Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20](O)[CH3:21]>>[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:20][CH3:21])=[O:4]
Reactant: CCO
Reactant: CCCCCCCCC(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCCCCCC(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Aminodecanoic acid (J. Am. Chem. Soc., 1946, 68 450) (16.0 g.) was added in portions to a cooled (-10° C.) mixture of absolute ethanol (70 ml.) and thionyl chloride (6 ml.) with stirring. The resulting solution was set aside for 2 h., at room temperature, refluxed for 1 h., cooled, poured into ice-water, and the pH of the solution was adjusted to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, the extract was dried, concentrated, then distilled, giving ethyl 2-aminodecanoate (75%) as a colourless oil, b.p. 82°-4° C./0.2 mm.
Reaction SMILES: [H][H].[NH3:3].[CH2:4]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@@H:21]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]2[O:23]C(=O)C)=[C:14](Cl)[N:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:4]([O:11][C:12]1[N:13]=[C:14]([NH2:3])[C:15]2[N:16]=[CH:17][N:18]([C:19]=2[N:20]=1)[C@@H:21]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]1[OH:23])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCc4ccccc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [H][H]
Product: Nc1nc(OCc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70 %

Procedure:
A compound having a structure of the above formula was prepared where the substituents R1 and R2 are hydrogen and R3 is benzyl (—CH2C6H5). The compound (C17H19N5O5) was prepared by reaction of ammonia with 2-benzyloxy-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 3) as described in Example 2, Step E. The final product was isolated in 70% yield as a solid with melting point of 178-179 ° C. 1H-NMR (DMSO-d6): δ 3.49 (m, 1H); 3.61 (m, 1H); 3.9 (m, 1H); 4.12 (m, 1H); 4.58 (m, 1H); 5.18 (d, 2H, J=4); 5.3 (s, 2H); 5.42 (d, 1H, J=6); 5.79 (d, 1H, J=6); 7.37 (m, 7H); 8.16 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][PH:28]([CH:30]([NH:34][C:35](=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([CH3:33])[CH3:32])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:46].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:30]([NH:34][C:35](=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:31]([CH3:33])[CH3:32])([OH:46])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
The benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)phosphinoyloxy)hexanoate (117 mg) obtained in the above step (b) was dissolved in a mixed solvent of dioxane (4.5 ml) and water (1.5 ml) and added with sodium periodate (40.4 mg), and then the mixture was stirred at room temperature for 15 hours. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium thiosulfate and saturated brine, successively, and dried over anhydrous magnesium sulfate. Then the solvent was evaporated to obtain benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate (100.8 mg, 84%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][CH:11]([CH3:15])[C:12](=O)[CH3:13].N1C=CC=CC=1.O>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:10][CH:11]([CH3:15])[C:12](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:13]
Reactant: CC(=O)C(C)C
Reactant: COC(=O)CC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(C(=O)OC)=C(C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 10 g (75.7 mmol) of dimethyl malonate in 20 ml of chloroform were slowly added dropwise to a solution of 16.6 ml (151.4 mmol) of titanium tetrachloride in 60 ml of chloroform. After the addition had ended, the reaction solution was stirred at 0° C. for another 30 min. At 0° C., 6.52 g (75.7 mmol) of 3-methyl-2-butanone in 20 ml of chloroform were then added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 4 h. The reaction solution was then once more cooled to 0° C., and 30.6 ml (378.5 mmol) of pyridine in 20 ml of chloroform were added. After the addition had ended, the solution was warmed to room temperature and stirred at this temperature overnight. The reaction solution was then once more cooled to 0° C., and 50 ml of water were added slowly. The resulting phases were separated, and the aqueous phase was extracted two more times with in each case about 50 ml of dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 9.4 g (62% of theory) of the target compound.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[CH3:2][O:23][C:22](=[O:24])[CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., TMSCHN2 (2.0 M in ether, 15 mL) was added dropwise to a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (6272 mg, 25.78 mmoL) in Toluene (60 mL) and MeOH (60 mL). After stirring at room temperature for 1 h, the mixture was concentrated. The crude tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate was used as it is without further purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][C@@H:22]([CH2:24][C:25]([O:27]C)=[O:26])[C:21](=[O:29])[NH:20][CH2:19][C:18]=2[CH:30]=1)=[O:13].[Li+].[OH-]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][C@@H:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21](=[O:29])[NH:20][CH2:19][C:18]=2[CH:30]=1)=[O:13]
Reactant: COC(=O)C[C@@H]1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CNC1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H]1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CNC1=O
Yield: 66 %

Procedure:
Methyl (S)-2,3,4,5-tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetate is hydrolyzed with 1M LiOH to yield the title compound (66%) as a white powder: [α]n25 −145.3° (c=1, CH3OH); MS (ES) m/e 394.2 (M+H)+. Anal. Calcd for C20H19N5O4.2 TFA.0.125 H2O: C, 46.22; H, 3.43; N, 11.23. Found: C, 46.13; H, 3.78; N, 11.49.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:21][C:22]([C@@H:24](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C@@:25]([OH:36])([CH2:33][CH2:34][OH:35])[C:26]([O:28][C:29](C)(C)C)=[O:27])=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]([NH:21][C:22]([C@@H:24](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C@@:25]([OH:36])([CH2:33][CH2:34][OH:35])[C:26]([O:28][CH3:29])=[O:27])=[O:23])[C:6]([O:5][CH3:1])=[O:7])=[CH:15][CH:14]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC)C(=O)OC)cc1
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of No. 4984967, tert-butyl (E)-(2S,3S)-3-[(S)-1-tert-butoxycarbonyl-2-(4-but-2-ynyloxy-phenyl)-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (112 mg, 0.152 mmol) and dichloromethane (1.3 mL) was cooled to 4° C., and acetic anhydride (35.8 μL, 0.379 mmol), triethylamine (23.3 μL, 0.167 mmol), and DMAP (1.9 mg, 0.02 mmol) were added. After stirring for 2 hours, the consumption of the starting materials was confirmed by LCMS. The solvent was distilled off under reduced pressure. Formic acid (10 mL) was added and the mixture was stirred at room temperature for 15 hours. Formic acid was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain the title compound (46 mg, 45% yield, colorless oil).
Reaction SMILES: N1C(C)=CC=CC=1C.[O:9]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])S(C(F)(F)F)(=O)=O.[F:24][C:25]([F:30])([F:29])[CH2:26][CH2:27]O>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[S:17]([O:9][CH2:27][CH2:26][C:25]([F:30])([F:29])[F:24])(=[O:18])=[O:19]
Reactant: OCCC(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330 g ISCO) and the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1)[CH2:23][OH:24].C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:21][C@H:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:23][OH:24])[CH:3]=[CH:4][C:5]=2[N+:17]([O-:19])=[O:18])[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: N[C@@H](CO)c1ccc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26, 0.2 g) and (2R)-2-amino-2-(5-fluoropyridin-2-yl)ethanol hydrochloride (Intermediate 23, 0.15 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.2 g of the title compound. MS (electrospray): 404 (M+1) for C17H18FN7O4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O.[C:23](=O)([O-])O.[Na+].Cl>CO.S(=O)(=O)(O)O>[CH3:23][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C([O-])O
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=CN1CCNCC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCCCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A 26.5 g (0.1 mole) quantity of 11-bromoundecanoic acid was dissolved in 300 ml of methanol, and 5 to 6 drops of sulfuric acid was added thereto and the mixture was stirred at room temperature for 24 hours and concentrated. A 500 ml quantity of ethyl acetate was added to the residue and the mixture was washed sequentially with 100 ml of water and 100 ml of a brine, followed by drying over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was dissolved in 200 ml of dimethylformamide. To the solution were added 11.4 g (0.1 mole) of formylpiperazine and 18.5 g (0.22 mole) of sodium hydrogen carbonate. The mixture was stirred at 80° C. for 3 hours and concentrated under reduced pressure. A 500 ml quantity of ethyl acetate was added to the residue and the mixture was washed sequentially with 100 ml of water and 100 ml of a brine, followed by drying over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure. To the residue were added 300 ml of methanol and 50 ml of concentrated hydrochloric acid, and the mixture obtained was refluxed for 3 hours. The solvent was evaporated under reduced pressure and the precipitated white crystals were washed with acetone, giving 25 g (yield: 70%) of 11-(1-piperazyl)undecanoic acid methyl ester as the hydrochloride.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:44])[C:40](=[O:43])[CH:41]=[CH2:42].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:42][CH2:41][C:40]([N:39]([CH3:44])[CH3:38])=[O:43])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93.2 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (951 mg, 1.75 mmol) was treated with N,N-dimethylacrylamide (540 mg, 5.44 mmol) and sodium hydride (60% in oil, 105 mg, 2.62 mmol) in tetrahydrofuran (17.5 ml) in the same manner as shown in Example 4(1) (at 5° C. for 14 hours), followed by work up and purification using column chromatography (hexane:ethyl acetate= 2:1) to give the titled compound (1.05 g, 92.7%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C(N(CC)C(C)C)C.[N:28]1([CH2:34][CH2:35]O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:28]1([CH2:34][CH2:35][O:18][C:17]([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:19])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OCCN1CCCCC1
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Agent: CCN(CC)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(OCCN1CCCCC1)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 0 °C
Yield: 38.4 %

Procedure:
Stir under N2 at 0° C. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (0.25 g, 1 mmol), benzotriazol-1-yloxytris(pyrrlidino)-phosphonium hexafluorophosphate (0.52 g, 1 mmol), diethylisopropylamine (0.175 mL, 1 mmol) and 1-methyl-2-pyrrolidinone (4.0 mL). Add 1-piperidineethanol (0.50 mL, 3.8 mmol) in one portion and stir at ambient temperature for 18.5 h. Pour the reaction into 5% aqueous potassium carbonate and extract with ethyl acetate (2×20mL). Wash the combined extract with water (20 mL), brine (20 mL), dry over MgSO4, filter and concentrate under vacuum to a dark residue. Chromatograph over silica gel (Redisep cartridge, 30 g) and elute with a step gradient of 10% methanol/dichloromethane (150 mL) to 20% methanol/dichloromethane. Concentrate like fractions under vacuum to an oil. Dry the oil under high vacuum at ambient temperature and obtain 0.14 g of the title compound as a tan foam: MS 365(M+H), TLC (silica gel, 0.5/9.5/90 ammonium hydroxide/methanol/dichloromethane) Rf=0.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](N2CCOCC2)=S)=[C:5]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=1.[OH-:25].[K+].[OH2:27]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:27])=[O:25])=[C:5]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(CC(=S)N2CCOCC2)c(Oc2ccccc2)c1
Reactant: O
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(CC(=O)O)c(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-methoxy-2-phenoxyphenyl)-1-morpholin-4-ylethan-1-thione (0.35 g, 1.02 mmole) in i-PrOH (15 mL) and H2O (15 mL) was added KOH (0.57 g, 10.2 mmole). The reaction was heated at reflux for 18 hr, then was cooled to RT, diluted with H2O, and washed with Et2O. The aqueous layer was acidified to pH≈4 with conc. HCl and was extracted with CHCl3. The combined extracts were dried over MgSO4 and concentrated to give the title compound (0.22 g) as a white solid. This was used without further purification: MS (ES) m/e 259.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2]C1N=CC(C2SC3C=CC=CC=3N=2)=CN=1.[S:18]1[C:22]2[CH:23]=[CH:24][C:25](N)=[CH:26][C:21]=2[N:20]=[CH:19]1.Br[C:29]1[CH:30]=[CH:31][C:32]([NH:35][CH3:36])=[N:33][CH:34]=1>>[CH3:1][O:2][C:25]1[CH:24]=[CH:23][C:22]2[S:18][C:19]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][CH3:36])=[N:33][CH:34]=3)=[N:20][C:21]=2[CH:26]=1
Reactant: Nc1ccc2scnc2c1
Reactant: CNc1ccc(Br)cn1
Reactant: COc1ncc(-c2nc3ccccc3s2)cn1
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
The title compound was prepared according to the method used for the preparation of 2-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole, now starting from 1,3-benzothiazol-5-amine (50 mg, 0.33 mmol) and 5-bromo-N-methylpyridin-2-amine (75 mg, 0.40 mmol). The crude material was purified on a preparative HPLC to give the title compound (12 mg) as a pale beige solid. 1H NMR δ ppm 8.62 (d, 1 H) 7.95 (dd, 1 H) 7.61 (d, 1 H) 7.19 (q, 1 H) 7.07 (d, 1 H) 6.69 (dd, 1 H) 6.56 (d, 1 H) 5.24 (s, 2 H) 2.85 (d, 3 H); MS m/z (M+H) 257.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[ClH:1].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc2nccc(Cl)c2c1
Reactant: c1ccc2c(c1)CCNC2
Product: Cl
Product: Fc1ccc2nccc(N3CCc4ccccc4C3)c2c1

Procedure:
The title compound, MS: m/e=279.2 (M+H+), was prepared 4-chloro-6-fluoroquinoline and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH2:9][CH:8]([CH3:10])[O:7][CH:6]([CH3:11])[CH2:5]1.[CH3:19][C:20](O)([CH2:22][CH3:23])[CH3:21]>>[C:20]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH:6]([CH3:11])[O:7][CH:8]([CH3:10])[CH2:9]2)=[CH:18][CH:17]=1)([CH2:22][CH3:23])([CH3:21])[CH3:19]
Reactant: CC(Cc1ccccc1)CN1CC(C)OC(C)C1
Reactant: CCC(C)(C)O
Product: CCC(C)(C)c1ccc(CC(C)CN2CC(C)OC(C)C2)cc1

Procedure:
4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine, b.p. 136°-138° C./0.04 Torr is prepared from 4-(2-methyl-3-phenyl-propyl)-2,6-dimethyl-morpholine and 2-methyl-2-butanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:9][C:10]([CH2:15][CH2:16][CH3:17])(CO)[CH2:11][OH:12]>CCCCCCC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:10]([CH2:11][OH:12])([CH3:9])[CH2:15][CH2:16][CH3:17]
Reactant: Clc1ccc(Cl)nn1
Reactant: CCCC(C)(CO)CO
Solvent: CCCCCCC
Product: CCCC(C)(CO)c1cc(Cl)nnc1Cl

Procedure:
Twenty g. of 3,6-dichloropyridazine was alkylated with 44.4 g. of 2-methyl-2-propyl-1,3-propanediol, following the process of Preparation 3 above. In this case the chromatography was run with 3:1 heptane:ethyl acetate as the eluant, and the residue from evaporation of the combined product-containing fractions was recrystallized from diethyl ether/heptane to obtain 0.43 g. of the desired intermediate product, m.p. 99°-100°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1([F:25])[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:13]1.[C:26](OC(C)(C)C)(=[O:31])[CH2:27][C:28]([O-])=[O:29].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([N:14]5[CH2:15][CH2:16][C:12]([F:25])([F:11])[CH2:13]5)=[CH:18][CH:19]=4)[C:28](=[O:29])[CH2:27][C:26]3=[O:31])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(N2CCC(F)(F)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCC(F)(F)C2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.80 g, 6.01 mmol), 4-(3,3-difluoropyrrolidin-1-yl)benzaldehyde (1.39 g, 6.0 1 mmol), mono-tert-butyl malonate (0.96 g, 6.01 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.03 g, 6.61 mmol) and sodium tert.-butoxide (1.04 g, 9.33 mmol) according to method 5.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)=[CH:6][CH:5]=[C:4]([O:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[N:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:11]=2)=[CH:6][CH:5]=[C:4]([O:18][CH:19]([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])[N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(C(=O)Nc2ccc(OC(C(F)(F)F)C(F)(F)F)nc2Br)c1
Product: O=C(Nc1cccc(C(=O)Nc2ccc(OC(C(F)(F)F)C(F)(F)F)nc2Br)c1)c1ccccc1

Procedure:
Using N-[2 bromo-6-(2,2,2-trifluoro-1-trifluoromethylethoxy)-pyridin-3-yl]3-aminobenzamide and benzoyl chloride, the desired title product was prepared according to the conditions as described in Example 1-4 (Yield: 76%).