Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([C:20]([N:17]1[CH2:18][CH2:19][S:14][CH2:15][CH2:16]1)=[O:21])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)N1CCSCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN(C)C(=O)N1CCSCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 111.5 %

Procedure:
N-t-Butoxycarbonyl-N,N'-dimethylethylenediamine (200 mg) was added to a solution of thiomorpholinocarbonyl chloride (228 mg) and triethylamine (123 mg) in methylene chloride (10 ml) which was cooled at 0° C. The mixture was stirred at ambient temperature for 20 minutes and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 0.6N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give N-t-butoxycarbonyl-N'-thiomorpholinocarbonyl-N,N'-dimethylethylenediamine (376 mg) as an oil. Rf: 0.43 (chloroform:methanol, 10:1, V/V)
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][C@@H:10]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[F-].[Na+].[F:32][C:33]([F:45])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>CCOC(C)=O>[F:32][C:33]1([F:45])[C@@H:9]2[C@H:8]1[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C@H:10]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1C=C[C@@H](c2ccccc2)C1
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](c2ccccc2)[C@@H]2[C@H]1C2(F)F
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of Example 54A (419 mg, 1.45 mmol), toluene (0.2 mL), and sodium fluoride (21.3 mg, 0.507 mmol) was heated in a 120° C. oil bath and trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.43 mL, 7.24 mmol) was added via syringe pump over 2 hours. After 2 hours, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (0-25% EtOAc/hexanes, gradient elution) to provide the title compound (145 mg, 0.427 mmol, 30% yield). MS (DCI) M/Z 357 [M+NH4]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10].O>CN(C=O)C>[Br:8][C:18]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of NBS (218 mg, 1 mmol) in DMF was added a solution of 2-tert-butylaniline (149 mg, 1 mmol) in DMF at rt. The reaction mixture was stirred for 4 h at rt, then water (30 mL) was added and the mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound P19a (180 mg, 79%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4](=[O:19])[CH2:5][C@@H:6]([CH2:16][CH:17]=[CH2:18])[C:7]([NH:9][CH:10]([CH2:14][OH:15])[C:11]([O-:13])=[O:12])=O.Cl.[CH2:23](N(CC)CC)[CH3:24].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:21][C:2]([CH3:1])([CH3:20])[CH2:3][C:4](=[O:19])[CH2:5][C@H:6]([C:7]1[O:15][CH2:14][C@@H:10]([C:11]([O:13][CH2:23][CH3:24])=[O:12])[N:9]=1)[CH2:16][CH:17]=[CH2:18]
Reactant: CCN(CC)CC
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)NC(CO)C(=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@H](CC(=O)CC(C)(C)C)C1=N[C@H](C(=O)OCC)CO1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of ethyl (2S)-2-{[(2R)-2-(4,4-dimethyl-2-oxopentyl)-4-pentenoyl]amino-3-hydroxypropanoate (Preparation 113) (23.8 g, 72.3 mmol) in anhydrous tetrahydrofuran (300 ml), under a nitrogen atmosphere, was treated with (methoxycarbonylsulfamoyl)triethylammonium hydroxide triethylamine hydrochloride salt (43.5 g, 79.4 mmol) and stirred at reflux for 1.5 hours. After allowing to cool to room temperature the mixture was filtered, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 (hexane:diethylether) gradually changing to 50:50 (hexane:diethylether) to afford the title compound as a colourless oil (11.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C>[Br:19][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[C:7]=1[CH3:10]
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1c(Br)sc2ccc(F)cc12
Yield: 95 %

Procedure:
A 3 neck 2 L round bottom flask is fitted with a septum, a mechanical stirrer, and stopper. The flask is charged with 5-fluoro-3-methylbenzothiophene (55.4 g, 0.311 moles) and acetonitrile (350 mL). The mixture is stirred with a mechanical stirrer and the reaction temperature is monitored. NBS is added portion wise. The reaction temperature rises slightly, and the reaction is cooled with ice water bath. A solid crashes out of solution. The solid is filtered and rinsed 2 times with a 1:1 mixture of acetonitrile and water (100 mL). The solid is dried in a vacuum oven overnight at room temperature to obtain the title product (69 g, 95%). 1H-NMR (DMSO-d6), δ 2.41 (s, 3H), 7.34 (td, J=10, 2 Hz, 1H), 7.69 (dd, J=10, 2 Hz, 1H), 8.04 (dd, J=9, 5 Hz, 1H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N>[CH3:12][N:11]([CH3:13])[S:8]([C:7]1[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CN(C)S(=O)(=O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1cccnc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
The product from Example 44A (1.29 g, 5.85 mmol), 4-carboxyphenylboronic acid (0.967 g, 5.82 mmol) and Pd(PPh3)4 (0.337 g, 0.292 mmol) were combined in 1:1 0.5 M Na2CO3:MeCN (46 mL) and heated at 85° C. overnight. The mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated to 50% volume. The aqueous layer was acidified with concentrated HCl and extracted with CH2Cl2. The organics were dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[C:20]([O:24][C:25]([NH:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30]OS(C)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[C:20]([O:24][C:25](=[O:26])[NH:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH2:11])=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=2)[C:2]([CH3:1])([CH3:19])[C:3]1=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1COS(C)(=O)=O
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 115.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.55 g) is alkylated using methanesulfonic acid 2-tert-butoxycarbonylamino-benzyl ester (0.69 g; 2.09 mmol) and K2CO3 (0.99 g; 7.19 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated in MeOH (50 ml) using DBU (0.3 ml) at reflux. After aqueous work-up [2-(5-amino-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (1.03 g) is obtained and used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][NH2:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](O)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][NH:44][C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCNC(=O)c4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-(2-amino-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester are reacted with benzoic acid to afford the title compound after flash chromatography (SiO2 60 F) as a colourless oil. Rf=0.50 (dichlormethane-methanol 10:1); Rt=5.33.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[N+](=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N-]>>[CH3:7][C:6]1([CH3:8])[CH:5]([CH:4]=[C:2]([CH3:3])[CH3:1])[CH:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: CC(C)=CC=C(C)C
Product: CC(C)=CC1C(C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
In a 50 mL Schlenk tube purged with nitrogen, 22 mg of 2,2-bis[2-[(4S)-1-naphthyloxazoline]]propane was added to a white suspension containing 18 mg of cuprous trifluoromethanesulfonate and 5 mL of dichloroethane and stirred at a room temperature for 10 minutes to prepare a blue color homogeneous solution of an asymmetric copper complex. After that, 7.8 g of 2,5-dimethyl-2,4-hexadiene was added thereto and the inner temperature was adjusted to 40° C. and 1.4 g of tert-butyl diazoacetate was dropwise added for 2 hours and the resulting mixture was stirred at the same time further for 30 minutes to effect reaction and tert-butyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained in a yield of 89% (based on tert-butyl diazoacetate). Trans-isomer/cis-isomer ratio=81/19. The optical purity of the trans-isomer was 86% e.e. and that of the cis-isomer was 60% e.e.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Yield: 59 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (1.38 g, 5.1 mmol) and 3,6-dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (11.0 g, 4.7 mmol) in di-chloromethane (20 ml) at room temperature was treated with DIEA (2.44 ml, 14.0 mmol), DMAP (627 mg, 5.1 mmol) and WSCD (1.16 g, 6.1 mmol). The solution was heated at re-flux for 2 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (1.29 g, 59%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:21][NH:22][C:23]1[CH:24]=[N:25][C:26]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH3:36].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([N:22]([CH3:21])[C:23]2[CH:24]=[N:25][C:26]([N:37]3[CH2:38][CH2:39][S:40][CH2:41][CH2:42]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of 8.5 g (26.6 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 12 ml dichloromethane was added dropwise at room temperature to a solution of 8.0 g (24.2 mmol) methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine and 4.7 ml (33.9 mmol) triethylamine in 65 ml dichloromethane. The reaction mixture was stirred for 1 hour and poured onto 50 ml 1 N aqueous sodium hydroxide. After extraction the phases were separated, the aqueous phase was extracted with dichloromethane and the organic phases were washed with water. The combined organic extracts were concentrated under reduced pressure and the solvent was exchanged for 150 ml ethanol. The solution was seeded at 40° C. with some crystals, 30 ml water were slowly added and the system was stirred for 1 hour at room temperature and for 1 hour at 0° C. The precipitate was filtered off, washed with cold ethanol (0° C.) and dried under high vacuum to yield 13.0 g (76% over 3 steps) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-isobutyramide as an off-white powder of
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18]>>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH3:13])[C:16]=1[C:17]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:18]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cccc(OC)c1C(=O)Cl
Product: COc1cccc(OC)c1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,6-dimethoxybenzoyl chloride according to the procedure of Example 19 to yield 5-(2,6-dimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 191°-192° C. after recrystallization from benzene.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:28]N>C(O)C>[C:6]1([C:5]2[C:4]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:3][NH:2][N:28]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To the compound tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate (4 g) dissolved in ethanol (40 ml), and hydrazine hydrate (1.17 g) was added and the reaction mixture was refluxed for 6 hrs with vigorous stirring. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(-c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared by reacting 2-bromonaphthalene (3.04 g, 14.7 mmol) with 4-methoxyphenylmagnesium bromide according to method used to prepared intermediate 10 to yield 2.89 g (89%) of a white solid: mp 114° C.; 1H NMR (CDCl3): δ 3.86 (3H, s), 7.01 (2H, d, J=9.06 Hz), 7.43-7.50 (2H, m), 7.65 (2H, d, J=8.73 Hz), 7.71 (1H, dd, J=1.84 Hz, J=8.56 Hz), 7.83-7.89 (3H, m), 7.98 (1H, d, J=0.67 Hz); MS (EI) m/z 234 (M)+.
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>O>[C:13]([C:15](=[C:9]1[CH2:10][CH2:11][CH:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCC/C=C/C1CCC(=O)CC1
Reactant: CCOC(=O)CC#N
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC/C=C/C1CCC(=C(C#N)C(=O)OCC)CC1

Procedure:
A mixture of 33.3 g of 4-(1E-pentenyl)cyclohexanone (prepared in accordance with EP-A-168683), 42 ml of ethyl cyanoacetate, 300 ml of toluene and 2.9 g of piperidinium acetate is boiled for 1.5 hours on a water separator. After cooling the reaction mixture is washed with three 50 ml portions of water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 750 g of silica gel with hexane/ethyl acetate (vol. 19:1) gives ethyl cyano-[4-(1E-pentenyl)cyclohexylidene]-acetate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([OH:28])=[C:4]([C:29]([O:31][CH3:32])=[O:30])[C:3]=1[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.CC(C)=O>[C:44]1([CH2:43][O:28][C:5]2[C:6]3[C:11](=[C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=[CH:8][C:7]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:2]([O:1][CH2:33][C:3]3[CH:4]=[CH:5][CH:6]=[CH:11][CH:2]=3)=[C:3]([C:33]([O:35][CH3:36])=[O:34])[C:4]=2[C:29]([O:31][CH3:32])=[O:30])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)c1c(C(=O)OC)c(O)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c(OCc2ccccc2)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10.00 g of dimethyl 1,4-dihydroxy-5,8-bis(phenylmethoxyl)-2,3-naphthalene dicarboxylate prepared in Step 2A-b above, 12.00 g of potassium carbonate and 8.0 mL of benzyl bromide in 100 mL of dimethyl formamide and 200 mL of acetone was stirred at room temperature for 2 days. The reaction was filtered. The filtrate was then concentrated and the solid was washed with mixed solvent of ethyl acetate and petroleum ether to give 12.50 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])=[O:10])=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](OC(=O)c1cccc(O)c1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC(=O)c1cccc(OC(=S)Cl)c1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 130 ml of thiophosgene in 250 ml of dry diethyl ether at -78° C. was added dropwise a mixture of 72 g of diphenyl- (2-methylprop-2-yl)silyl 3-hydroxybenzoate and 29 ml of triethylamine in 200 ml of dry diethyl ether. The mixture was stirred at -78° C. for 30 minutes, at room temperature for 120 minutes, and then partitioned between diethyl ether and water. The organic layer was washed with cold water and with brine, and was dried over anhydrous calcium chloride. Evaporation in vacuo, and repeated addition of dry diethyl ether and re-evaporation in vacuo afforded 86.5 g of the title compound as a viscous orange oil.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1csc(CO)c1
Solvent: ClCCl
Product: COC(=O)c1csc(CCl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixed liquid of 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate and 50 ml of dichloromethane was added 4.12 ml of thionyl chloride under ice-cooling, followed by stirring at room temperature for 15 hours. The reaction solution was concentrated, added with ethyl acetate, and then washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was then evaporated to obtain 4.90 g of methyl 5-(chloromethyl)thiophene-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCC#CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCC#CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of dec-3-yn-1-ol (1.54 g, 10.0 mmol) in DMF (25 mL) was added triphenylphosphine (2.92 g, 11.2 mmol). The solution was cooled to 0° C. and NBS (1.92 g, 10.8 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (150 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 1-bromo-dec-3-yne (1.57 g, 72%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, d, J=7.2 Hz), 2.70 (2H, m), 2.14 (2H, m), 1.20–1.55 (8H, m), 0.88 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 82.89, 77.05, 31.62, 30.68, 29.06, 28.78, 23.65, 22.86, 18.99, 13.38.