Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([S:13]([OH:16])(=[O:14])=[O:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)O)cc21
Agent: O=S(=O)(O)O
Product: CC(=O)N1CCc2cc([N+](=O)[O-])c(S(=O)(=O)O)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
16.0 g (66 mmol) of 1-acetylindoline-6-sulfonic acid (Compound 2-2 in Scheme II) was dissolved in 160 mL of cone, sulfuric acid. The solution was cooled to 0° C. using ice/water bath. Nitric acid (90%, fuming) (3.0 mL, 1.1 eqv.) was added dropwise over 10 min. The resulting pale yellow solution was stirred at 0° C. for 2 h and then slowly poured onto 200 g of ice. The crystals formed were collected by filtration and washed successively with cold water acetone and ether. Drying under vacuum over P2O5 afforded 18.2 g of the title compound. 1H MNR (d6-DMSO) δ: 8.47 (s, 1H), 7.40 (s, 1H), 5.54 (OH+H2O), 4.12 (t, J=8.5 Hz, 2H), 3.13 (t, J=8.5 HZ, 2H) and 2.17 (s, 3H). 13C NMR (d6-DMSO) δ: 169.19, 144.18, 143.17, 139.54, 133.54, 119.10, 115.23, 48,67, 26.75 and 24.01.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[C:11](O)=O.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:11]1[NH2:14]
Reactant: O=C(O)[C@@H]1Cc2ccccc2[C@H]1O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H]1CCc2ccccc2[C@@H]1O
Temperature: 2.5 °C

Procedure:
The hydrazide of (1S,2R)-1-hydroxy-2-carboxyindane (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-hydroxy-2-aminotetralin is isolated as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)CCCOc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(OCCCC(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
ethyl 4-[(4-{[3-methyl-6-(methyloxy)-2-phenyl-1 naphthalenyl]oxy}phenyl)oxy]butanoate (288) (0.300 g, 0.638 mmol) was dissolved in a 1:1 THF:EtOH (1:1, 30 mL) mixture. To the above mixture was added 1 N NaOH (6.4 mL) at room temperature and heated to 70° C. The reaction mixture was kept at that temperature for 2 h and cooled at RT. Reaction mixture was concentrated under reduced pressure to afford the residue and the residue was acidified with 25% aqueous HCl (30 mL), and then extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (1×30 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the crude product which was purified by flash SiO2 column chromatography using hexanes:EtOAc (19:1 to 1:1) as an eluent to afford 0.247 g (88%) of the title product (289) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 2H), 7.24 (m, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.05 and 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.66 (d, J=9.2 Hz, 2H), 6.47 (d, J=9.2 Hz, 2H), 3.85 (s, 3H), 3.79 (t, J=6.4 Hz, 2H), 2.30 (t, J=7.2 Hz, 2H), 2.16 (s, 3H), 1.83 (quintet, J=6.8 Hz, 2H). LCMS (ESI) m/z 443.18 (M+H)+.
Reaction SMILES: [OH-].[Na+].O.[CH:4]([O:7][C:8](Cl)=[O:9])([CH3:6])[CH3:5].[CH2:11]([N:18]1[CH2:25][CH:24]2[CH2:26][CH:20]([CH2:21][NH:22][CH2:23]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:19][CH:20]2[CH2:26][CH:24]([CH2:23][N:22]([C:8]([O:7][CH:4]([CH3:6])[CH3:5])=[O:9])[CH2:21]2)[CH2:25]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CN2CC3CNCC(C3)C2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N1CC2CC(CN(Cc3ccccc3)C2)C1
Reaction time: 3 h
Yield: 95 %

Procedure:
NaOH (6.0 mL; 10M), H2O (10 mL) and iso-propylchloroformate (55 mmol) were added to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (10.8 g; 50 mmol; see Example E above)-in DCM (50 mL) The reaction mixture was stirred for 3 h and the phases were then separated. The organic phase -was washed with H2O and brine, dried and concentrated to give the sub-title compound in a 95% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:16][C:4]1[S:3][C:2]2=[N:1][C:21]([CH3:22])=[C:20]([C:19](=[O:24])[C:18]([F:26])([F:25])[F:17])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)=[C:6]2[CH:5]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc(Cl)cc1C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(Cl)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-5-chloro-thiophen-3-yl)-(4-fluoro-phenyl)-methanone in 2 ml acetic acid was added 0.025 ml (0.19 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 70° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 8 mg (11%) 1-[2-chloro-4-(4-fluoro-phenyl)-6-methyl-thieno[2,3-b]pyridin-5-yl)-2,2,2-trifluoro-ethanone as an orange oil. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:10]([P:14](Cl)[C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>O1CCCC1.[Cu](Br)Br.C1(C)C=CC=CC=1>[C:10]([P:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Br[Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
In a 200 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 8.2 g (0.065 mol) of benzyl chloride and 2.1 g (0.085 mol) of metallic magnesium in 50 ml of tetrahydrofuran, and 0.055 g (0.0003 mol (corresponding to 0.6% by mol)) of copper(II) bromide were placed. To the contents of the flask, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride was dropwise added as it is without being dissolved in a solvent, over a period of 1 hour at a temperature in the vicinity of 40° C. After the dropwise addition was completed, stirring was conducted at a temperature of 40° C. to 45° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 145° C. to 150° C. under reduced pressure of 0.5 Torr were collected. As a result, 10.6 g (purity: 98.5%) of the aimed di-tert-butylbenzylphosphine was obtained as an oily substance. The yield was 88.3%.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])C.[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](F)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:32]#[C:33][CH3:34]>C1COCC1>[CH3:13][O:15][C:16]([C:18]1([S:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:31][C:32]#[C:33][CH3:34])=[CH:41][CH:40]=2)(=[O:44])=[O:43])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17]
Reactant: CC#CCOc1ccc(S(=O)(=O)F)cc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
To a solution of diisopropylamine (1.58 mL, 11.3 mmol) in THF (25 mL) at 0° C. was added 2.5M n-BuLi (4.68 mL, 11.7 mmol) and the resulting mixture was stirred for 15 min at that temperature. The reaction mixture was cooled to −78° C. and a solution of 1-(tert-butyl)-4-methyl 1,4-piperidinecarboxylate (prepared from example 30, step 1) (2.67 g, 11.0 mmol) in THF (40 mL) was added. The resulting mixture was stirred for 1 hand a solution of 4-but-2-ynyloxy benzenesulfonyl fluoride (2.5 g, 11.0 mmol) in THF (25 mL) was added into it. After sting for 4 h at rt, the reaction was quenched with satd. aqueous NH4Cl solution and extracted with EtOAc, dried over anhydrous Na2SO4. The crude product was purified by silica gel chromatography to obtain 2.6 g (53%) of the product as a solid; 1H NMR (300 MHz, CDCl3) δ1.44 (s, 9H), 1.87 (m, 3H), 1.98 (m, 2H), 2.32 (m, 2H), 2.62 (m, 2H), 3.74 (s, 3H), 4.17 (m, 2), 4.74 (m, 2H), 7.09 (d, 2H, J=7.2 Hz), 7.71 (d, 2H, J=7.2 Hz).
Reaction SMILES: B.CSC.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH3:17])([CH3:16])[CH2:13][OH:14]
Reactant: CC(C)(C(=O)O)c1ccccc1F
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccccc1F
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Borane-methyl sulfide (2M in THF, 12.35 mL) was added dropwise to a solution of 2-(2-fluorophenyl)-2-methylpropanoic acid (example 90, step c) (1.5 g) in THF (30 mL). The reaction mixture was stirred at 20° C. for 8 hours. The mixture was quenched by careful addition of methanol until evolution of gas ceased. The solvents were removed under reduced pressure and the residue azeotroped with toluene. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.3 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH2:7].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CN(C)C(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: Nc1ncccn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ncccn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of pyrimidine-2-amine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.0 mmol) in N,N-dimethylacetamide (50 ml) was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, and the mixture was stirred for 40 minutes with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (2.57 g, 45.2%) as a solid was collected by filtration.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17].[CH2:43]([O:55][CH2:56][CH:57]([CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].N1C=CC=CC=1>O1CCCC1>[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[CH:31]([C:35]([O:37][CH:57]([CH2:56][O:55][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:36])[CH:32]=[CH:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: CCCCCCCCCCCCOCC(O)COCCCCCCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOCC(COCCCCCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
Dicyclohexylcarbodiimide (3.96 g) was added to a stirred solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.58 g] and 2-n-dodecyloxy-1-n-dodecyloxymethylethanol (8.23 g) in a mixture of dry pyridine (60 ml) and dry tetrahydrofuran (20 ml) at 3° C., and then stirred at 0° to 5° C. for 4.75 hours and further at room temperature for an hour. The resultant mixture was poured into ice water (350 ml) and extracted with ethyl acetate (500 ml). Water (50 ml) was added to the extract and adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (100 ml×2) and an aqueous solution of sodium bicarbonate in turn, and dried over anhydrous magnesium sulfate. After evaporating the solution in vacuo, the residue was subjected to column chromatography on silica gel (266 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [6.24 g] of 2-n-dodecyloxy-1-n-dodecyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer).
Reaction SMILES: COP(=O)OC.[C:7](=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([CH:25]=O)[N:22]=[C:21]2[CH3:27])=[CH:16][CH:15]=1>CO>[C:25]([C:23]1[N:22]=[C:21]([CH3:27])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH:24]=1)#[CH:7]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(C=O)cn1-c1ccc(F)cc1
Agent: CO[PH](=O)OC
Agent: [K+]
Solvent: CO
Product: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester is dissolved in methanol. Potassium carbonate is added. A solution of 1-(4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde in methanol is added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight. The desired compound 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is obtained.
Reaction SMILES: O.Cl.Cl[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[OH:9]/[N:10]=[C:11]1/[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[C:14]2[C:18]([CH3:19])=[CH:17][S:16][C:15]/1=2.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:7][N:6]([CH2:5][CH2:4][O:9]/[N:10]=[C:11]1/[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[C:14]2[C:18]([CH3:19])=[CH:17][S:16][C:15]/1=2)[CH3:8]
Reactant: CN(C)CCCl
Reactant: Cc1csc2c1-n1cccc1/C2=N/O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCN(C)C
Yield: 77 %

Procedure:
1.32 g of water and then 3.91 g of 1-chloro-2-(N,N-dimethylamino)ethane hydrochloride and 5 g of (Z)-8-hydroxyimino-3-methylthieno[2,3-d]pyrrolo[1,2-a]pyrrole (Preparation 36) are added to 6.99 g of sodium carbonate in 200 ml of anhydrous acetone. The reaction mixture is heated at reflux for 40 hours, then the acetone is removed and the residue is taken up in 100 ml of water and then extracted with 200 ml of diethyl ether. The ethereal phase is washed with water, decanted off and then dried over magnesium sulfate, and subsequently concentrated to dryness to yield the title product in the form of an oil.
Reaction SMILES: [CH:1]([N:4]([CH:36]([CH3:38])[CH3:37])[CH2:5][CH2:6][O:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:15]=2[CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=3)[CH2:23]2)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(C(C)C)CCOC1C=CC(CNC2C=C(O)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=CC=1)(C)C>>[CH:36]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][O:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[CH:10][CH:9]=1)([CH3:37])[CH3:38]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(O)cc1NCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Product: CC(C)N(CCOc1ccc(CNc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1)C(C)C
Yield: 43.8 %

Procedure:
Synthesized from [4-(2-diisopropylaminoethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (70 mg) according to an analogous synthetic method to Example 111, 3-[4-(2-diisopropylaminoethoxy)benzylamino]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenol (25 mg) and 6-{2-[4-(2-diisopropylaminoethoxy)benzylamino]-4-hydroxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol (29 mg) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2C(=O)C3=CC=CC=C3[C:10]2=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1.O.[NH2:30]N>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:30])=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1
Reactant: NC(N)=Nc1nc(-c2cc(Cl)cc(CN3C(=O)c4ccccc4C3=O)n2)cs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NC(=O)NCc1cc(Cl)cc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A mixture of 4-(4-chloro-6-phthalimidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.10 g) and hydrazine mono-hydrate (400 mg) in ethanol (200 ml) was refluxed for 5 hours. After the solvent and excess hydrazine monohydrate were removed by concentration, water (10 ml) was added to the residue and the suspension was adjusted to pH 2 with 6N-hydrochloric acid. The resulting precipitate was filtered off, washed with water (5 ml) and the filtrate and the washing solution were combined. After the solution was readjusted to pH 4 with aqueous sodium bicarbonate, potassium cyanate (320 mg) was added to the solution and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was readjusted to pH 4 with 6N-hydrochloric acid, additional potassium cyanate (215 mg) was added and the solution was further stirred for 8 hours. The mixture was made basic to pH 10 with aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-chloro-6-ureidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:17][NH2:18]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:18][CH3:17])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while 5 ml (0.06 mole) of 40% aqueous methylamine was added slowly, stirring was continued for 18 hr. The reaction mixture was diluted with 200 ml of ice water, and the solid which formed was collected by filtration, 6.9 g. The crude wet solid was recrystallized from ethanol/water to yield 3.65 g (66.3%) of greenish-gray plate-like crystals, m.p. 158°-159° C.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccc(CC(=O)O)cc1
Agent: Cl
Product: COc1ccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)cc1
Yield: 66.1 %

Procedure:
By working in accordance with Use Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride and 0.28 g of (4-methoxyphenyl)-acetic acid, 0.61 g of (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-methoxyphenyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 211° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>[Cu]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.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(N2CCC(C)(C)c3ccc(Br)cc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Temperature: 75 °C

Procedure:
To a solution of 0.20 g (0.6 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)-7-bromoquinoline (Compound 1) in 2.90 g (4.0 mL, 29 mmol) of triethylamine were added 0.030 g (0.16 mmol) of copper(I) iodide, 0.35 g (0.50 mL, 3.5 mmol) of (trimethylsilyl)acetylene and 0.074 g (0.11 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting mixture was heated at 75° C. for 20 hours. The reaction mixture was cooled, methylene chloride was added and the mixture was adsorbed onto silica gel. The mixture was separated by flash chromatography (hexanes) to give the title compound as a yellow solid. PNMR (300 MHz, CDCl,) d 0.20 (9 H, s), 1.35 (6 H, s), 1.84 (2 H, t, J=6.0 Hz), 2.39 (3 H, s), 3.59 (2 H, t, J=6.0 Hz), 6.78 (1 H, d, J=1.7 Hz), 6.84 (1 H, rid, J=7.8,1.7 Hz), 7.12-7.17 (5 H, several overlapping d's).