3].[CH3:29][S:30]([CH3:32])=[O:31].[Na+:24].[Cl-:1]
Reactant: O=[N+]([O-])[O-]
Reactant: Cl
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)O
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HA-TBA prepared in Example 2-2 using HA-Na (50 kDa) as a starting material was dissolved at 10 mg/mL in anhydrous DMSO. Thereafter, the Chol-C2 hydrochloride prepared in Example 1-2 was added to each solution at the ratio relative to HA-TBA units indicated in Table 2 below. Then, DMT-MM was added at the ratio relative to HA-TBA units indicated in Table 2 below and stirred overnight at room temperature. Sodium nitrate was added to the reaction solution to 0.3M, and isopropyl alcohol (IPA) was added. The resulting precipitate was recovered, washed with IPA and ethanol. Thereafter, the precipitate was dissolved in ultrapure water and dialyzed successively against 0.15M NaCl aqueous solution and ultrapure water (SpectraPor 4, molecular weight cutoff (MWCO): 12 k-14 kDa). The resulting dialysate was lyophilized to give HA-C2-Chol as a white solid. HA-C2-Chol can also be obtained by subjecting the above reaction solution to the same treatment as that in Example 2-3-1 (lyophillization of the dialysate obtained by dialysis successively against 0.3M ammonia acetate/DMSO solution, 0.15M NaCl aqueous solution, and ultrapure water). The 1H-NMR spectrum of the product (introduction ratio 8%) as measured under the same conditions as those in Example 2-3-1 is shown in FIG. 7. The introduction ratio of cholesteryl groups relative to HA units calculated according to the formula indicated in Example 2-3-1 is shown in Table 2.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])(=O)[CH3:2].[C:27]([NH:35][NH2:36])(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:5]1[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][N:8]2[C:4]=1[C:1]([CH3:2])=[N:36][N:35]=[C:27]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1-c1ccccc1F
Reactant: NNC(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2-c2ccccc2F)cc1
Temperature: 25 °C

Procedure:
Toluene-4-sulfonic acid 5acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (1.0 g, 2.7 mmol; prepared as described in Example 1, steps a to c) was stirred with benzhydrazide (400 mg, 2.9 mmol) in xylene (30 ml) at reflux overnight. The mixture was allowed to cool to room temperature. A solid crystallised out of solution This was separated by filtration, and was recrystallised from ethyl acetate, yielding toluene-4-sulfonic acid 3-(2-fluorophenyl)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester as a white solid (694 mg). 1H NMR (400 MHz, CDCl3) δ 2.47 (3H, s), 2.52 (3H, s), 7.19 (1H, t, J=8.9 Hz), 7.28 (3H, m), 7.41-7.52 (4H, m), 7.61 (1H, m), 7.79 (2H, d, J=8.3 Hz), 8.25 (2H, d, J=7.5 Hz); MS (ES+) m/e 475 [MH]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=[O:13])[CH2:7][C:8](OCC)=O)C.[CH:15]([O:22]CC)([O:19][CH2:20][CH3:21])OCC.C(OC(=O)C)(=O)C.[NH3:32]>C(Cl)Cl>[OH:13][C:6]1[C:7]([C:15]([O:19][CH2:20][CH3:21])=[O:22])=[CH:8][N:32]=[C:4]([OH:3])[CH:5]=1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: N
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(O)cc1O
Temperature: 120 °C
Yield: 60 %

Procedure:
3-Oxo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120° C. for 2 h. The resulting mixture was cooled to RT and dissolved in DCM (1 L). After further cooling to 0° C., ammonia (30%, 80 mL) was added and the reaction mixture was allowed to warm to RT overnight. The product was extracted with water (2×) and the aqueous layer was acidified to pH 5 with conc. HCl. The precipitate was collected by filtration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 5.58 (s, 1H), 4.23 (q, J=6.8, 14.0 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 184.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23]([C:25]1[N:26]([CH2:37][CH3:38])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([N+:34]([O-])=O)=[CH:29][CH:28]=2)=[O:24])[CH3:21].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[N:26]([CH2:37][CH3:38])[C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH:34][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])=[CH:29][CH:28]=2)=[O:24])[CH3:21]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
4′-Trifluoromethyl-biphenyl-2-carboxylic acid (5.04 g, 18.95 mmol) and 1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (4.00 g, 17.23 mmol) were dissolved in DCM (100 mL). DIEA (8 g, 61.8 mmol) was added to the above mixture and the mixture was stirred at room temperature for 5 minutes. PyBroP (9.63 g, 20.67 mmol) was added to the above solution in one portion. The reaction mixture was stirred for another 3 hours. The precipitate was filtered off and washed with cold DCM to provide the title compound (4.5 g, 54.4%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][C:10]([CH2:18][CH2:19][OH:20])([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([OH:32])=[O:31])[CH:25]=[C:26](O)[CH:27]=1.[CH2:33](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O.O1CCCC1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][C:24]1[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([O:20][CH2:19][CH2:18][C:10]2([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:11][CH2:12][N:7]([C:5]3[S:6][C:2]([Br:1])=[CH:3][N:4]=3)[CH2:8][CH2:9]2)[CH:25]=1
Reactant: OCCC1(N2CCCC2)CCN(c2ncc(Br)s2)CC1
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(Br)s3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethanol (1.30 g), (3-chloro-5-hydroxy phenyl)acetic acid (796 mg), tri-n-butylphosphine (0.99 mL), 1,1′-(azodicarbonyl)dipiperidine (1.00 g) and tetrahydrofuran (20 mL) was stirred at room temperature for 4 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (1.45 g). Yield: 74%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH2:29][CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3-ethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [C:1]1([CH2:7]/[C:8](=[N:16]/[NH:17]C(OC)=O)/[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22](Cl)(Cl)=O>ClCCl>[C:1]1([C:7]2[S:22][N:17]=[N:16][C:8]=2[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)N/N=C(/Cc1ccccc1)Sc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: c1ccc(Sc2nnsc2-c2ccccc2)cc1

Procedure:
A solution of (Z)-[2-phenyl-1-(phenylthio)ethylidene]hydrazinecarboxylic acid, methyl ester in 450 ml of dry dichloromethane was treated with 29.7 g of thionyl chloride. This mixture ws refluxed for one hour, then poured into chipped ice and extracted three times with ether. The extracts were combined, washed with 0.1N sodium hydroxide twice, water and saturated sodium chloride and dried. This material was evaporated onto 100 g of silica gel which was then poured onto a column of silica gel packed in petroleum ether. The column was eluted with a gradient of 20-60% dichloromethane in petroleum ether, giving 35 g of the desired compound as an orange oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 7.28 (bs, 5H, C6H5); 7.30-7.65 (m, 5H, C6H5). Infrared absorption spectrum (neat): 1580(m); 1475(s); 1440(s); 1286(w); 1265(m); 1255(m); 1240(w); 1025(w); 1005(w); 985(w); 935(m); 915(m); 805(m); 765(m); 745(s); 695(s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH:17]([C:36]([N:43]3[CH2:44][CH2:45][CH:40]([OH:39])[CH2:41][CH2:42]3)=[O:37])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:27][CH2:28]3)[C:19](=[O:21])[CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Reactant: OC1CCNCC1
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)N1CCC(O)CC1
Product: Cl
Yield: 107.1 %

Procedure:
Similarly to Example 116 and using 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylic acid (0.20 g) obtained in Example 110 and 4-hydroxypiperidine (0.051 g), the title compound (0.13 g) was obtained as a yellow powder.
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1.[Li].[B:30](OC)([O:33]C)[O:31]C>C1COCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[C:17]=1[B:30]([OH:33])[OH:31]
Reactant: COB(OC)OC
Reactant: COc1cccc(C(=O)N2CCCC2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)N2CCCC2)c1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.3 %

Procedure:
s-BuLi (70 mL, 1.3M in cyclohexane) was added to TMEDA (15.3 g, 131.9 mmol) at −78° C. dropwise within 30 min. After stirring for 20 min, (3-methoxyphenyl)(pyrrolidin-1-yl)methanone (16 g, 78 mmol) in THF (40 mL) was added into the lithium solution slowly. The solution was stirred at −78° C. for 1.5 h and trimethyl borate (36 mL, 322.6 mmol) was added. The mixture was warmed to room temperature and stirred at rt overnight. The solution was acidified to pH=5-6 and the precipitate were filtered. The filter cake was washed with water and ethyl acetate to give 2-methoxy-6-(pyrrolidine-1-carbonyl)phenylboronic acid (5.5 g, 28%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH2:30][CH3:31])[CH2:28]N.[H][H].[S]>C(O)C>[CH3:26][CH:27]([CH2:30][CH3:31])[CH2:28][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: [H][H]
Reactant: CCC(C)CN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: [S]
Solvent: CCO
Product: CCC(C)CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 115 °C

Procedure:
A stirred suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g) and 2-methylbutylamine (3 cc) in anhydrous ethanol (15 cc) is saturated with hydrogen sulphur and heated for 1 hour to a temperature in the region of 115° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residual yellow paste is taken up with ethyl acetate (30 cc) and distilled water (20 cc). The organic phase is separated, washed with saturated aqueous sodium chloride solution (20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual viscous yellow oil (2.2 g) is purified by chromatography on a column (height: 40 cm; diameter: 3.2 cm) of silica gel (0.04-0.063 mm), eluting with a mixture (92:8 by volume) (300 cc) of ethyl acetate and methanol and collecting 25-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-[(2RS)-2-Methylbutyl]-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.8 g) is thereby obtained in the form of a viscous yellow oil. 0.4 g of this oil is dissolved in isopropyl ether (15 cc), and a 3.3N solution (0.4 cc) of hydrochloric acid in isopropyl ether is added. The precipitate formed is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. N-[(2RS)-2-Methylbutyl]-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (0.4 g is thereby obtained in the form of a yellow powder, m.p. 155°-160° C. (melts forming a paste).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH2:15][CH2:16][C:7]=2[C:6]([C:17]([O:19]C)=[O:18])=[CH:5]1.O.O.[Li]>C1COCC1.O.CO>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH2:15][CH2:16][C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: COC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2

Procedure:
To a solution of methyl 1-(2,2,2-trifluoroethyl)-4,5-dihydro-1H -pyrrolo[2,3-f]isoquinoline-3-carboxylate E3 (0.13 mmol) in THF/water/MeOH 8:1:1 lithium hydrate monohydrate (0.39 mmol) was added. The reaction mixture was refluxed for 8 h then the solvent was removed under reduced pressure. The residue was dissolved in water, the solution was neutralized with diluted aq potassium hydrogenosulphate and extracted with DCM/water 9:1. The organic layer was dried (Na2SO4) and evaporated to dryness. Trituration with diethylether provided the title compound. The aqueous layer was concentrated and the residue was cromatographed on silica gel (eluant: DCM/MeOH/30% NH3 90:9:1). The title compound was isolated in 60% overall yield. ESI (+) MS: m/z 297 (MH+). MS (ES−) 295. 1H NMR: 5.43 (q, J=8.98, 2H), 7.70 (d, J=5.73, 1H), 7.76 (s, 1H), 8.48 (d, J=5.61, 1H), 8.51 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[CH2:16]=[O:17]>CN(C)C=O>[OH:17][CH2:16][N:13]1[C:14](=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: C=O
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CO
Reaction time: 8 h

Procedure:
30 g. (0.15 mole) of 1,8-naphthalimide and 12.5 ml. of 37% aqueous formaldehyde (0.17 mole) are combined in 100 ml. of dimethylformamide and heated on a hot plate (90°-110°) until all the materials dissolve. The solution is then allowed to stand overnight at 25°. The resulting precipitate is filtered off, washed with water and recrystallized from dioxane. This material is dried overnight at 25° (0.1 mm.) to yield 26.4 g. of the titled compound which has an indistinct melting point.
Reaction SMILES: [CH2:1]([C:3]([CH3:14])([O:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])[CH2:4][CH3:5])[CH3:2].[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl.CN(C)C=O>[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:31][CH2:32][N:33]([C:11](=[O:13])[CH2:10][NH:9][C:7](=[O:8])[O:6][C:3]([CH2:1][CH3:2])([CH3:14])[CH2:4][CH3:5])[CH2:34][CH2:35]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C)(CC)OC(=O)NCC(=O)O
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(CC)OC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
284 mg (1.40 mmol) of {[(1-ethyl-1-methylpropoxy)carbonyl]amino}acetic acid, 320 mg (1.17 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-piperidine and 322 mg (1.68 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in a mixed solvent of 15 ml of dichloromethane and 5 ml of dimethylformamide. 0.23 ml (1.68 mmol) of triethylamine and 14.7 mg (0.12 mmol) of dimethylaminopyridine were added to the obtained solution, and they were stirred at room temperature overnight. After the concentration under reduced pressure, ethyl acetate was added to the reaction mixture. The resultant mixture was washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by the silica gel chromatography (hexane: dichloromethane=95:5 to 2:3) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:4][C:5](SC)=[N:6][CH:7]=1.O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]O>>[CH3:22][S:18]([C:5]1[N:4]=[C:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:2]([CH3:1])=[CH:7][N:6]=1)(=[O:20])=[O:17]
Reactant: CSc1ncc(C)c(-c2cccnc2)n1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Product: Cc1cnc(S(C)(=O)=O)nc1-c1cccnc1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A solution of 5-methyl-2-methylsulfanyl-4-pyridin-3-yl-pyrimidine (1.28 g, 5.90 mmol) in MeOH (45 ml) was cooled at 0° C. and then an aqueous solution of oxone (11 g, 17.95 mmol in 45 ml of water) was added dropwise. After 15 minutes, ice bath was removed and the stirring continue for 3 hours. The mixture was neutralized with solid NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 1.3 g of the title compound as a white powder (88% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:22])=O>ClCCl.CN(C)C=O>[ClH:22].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([Cl:22])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
To a suspension of 1-(4-nitrophenyl)piperidine-4-carboxylic acid (0.75 g, 3.0 mmol) in dichloromethane (15 mL) is added oxalyl chloride (0.32 mL, 3.6 mmol) and then one drop of N,N-dimethylformamide. The reaction mixture is heated in a 60° C. oil bath under a nitrogen atmosphere for 30 minutes, concentrated under reduced pressure to provide 1-(4-nitrophenyl)piperidine-4-carboxylic acid chloride hydrochloride. N,N-dimethylethylenediamine (1.0 mmol) is added neat to 1-(4-nitrophenyl)piperidine-4-carboxylic acid chloride hydrochloride (0.15 g, 0.5 mmol). The resulting solid is purified by reverse-phase HPLC to provide 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid (2-dimethylamino-ethyl)-amide trifluoroacetate.