Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[O:12])=CN(C)C)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.O1CCOCC1>O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[O:12])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccsc1C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 59.9 %

Procedure:
A stirred solution of 6.0 g of 4-chloro-β-(dimethylamino)-α-(3-methyl-2-thienoyl)-2-nitrosty rene, 50 ml of 1,4-dioxane and 10 ml of water was refluxed for 16 hr and allowed to cool. The cooled solution was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. A stirred solution of the residue, dioxane and water was refluxed overnight and was worked-up as above. The residue was purified by preparative HPLC (Waters Associates Prep LC/Model 500, silica gel, sample applied in dichloromethane (20 ml), eluted with dichloromethane, 200 ml/min flow rate, Gow Mac Model 80-800 UV detector). The appropriate fractions were concentrated and the residue was recrystallized from 95% ethanol to give 3.03 g of product, mp 105°-107° C.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([C:34](=[O:39])[N:35]([O:37][CH3:38])[CH3:36])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(Cl)[Cl:41].[ClH:44]>CCOCC>[ClH:41].[ClH:44].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([C:34]([N:35]([O:37][CH3:38])[CH3:36])=[O:39])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CCOCC
Product: CON(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To the product from Step A (0.032 g, 0.0601 mmol) was added CHCl3 (0.600 mL) and HCl (0.451 mL, 1.80 mmol, 4.0M in dioxane). The mixture was stirred at ambient temperature for 9 hours, then diluted with Et2O (5 mL) and filtered. The solid was washed with Et2O and dried in vacuo. This provided 0.026 g (82%) of the desired product as a pale yellow solid. MS ESI (+) m/z 433.1 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: OCc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cccc(COC2CCCCO2)n1
Reaction time: 24 h
Yield: 83.8 %

Procedure:
2-Bromopyridine-6-methanol (prepared as described in Tetrahedron Lett., 1996, 50, 2537) (5 g, 26.5 mmol) was added to a solution of dihydropyran (2.65 ml, 29.2 mmol), and p-toluenesulfonic acid (506 mg, 2.7 mmol) in dichloromethane (150 ml) at room temperature under nitrogen. After 24 h, the mixture was washed with sodium carbonate solution (×1) and water (×1), dried (MgSO4), evaporated in vacuo and the residue flash chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give the title-compound (6.04 g, 84%), 1H NMR (250 MHz, CDCl3) δ 1.5-1.9 (6H, m, 3 of CH2), 3.56 (1H, m, CH2O), 3.88 (1H, m, CH2O), 4.62 (1H, d, J=14.2 Hz, CH2O), 4.76 (1H, t, J=3.4 Hz, CHO), 4.93 (1H, d, J=14.6 Hz, CH2O), 7.37 (1H, d, J=7.6 Hz, Ar—H), 7.46 (1H, d, J=6.6 Hz, Ar—H), 7.56 (1H, t, J=7.6 Hz, Ar—H); MS (ES30) m/e 272 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]=4[O:23][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][N:20]([C:24](=[O:26])[CH3:25])[CH2:19][C:18]=4[O:23][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)c1ccc2c3c(oc2c1)CNCC3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2c(oc3cc(S(=O)(=O)c4cccc(Cl)c4)ccc23)C1

Procedure:
Prepared as described for Example 612 using 7-[(3-chlorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (Example 344) and acetic anhydride. MS m/z 390 [M+H]+.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][CH2:16]2
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Reactant: ICCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)CCC1(CCC(N3CCCCC3)CC1)C2

Procedure:
The amine prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C), 1.9 g. of 1,5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanol is stirred at reflux temperature for about 18 hours. The mixture after cooling is diluted with water, the solid collected on a filter and recrystallized from methanol to give 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:19][CH:20]=1)[CH3:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-ethylaniline to yield 2-[(3-ethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nc(C)nc3nc[nH]c23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-methyl-6-chloropurine (1.69 g; 0.01 mol) and m-anisidine (1.23 g; 0.01 mol) in n-butanol (20 ml), triethylamine (3.5 ml; 0.025 mol) was added. The resulting thick suspension was stirred at 110° C. for 3 hours, when TLC showed the absence of starting material and the presence of desired product. The reaction mixture was then cooled to room temperature. The white precipitate was filtered off, rinsed with n-butanol (2×10 ml) and water (3×10 ml) and dried into constant weight. Yield: 1.92 g (75%). The crude product was purified as hydrochloride salt by the crystallization from 2.5 M methanolic hydrochloric acid. TLC (chloroform-methanol-NH4OH; 4:1:0.05): one single spot, free of starting material. HPLC purity: 99+%.
Reaction SMILES: ClC1C=C2C(=CC=1)OC(C)(C)C(O)C2CS(N[CH2:20][C:21]([O:23][CH3:24])=[O:22])(=O)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][C:31]([CH3:37])([CH3:36])[CH:30]([OH:38])[CH:29]2[NH:39][S:40]([CH3:43])(=[O:42])=[O:41].[H-].[Na+].BrCC(OC)=O>CN(C=O)C.CC(=O)OCC>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][C:31]([CH3:37])([CH3:36])[CH:30]([OH:38])[CH:29]2[N:39]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CC1(C)Oc2ccc(Cl)cc2C(NS(C)(=O)=O)C1O
Reactant: COC(=O)CNS(=O)(=O)CC1c2cc(Cl)ccc2OC(C)(C)C1O
Agent: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(C1c2cc(Cl)ccc2OC(C)(C)C1O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl [(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]acetate A solution of 3.0 g (10 mmol) of N-(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonamide was added dropwise to a solution of 0.33 g (11.3 mmol) of 80 percent sodium hydride in 25 ml of DMF and the mixture was additionally stirred at RT for 1 h. 1.53 g (10 mmol) of methyl bromoacetate were then added, the mixture was stirred overnight at RT and then the solvent was stripped off in vacuo. The residue was taken up in EA and water, the organic phase was concentrated and the product was purified by chromatography on silica gel using cyclohexane/ethyl acetate 9:1. 2.0 g of methyl [(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)-methanesulfonylamino]acetate were obtained; m.p. 148-150° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[O:4]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=O)[CH3:20])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.[OH-].[Na+].C(O)C>[O:4]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[N:2][OH:3])[CH3:20])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(=O)CCc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCc1ccc(Oc2ccccc2)cc1)=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Over about 30 minutes, a freshly prepared solution of 15.3 g (0.22 mole) of hydroxylamine hydrochloride in 100 ml of water and 200 ml of 1N sodium hydroxide solution is added dropwise at room temperature to a solution of 48 g (0.2 mole) of 4-(4-phenoxyphenyl)-2-butanone*) in 500 ml of ethanol. Subsequently, the mixture is heated for 1.5 hours at reflux temperature and then stirred for 16 hours at room temperature. The ethanol is distilled off in a water jet vacuum and the residue is extracted repeatedly with ether. The combined ethereal phases are washed repeatedly with water and dried over sodium sulfate and the ther is distilled off entirely. The crude oxime is chromatographed over silica gel (eluant: a 1:1 mixture of diethyl ether and n-hexane). The resultant 4-(4-phenoxyphenyl)-2-butanone oxime melts at 80°-82° C. after recrystallisation in a mixture of diethyl ether and n-hexane.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].FC(F)(F)C(O)=O.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1.[NH4+].[OH-]>ClCCl>[NH2:1][C:2]([NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1)=[O:3]
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Reactant: [N-]=C=O
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of potassium isocyanate (1.5 g) dissolved in dichloromethane (20 ml) was cooled to 5° C. and a solution of trifluoroacetic acid (1.9 g) In dichloromethane (20 ml) was added dropwise. To the resulting mixture was added dropwise a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) in dichloromethane (10 ml). The temperature was allowed to raise to room temperature. After stirring for another 3 hours the mixture was poured on ice (500 g) and diluted aqueous NH4OH was added until pH>9. The organic phase was separated and worked-up as above. The crude title product was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethanol/ethyl acetate 1:3). The purled product (2 g) was dissolved in acetone (20 ml) and added to a solution of fumaric acid (0.6 g) in ethanol (20 ml). The precipitated hemifumarate salt was filtered off and dried. Yield: 1.6 g, mp: 172-174° C. 1H NMR (DMSO-d6): δ 1.65-1.90 (m, 5H); 2.10-2.35 (m, 3H); 2.45-2.90 (m, 5H); 3.10-3.25 (m, 2H); 3.45 (qui, 1H); 6.85 (s, 2H); 6.60 (s, 1H); 7.00-7.15 (m, 4H); 7.30 (dd, 2H); 7.45 (s, 1H); 8.45 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([F:14])[CH:8]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:17]=[O:19])=[C:9]([F:14])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)COc1ccc(N)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, (4-amino-3-fluoro-phenoxy)-acetic acid methyl ester hydrochloride (Kori, Masakuni; Mild, Takashi; Nishimoto, Tomoyuki; Tozawa, Ryuichi. PCT Int. Appl. (2001), WO 2001098282 A1) was reacted with triphosgene in the presence of Et3N (3.5 eq.) in CH2Cl2 under reflux conditions for 14 h to give the title compound as brown solid. MS: m/e=243.1 [M+NH4+].
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.[I-].[Na+].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[OH:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: O=C1CCc2cc(C(O)CCCCl)ccc2N1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.8 Grams of 6-(1-hydroxy-4-chlorobutyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 60 ml of dimethylformamide and the mixture was stirred at a room temperature for 7 hours. To the reaction mixture were added 2 g of triethylamine and 2.5 g of 4-phenylpiperazine and stirred at a room temperature for 24 hours. The reaction mixture was poured into 200 ml of 1%-sodium hydrogencarbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduced pressure. The obtained residue was recrystallized from isopropanol to obtain 2.5 g of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].O>CO>[N:1]1([CH2:6][CH2:7][CH2:8][CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[OH:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCn1ccnc1)c1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CCCn1ccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)-1-(2-naphthyl)-1-butanone (0.793 g) in MeOH (5 ml) was added NaBH4 (0.213 g) and the mixture was stirred at room temperature for 2 hours. Water was added and the whole was concentrated. The residue was extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (ethyl acetate-MeOH=20:1) followed by crystallization to give the titled compound (0.615 g) as a colorless solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]([C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[C:23]([CH3:35])[CH:22]=1)([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)[CH2:11][CH3:12])[CH3:9].[C:36]([C:38]1([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)#[CH:37]>C(#N)C>[CH2:8]([C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)([C:21]1[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:23]([CH3:35])[CH:22]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: C#CC1(O)CCCCC1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
Triethylamine (8.0 mL, 57.6 mmol), tetrakistriphenylphosphine palladium (2.2 g, 1.92 mmol) and cuprous iodide (0.36 g, 1.92 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 8.0 g, 19.2 mmol) and 1-ethynyl-cyclohexanol (3.5 g, 28.8 mmol) in acetonitrile (96 mL), and the mixture was stirred at 110° C. for 1.5 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (4.75 g, 63%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:20]([O:24][C:25](=[O:53])[NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[O:50][CH3:51])[C:34]=2[NH2:52])[CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:20]([O:24][C:25](=[O:53])[NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]3[N:40]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=4[O:50][CH3:51])[C:2](=[O:4])[NH:52][C:34]=23)[CH2:28]1)([CH3:22])([CH3:21])[CH3:23]
Reactant: COc1ccc(CNc2nc(C)cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2N)c(OC)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)[nH]c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Temperature: -10 °C
Yield: 65.1 %

Procedure:
1.42 g triphosgene (4.78 mmol) was dissolved in 10 mL dichloromethane, and cooled to −10° C. 1.77 mL triethylamine (12.72 mmol) was added. A solution of 1.5 g (R)-1-[2-(2,4-dimethoxybenzyl)amino-6-methyl-3-aminopyridin-4-yl]piperidine-3-carbamic acid tert-butyl ester (3.18 mmol) in dichloromethane (20 mL) was slowly added dropwise at −10° C. After they were completely reacted, the reaction solution was adjusted to be basic by adding saturated sodium carbonate solution, and extracted twice with dichloromethane. The combined organic phase was washed with brine, dried with anhydrous sodium sulfate, and evaporated to dryness. The resultant crude product was recrystallized with dichloromethane and ethyl acetate to afford 1.03 g titled product with a yield of 65.2%.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:23][CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: CCS(=O)(=O)Nc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(CNC(=O)COc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a N,N-dimethylformamide (DMF) (5 ml) solution of (4-tert-butylphenoxy)acetic acid (330 mg, 1.50 mmol) and N-[4-(aminomethyl)phenyl]ethanesulfonamide hydrochloride (451 mg, 1.80 mmol, Journal of Medicinal Chemistry 2003, 46(14), 3116–3126), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (431 mg, 2.25 mmol), 4-(dimethylamino)pyridine (DMAP) (46 mg, 0.38 mmol) and triethylamine (506 mg, 5.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=100/1 to furnish the title compound. Further, the title compound was recrystallized from ethyl acetate and hexane to furnish 341 mg (56% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[C:12]([C:20]1[C:21](Cl)=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:12]([C:20]1[C:21]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3)cnc21
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccccc3)cnc21
Yield: 72.7 %

Procedure:
In 25 ml of dry tetrahydrofuran (THF hereafter) was dissolved 1.6 g of acetone oxime, followed by 2.46 of potassium t-butoxide. After stirring 0.5 hour 5.0 g of 5-benzoyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine in 50 ml of THF was added to the solution. After an additional 0.5 hour the reaction was quenched with ammonium chloride solution and the product was extracted with ether. Evaporation of the organic phase and recrystallization of the residue from ethanol gave 4.1 g of product, mp 115°-116° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:22]([CH3:27])[CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(Br)CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCCCN)cc1OC
Yield: 55 %

Procedure:
2.5 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 25 ml of N,N-dimethylformamide, followed by the addition of 1.95 g of anhydrous potassium carbonate and 1.65 ml of 4-bromovaleronitrile. The obtained mixture was reacted at a room temperature for 16 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. 40 ml of ethanol, 3.2 ml of concentrated hydrochloric acid and 0.3 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm2 for 6 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol/concentrated aqueous ammonia (100:10:1)] to obtain 1.95 g of the title compound as a yellow oil (yield: 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.[F:28]C1C=C(F)C=CC=1I>>[F:1][C:2]1[CH:7]=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Reactant: Fc1ccc(I)c(F)c1
Agent: Nc1cccc2[nH]ncc12
Product: Nc1cccc2c1cnn2-c1ccc(F)cc1F

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and 2,4-difluoro-1-iodobenzene.