Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[C:23][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Reactant: C#CC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=NC2(N=C1N)c1cc(C#CC(C)(C)C)ccc1CC21CCC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To a solution of 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 0.100 g, 0.31 mmol) in DMF (10 mL) under argon was added 3,3-dimethyl-but-1-yne (0.039 g, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) and triethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred at r.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol). The reaction mixture was stirred overnight at 65° C. and then partitioned between sat aq. NaHCO3 and EtOAc. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by preparative chromatography to afford the title compound (0.039 g, 38% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (s, 9 H), 1.47-1.66 (m, 4 H), 1.73-1.84 (m, 1 H), 2.09-2.17 (m, 1 H), 2.18 (s, 3 H), 3.16 (d, 2 H), 6.53 (d, 1 H), 6.60 (s, 2 H), 7.14 (dd, 1 H), 7.24 (d, 1 H); MS (ES+) m/z 320 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:71][C@@H:72]([CH2:75][CH3:76])[CH2:73][OH:74]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:71][C@@H:72]([CH2:75][CH3:76])[CH2:73][OH:74])=[O:19])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](N)CO
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](CO)NC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 42 mg, 0.089 mmol) in DMF (4 ml) was added BOP (48 mg, 0.11 mmol) and DIPEA (23 mg, 0.10 mmol), followed by (S)-2-aminobutan-1-ol (16 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:17]
Reactant: [Br-]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C(C)(C)O)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
1-[3-tert-Butyl-5-(1-hydroxy-1-methylethyl)phenyl]ethanone (O2.100; 50 mg) was initially charged in THF (5 ml) while stirring at RT, and admixed with phenyltrimethylammonium tribromide (80 mg). After stirring at RT for 3 h, the mixture was left to stand overnight and admixed with water and saturated sodium hydrogencarbonate solution. Then it was extracted three times with EA, and the combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (10 g cartridge, n-heptane/EA gradient). 42 mg of the title compound were obtained. LC-MS rt: 1.10 min [M+H—H2O]+: 295.1 (met. b)
Reaction SMILES: [F:1][C:2]1[C:3]([S:13][CH:14]([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.[CH3:17][NH2:18].[BH4-].[Na+].[CH3:21][C:22]([O:25][C:26]([O:28]C(OC(C)(C)C)=O)=O)([CH3:24])[CH3:23]>CO>[F:1][C:2]1[C:3]([S:13][CH:14]([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][N:18]([CH3:17])[C:26](=[O:28])[O:25][C:22]([CH3:24])([CH3:23])[CH3:21]
Reactant: CN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)Sc1c(F)cc([N+](=O)[O-])cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Sc1c(F)cc([N+](=O)[O-])cc1CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 20A (635 mg, 2.61 mmol) in MeOH (10 mL), was added methylamine (33% in EtOH) (0.390 mL, 3.13 mmol). The mixture was stirred at rt for 3 h, then was cooled to 0° C. and treated with NaBH4 (119 mg, 3.13 mmol). The reaction was stirred at 0° C. for 2 h, then was concentrated. The residue was dissolved in THF (10 mL), treated with H2O (10 mL) and sat. NaHCO3 (10 mL). After stirring for 10 min, Boc2O (684 mg, 3.13 mmol) was added. The mixture was stirred at rt for 2 h, then the THF was evaporated. The mixture was extracted with EtOAc (2×). The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 40% ethyl acetate/hexanes) to give 20B (864 mg, 2.411 mmol, 92% yield) as a pale yellow oil. MS (ESI) m/z: 381.1 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.80-7.94 (2H, m), 4.68 (2H, d, J=20.6 Hz), 3.60-3.71 (1H, m), 2.92 (3H, d, J=10.5 Hz), 1.53 (5H, s), 1.43 (4H, br. s.), 1.27 (6H, d, J=6.3 Hz), 3:2 ratio of rotamers.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2C)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-methylphenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H22NO3 (M+H): 348.1594. Found 348.1603
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:60][CH:61]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[CH2:62][CH2:63][NH:64][C:65](=[O:67])[CH3:66]>CN1C(=O)CCC1.C(OC(NC1(C(O)=O)CCN(C2C3C=CNC=3N=CN=2)CC1)=O)(C)(C)C.NC(C1C=CC(Cl)=CC=1)CCNC(=O)C>[C:65]([NH:64][CH2:63][CH2:62][CH:61]([NH:60][C:48]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1)=[O:50])[C:68]1[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=1)(=[O:67])[CH3:66]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CC(=O)NCCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (98 mg, 0.26 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (62.2 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.085 mL, 0.52 mmol) in NMP (2 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. N-(3-amino-3-(4-chlorophenyl)propyl)acetamide (Intermediate 27) (39 mg, 0.17 mmol) in NMP (2 mL) was then added to the reaction and stirred for 1 hour. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-acetamido-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (1.04 g, 86%) as a white solid. m/z (ESI+) (M+H)+=570; HPLC tR=1.95 min.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:19](=[O:22])[CH2:20]Br)[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].[BrH:28]>C1C=CC=CC=1>[OH2:4].[BrH:1].[BrH:28].[CH2:23]([N:25]([CH2:2][C:3]([C:5]1[C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:19](=[O:22])[CH2:20][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH:8]=[CH:7][CH:6]=1)=[O:4])[CH2:26][CH3:27])[CH3:24].[CH2:23]([N:25]([CH2:2][C:3]([C:5]1[C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:19](=[O:22])[CH2:20][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH:8]=[CH:7][CH:6]=1)=[O:4])[CH2:26][CH3:27])[CH3:24].[BrH:1].[BrH:1]
Reactant: O=C(CBr)c1cccc2cc3c(C(=O)CBr)cccc3cc12
Reactant: CCNCC
Agent: Br
Solvent: c1ccccc1
Product: CCN(CC)CC(=O)c1cccc2cc3c(C(=O)CN(CC)CC)cccc3cc12
Product: O

Procedure:
A solution of 18.2 g of 1,5-bis(bromoacetyl)anthracene, (0.042 mole) and 12.5 g of diethylamine (0.17 mole) in 1.6 liters of benzene is refluxed for 2.5 hours. On cooling, excess saturated ethereal hydrobromic acid is added to precipitate the product as the dihydrobromide hemihydrate. Recrystallization of this salt from 200 ml of methanol yields 12 g of 1,5-bis(diethylaminoacetyl)anthracene dihydrobromide hemihydrate, m.p. 285°-6° C.
Reaction SMILES: P(Cl)(Cl)Cl.[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].O>N1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][CH2:13][C:14]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[Cl:17])=[O:16]
Reactant: O=C(O)CSc1ccccc1Br
Reactant: Nc1ccccc1Cl
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(CSc1ccccc1Br)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
PCl3 (0.39 mL, 4.45 mmol) was added to an ice-cold solution of 2-{(2-bromophenyl)thio}acetic acid (1.00 g, 4.05 mmol) and 2-chloroaniline (0.47 mL, 4.45 mmol) in pyridine (15 mL). The reaction mixture was stirred at room temperature for 30 min. Water (few drops) was added and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2) to give the title compound (957 mg, 66% yield) as a yellow solid.
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].[C:18](=[O:22])([O:20][CH3:21])[NH2:19]>C1(C)C=CC=CC=1>[CH3:21][O:20][C:18]([NH:19][C:2]1[C:3](=[O:5])[O:4][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH:6]=1)=[O:22]
Reactant: COC(N)=O
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Solvent: Cc1ccccc1
Product: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Temperature: 105 °C
Yield: 94 %

Procedure:
300 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid, 2680 ml of toluene, 13.4 g of p-totuenesulfonic acid and 133.8 g of methyl carbamate are placed into a 6 l 4-necked round-bottomed flask in an oil-bath, the mixture is heated to 105° C. for 4 hours with stirring, and the present water is removed azeotropically, the mixture is filtered and the solution is evaporated to dryness under vacuum, then the residue is triturated for about 2 hours with 1260 ml of Et2O, filtered washing with petroleum ether (40°-70° C.) and dried under vacuum at 60° C. 313.00 g are obtained. (Yield 94%).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21](=[S:24])[NH:22][N:23]=1.CC[O-].[Na+]>CCO>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[C:18]1[N:23]=[N:22][C:21]([S:24][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2ccc(=S)[nH]n2)c(C)c1
Reactant: BrCc1ccccn1
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(SCc3ccccn3)nn2)c(C)c1
Yield: 34.7 %

Procedure:
To a mixture of 2-(bromomethyl)pyridine hydrobromide (116 mg; 0.46 mmol) and 6-(2,4-dimethylphenyl)pyridazine-3(2H)-thione (Example 13a) (100 mg, 0.46 mmol) in EtOH (3 mL) was added EtONa (20% in EtOH, 25 μl) and the reaction was irradiated in a microwave at 140° C. for 4 min. The crude mixture was dried down and purified on silica gel (Eluent: 5% MeOH in DCM) to give 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethylthio)pyridazine (49 mg, 35%) as a white solid solid. 1H NMR (300 MHz, dMSO: δ 2.49 (s, 3H), 2.54 (s, 3H), 4.09 (s, 2H), 6.32-6.37 (m, 2H), 6.45-6.52 (m, 2H), 6.75-6.78 (d, 1H), 6.84-6.87 (m, 2H), 6.95-6.98 (t, 1H), 7.67-7.68 (d, 1H); MS (M+H, 308).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([C@@H:27]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:28]([O:53][CH3:54])[CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C@H:37]([O:51][CH3:52])[C@@H:38]([CH3:50])[C:39](=[O:49])[NH:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:31])[CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>O1CCCC1>[CH3:54][O:53][C@@H:28]([C@@H:27]([N:25]([CH3:26])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH2:18])[C@@H:55]([CH3:58])[CH2:56][CH3:57])[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C@H:37]([O:51][CH3:52])[C@@H:38]([CH3:50])[C:39](=[O:49])[NH:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:31]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To #72 (5.16 g, 6.47 mmol, 1 eq.) in tetrahydrofuran (10 mL, 0.65 M) was added diethylamine (10 mL). After 2 hours, the reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #73 (2414 mg, 65%). LC-MS: m/z 576.5 [M+H+], retention time=0.64 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.80-7.88 and 7.99-8.10 (2 m, total 1H), 7.14-7.31 (m, 5H), 3.17 and 3.18 (2 s, total 3H), 2.87 and 3.03 (2 br s, total 3H), 1.02-1.08 (m, 3H).
Reaction SMILES: CO[CH:3](COCCCCCCCC1C=CC(CCCCCCCC)=CC=1)[CH2:4]O.[CH2:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[C:43]([OH:53])(=O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:3]([O:51][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:42][CH:41]=1)=[O:53])[CH3:4]
Reactant: O=C(O)CCCCCC(=O)O
Reactant: CCCCCCCCc1ccccc1
Reactant: CCCCCCCCc1ccc(CCCCCCCOCC(CO)OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCCc1ccc(C(=O)CCCCCC(=O)OCC)cc1

Procedure:
The 2-methoxy-3-[7-(4-octylphenyl)-heptyloxy]-1-propanol used as starting material is obtained in the following manner: 4-octylbenzene is reacted with the ethyl ester acid chloride of pimelic acid in the presence of aluminium chloride in nitrobenzene to give 7-(4-octylphenyl)-7-oxoheptanoic acid ethyl ester (m.p. 38°-40° C.). Subsequent hydrogenation in the presence of palladium on charcoal in ethanol with the addition of some perchloric acid gives 7-(4-octylphenyl)-heptanoic acid ethyl ester (oily substance), reduction of which with lithium aluminium hydride gives 7-(4-octylphenyl)-heptanol (oily substance). Reaction with phosphorus tribromide gives the corresponding bromide (oil) which is reacted with the monosodium salt of 2-methoxy-1,3-propandiol.
Reaction SMILES: [CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[N:20]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH:23]=[CH:22][CH2:21]1>C(O)C>[ClH:7].[N:20]1([CH2:25][CH2:26][NH:27][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH2:24][CH:23]=[CH:22][CH2:21]1
Reactant: NCCN1CC=CC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: Cl
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCN4CC=CC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
To a suspension of 6 chloropurine riboside (1.27 g, 4.42 mmol) in 10 ml of absolute ethanol was added 2-(2,5-dihydro-1H-pyrrol-1-yl)-1-ethanamine (prepared in accordance with Arzneim. Forsch. 21 (12) 2089 (1971)) in an amount of 0.54 g (4.9 mmol). The reaction mixture was heated under reflux for 40 hours. Concentration of the reaction mixture in vacuo gave a residue which was chromatographed on cellulose powder (Whatman CC 31). The eluent was 85 parts n-butanol and 15 parts water. Fraction monitoring was accomplished by thin layer chromatography on silica gel (Kieselgel 60 F254) eluting with a mixture of 20 parts methanol, 79 parts methylene chloride and one part ammonium hydroxide. The chromatography gave a glass which was azeotroped with water 3 times to remove the n butanol. Lyophilization of the aqueous solution gave the title compound in an amount of 0.41 g (21g yield) as a white powder (mp 88°-105° C.)
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:3].[OH2:22].[CH2:23]([OH:25])[CH3:24]>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:1].[CH3:24][C:23]([OH:22])=[O:25]
Reactant: CCO
Reactant: O
Agent: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(CN)CCC[C@]21C
Product: CC(=O)O

Procedure:
The acetate salt of dehydroabietylamine was available in the form of technical-grade compositions. One was a tan colored paste containing 70% solids and 30% water. The other was an aqueus alcoholic solution of the salt which held 50% of solids. Each water soluble amine acetate was used as obtained to prepare 5% alcoholic solutions and then diluted with ethanol for 2.5% and 1.25% solutions.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[N:15]=[C:16]4[N:21]([C:13]=3[C:12]([CH3:23])=[C:11]([CH3:24])[N:10]=2)[C@@H:20]([CH3:22])[CH2:19][O:18][CH2:17]4)=CC=1.[OH-].[Na+].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[CH3:22][C@H:20]1[CH2:19][O:18][CH2:17][C:16]2=[N:15][C:14]3[C:9]([NH2:8])=[N:10][C:11]([CH3:24])=[C:12]([CH3:23])[C:13]=3[N:21]12
Reactant: COc1ccc(CNc2nc(C)c(C)c3c2nc2n3[C@@H](C)COC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc3n(c2c1C)[C@@H](C)COC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(4S)—N-(4-Methoxybenzyl)-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazin-9-amine (350 mg, 0.99 mmol) was dissolved in 15 mL of trifluoroacetic acid and stirred at ambient temperature overnight. The solvent was removed under reduced pressure to give an orange residue which was then treated with 30 mL of aqueous 10% NaOH solution and the mixture was stirred for 2 hours. The solution was then extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange solid. Chromatography (SiO2, 10-30% CMA/CHCl3) gave an off-white solid. Crystallization from acetonitrile gave (4S)-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazin-9-amine (115 mg) as a white powder, mp 264-267° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=[C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[CH:18][C:10]=4[C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)[NH:14][C:13]3=[O:19])[NH:34][C:33]=2[CH3:40])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-ylethyl)amide as a yellow solid (49.6 mg, 37%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26][C:27]([CH3:29])=O>C1COCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:26]([C:25]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH3:29])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[C:10](=[S:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
3-Trifluoromethylphenyl thiourea (3.00 g, 13.6 mmol), 4-cyanobenzaldehyde (3.57 g, 27.3 mmol) and ethyl acetoacetate (3.55 g, 27.3 mmol) are dissolved in 50 ml THF. Ethyl polyphosphate (4.50 g) is added and the reaction mixture is stirred at reflux temperature overnight. After cooling to room temperature, it is quenched with 50 ml of water and extracted with 100 ml ethyl acetate (2×). The combined organic layers are dried with sodium sulfate and the solvent is removed in vacua. The product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).