Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CC(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([O:1][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reaction time: 48 h

Procedure:
29.1 g of 4-hydroxy-4'-methoxybenzophenone (R. Martin et al., Monatsh, Chemie 110, 1057-1066 (1979)) are dissolved in 400 ml of dry acetone. Then, while stirring, 19.3 g of finely powdered K2CO3 and 16 ml of methyl bromoacetate are added, and the mixture is stirred at room temperature. The reaction is complete after 2 days. The precipitated mixture of salt and substance is filtered off with suction, and the filtrate is concentrated. Both residues are suspended in water, and the pH is adjusted to 3 with 2N HCl. The solid is filtered off with suction, washed with water and dried under high vacuum in a desiccator.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 94.9 %

Procedure:
The title compound (122 mg) was prepared according to Example 263 using 198 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 88 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C17H20FN3, 285.16; found, m/z 286.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.27 (m, 4H), 4.65-4.59 (m, 2H), 3.95-3.3.40 (m, 2H), 3.32-3.05 (m, 3H), 3.00-2.75 (m, 2H), 2.67-2.59 (m, 2H), 2.29-2.23 (m, 2H), 1.84-1.73 (m, 2H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)C>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([OH:33])=[O:42])=[CH:40][CH:39]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: O=C(O)c1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-amino-benzoic acid ethyl ester according to the procedure of Example 66. MS m/z 527; MS m/z 525.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:11][C@@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:10]([NH:11][C@@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(N[C@H](C)C2CCCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(N[C@H](C)C2CCCCC2)c2cccc(N)c2)cc1
Yield: 76.6 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(R)-1-cyclohexylethyl]amine (2.60 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.35 g) and sodium borohydride (1.12 g) were reacted, to afford the title compound (1.83 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (25 g, 124 mmol), 2-hydroxy-benzotrifluoride (22 g, 136 mmol) and triphenylphosphine (39 g, 149 mmol) in THF was added diethyl azodicarboxylate (23.5 mL, 149 mmol) dropwise at 0° C. The mixture was then warmed to room temperature and stirred for 14 h. The mixture was concentrated and diluted with Et2O, washed with 1 N NaOH and water and then dried over Na2SO4. The mixture was concentrated and diluted with Et2O/hexanes (35:65). The precipitated phosphine oxide was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with 35% Et2O/hexanes) to give tert-butyl 4-[2-(trifluoromethyl)phenoxy]-piperidine-1-carboxylate as a solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1([C:25]([CH2:27][N:28]2[C:34]3[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([CH:40]=O)=[N:31][CH:30]([NH:42][C:43]([NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[CH:47]=3)=[O:44])[C:29]2=[O:53])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:17]1([C:25]([CH2:27][N:28]2[C:34]3[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([CH:40]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:31][CH:30]([NH:42][C:43]([NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[CH:47]=3)=[O:44])[C:29]2=[O:53])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1cccc(NC(=O)NC2N=C(C=O)c3cccc(C)c3N(CC(=O)N3CCCCCCC3)C2=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(CC(=O)N2CCCCCCC2)c2c(C)cccc21
Yield: 77.8 %

Procedure:
To a suspension of sodium hydride (31 mg, 60% in mineral oil) in tetrahydrofuran was added ethyl diethylphosphonoacetate (195 mg) under stirring and cooling in an ice-bath. After stirring for 15 minutes, a solution of N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (300 mg) in tetrahydrofuran (5 ml) was added to the reaction mixture under the same conditions. The mixture was stirred at ambient temperature for 4 hours. To a reaction mixture was added 0.1N aqueous hydrochloric acid (20 ml) and the resultant mixture was extracted with ethyl acetate. The separated organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a residue, which was subjected to column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-((EZ)-2-(ethoxycarbonyl)ethenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin -3-yl]-N′-(3-methylphenyl)urea (266 mg, 77.8% yield) as crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH2:32]([N:34]([CH2:49][CH3:50])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](O)=[O:44])[CH3:38])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:49]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[N:8]=1)=[O:5])=[O:44])[CH3:38])[CH3:50]
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 30 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (74 mg, 0.28 mmol, 1.20 equiv), EDC.HCl (90 mg, 0.47 mmol, 2.01 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv). The resulting solution was stirred overnight at 30° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 1×10 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 58.5 mg (32%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.502-8.532(d, J=9.0 Hz, 1H), 8.277-8.286(m, 1H), 8.060(s, 1H), 7.851-7.966(m, 4H), 7.475-7.610(m, 5H), 6.949-6.958(m, 1H), 3.922(s, 2H), 3.450-3.485(m, 4H), 3.273-3.316(m, 2H), 3.035-3.108(m, 4H), 2.957-2.998(m, 2H), 2.449-2.475(m, 3H), 1.857-1.872(m, 4H), 1.666-1.683(m, 2H), 1.139-1.200(m, 6H). MS (ES, m/z): 676 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])(=O)=O.CC1C=CC=C(C)N=1.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:25])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[O:14][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: C[C@H](NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-hydroxypropyl)cyclopropanecarboxylate (1.58 g) in THF (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.56 mL) and 2,6-dimethylpyridine (1.05 mL) were added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give the title compound as a colorless oil (yield: 1.57 g, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:41]>C(N(CC)CC)C>[CH2:30]([O:29][CH2:28][CH2:27][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1](=[S:41])[NH2:2])=[CH:34][CH:33]=2)=[O:32])=[CH:13][CH:14]=1)[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH3:31]
Reactant: S
Reactant: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (e) (600 mg), pyridine (42 ml), triethylamine (6 ml) and H2S gas were reacted to give t-butyl 2-(2-ethoxyethyl)-3-(4-[3-(4-thiocarbamoylbenzoyl)ureido]phenyl)propionate (585 mg) as a yellow solid: m.p. 199°-201° C.; NMR Spectrum (DMSO-d6) 1.10 (3H, t), 1.30 (9H, s), 1.70 (2H, m), 2.62 (1H, m), 2.72 (2H, m), 3.37 (4H, m), 7.15 (2H, d), 7.49 (2H, d), 7.95 (2H, d), 8.03 (2H, d), 9.67 (1H, br s), 10.06 (1H, br s), 10.72 (1H, s), 11.09 (1H, s); Mass Spectrum m/Z 522 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: Nc1cncc(F)c1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene (5.69 g, 25.9 mmol) and 3-amino-5-fluoropyridine (2.6373 g, 23.53 mmol) in DMF (39.2 mL) was added potassium tert-butoxide (5.28 g, 47.1 mmol) and the solution was stirred under nitrogen at rt overnight. After 5 additional h, the mixture was poured into water (150 mL) and extracted with EtOAc (2×100 mL). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to provide the crude material as a orange solid. The orange solid was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(2-bromo-6-nitrophenyl)-5-fluoropyridin-3-amine as orange syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, s), 8.09 (1H, dd, J=8.1, 1.5 Hz), 8.03 (1H, dd, J=8.2, 1.4 Hz), 7.97 (1H, d, J=2.5 Hz), 7.88 (1H, t, J=1.9 Hz), 7.44 (1H, t, J=8.1 Hz), 6.77 (1H, dt, J=11.2, 2.3 Hz); LC-MS (ESI) m/z 312.0 [M+H (79Br)]+ and 313.9 [M+H (81Br)]+.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH3:10][C:11]1([CH3:32])[CH:20]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]([OH:31])=[CH:16][CH:17]=2)[O:12]1>>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:31][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:20][C:11]([CH3:32])([CH3:10])[O:12]2)=[CH:17][CH:16]=1)[CH3:3]
Reactant: CCN(CC)CCCl
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Agent: Cl
Product: CCN(CC)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1
Yield: 49 %

Procedure:
Reaction of 2-diethylaminoethylchloride hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7ol by an analogous method to that described in Example 7 (c) gave the title compound as a colourless oil in 49% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(O)C>Cl>[ClH:1].[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[N:11]=[C:10]([NH:12][C:13]34[CH2:14][CH:15]5[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]5)[CH2:20]3)[CH2:22]4)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: Clc1nc(NC23CC4CC(CC(C4)C2)C3)c2ccccc2n1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCO
Product: c1ccc2c(NC34CC5CC(CC(C5)C3)C4)nc(N3CCOCC3)nc2c1

Procedure:
A mixture of 5 g of 2chloro-4-(1-adamantylamino)quinazoline, 5 ml of morpholine, and 10 ml of ethanol was refluxed for 16 hours. The reaction mixture was suspended in 100 ml of 6 N hydrochloric acid. The precipitate which resulted was collected by filtration and recrystallized twice from 95 percent ethanol, giving 3.5 g of 2-morpholino-4-(1-adamantylamino)quinazoline hydrochloride; m.p. 319°-321°. The following analytical data were obtained:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:15]O)[CH2:13][CH3:14])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH2:15])[CH2:13][CH3:14])=[CH:10][CH:11]=1
Reactant: CCC(=NO)c1ccc(OCCOC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(N)c1ccc(OCCOC)cc1
Yield: 95.6 %

Procedure:
A solution of 1-(4-(2-methoxyethoxy)phenyl)propan-1-one oxime (1.5 g, 6.7 mmol) in tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (0.78 g, 20.55 mmol) in tetrahydrofuran (48 mL) at room temperature under nitrogen. After 18 hours the mixture was heated at reflux for 3 hours, then allowed to cool. 0.8 mL of water was added drop-wise, followed by 0.8 mL of 15% aq sodium hydroxide, and then 2.4 mL of water. After several minutes the mixture was filtered, and the residue washed twice with tetrahydrofuran. The combined filtrate and washings were concentrated in vacuo, leaving 1.34 g of clear golden oil, which was flash chromatographed on a column (5×10 cm) of silica gel eluting with Hxa/EtOAc/acetone 8:1:1 to afford 0.83 g of the product as a clear golden oil; mass spec ES+m/z=210 (m+1).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[NH:23][N:22]=[N:21][N:14]=2)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCC#N)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Reaction time: 6 h

Procedure:
A solution of 20.73 g. (75 mmoles) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentane nitrile, 14.63 g. (225 mmoles) of sodium azide, and 12.04 g. (225 mmoles) of ammonium chloride in 200 ml. of dimethylformamide was heated at 125° C. for about 17 hours. At this time an additional 9.75 g. (150 mmoles) of sodium azide and 8.02 g. (150 mmoles) of ammonium chloride were added and the heating was continued for an additional 6 hours. The reaction mixture was filtered hot and evaporated to dryness in vacuo yielding a viscous dark oil. The residue was treated with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo yielding an oil which crystallized upon cooling. The crystals were boiled with decolorizing carbon in ethyl acetate for about 30 minutes. The solution was filtered hot, and the filtrate was cooled in the refrigerator to yield orange-amber crystals. The crystals were collected by vacuum filtration and washed with ethyl acetate to give 6.49 g. of the title product, m.p. about 113.5°-115° C.
Reaction SMILES: C1(S([CH:10]([C:42]2[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]=2[CH3:50])[CH:11]=[C:12]([CH3:41])[CH:13](Cl)[CH2:14][CH2:15][C:16]([CH3:39])=[CH:17][CH:18]=[CH:19][CH:20]=[C:21]([CH3:38])[CH:22]=[CH:23][CH:24]=[C:25]([CH3:37])[CH:26]=[CH:27][C:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=2[CH3:36])(=O)=O)C=CC=CC=1.[OH-].[K+].O.C1(C)C=CC=CC=1>C(O)C>[CH3:50][C:43]1[CH2:44][CH2:45][CH2:46][C:47]([CH3:48])([CH3:49])[C:42]=1/[CH:10]=[CH:11]/[C:12](/[CH3:41])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36]
Reactant: CC(C=CC=C(C)C=CC1=C(C)CCCC1(C)C)=CC=CC=C(C)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Yield: 81.6 %

Procedure:
In a 50-ml round-bottom flask 1.32 g (purity: 40.9%, 0.76 mmole) of 1-phenylsulfonyl-4-chloro-1,18-di(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyloctadeca-2,7,9,11,13,15,17-heptaene was reacted with 0.8 g (purity: 85%, 12.1 mmoles) of potassium hydroxide in 15 g of ethanol at 45° C. for 3 hours. Then water and toluene were added and the reaction mixture was separated. The organic layer obtained was washed with water and the solvent was removed therefrom to obtain 1.95 g (purity: 17.2%, 0.62 mmole, yield: 81.6%) of β-carotene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([OH:19])[CH:5]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([O:19][C:21](=[O:23])[CH3:22])[CH:5]=1
Reactant: COC(=O)c1cc(O)c(N=Nc2ccccc2)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)c(N=Nc2ccccc2)c(OC(C)=O)c1

Procedure:
A mixture of 27 g. of 3,5-dihydroxy-4-phenylazo-benzoic acid methyl ester, 250 ml. of glacial acetic acid and 21 g. of acetic anhydride was stirred at 100° C. for 3 hours, complete solution occurring. The resulting solution was evaporated to dryness under reduced pressure. The residue was taken up in methanol and again evaporated to dryness. The residue was recrystallized from dimethylformamide/methanol and there was obtained 3-acetoxy-5-hydroxy-4-phenylazo-benzoic acid methyl ester having a melting point of 162° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1C

Procedure:
210 g of methyl 2-methyl-3-nitrobenzoate (1.08 mol) were dissolved in 4 l of methanol, 21 g of Pd/C were added and the mixture was subsequently hydrogenated at ambient pressure. After the reaction had ended, the catalyst was filtered off and the solvent was removed. Yield: 178 g (quant.).
Reaction SMILES: I[C:2]1[N:19]=[C:18]2[C:5](=[N:6][CH2:7][N:8]2[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:4]([NH:21][CH3:22])(N)[N:3]=1.[CH2:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]#[CH:25].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:16][CH2:15][C@H:14]1[O:17][C@@H:9]([N:8]2[CH:7]=[N:6][C:5]3[C:18]2=[N:19][C:2]([C:25]#[C:24][CH2:23][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3][C:4]=3[NH:21][CH3:22])[C@H:10]([OH:11])[C@@H:12]1[OH:13]
Reactant: C#CCOc1ccccc1
Reactant: CNC1(N)N=C(I)N=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1nc(C#CCOc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 2-iodo-6-methylamino adenosine (50 mg) and prop-2-ynyloxybenzene (0.022 mL, 0.16 mmol) in N,N-dimethylformamide (1 ml) and triethylamine (0.021 mL, 0.16 mmol) at 23 C was added copper iodide (5 mg, 0.026 mmol) and dichlorobis-(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) catalyst. After being stirred in a sealed reaction-vial at 80° C. for 6 hours, the reaction was concentrated in vacuo, and the residue purified by preparatory thin layer chromatography (methylene chloride:methanol 9:1) to afford (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol, a compound of Formula I. MS: 412.1 (M+1).