Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1)([CH3:4])(=[O:3])=[O:2].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][C:6]([O:5][S:1]([CH3:4])(=[O:2])=[O:3])=[CH:7][CH:8]=2)[C:12]1=[O:15])[CH:17]=[CH:18][CH3:19]
Reactant: C=CC(C)O
Reactant: CS(=O)(=O)Oc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(OS(C)(=O)=O)cc2C1=O
Yield: 50 %

Procedure:
A solution of 18.3 g of 6-mesyloxy-1-indanone, 16.7 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 400 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). In addition to 8.31 g of educt, there were obtained 11.3 g (50%) of (RS)-2-(2-buten-1-yl)-6-mesyloxy-1-indanone as a yellow oil.
Reaction SMILES: [C:1]1([C:7]([C:24]2[NH:28][N:27]=NN=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[ClH:29].[C:1]1([C:7]([C:24]2[O:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][N:28]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2nnn[nH]2)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2ccccc2)o1
Product: Cl

Procedure:
Thus 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile described in U.S. Pat. No. 3,318,869 is reacted with sodium azide in DMF to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. This tetrazole is reacted with ethyl chloroglyoxylate in pyridine at -6° C to provide ethyl [1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylate hydrochloride. This ester is hydrolysed in aqueous potassium hydroxide to provide 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylic acid. Heating this acid for 15 minutes in an oil bath at 130°-140° provides 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole. The hydrochloride salt melts at 233°-234.5° C.
Reaction SMILES: C(OC1C(OC)=CC([B:12]([OH:14])[OH:13])=CC=1OC)C.C(OC1C(OC)=CC(I)=CC=1OC)C.I[C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[C:34]([O:46][CH3:47])[CH:33]=1>>[CH3:47][O:46][C:34]1[CH:33]=[C:32]([B:12]([OH:14])[OH:13])[CH:37]=[C:36]([O:38][CH3:39])[C:35]=1[O:40][CH2:41][C:42]([F:45])([F:44])[F:43]
Reactant: CCOc1c(OC)cc(B(O)O)cc1OC
Reactant: COc1cc(I)cc(OC)c1OCC(F)(F)F
Agent: CCOc1c(OC)cc(I)cc1OC
Product: COc1cc(B(O)O)cc(OC)c1OCC(F)(F)F

Procedure:
Applying the synthetic procedure of 4-ethoxy-3,5-dimethoxyphenylboronic acid from 4-ethoxy-1-iodo-3,5-dimethoxybenzene in Reference Example 3, the title compound was prepared as a colorless amorphous powder (369.0 mg, yield: 48%) from 1-iodo-3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)-benzene (1.00 g, 2.76 mmol).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH2:31].C(O)(=O)C>CO>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:30][CH2:31][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: C=Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc2c(c1)CCN(CCc1ccccn1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Compound (II) (300 mg, 0.76 mmole), 2-vinylpyridine (95 mg, 0.91 mmole) and glacial acetic acid (24 mg, 0.40 mmole) were combined in 15 mL of methanol and heated to reflux for 24 hrs. The solvent was removed under vacuum and the residue was purified using silica gel chromatography with a gradient of 0 to 3% methanol in ethyl acetate as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[O:32]1[C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=[N:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:37]([C:36]4[O:32][N:33]=[CH:34][CH:35]=4)=[O:38])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Reactant: O=C(O)c1ccno1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3ccno3)COC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with isoxazole-5-carboxylic acid to yield the title compound as yellow oil. MS: 538.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[N:7]([CH3:14])[C:8]3[C:13]([C:5]2([CH3:15])[CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.N1C=CC=CC=1.[BrH:22].[NH+]1C=CC=CC=1.O>C(Cl)Cl>[Br:22][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]1[N:2]([CH3:1])[CH2:3][CH2:4][C:5]21[CH3:15]
Reactant: Br
Reactant: CN1CCC2(C)c3ccccc3N(C)C12
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Temperature: 0 °C

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.41 g) in methylene chloride (20 ml) was added pyridine (1.41 ml) under an atmosphere of N2. Solid pyridinium hydrobromide perbromide (2.23 g) was added with stirring to the mixture and the resulting solution was maintained at 0° C. for 1 hour. The mixture was poured into water (100 ml) and the aqueous and organic phases separated. The organic phase was washed twice with 50 ml portions of brine and 50 ml portions of saturated sodium bicarbonate and then with 50 ml of brine. After drying the organic phase over Na2SO4 and filtering, the solvent was removed under reduced pressure. The resulting oil was purified using column chromatography on silica gel with 10% methanol in ethyl acetate as eluent. The appropriate fractions were combined, evaporated and repurified using column chromatography on silica gel with 5% methanol in ethyl acetate as eluent to afford 1.5 g of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole, as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[N:7]([CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[CH3:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C(=O)C.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([NH:25][C:26]2[CH:27]=[C:28]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]5[CH2:43][CH2:44]5)=[O:41])[N:38]=4)[N:35]=3)[CH:45]=[CH:46][C:47]=2[CH3:48])=[O:12])[N:7]([CH3:13])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C(C)(C)C)nn1C
Yield: 40.3 %

Procedure:
Using 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (61 mg, 0.33 mmol), tetrahydrofuran (1.8 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (44 μL, mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (90 mg, 0.28 mmol) and N,N-dimethylacetamide (1.8 mL), and in the same manner as in Example 119, the title compound (55 mg, 41%) was obtained as a white powder.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:47]([NH2:57])[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1>CN(C=O)C.C(Cl)Cl>[C:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:57][CH2:47][C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
Boc-D-Pro-OH (209 mg, 0.970 mmol) was dissolved in DMF (4 mL), followed by addition of the HBTU (552 mg, 1.46 mmol) and Triethylamine (270 μL). The solution was stirred at room temperature for 30 minutes prior to the addition of piperonylamine (121 μL, 0.970 mmol). The reaction mixture stirred at rt for 16 h then the solution was transferred to a separatory funnel containing DCM (50 mL). The organic layer was washed with NaHCO3 (2×50 mL, sat. aq.) and dried over Na2SO4. The solution was concentrated and purified by prep LCMS to afford 278.0 mg (82.5%) of 2-[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. [M+H]+ 349.09.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:15]#[N:16].[K+].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>C(O)(C)C>[C:19]1([NH:18][C:11]2([C:15]#[N:16])[CH2:12][CH2:13][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Reactant: Nc1ccccc1
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
1-Phenylmethyl-4-piperidinone (20.00 g, 0.106 mol), KCN (9.60 g, 0.147 mol), and aniline (13.60 g, 0.146 mol) in 180 mL isopropanol were cooled in an ice bath. Acetic acid (20 mL) was added dropwise and the addition funnel was rinsed with 20 mL isopropanol. The solution was heated at reflux for 4 h. The mixture was allowed to cool to room temperature and poured over an ice (120 g)/concentrated ammonium hydroxide (80 mL) mixture. The aqueous solution was extracted three times with chloroform. The organic layer was washed with brine. The organic solution was dried with MgSO4, filtered, and the volatiles were evaporated. The residue was recrystallized from isopropanol to provide 24.04 g of a white solid in a 78% yield. mp 145-147° C.; 1H NMR (CDCl3) δ 7.35-7.23 (m, 6H), 6.93-6.90 (m, 4H), 3.65, (br s, 1H), 3.56 (br s, 2H), 2.81 (br d, 2H, J=11.91 Hz), 2.46 (t, 2H, J=10.30 Hz), 2.33 (d, 2H, J=13.28 Hz), 1.93 (t, 2H, J=10.30 Hz); 13C NMR (CDCl3) δ 143.4, 138.1, 129.4, 129.1, 128.5, 127.4, 62.7, 53.2, 49.4, 36.2.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16](CC2C=CC=CC=2)[CH2:15][CH2:14]1)=[O:12].CCOCC>C(O)C.[H][H].[Pd]>[ClH:1].[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[O:12]
Reactant: [H][H]
Reactant: O=C(Cc1ccc(O)cc1O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C(Cc1ccc(O)cc1O)N1CCNCC1
Yield: 122.2 %

Procedure:
To a solution (10 ml) of 1-(2,4-dihydroxyphenyl-acetyl)-4-benzylpiperazine.hydrochloride (160 mg) obtained in Example 9, ii) in ethanol is added palladium-black (30 mg) to subject to catalytic reduction in hydrogen at 40° C. under twice atmospheric pressure for 10 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The glass-like substance obtained is digested with ether into powder. This is filtered and dried to obtain 1-(2,4-dihydroxyphenylacetyl)piperazine.hydrochloride (147 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([CH:9]=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.I[CH2:14]Cl.C[Li]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][O:10]1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: ClCI
Agent: [Li]C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1CO1
Temperature: -78 °C

Procedure:
α,α,α-trifluoro-o-tolualdehyde (3 g) was dissolved in anhydrous tetrahydrofuran and cooled to -78° C., iodochloromethane (1.38 ml) was then added, followed by methyllithium (1.5M complexed with lithium bromide) (12 ml) added over 5 minutes. The reaction was left to warm up to room temperature overnight. The reaction was quenched using saturated ammonium chloride solution and extracted using diethyl ether (2×50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to afford a brown oil. Purification on flash silica eluted with 100% hexane up to 5% EtOAC in hexane afforded a colourless oil (1.1 g). 1H NMR (250 MHz, CDCl3) δ2.61-2.71 (1H, dd), 3.14-3.25 (1H, dd), 4.17-4.27 (1H, m), 7.33-7.70 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[C:5](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].O=P(Cl)(Cl)Cl.[NH4+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:17][C:16]([NH:18][CH:2]3[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]3)=[N:15][N:14]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: COc1cc(C(=O)O)cc(Cl)c1O
Reactant: NNC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(-c2nnc(NC3CCCCC3)s2)cc(Cl)c1O
Temperature: 95 °C
Yield: 161 %

Procedure:
To a mixture of 3-chloro-4-hydroxy-5-methoxybenzoic acid (2.468 mmol, 500 g), thiosemicarbazide (5b) (2.468 mmol, 427 mg) in dioxane (10 mL) at 65° C., POCl3 (3.2 mmol, 300 μL) was added, and the mixture was warmed at 95° C. for 3 hours 30 minutes. The solvent was removed by distillation under reduced pressure to give a crude material which was basified with a solution of diluted NH4OH. The precipitate obtained was collected by filtration, washed with water before drying under vacuum over P2O5 to give 675 mg of the desired product. Yield: 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:21][CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[CH3:34].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:29]2[C:28]2[CH:31]=[C:32]([CH3:33])[C:25]([O:24][CH2:23][CH2:22][OH:21])=[C:26]([CH3:34])[CH:27]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (1.27 g, 4.73 mmol) in N,N-dimethyl acetamide (20 mL) were added 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (D) (0.92 g, 4.7 mmol), sodium hydrogen sulphite (58.5 wt %) (0.95 g, 5.2 mmol) and p-toluenesulfonic acid (0.18 g, 0.95 mmol). The reaction mixture was stirred at 120° C. overnight, and cooled to room temperature. The solvent was removed under reduced pressure and water (100 mL) was added. The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with water (2×100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave crude compound, which was purified by the Simpliflash system (30% ethyl acetate in hexanes as eluent) to give the title compound (E) as a white solid. Yield: 0.34 g (16%). MP 152-153° C. 1H-NMR (400 MHz, CDCl3): δ 8.36-8.34 (m, 1H), 7.81-7.80 (m, 2H), 7.54-7.50 (m, 1H), 7.13 (d, J=6.26 Hz, 2H), 7.06 (d, J=8.21 Hz, 2H), 6.98 (s, 2H), 3.92-3.88 (m, 2H), 3.78-3.76 (m, 2H), 2.56-2.54 (m, 1H), 2.13 (s, 6H), 2.06 (t, J=6.26 Hz, 1H), 1.60-1.48 (m, 2H), 1.20 (d, J=7.04 Hz, 3H), 0.727 (t, J=7.43 Hz, 3H). MS (ES+) m/z: 443.01 (M+1) (100%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.CO.[CH:16](=O)[CH3:17].[BH4-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([NH:7][CH2:16][CH3:17])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1cn(-c2cccnc2)nc1Cl
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
A 3-neck, 100 mL round bottom flask was charged with 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d) (500 mg, 2.57 mmol) and methanol (5 mL). The mixture was stirred for 5 minutes to give a clear solution. Acetaldehyde (136 mg, 3.09 mmol) was added and the reaction was stirred at 20° C. for 6 hours. Sodium borohydride (194 mg, 5.14 mmol) was added and the reaction was stirred at 20° C. for 1 hour, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that some starting material remained and a major product formed. The reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure to remove methanol. Ethyl acetate (10 mL) was added and the organic layer was concentrated to dryness. The residue was purified by flash column chromatography using 20-40% ethyl acetate/hexanes as eluent. The fractions containing pure product were combined and concentrated to afford a white solid (328 mg, 58%). The spectral characterization was in agreement with the product prepared previously.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]=1N1CCCC1.[OH2:26]>C1(C)C=CC=CC=1>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:26]
Reactant: O=C(CBr)c1ccccc1
Reactant: O
Reactant: C1=C(N2CCCC2)CCc2ccccc21
Solvent: Cc1ccccc1
Product: O=C(CC1C(=O)CCc2ccccc21)c1ccccc1
Yield: 70 %

Procedure:
A solution of phenacylbromide (5.21 g, 26.1 mmol) in toluene (16 mL) was added over 15 minutes to a boiling, stirred solution of 1-(3,4-dihydro-2-naphthyl)pyrrolidine (5.21 g, 26.2 mmol) in toluene (17 mL). The reaction was refluxed 3 hours, diluted with water (15 mL) and refluxed for 4 hours then cooled. The layers were separated and the aqueous phase was extracted with toluene and dried over MgSO4 and concentrated. The material was purified by MPLC using a gradient from 0 to 20% ethyl acetate/hexanes to afford 4.85 g (70% yield) title product as a yellow oil.
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[H][H]>[Pt]=O.C(O)(=O)C>[NH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:10][CH2:11][NH2:12])=[CH:2][CH:3]=1.[NH2:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][CH:1]([CH2:10][CH2:11][NH2:12])[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: N#CCc1ccc(CC#N)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NCCC1CCC(CCN)CC1
Product: NCCc1ccc(CCN)cc1
Temperature: 25 °C
Yield: 339.5 %

Procedure:
Into a 250 mL reduction vessel were placed 1,4-phenylenediacetonitrile (2 g, 12.8 mmol), acetic acid (95 mL), and platinum oxide (0.25 g) and the mixture was heated at 60° C. under 60 psi (413.7 kPa) of hydrogen gas for 6 hours. The reaction was cooled to room temperature and filtered through a Celite® cake and the filtrate was concentrated under reduced vacuum to give the intermediate title compound, 2-[4-(2-aminoethyl)cyclohexyl]ethylamine, (3.7 g, 100%) as an oil. Electron spray M.S. 171 (M*+1).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])=[CH:4][C:3]=2[O:2]1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=1)[O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]([CH2:30][Cl:31])[CH2:24]1>>[ClH:31].[CH3:15][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=1)[O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]([CH2:30][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]4[O:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:9]2=[O:14])[CH2:24]1
Reactant: Cc1cccc(OCCCN2CCCCC(CCl)C2)c1
Reactant: O=C1NCCc2cc3c(cc21)OCO3
Product: Cc1cccc(OCCCN2CCCCC(CN3CCc4cc5c(cc4C3=O)OCO5)C2)c1
Product: Cl

Procedure:
Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydroisoquinoline and N-[3-(3-methyl-phenoxy)-propyl]-3-chloromethylhexahydro-azepine analogously to Example 2.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=2)[CH:39]=1>>[ClH:36].[ClH:36].[ClH:36].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:15][CH2:16]3)[CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]4[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=4)[CH:39]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)c4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (142 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as white powder after converting a free base to a trihydrochloride.