Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][S:33](=[O:37])(=[O:36])[CH2:34][CH2:35]3)=[CH:27][N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=S1(=O)CCN(Cc2ccc(Cl)nc2)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (41 mg, 0.13 mmol) and 4-[(6-chloropyridin-3-yl)methyl]thiomorpholine 1,1-dioxide (34 mg, 0.13 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([Cl:21])=[C:16]([Cl:22])[CH:15]=2)[C:6](O)=[O:7].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH2:44][CH:45]1[CH2:50][C:49]([CH3:52])([CH3:51])[N:48]([CH3:53])[C:47]([CH3:55])([CH3:54])[CH2:46]1>CN(C=O)C.O>[Cl:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[Cl:22])[NH:13][C:12]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][CH:45]3[CH2:46][C:47]([CH3:54])([CH3:55])[N:48]([CH3:53])[C:49]([CH3:52])([CH3:51])[CH2:50]3)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])=[CH:20]2
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: COc1cc(C(=O)O)ccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A mixture of 3-methoxy-4-(5,6-dichloro-1H-indol-2-yl)-benzoic acid (0.15 g, 0.45 mmol), WSC (0.094 g, 0.5 mmol), HOAT (0.067 g, 0.5 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (0.15 g, 0.9 mmol) in DMF (2 ml) was stirred at 50° C. for 18 h. The mixture was then poured in a large volume of water and extracted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; CH2Cl2—MeOH—NH4OH: 91.5-7.5-1) then crystallised in di-isopropyl ether to afford 0.13 g (0.26 mmol. yield 59%) of the title compound, mp=260° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]12(O)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>CC(O)=O.CCOC(C)=O>[C:15]12([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=4)[CH:13]=[CH:12][C:11]=3[OH:14])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc(-c2ccc(I)cc2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc(I)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a mixture of 4′-iodobiphenyl-4-ol (0.332 g, 2 mmol) and 1-admantanol (0.15 g, 0.51 mmol) in AcOH (2 ml) concentrated H2SO4 (0.5 ml) was added and the reaction mixture was stirred for 50 h at room temperature. This was diluted to 100 ml with EtOAc and washed with NaHCO3 solution, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was crystallized from MeOH to give the product (0.195 g; 93%), as a colourless paste. 1H NMR (CDCl3) 1.78 (m, 6H); 2.07 (s, 3H); 2.15 (s, 6H); 6.69 (d, 1H, J=8.15 Hz); 7.21-7.28 (m, 3H); 7.37 (d, 1H, J=2.28 Hz); 7.69 (d, 2H, J=8.45 Hz).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 5.3 g of 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoic acid in 30 mL of methanol was added 2.3 g of Pd/C (10% wt). The suspension was stirred under H2 (balloon) for 1 h, filtered through celite pad and concentrated to dryness to give the desired product (5.2 g, yield: 97%) as a white solid: 1H NMR (CDCl3) δ 8.06-8.01 (2H, m), 7.58-7.53 (2H, m), 4.02 (4H, s), 2.73-2.67 (2H, m), 2.70-2.61 (1H, m), 1.93-1.64 (8H, m); MS: 262 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:26]I>CN(C=O)C>[CH3:26][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tert-butyloxycarbonyl-3-azetidinyloxy)benzoate from Step 3 above (1.30 g, 4.02 mmol) in DMF (40 mL) under N2 was added NaH (241 mg, 6.03 mmol). The reaction mixture was cooled, and CH3I (0.50 mL, 8.04 mmol) was added via syringe. The reaction mixture was allowed to warm to ambient temperature, then stirred for an additional 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography, eluting with 20% ethyl acetate in hexanes. Methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-azetidinyloxy)benzoate was obtained as a colorless oil which crystallized on standing overnight.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one (0.30 g, 0.74 mmol) in DMF (5 mL) was added pyrrolidine (0.31 g, 4.36 mmol) and the reaction mixture was stirred at room temperature for 15 hours. DMF was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.13 g (44%). MP 218-220° C. 1H NMR (400 MHz, DMSO-d6): δ 12.13 (br s, 1H), 8.03 (d, J=8.98 Hz, 1H), 7.90 (s, 2H), 7.16 (d, J=2.3 Hz, 1H), 7.07 (dd, J=8.9 and 2.7 Hz, 1H), 3.92-3.89 (m, 5H), 2.83 (t, J=5.8 Hz, 2H), 2.54-2.50 (m, 4H), 2.31 (s, 6H), 1.73 (m, 4H). MS (ES+) m/z: 394.62 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[CH2:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:16])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C1COc2ccc(F)cc2N1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3ccc(F)cc32)CC1
Yield: 82 %

Procedure:
4-(3-Chloropropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.102 g, 0.42 mmol), K2CO3 (0.12 g, 0.84 mmol), NaI (0.13 g, 0.84 mmol) and 4-butylpiperidine (0.06 g, 0.44 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (8183MF55F) (0.12 g, 80%). 1H NMR (CDCl3) δ6.96 (dd, J=10.4 Hz, J=2.8 Hz, 1H), 6.87 (dd, J=9.6 Hz, J=5.2 Hz, 1H), 6.66-6.12 (m, 1H), 4.51 (s, 2H), 3.91 (t, J=7.2 Hz, 2H), 2.84 (d, J=11.2 Hz, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.91-1.77 (m, 4H), 1.64 (d, J=9.6 Hz, 2H), 1.29-1.16 (m, 9H), 0.86 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 164.2, 158.5 (d, J=239.5 Hz), 141.4 (d, J=2.7 Hz), 130.0 (d, J=10.4 Hz), 117.5 (J=9.3 Hz), 109.5 (d, J=23.5 Hz), 103.2 (d, J=28.8 Hz), 67.7, 55.7, 54.3, 40.0, 36.4, 35.9, 32.6, 29.1, 24.7, 23.0, 14.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:14][CH2:11][C:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:13])=[O:12]
Reactant: [Br-]
Reactant: COc1cc(C)c(C(C)=O)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 111.1 %

Procedure:
To a solution of 1-(4-methoxy-2,6-dimethylphenyl)ethanone (5.7 g, 32 mmol) in acetonitrile (64 mL) was added tetrabutylammoniumtribromide (TBABr3, 15.4 g, 32.0 mmol). The reaction was stirred at room temperature for 80 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-methoxy-2,6-dimethylphenyl)ethanone (9.14 g), which was used directly for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:21])([CH3:20])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2].F[B-](F)(F)F.[O:29]=[N+:30]=[O:31]>C(Cl)Cl>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:20])([CH3:21])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][O:18][N+:30]([O-:31])=[O:29])[CH:14]=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2cc(CO)ccc2=O)c2cc(C#N)ccc2O1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(C)C=C(n2cc(CO[N+](=O)[O-])ccc2=O)c2cc(C#N)ccc2O1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
In 10 ml of anhydrous methylene chloride, is suspended 581 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro- 2-oxo-5-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 14. Then, 270 mg of nitronium tetrafluoroborate is added at room temperature and reacted at that temperature for 30 minutes. After stopping the reaction by adding ice water, the reaction mixture is extracted with methylene chloride, and the organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/25 mixture of ethyl acetate/ether as a developing solvent. Thus, 328 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-nitroxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:36][CH3:37])[N:30]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:37][O:36][CH2:35][C:31]1[N:30]=[C:29]([CH2:28][N:11]([CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: COCc1cccc(CBr)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cccc(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)n1

Procedure:
Using General Procedure A: Reaction of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione, 2-bromomethyl-6-methoxymethyl-pyridine (Gillespie, R. J. et al. PCT Int. Appl. (2002), WO 2002055083), and DIPEA in CH3CN gave 2-{4-[(6-methoxymethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a yellow oil. Deprotection with H2NNH2.H2O following General Procedure E gave the free base. Conversion to the HBr salt using General Procedure D gave COMPOUND 356 as a white solid. 1H NMR (D2O) δ 1.52-1.70 (m, 4H), 1.75-1.89 (m, 1H), 1.98-2.10 (m, 1H), 2.16-2.22 (m, 1H), 2.39-2.43 (m, 1H), 2.59-2.68 (m, 1H), 2.84-3.02 (m, 5H), 3.53 (s, 3H), 4.28 (d, 1H, J=15.9 Hz), 4.36 (d, 1H, J=15.9 Hz), 4.49 (dd, 1H, J=5.7, 10.5 Hz), 4.88 (s, 2H), 7.80 (dd, 1H, J=5.7, 7.8 Hz), 7.91 (d, 1H, J=7.8 Hz), 8.08 (d, 1H, J=7.8 Hz), 8.26 (d, 1H, J=8.1 Hz), 8.47 (dd, 1H, J=7.8, 8.1 Hz), 8.57 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 20.42 (2 carbons), 24.93, 25.01, 27.62, 39.53, 51.42, 53.24, 59.28, 60.01, 70.38, 125.20, 125.72, 126.27, 140.04, 140.29, 146.84, 146.93, 151.24, 153.50, 153.82; ES-MS m/z 355 (M+H). Anal. Calcd. for C21H30N4O.3.4HBr.1.2H2O: C, 38.73; H, 5.54; N, 8.60; Br, 41.72. Found: C, 39.06; H, 5.54; N, 8.44; Br, 41.42.
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1.O>C(O)C.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCCC(Oc1ccc2c(c1)CC(NCc1ccccc1)CC2)C(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCC(Oc1ccc2c(c1)CC(N)CC2)C(=O)OCC

Procedure:
A solution of 2-benzylamino-7-(ethoxycarbonylbutan-4-yloxy)tetralin hydrochloride (10.7 g), prepared as described in Example 5, in 95% ethanol (250 ml) and water (25 ml) is hydrogenated at 60° C. and atmospheric pressure using 10% Pd/C (1.2 g) as the hydrogenation catalyst. After 6 hours the catalyst is filtered off, the filtrate is concentrated and the residue is taken up in absolute ethanol and concentrated to dryness a few times. The obtained product is then triturated with ethyl ether and filtered. The residue is crystallized from isopropanol yielding 8 g of the compound indicated in the title. M.p. 131°-133° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[CH:5]2.[H-].[Na+].[CH3:20][C@H:21]1[CH2:23][O:22]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[C:3]([C:14]([F:15])([F:16])[F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C@H:21]([OH:22])[CH3:23])[CH:6]=[CH:5]2
Reactant: C[C@H]1CO1
Reactant: O=C(O)c1cc2c(C(F)(F)F)c(F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[C@@H](O)Cn1ccc2c(C(F)(F)F)c(F)ccc21
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A suspension of 0.8 g of 5-fluoro-4-trifluoromethylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 16 ml of tetrahydrofuran. 122 mg of sodium hydride dispersion were added and the mixture was stirred for 1 hour. Subsequently, 0.46 ml of (S)-methyloxirane was added and the reaction mixture was stirred at room temperature for 60 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 40 g of silica gel with hexane-toluene (1:1) and subsequently with toluene-ethyl acetate (15:1). There was obtained 0.3 g (35.5%) of (R)-1-(5-fluoro-4-trifluoromethyl-indol-1-yl)-propan-2-ol as light brown crystals.
Reaction SMILES: [CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([C:12](O)=[O:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Li].[H-].Cl>O1CCCC1.O>[CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CCC(C(=O)O)CC1
Agent: Cl
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC1=CCC(CO)CC1
Temperature: 25 °C

Procedure:
A solution of 4-pentyl-3-cyclohexen-l-carboxylic acid (3.4 g) in tetrahydrofurn (THF; 55 ml) was added dropwise to a cold (0° C.) solution of lithium aluminim hydride (1.37 g) in tetrahydrofuran (THF, 55 ml), in a flask equipped with a condenser. The reaction mixture was stirred at room temperature for at least three hours, re-cooled to 0° C., and water (8 ml) was then added dropwise. An additional 55 ml of THF was added, and the reaction mixture stirred for three hours. The reaction mixture was then acidified with 2 M HCl (150 ml), and extracted with a 1:1 (v:v) ethyl acetate:hexane mixture. The combined organic layers were extracted with saturated sodium chloride and dried over sodium sulfate. The solvent was removed in vacuo, and the resultant oil was distilled (92°-95° C. at c.a. 1 mm Hg) to produce 4-pentyl-3-cyclohexen-1-methanol.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:20]([C:26]([O:28][CH3:29])=[O:27])=[N:21][C:22](Br)=[CH:23][N:24]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:19]1[C:20]([C:26]([O:28][CH3:29])=[O:27])=[N:21][C:22]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[CH:23][N:24]=1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCCC3)cc2)cnc1N
Temperature: 160 °C
Yield: 245.3 %

Procedure:
4-(Pyrrolidin-1-ylsulfonyl)phenylboronic acid (0.33 g, 1.29 mmol), methyl 3-amino-6-bromopyrazine-2-carboxylate (0.25 g, 1.08 mmol; described in: H. Ellingson, J. Amer. Chem. Soc. 1949, 2798), K3PO3 (3 M, 1.1 mL, 3.2 mmol), and Pd(dppf)Cl2 (0.044 g, 54 μmol) were suspended in ethylene glycol dimethyl ether/water (1.5:0.5 mL) and heated in a microwave oven at 160° C. for 10 min. The reaction was repeated 3 times. The combined product mixtures were evaporated with silica gel and the crude product was purified by chromatography on silica gel using a heptane to ethyl acetate gradient to give 0.96 g (82% yield) of the title compound: MS (ES) m/z 363 (M++1).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)/[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:28]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[N:12][N:11]=[C:9]12)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCn1/c(=N/NC(=O)CCc2nnc(-c3ccccc3)o2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3nnc(-c4ccccc4)o3)nnc12
Yield: 66.7 %

Procedure:
The mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanohydrazide (485 mg, 1.11 mmol) in toluene (50 mL) was heated to reflux overnight. The mixture was concentrated to yield the desired product (310 mg, 66.7%). LCMS calculated for C21H23N8O2(M+H): 419.2; found 419.2.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@@H:9]2[C:14]3=[C:15](O)[C:16]4[C:28](=O)[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5OC)[C:20](=O)[C:17]=4[C:18](O)=[C:13]3[CH2:12][C@@:11](O)(C(C)=O)[CH2:10]2)C[C@H](N)[C@@H]1O.[ClH:39].C(O)(=O)C.[NH2:44][NH:45][C:46]([NH2:48])=[S:47]>C(O)C>[ClH:39].[N:44](=[C:20]1[C:17]2[C:16](=[CH:15][C:14]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[CH:18]=2)[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2)[NH:45][C:46]([NH2:48])=[S:47]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=S)NN=C1c2ccccc2Cc2cc3c(cc21)CCCC3
Yield: 187.5 %

Procedure:
Daunorubicin hydrochloride (0.4 g.) is dissolved in ethanol (60 cc.) containing 2.5% of acetic acid, and thiosemicarbazide (0.135 g.) is then added. The resulting mixture is heated for 12 hours to 45° C. with stirring, then evaporated to dryness under reduced pressure, and the residue is taken up in water (50 cc.). The resulting solution is lyophilised to give 4-methoxy-5- (or 12-) oxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-amino-1-L-lyxohexosyl)-9-[1-(thiosemicarbazono)ethyl]-12- (or 5-) (thiosemicarbazono)-5,7,8,9,10,12-hexahydro-naphthacene hydrochloride (0.476 g.) in a yield of 89%.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:28])=[O:24])=[CH:26][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 101.6 %

Procedure:
To a freshly-prepared solution of (±)-4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoic acid (1) (10 g, 25.6 mmol) in dry N,N-dimethylformamide (86 ml) contained in a 250 ml round bottom flask is added finely-ground potassium carbonate (3.54 g, 25.6 mmol) followed by methyl iodide (1.6 ml, 25.6 mmol). The resulting suspension is protected from atmospheric moisture with a magnesium sulfate drying tube and is stirred at room temperature for 19.5 hours. The reaction mixture is poured into water (175 ml) contained in a separatory funnel and then is extracted with ether (3×40 ml). The organic extracts are combined, washed with saturated aqueous sodium bicarbonate (3×30 ml), dried over sodium sulfate and filtered. Evaporation (in vacuo) of the filtrate leaves the desired ester 2 as a pale yellow oil (10.55 g): tlc, Rf =0.4 (homogeneous, UV detection) on silica gel with ethyl acetate:hexane (7:3; v:v) as eluent; ir (2% solution in chloroform) 3400 (w), 1710 (s), 1600 (s) and 1280 (s) cm-1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].C(=O)(O)[O-].[Na+:29].O>O1CCCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[N:8][C:9]([C:15]2[NH:16][C:17](=[O:24])[C:18]([CH:21]([CH3:22])[CH3:23])([CH3:20])[N:19]=2)=[C:10]([CH:14]=1)[C:11]([O-:13])=[O:12].[Na+:29]
Reactant: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)[O-])NC1=O
Yield: 76.8 %

Procedure:
5-(1,3-Dioxolan-2-yl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (0.507 g, 0.00152 mol), sodium bicarbonate (0.12 g, 0.00143 mol), water and tetrahydrofuran is heated at reflux temperature for 1 hour. Concentration in vacuo yields a solid which is triturated with ether to give the title compound as an orange solid (0.39 g, 72%), mp 209°-210° C., identified by IR and NMR spectral analyses.