Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[C:21]([CH2:32][C:33]([O:35]C)=[O:34])([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:20][CH2:19]4)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[C:21]([CH2:32][C:33]([OH:35])=[O:34])([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:20][CH2:19]4)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4cccc(Cl)c4)s3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4cccc(Cl)c4)s3)ccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Lithium hydroxide (0.05 g, 1.18 mmol) was added to a solution of 26D2 (0.12 g, 0.236 mmol) in 8 mL of ethanol-water (3:1) mixture, and the reaction mixture was stirred at room temperature for 1 h. After the solvent was removed in vacuo, the residue was dissolved in water. The aqueous layer was acidified by addition of saturated citric acid solution until pH 2 was attained. The resulting solution was cooled to 0° C. and solids obtained were filtered off and dried under vacuum to afford the title compound (0.07 g, 59%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.95 (m, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.5 (m, 2H), 7.35 (t, J=8.1 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.14-2.80 (m, 4H), 2.69 (d, J=18.4 Hz, 1H), 2.46-2.31 (m, 2H), 2.12 (m, 1H). ESI-MS m/z: 495 (M+H)+; HPLC purity: 99%
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=[C:3]1[C:22]([O:24]CC)=O.[ClH:27].[NH2:28][C:29]([NH2:31])=[NH:30].[CH3:32][O-].[Na+]>CO>[ClH:27].[CH3:32][NH:30][C:29]([NH2:31])=[N:28][C:22]([C:3]1[NH:2][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:24]
Reactant: N=C(N)N
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)CCc3ccccc3)c2n1C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2cccc(NC(=O)CCc3ccccc3)c2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 0.42 g (1.21 mmol) of ethyl 1-methyl-7-(3-phenylpropionamido)-2-indolecarboxylate, 2.31 g (24.2 mmols) of guanidine hydrochloride and a solution of 1.31 g (24.2 mmols) of sodium methoxide in 30 ml of methanol. 1-Methyl-7-(3-phenylpropionamido)-2-indoloylguanidine hydrochloride was obtained in an amount of 0.16 g (34.9%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].[CH2:12]([N:14]([CH2:23][CH3:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH3:13].O>CN(C)C=O>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([N:14]([CH2:12][CH3:13])[CH2:23][CH3:24])=[CH:16][CH:17]=2)[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1ccc(C=C2SC(=S)N(CC(=O)O)C2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In 30 ml of dimethylformamide were dissolved 3.82 g of 3-carboxymethylrhodanine and 3.54 g of p-diethylaminobenzaldehyde, and the solution was stirred at 100° C. for 3 hours. After termination of the reaction, the solution was poured into water, and the formed precipitate was recovered by filtration, washed with water and recrystallized from acetone to obtain 3-carboxymethyl-5-(p-diethylaminobenzylidene)rhodanine (the yield was 87%).
Reaction SMILES: C([C:4]1[N:5]=[C:6]2[C:12]([CH2:13][CH3:14])=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([CH3:26])[O:25][CH2:24][CH2:23][O:22]4)=[CH:17][CH:16]=3)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:7]2=[N:8][CH:9]=1)C=C.C[N+]1([O-])CC[O:39]CC1.[CH3:43][C:44]([CH3:46])=[O:45]>O.CC(O)(C)C>[CH2:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH2:43][CH:44]([OH:45])[CH2:46][OH:39])[N:5]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:11]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH3:26])[O:25][CH2:24][CH2:23][O:22]2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cnc2c(n1)c(CC)c(-c1ccc(C3(C)OCCO3)cc1)n2COCC[Si](C)(C)C
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(CC(O)CO)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
2-Allyl-7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.323 g, 0.673 mmol, Preparation #14) in acetone (9 mL) and water (1 mL) was treated with NMO (0.083 g, 0.707 mmol) and 2.5 wt % OSO4 in t-BuOH (0.42 mL, 0.034 mmol). The mixture was stirred at rt for about 1.5 h. The mixture was concentrated under reduced pressure and then the material was purified using a 10 g silica column with 95:5 DCM/MeOH as an eluent to give 3-(7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)propane-1,2-diol (0.21 g, 61%): LC/MS (Table 2, Method b) Rt=2.55 min; MS m/z 514 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31].O>C1C=CC=CC=1>[CH2:29]([NH:32][C:33]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=2)[C:13]1=[O:26])=[O:34])[CH:30]=[CH2:31]
Reactant: C=CCN=C=O
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCNC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.040 g, 0.10 mmol) and potassium fluoride (0.009 g, 0.147 mmol) in dry benzene (6 ml) was added allylisocyanate (0.010 g, 0.10 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was triturated with ethyl acetate, filtered and filtrate was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 0.020 g (41%); 1H NMR (DMSO-d6, 300 MHz): δ 9.653 (s, 1H), 8.723-8.761 (t, 1H), 7.971-8.001 (d, 1H, J=9 Hz), 7.874-7.903 (d, 2H, J=8.7 Hz), 7.769-7.798 (d, 2H, J=8.7 Hz), 7.723-7.761 (dd, 1H, J=9, 2.1 Hz), 6.808-6.814 (d, 1H, J=1.8 Hz), 5.904-5.996 (m, 1H), 5.234-5.296 (dd, 1H, J=17.1, 1.2 Hz), 5.134-5.173 (dd, 1H, J=10.5, 1.2 Hz), 4.010-4.045 (t, 2H), 1.806 (s, 6H); MS: m/z 492 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(C)(CCO)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCOCc1cc(Br)ccc1F)CNC(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-3,3-dimethylbutan-1-ol (1.0 g, 4.60 mmol) in tetrahydrofuran (33 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.06 ml, 5.06 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0° C. and stirred for about four hours. The cloudy reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.38 grams (74%) of the title intermediate as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[S:15][N:14]=1.C(OC(C)C)(C)C>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: Oc1nsc(SCc2ccc(Cl)cc2)n1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)n1sc(SCc2ccc(Cl)cc2)nc1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.2 ml of triethylamine and 6 ml of methyl isocyanate were added to a solution of 12.9 g of 3-hydroxy-5-(p-chlorobenzylthio)-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and after stirring the mixture for 2 hours at 20° C, isopropyl ether was added thereto. The mixture was filtered and the crystals were empasted with isopropyl ether and dried to obtain 15 g of 2-(N-methylcarbamoyl)-5-(p-chlorobenzylthio)-1,2,4-thiadiazole-3-one melting at 140° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:31][C:22]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1ccc(C(=O)NNC(=O)c2ccc3nc(-c4c(C)cccc4C)[nH]c3c2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(-c3ccc4nc(-c5c(C)cccc5C)[nH]c4c3)o2)cc1
Reaction time: 0.25 h

Procedure:
To a 5 mL microwave vial was added 0.2225 g (0.537 mmol) of 4-Methoxy -benzoic acid N′-[2-(2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide, 4 mL of THF, and 0.2558 g (1.07 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 15 min. The crude solution was concentrated and the residue was purified by silica gel column chromatography (EtOAc/DCM, 1:9 to 6:4) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 6 H) 4.02 (s, 3 H) 7.35 (dd, J=15.73, 8.27 Hz, 4 H) 7.50 (t, J=7.64 Hz, 1 H) 7.87 (d, J=8.34 Hz, 0.5 H) 8.04 (d, J=8.46 Hz, 0.5 H) 8.15 (dd, J=12.19, 8.65 Hz, 1 H) 8.24-8.29 (m, 2 H) 8.38 (s, 0.4 H) 8.60 (s, 0.5 H) 13.15 (d, J=14.27 Hz, 1 H). MS (m/z) 397.2 M (+1), tR=1.48, Meth 10
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1)([CH3:42])[CH3:43]
Reactant: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of Intermediate A (102 mg, 0.63 mmol) in DMF (1.5 mL) was added NaH (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was stirred at RT for 5 min, then a solution of Intermediate 94b (240 mg, 0.57 mmol) in DMF (1.5 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (219 mg, 68%). LCMS (Method 3): Rt 2.65 min, m/z 565 [MH+].
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH3:30])[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH:28]([CH3:30])[CH3:29]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3C(C)C)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[C:15]([CH3:20])=[N:16][O:17][C:18]=2[CH3:19])[CH:12]=1)=[O:6].[H-].[Na+]>CN(C=O)C>[CH3:20][C:15]1[C:14]([CH2:13][N:11]2[CH:12]=[C:8]([N:7]3[CH2:2][CH2:3][NH:4][C:5]3=[O:6])[CH:9]=[N:10]2)=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCCCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCNC2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
1-(2-chloroethyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)1H-pyrazol-4-yl)urea (example 10-88b) (115 mg, 0.39 mmol) and 60% sodium hydride (17 mg, 0.42 mmol) in DMF (2 mL) were stirred at 0° C. for 15 minutes then allowed to warm up to room temperature with stirring for 2 hours. The reaction was quenched with methanol and concentrated on the rotovap. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (98 mg, 97%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.10 (s, 3H), 2.37 (s, 3H), 3.35-3.39 (m, 2H), 3.61 (d, J=8.8 Hz, 1H), 3.63 (d, J=10.4 Hz, 1H), 5.07 (s, 2H), 6.71 (s, 1H), 7.42 (s, 1H), 7.74 (s, 1H). MS M+H calculated 262.12. Found 262.1.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[CH2:5]([Mg]Br)[CH3:6].[NH:9]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][O:16][C:17]2=[O:18])[C:10]([CH3:12])=[O:11].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:5]([C:17]([OH:18])([CH2:2][CH3:3])[C:19]1[CH:20]=[CH:21][CH:22]=[C:13]([NH:9][C:10]([CH3:12])=[O:11])[C:14]=1[CH2:15][OH:16])[CH3:6]
Reactant: CC(=O)Nc1cccc2c1COC2=O
Reactant: CC[Mg]Br
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cccc(NC(C)=O)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 9.5 g of metallic magnesium and 60 ml of diethyl ether was slowly added with stirring a solution of 43 g of ethyl bromide in 120 ml of diethyl ether. The mixed solution was heated for 15 minutes under refluxing and left to stand for cooling. The solution of ethylmagnesium bromide thus prepared above in ether was slowly added with stirring at inner temperature of below 10° C. to a solution of 7.5 g of 4-acetaminophthalide in 120 ml of tetrahydrofuran, followed by stirring at room temperature overnight. After the reaction was over, the reaction mixture was poured into aqueous ammonium chloride solution (saturated) under ice cooling and extracted twice with 400 ml of ethyl acetate. The combined extracts were concentrated to obtain an oily substance. The oily substance was purified by silica gel column chromatography to obtain 8.0 g of α,α-diethyl-2-hydroxymethyl-3-acetaminobenzyl alcohol in the colorness oily substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[S:23][C:24]([CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[S:23][C:24]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1sc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(-c3ccccc3)c(CCC(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionate (360 mg), lithium hydroxide hydrate (83.5 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2.1 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionic acid (338 mg, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 121–122° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13]NN(CC)NC.[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([CH:30]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>O1CCCC1.C(Cl)Cl>[ClH:20].[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([CH:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:1]([NH:8][CH2:12][CH2:11][N:10]([CH3:9])[CH3:13])=[O:2])[CH2:31]2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(NC)NC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCNC(=O)N1CCCC(S(=O)(=O)c2cccc(Cl)c2)C1
Product: Cl

Procedure:
A solution of 3.57 g (0.022 mole) of 1,1'-carbonyldiimidazole and 1.78 g (0.020 mole) of N,N-dimethylaminoethylamine in 200 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 4.63 g (0.0179 mole) of 3-[(3-chlorophenyl)sulfonyl]piperidine (free base) in 100 ml of tetrahydrofuran was added and the mixture was refluxed for 22 hr. The solvent was removed in vacuo to give an oil. The oil was dissolved in methylene chloride and the solution was extracted with 6 portions of water, the water washes being discarded. The methylene chloride phase was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil, the free base of the title compound. The free base was converted to the hydrochloride salt as in Example 14 to give 3.39 g (46.2%) of white crystals, m.p. 181°-183° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)=[O:4].[C:11]12([C:21](O)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8](=[N:10][C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cnc(N)s1
Product: COC(=O)c1c[nH]c(=NC(=O)C23CC4CC(CC(C4)C2)C3)s1
Yield: 39.3 %

Procedure:
2-Amino-thiazole-5-carboxylic acid methyl ester (1.58 g, 10.0 mmole) and 1-adamantanecarboxylic acid (1.98 g, 11 mmol) were processed as described in Example 3B to afford 1.26 g (49%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62-1.79 (m, 6 H) 1.86 (d, J=3 Hz, 6 H) 1.99 (s, 3 H) 3.26 (s, 3 H) 3.64-3.81 (s, 3 H) 8.30 (s, 1 H); MS (DCI/NH3) m/z 321 (M+H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH3:10])[CH2:3][CH2:2]1.I>C(O)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1
Agent: I
Solvent: CC(=O)O
Product: CC(CCN1CCOCC1)c1ccccc1-c1ccccc1

Procedure:
A mixture of 3.1 g of 1-morpholino-3-p-biphenylyl-butan-3-ol, 10 ml of 67% hydriodic acid and 18 ml of acetic acid is heated at 150° for 1.5 hours. 1-Morpholino-3-p-biphenylyl-butane is obtained after cooling and working up in the customary manner.
Reaction SMILES: [CH:1]1[C:10]([OH:11])=[C:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][C:2]=1[CH3:3].C(O)(=O)C.S(=O)(=O)(O)O.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>O.CCCCCC>[CH3:22][C:21]([C:5]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:10]([OH:11])[CH:1]=[C:2]([CH3:3])[CH:4]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(O)c(C(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Thymol (360.0 g, 2.4 mol) was added to a cooled (0° C.) mixture of acetic acid (600 mL) and sulfuric acid (144 mL). The mixture was allowed to warm to 20°-25° C., after which, t-butanol (228 mL, 2.4 mol) was added dropwise over a one hour period. The mixture was stirred at 25° C. for one hour. An additional portion of t-butanol (114 mL, 1.2 mol) was then added dropwise over a one hour period. The mixture was stirred at 25° C. for 4 hours after which the mixture was poured into hexane (1 L) and water (1 L) and the layers separated. The aqueous layer was extracted with hexane (2×100 mL). The combined extracts were washed with water (3×200 mL), saturated sodium bicarbonate solution (2×100 mL), water (200 mL) and brine (2×100 mL). The solvents were evaporated and the residue distilled to provide 262 g (bp 135°-145° C., 6 mm) of material which was crystallized from hexane to give 215.2 g (43% yield, GLC purity 99.5%) of 4-(1,1-dimethylethyl-2-(1-methylethyl)-5-methylphenol; mp 75.5°-76.5° C.; 1H-NMR (CDCl3)δ 1.24 (6H, d, J=7 Hz), 1.38 (9H, s), 2.42 (3H, s), 2.95-3.42 (1H, m), 4.67 (1H, broad s), 6.48 (1H, s), 7.13 (1H, s); IR (CHCl3)νmax 3575, 3340, 2940, 1605, 1670, 1490, 1450, 1400 cm-1 ; MS m/e 206, 191, 149, 121; UVλmax (ethanol) 223 nm (ε=5650), 253 nm (ε=2260).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([CH2:32][CH2:33]Br)=[CH:27][C:26]=1[Cl:35]>>[ClH:31].[NH2:24][C:25]1[C:26]([Cl:35])=[CH:27][C:28]([CH2:32][CH2:33][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[C:14](=[O:15])[CH2:13][C:12]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=4[CH2:10][CH2:9]3)[CH2:2]2)=[CH:29][C:30]=1[Cl:31]
Reactant: Nc1c(Cl)cc(CCBr)cc1Cl
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3cc(Cl)c(N)c(Cl)c3)C1)CC2
Product: Cl

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(4-amino-3,5-dichloro-phenyl)-ethylbromide analogously to Example 1.