Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH3:9]>CO>[CH2:1]([NH:6][C:7]([NH2:9])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N
Reactant: CCCCCN=C=S
Solvent: CO
Product: CCCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Pentylisothiocyanate (10 g, 0.08 mol) was added slowly (about 10 mins) to a mixture of ammonia (50 mL, 0.2 mol) in methanol (7 N) at 0° C. After being stirred at room temperature for 1 h, the solvent was stripped off and the product was obtained as a white solid (10 g, 88.4%), which was used for next step without further purification. LCMS calculated for C6H15N2S: (M+H) 147.1. Found 147.1.
Reaction SMILES: [CH:1]1([C:5]2[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[N:6][N:7]=1)=[O:12])[CH2:14][CH3:15]
Reactant: CCCNCC=O
Reactant: O=C=Nc1nnc(C2CCC2)s1
Solvent: c1ccccc1
Product: CCCN(CC=O)C(=O)Nc1nnc(C2CCC2)s1

Procedure:
A mixture of 5-cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5cyclobutyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)(=[O:38])=[O:37])=[CH:32][C:31]=1[CH3:55].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:42]2[CH:41]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([CH3:55])[CH:32]=3)(=[O:38])=[O:37])[CH:45]=[CH:44][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: Cc1cc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)ccc1O
Yield: 53.1 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with 4-hydroxy-3-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (133 mg, 0.34 mmol), 2M cesium carbonate (340 μl, 0.68 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) according to the method described in Example 3 to give 76 mg (53% yield) of the title compound. Purity 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(c2nc(Cl)ncc2[N+](=O)[O-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCCN(c2nc(Cl)ncc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
To an ice cooled mixture of 1 g (0.0032 mole) of (rac)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (IV-67), 1.96 mL of trifluoracetic acid and 15 mL of ethyl acetate, was added 2.76 g (0.02 mole) of stannous chloride dihydrate. The mixture was stirred overnight at ambient temperature. The mixture was made basic (pH 14) by the addition of 15% sodium hydroxide solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.086 g of (rac)-1-(5-amino-2-chloro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (V-67).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[O:17])[CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C1CCC1
Product: O=C(O)Cc1ccc(NC(=O)C2CCC2)cc1

Procedure:
(4-Cyclobutanecarbonylaminophenyl)-acetic acid was prepared as described in Example 3 from 7.0 g (0.0464 mol) of (p-aminophenyl)-acetic acid and 6.6 g (0.0557 mol) of cyclobutanecarboxylic acid chloride.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=C)[N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:8])[CH3:5].[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:1])[N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:8])[CH3:5]
Reactant: C=CCC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC(CCO)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Ozone was passed at −78° C. through a solution of 1.00 g of 169 (3.53 mmol) in a mixture of 12 ml of MeOH and 6 ml of CH2Cl2 until the solution turned blue. The reaction was subsequently terminated and excess ozone removed by purging with oxygen. Thereafter, 270 mg of NaBH4 (7.06 mmol, 2 eq.) was added and the mixture stirred overnight to allow warming to RT. After checking completion of the reaction by means of TLC (EE/CH 1:1), the batch was concentrated and the remaining residue taken up in 60 ml of CH2Cl2 and 40 ml of half-conc. NaCl solution. The aqueous phase was extracted with 3×20 ml of CH2Cl2, the combined organic phases were dried over MgSO4 and concentrated. The residue was purified using silica gel column chromatography (EEICH 1:1) to obtain 691 mg (2.40 mmol, 68%) of alcohol 170 as a mixture of epimers (colorless oil).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>CCO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(N(C)C)cc1
Temperature: 25 °C

Procedure:
A slurry composed of 1-(4-carboxyphenyl)-3-methyl-2-pyrazolin-5-one (21.8 g, 0.10 mol), 4-dimethylamino-benzaldehyde (14.9 g, 0.10 mol) and EtOH (250 ml) was heated at reflux for two hours. The reaction mixture was cooled to room temperature, resulting in a crude orange product which was isolated by filtration. The product was then washed with ether and dried. The product was purified further by making a slurry of the solid in EtOH (700 ml) at refluxing temperature and filtering the slurry to recover the dye. The treatment was repeated. The mp of the product was above 310° C. The NMR and IR spectra were consistent with the structure assigned. The C, H, and N elemental analyses were in agreement with those calculated for the empirical formula.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[N:40]=[CH:41][C:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:43][CH:44]=1>CN(C=O)C>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][CH2:38][C:39]4[N:40]=[CH:41][C:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[N:43][CH:44]=4)[CH:3]=3)=[O:30])=[CH:12][C:13]=2[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:20]1)[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(N)c3)cc2C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(NCc4cnc(NC(=O)OC(C)(C)C)cn4)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a solution N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (70 mg, 0.17 mmol) in DMF (0.5 mL) were added K2CO3 (69 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (48 mg, 0.17 mmol). The reaction mixture was stirred for 8 hours at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography using (5% MeOH/CH2Cl2) as a solvent to afford title compound (50 mg, 47% yield). MS m/z: 628 [M+1].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:3][CH2:2][CH2:41][CH2:36]5)[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCCC5)ccc4F)cc23)CC1
Yield: 62.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (44 μL, 0.524 mmol) for methanamine to afford 10 mg of the title compound (62.7%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1)(=O)=O.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23]
Reactant: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC(Cn4cncn4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 60 °C
Reaction time: 15 h
Yield: 59.3 %

Procedure:
A mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl methanesulfonate (1.0 g), 1H-1,2,4-triazole (290 mg), potassium carbonate (580 mg) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 15 hr. Water 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. The residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (50:50:0-0:100:0-0:95:5, volume ratio) to give N-methyl-N-{2-[5-(1H-1,2,4-triazol-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (560 mg, yield 59%) as a pale-yellow amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:20][C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: Brc1ccc(OCc2ccc3ccccc3c2)cc1
Yield: 99 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with 4-bromophenol to give 4-(naphth-2-ylmethoxy)bromobenzene (99%), m.p. 104°-106° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N+:24]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([NH2:24])[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a 100 mL round-bottom flask containing MeOH (25 mL) was added 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (5.3 g, 11.81 mmol), tin(II) chloride dihydrate (8.00 g, 35.4 mmol) and hydrochloric acid (4.92 mL, 59.1 mmol). The resultant suspension was heated to 50° C. and monitored by LC/MS. By LC/MS the reaction was complete in 30 minutes. After the reaction had cooled to room temperature, the majority of the MeOH was removed in-vacuo and 6N aqueous sodium hydroxide solution was added to adjust the pH to pH>10 and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with H2O and brine then dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude solid was purified by chromatography on silica gel eluted with chloroform/(solution of 2N ammonia in methanol) [95:5]. The fractions corresponding to product were combined, then concentrated in vacuo to provide 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-amine (3.78 g, 9.03 mmol, 76% yield) as a light yellow solid. MS (ES+) m/e: 419.0, 420.0 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 (d, J=8.08 Hz, 1H) 6.95-7.05 (m, 2H) 6.21-6.32 (m, 2H) 5.39 (s, 2H) 3.84 (s, 2H) 2.49 (s, 3H)
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1ccccc1Oc1ccccc1
Yield: 109.7 %

Procedure:
Into a three-necked 500 ml round-bottom flask are charged 25 g (0.125 mole) of o-phenoxy benzyl alcohol and 200 ml of benzene. To this solution is added 18 g (0.15 mole) of thionyl chloride dropwise with stirring. The reaction mixture is then heated to reflux for four hours. Solvent and excess thionyl chloride are removed under vacuum to give 30 g of product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17](Cl)=[O:18])[O:10][CH2:9][CH2:8]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:18])[O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: O=C(Cl)C1CCCCC12OCCO2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(C1CCCCC12OCCO2)N1CCOCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Morpholine (0.22 mL, 2.5 mmol) was added at 0° C. to a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aqueous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (59 mg, 23%) as white solid. MS ISP (m/e): 256.3 (100) [(M+H)+].
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:7]2[C:8](N[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1)=[O:9])#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.[Cl-].[NH4+]>ClCCl>[OH:9][CH2:8][C:7]1[CH:13]=[C:3]([CH:4]=[CH:5][C:6]=1[C:11](=[O:12])[C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:1]#[N:2]
Reactant: N#Cc1ccc2c(c1)C(=O)NC2=O
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C#N)cc2CO)cc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
20.0 g (125.6 mmol) of 5-cyanophthalimide was dissolved in 200 ml of anhydrous dichloromethane. The solution was cooled to −78° C., and 188 ml of 4-methoxyphenylmagnesium bromide (1 M in THF, 188 mmol) was added dropwise. The mixture was raised to room temperature and stirred for 16 hrs, followed by addition of a saturated ammonium chloride solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, thereby yielding a yellow compound, represented by Formula 3. The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13](=[O:16])[S:14][CH3:15])=[C:5]([NH2:17])[C:4]=1[C:18](=[O:21])SC.C(O)C.[OH-:26].[Na+]>C(OCC)(=O)C>[NH2:17][C:5]1[C:4]([C:18]([OH:21])=[O:26])=[C:3]([CH:2]([F:1])[F:22])[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]=1[C:13]([S:14][CH3:15])=[O:16]
Reactant: [OH-]
Reactant: CSC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)SC)c1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)O)c1N
Reaction time: 24 h

Procedure:
A solution of 40.8 g (0.113 mol) of product of Example 191, 400 ml of ethanol and 4.5 g (0.113 mol) of 10% aqueous sodium hydroxide was stirred at 25° C. for 5 days. Another 2 g (0.05 mol) of sodium hydroxide was added and stirring continued for 24 hours. The reaction mixture was then diluted with ethyl acetate and washed with three 500 ml portions of 5% HCl, dried (CaSO4), filtered and concentrated to 31.4 g (84%) of product as a yellow solid; mp 219° C. (dec).
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[C:3]1=[O:14].[Cl-].[Cl-].[Cl-].[Al+3].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[C:12]=1[CH2:13][CH:2]([CH3:1])[C:3]2=[O:14]
Reactant: BrBr
Reactant: CC1Cc2cc3c(cc2C1=O)CCC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1Cc2c(cc3c(c2Br)CCC3)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
31 g (162 mmol) of 2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (1a) were added to a suspension of 50 g (0.37 mol) of anhydrous aluminum trichloride in 200 ml of chloroform while stirring vigorously at 0° C. After stirring for one hour, a solution of 8 ml (160 mmol) of bromine in 20 ml of chloroform was added dropwise to the mixture at 0° C. and the mixture was subsequently stirred overnight. The reaction mixture was poured into 500 g of an ice/water mixture. The organic phase was separated off, washed with 5% strength sodium hydrogencarbonate solution and water and subsequently dried over magnesium sulfate. Filtration and removal of the solvent under reduced pressure gave 51 g of a red oil. GC-MS analysis indicated that the oil contained 84% of the desired compound (1b) and 14% of a dibromide by-product. The mixture was separated by column chromatography on silica gel using methylene chloride as eluant. This gave 18.7 g (44% yield) of the compound (1b).
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:21]/[O:22][CH3:23])/[C:16]([O:18]CC)=[O:17])[N:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+].O>O1CCOCC1>[CH2:7]([O:6][P:4]([NH:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:21]/[O:22][CH3:23])/[C:16]([OH:18])=[O:17])[N:14]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)/C(=N\OC)c1csc(NP(=O)(OCC)OCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Yield: 59.3 %

Procedure:
A solution of 8.4 g (0.023 mol) (Z)-2-[(diethoxyphosphinyl)amino]-α-(methoxyimino)-4-thiazoleacetic acid, ethyl ester, 9.25 ml (0.046 mol) 5N sodium hydroxide, 30 ml water, and 50 ml dioxane was stirred at room temperature for 18 hours. The solvent was evaporated, 30 ml of 50% saturated sodium chloride was added, the pH was adjusted to 4.5, and 3×30 ml ethyl acetate was added. The aqueous layer was then adjusted to pH 2.5, and extraction with ethyl acetate followed by evaporation yielded 4.6 g of a yellow oil; MS ((+) FAB), 338 (M+H); NMR (300 MHz, DCCl3) δ 1.36 (2t, 6, OCH2CH3), 4.01 (s, 3, OCH3), 4.18 (m, 4, OCH2), 7.10 (s, 1, thiazole H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](OC)=[O:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH:30]=[CH:29]2>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([S:36]([C:31]4[CH:30]=[CH:29][C:28]5[C:33](=[CH:34][CH:35]=[C:26]([Cl:25])[CH:27]=5)[CH:32]=4)(=[O:37])=[O:38])[CH2:44][CH2:43]3)=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: COC(=O)c1ccc2c(c1)CCC(CNC(=O)OC(C)(C)C)C2
Agent: Cl
Product: CC(C)(C)OC(=O)NCC1CCc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)ccc2C1

Procedure:
In a similar manner to Referential Example 48 except for the use of (2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].O>CN(C)C=O>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH3:17]
Reactant: CCI
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of 3-piperidinemethanol (2 g) and potassium carbonate (6 g) in dry N,N-dimethylformamide (15 ml) was added iodoethane (1.53 ml). The reaction became warm and was cooled back to ambient temperature using a cold water bath. After 2 hours, the solvent was stripped, the residue treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and evaporated to give the title compound as a clear oil, yield 1.53 g, 61%.