Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11]C)(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][NH2:22])[CH:18]=[CH:19][CH:20]=1>CO>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[C:1](=[O:11])[C:2]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:3][NH:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(Cl)c1
Yield: 79.9 %

Procedure:
A mixture of 10.5 grams of the atropic acid, methyl ester, 9.1 grams 3-chlorophenylhydrazine hydrochloride, and 200 ml. methanol was refluxed overnight. The reaction product mixture was washed up in the usual manner to yield 11 grams of crude 1-(3-chlorophenyl)-4-phenyl-3-pyrazolin-5-one. A sample recrystallized from methanol had a melting point of about 211°-212° C.
Reaction SMILES: Br[C:2]1[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][S:4][CH:3]=1.[C:14](C1C(Br)=CSC=1)(=[O:16])[CH3:15]>>[C:14]([C:2]1[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][S:4][CH:3]=1)(=[O:16])[CH3:15]
Reactant: Brc1cscc1Sc1ccccc1
Reactant: CC(=O)c1cscc1Br
Product: CC(=O)c1cscc1Sc1ccccc1
Yield: 66 %

Procedure:
Prepared from 3-bromo-4-phenylsulfanyl-thiophene in 66% yield according to the procedure for the preparation of 4-acetyl-3-bromo-thiophene. 1H NMR (300 MHz, CDCl3) δ8.09 (d, 1H, J=3.3 Hz), 7.57 (d, 2 H, J=7.2 Hz), 7.38-7.42 (m, 3H), 6.31 (d, 1H, J=3.3 Hz), 2.57 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[C:10](C#CC(O)(C)C)[N:9]=[C:8]2[C:4]=1[N:5]=[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[CH:26]=1)[N:7]2[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1.Cl.[CH2:33](N)C#CC>>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:1])[CH:26]=1)[N:7]2[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH3:33])[CH:23]=1
Reactant: CC#CCN
Reactant: CC(C)(O)C#Cc1nc(N)c2nc(-c3cccc(F)c3)n(-c3ccc(=O)[nH]c3)c2n1
Agent: Cl
Product: Cn1cc(-n2c(-c3cccc(Cl)c3)nc3c(N)ncnc32)ccc1=O

Procedure:
The title compound was synthesized in the same manner as in Example 1 (2), (3) and (4), and Examples 2 and 5.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(#N)C.C(N(CC)CC)C.[CH:34]1[CH:39]=[CH:38][C:37]([O:40][C:41](OC2C=CC=CC=2)=[N:42][C:43]#[N:44])=[CH:36][CH:35]=1>>[C:43](/[N:42]=[C:41](\[O:40][C:37]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)/[N:7]1[CH2:8][CH2:9][C@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:44]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 88.2 %

Procedure:
To a stirred solution of (3R,4S)-4-((R)-3-Phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylic acid methyl ester (654 mg, 0.00207 mol) in anhydrous acetonitrile (11.0 mL, 0.211 mol) at rt was added triethylamine (0.579 mL, 0.00413 mol) and diphenyl cyanocarbonimidate (762 mg, 0.00310 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product as a colorless solid (841 mg, 88% in yield). MS (ESI): (M+H)+=461.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])C)=[O:8].[CH2:14]1[N:19]([C:20]2[C:25](C#N)=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:12]=[C:6]2[C:5]([CH:13]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[NH:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1N1CCOCC1
Reactant: Cc1ccc(Cl)cc1C(=O)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2N2CCOCC2)cc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A 1.8 M lithium diisopropylamide THF solution (5.39 ml, 9.69 mmol) was diluted with THF (10 ml). To the diluted solution, a solution obtained by dissolving the 5-chloro-2,N,N-trimethylbenzamide (383 mg, 1.94 mmol) prepared in step A in THF (5 ml) was added dropwise at −78° C. A solution obtained by dissolving 2-(4-morpholino)benzonitrile (438 mg, 2.33 mmol) in THF (5 ml) was further added to the mixture. The obtained mixture was stirred at −78° C. for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained yellow oil product was crystallized from hexane/ethyl acetate (3:1), so as to obtain 7-chloro-3-(2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one (575 mg; yield: 87%) in the form of a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(N=C=NC2CCCCC2)CCCC[CH2:28]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C/C(=C\c1ccc(C(=O)O)s1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 0.161 g (0.437 mmol) of 5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylic acid, (Compound 21, 0.03 g, 0.655 mmol) in ETCH, 0.099 g (0.48 mmol) of 1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate washed with water and brine. The organic layers were combined and dried (MgSO4), The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>>[CH2:24]([NH:26][C:27]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:23][CH2:22]1)=[O:28])[CH3:25]
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Reactant: CCN=C=O
Product: CCNC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and ethyl isocyanate (Aldrich 98%) using the procedure described in Example 12. HRMS, observed: 385.1917, calcd for M+: 385.1914.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>C(#N)C>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH2:8][CH2:7][CH2:6][N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)=[O:26])[CH2:29][CH2:30]1
Reactant: c1c[nH]cn1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCn2ccnc2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (218 mg, 0.5 mmol) obtained in Example 1201a), potassium carbonate (83 mg, 0.6 mmol, 1.2 eq.) and imidazole (41 mg, 0.6 mmol, 1.2 eq.) were suspended in acetonitrile (5.0 ml) and the mixture was stirred at 80° C. for 10 hr. The mixture was concentrated to dryness, and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (42 mg, 21%).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:7]=3[C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:4]=1.[Cl:29]N1C(=O)CCC1=O.C(O)C>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:6]([N:5]([C:18]4[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=4)[N:4]=[C:3]3[CH:2]([F:1])[F:28])=[C:7]2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)CCc1c(C(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc2c(ccc3c(C(F)F)nn(-c4ccc(S(N)(=O)=O)cc4)c32)c1Cl
Temperature: 50 °C

Procedure:
4-[3-(Difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (1.0 g, 1.23 mmol) from Step 2 was suspended in chloroform (100 ml), and N-chlorosuccinimide (NCS) (329 mg, 1.23 mmol) was added. The reaction was heated to 50° C. for 16 hours. At this point, ethanol (20 ml) was added to dissolve the suspended reagents. The reaction was again heated to 50° C. for 24 hours. At this time, an additional equivalent of NCS (329 mg) was added, and the reaction was heated to 50° C. for an additional 4 days. Upon cooling, a precipitate which had formed was collected. This solid was pure 4-[6-chloro-3-(difluoromethyl)-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide (350 mg, 65%): 1H NMR (acetone d6) δ=4.0 (s, 3H), 7.2 (t, 1H, j=54.0 Hz), 7.3 (d, 1H j=9.3 Hz), 7.6 (d, 1H j=9.3 Hz), 7.9 (d, 2H j=8.7 Hz), 8.0 (d, 1H j=9.3 Hz), 8.1 (d, 1H j=9.3 Hz), 8.2 (d, 2H j=8.7 Hz); 19F NMR (acetone d6) δ-113.5 ppm (d, 2F).
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CS(C)=O>[Cl:14][C:13]1[C:6]2[C:7](=[O:9])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Cl)c(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
A mixture of 22 g (94.8 mmol) of 5,6-dichloroisatoic acid anhydride, 10.85 g (94.8 mmol) of L-proline and 100 ml of dimethyl sulphoxide is heated to 90° for 0.5 hour, subsequently evaporated to dryness in a high vacuum and the residue is heated to 150° for 1 hour. By chromatography on silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate and hexane there is obtained (S)-6,7-dichloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Reactant: Cc1ncc[nH]1
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[Cl:45])=[O:35])[CH2:17][O:18][C:19](=[O:32])[NH:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([F:31])=[CH:26][CH:25]=2)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][C:21]([NH:20][C:19](=[O:32])[O:18][CH2:17][C@@H:16]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[Cl:45])=[O:35])[CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])=[CH:30]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CN)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of (6-Fluoro-isoquinolin-3-yl)-carbamic acid (S)-5-(2-tert-butoxycarbonylamino-acetylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (105 mg, 0.16 mmol) in DCM (10.0 mL) was added TFA (1.0 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated and re-dissolved DCM. The DCM layer was washed with K2CO3 (2 N), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-5-(2-aminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (71 mg, 79%). LRMS (M+H+) m/z 563.2.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.CN(C)C=O>[OH:13][CH2:12][C:10]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
80 grams 1-phenyl-3-(p-chlorophenyl)-pyrazol-4-aldehyde were dissolved in a mixture of 800 milliliters ethanol and 1200 milliliters dimethylformamide. To the solution thus obtained, 5.5 grams 95% sodium borohydride were added in small portions at 20°-25° C. The mixture was then stirred for one hour at room temperature. Thereafter, the reaction mixture was evaporated and the residue was taken up, with rubbing, with ethanol and water were thereafter added. The precipitate formed thereby was separated, dispersed and stirred in warm water, the precipitate was filtered off by suction, dried and recrystallized from benzene. 75 grams 4-hydroxymethyl-1-phenyl-3-(p-chlorophenyl)-pyrazol, melting at 141°-142° C., were obtained, representing a yield of 93%.
Reaction SMILES: C(O)C.[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([O:18]CC)=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5].[OH-].[Na+]>O>[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)c1cccc2c1CCCC2C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC1CCCc2c(C(=O)O)cccc21
Temperature: 50 °C

Procedure:
In 90 ml. of ethanol is dissolved 9.6 g. of ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate and a solution of 2.5 g. of sodium hydroxide in 90 ml. of water is added. The mixture is stirred under heating at 50° C for 3 hours, after which the ethanol is distilled off. Then, following the addition of 2N hydrochloric acid, the residue is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the crystalline residue is recrystallized from benzene. The described procedure gives 1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid, melting point: 177°-179° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of (E)-3-(trans-4-pentylcyclohexyl)allyl alcohol, 0.3 g of 4-methoxyphenol, 0.4 g of diethyl azodicarboxylate, 0.6 g of triphenylphosphine and 25 ml of absolute tetrahydrofuran was stirred at room temperature overnight and then concentrated. The residue was suspended with 50 ml of hot hexane and filtered. The filtrate was concentrated. Chromatography of the residue on silica gel with toluene/hexane (vol. 1:1) and recrystallization from methanol gave pure 4-methoxyphenyl (E)-3-(trans-4-pentylcyclohexyl)allyl ether with m.p. (C-N) 45° C. and cl.p. (N-I) 46° C.
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=O)[C:2]=1[CH2:3][CH2:4][C:5]1[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>C(O)(=O)C>[OH:17][CH2:16][CH2:18][N:19]1[C:11](=[O:13])[C:2]2[CH2:3][CH2:4][C:5]3[C:10]([C:1]=2[C:14]1=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NCCO
Reactant: O=C1OC(=O)C2=C1CCc1ccccc12
Solvent: CC(=O)O
Product: O=C1C2=C(C(=O)N1CCO)c1ccccc1CC2

Procedure:
A solution of 70 g (0.35 mol) of 3,4-dihydronaphthalene-1,2-dicarboxylic acid anhydride [prepared according to Org. Synthesis, Col., Vol. 2, 194 (1943)] and 23.5 g (0.385 mol) of ethanolamine in 1.7 liters of glacial acetic acid is kept under reflux for 24 hours. The glacial acetic acid is then removed by distillation, the residue is dissolved in 2 liters of absolute ethanol, 50 g of an ion exchanger ("Dowex 50 W" from Fluka AG) are added and the suspension is kept under reflux for 24 hours. The ion exchanger is then filtered off, the ethanol is distilled off and the residue is recrystallised from diethyl ether/ethanol. This yields 61.8 g (73% of theory) of N-(2'-hydroxyethyl)-3,4-dihydronaphthalene-1,2-dicarboximide; melting point 120.5°-121° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:47][C:48]([F:55])([F:54])[CH2:49][CH:50]([CH3:53])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][CH2:51][CH:50]([CH3:53])[CH2:49][C:48]([F:55])([F:54])[F:47])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Reactant: CC(CN)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Yield: 81.6 %

Procedure:
A solution of methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (2.0 g), 4-dimethylaminopyridine (0.71 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g), triethylamine (1.0 mL) and 4,4,4-trifluoro-2-methylbutylamine hydrochloride (1.2 g) in methylene chloride (28 mL) was stirred under a nitrogen atmosphere for 18 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water and brine), dried (MgSO4), and evaporated. The resulting ivory foam was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane to afford methyl 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate as a white powder (2.2 g, 82%); mp 168°-170° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CHCH3), 2.00 (m, 1H), 2.22 (m, 2H), 3.34-3.52 (m, 2H, NCH2), 3.75 (s, 3H, NCH3), 3.90 (s, 3H, CO2CH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, CH2), 6.21 (t, 1H, NH), 6.82 (s, 1H, indole-H(2)), 8.02 (s, 1H, indole-H(4)).
Reaction SMILES: [H-].[Na+].C(OC([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=O)C1C=CC=CC=1.CI.[CH3:29]N(C)C=O>[Pd].C(O)C>[C:23]([O:22][C:20](=[O:21])[N:19]([CH3:29])[CH:15]1[CH2:16][CH2:17][CH2:18][NH:13][CH2:14]1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a water bath at room temperature, sodium hydride (60% in oil) (0.4 g) was added to a mixture of 3-t-butoxycarbonylaminopiperidin-1-carboxylic acid benzyl ester (compound 25a) (3.3 g), methyl iodide (0.75 mL), and N,N-dimethylformamide (20 mL), and this was stirred at room temperature for four hours. The reaction solution was extracted using ethyl acetate and water, the organic layer was washed with water, and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography using 10% to 20% ethyl acetate/hexane to give an oily substance (3.04 g). A mixture of all of the resulting material with ethanol (20 mL) and 10% palladium on carbon was stirred under hydrogen atmosphere at room temperature for five hours. The catalyst was filtered off, and the filtrate was concentrated to give the title compound (1.82 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](OS(OCC)(=O)=O)[CH3:36]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([O:28][CH2:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(-c2ccc(OCc3ccccc3)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a suspension of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole 2.0 g and K2CO3 2.23 g in DMSO 20 ml was added diethylsulfate 1.24 g. After stirring at ambient temperature for 2 hours, the reaction was quenched by adding 28% aqueous ammonium hydroxide solution and ice. The mixture was partitioned between AcOEt and H2O. The organic layer was washed with H2O and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=40% and the solvent was evaporated in vacuo. The reisual solid was recrystallized from IPE to give 5-[4-(benzyloxy)phenyl]-3-ethoxy-1-(4-methoxy-phenyl)-1H-pyrazole 1.44 g as a powder.