Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:2][C:3]#[N:4])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C2CCNCC2)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCN(CC#N)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
A mixture of bromoacetonitrile (0.70 mL, 10 mmol), 4-(3-methoxyphenyl)piperidine (1.74 g, 9.1 mmol) and K2CO3 (1.3 g) in MeCN was stirred at room temperature for 3 days. The reaction mixture was partitioned between CH2Cl2 and H2O, and the organic extract was dried (Na2SO4). The solvent was then removed in vacuo to afford [4-(3-methoxyphenyl)-1-piperidinyl]acetonitrile as an amber oil (2.03 g, 97%): MS (DCl) m/z 231 (MH+). Anal. Calcd. for C14H18N2O.0.5 H2O: C, 70.27; H, 8.00; N, 11.71. Found: C, 70.12; H, 7.67; N, 11.87.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH2:13][CH3:14]
Reactant: CCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 4-methyl-benzoyl chloride (6.12 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.41 g of yellow liquid. MS: m/e 319(M+′+1), 318(M+′), 317(M+′−1), 259, 230, 199, 182, 153, 105(base), 77.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH:26](C(OCC)=O)[C:27]([O:29]CC)=[O:28])[C:22]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:43]=[CH:42][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3cccs3)n2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of diethyl [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (6.08 g), 4N sodium hydroxide solution (10 ml), and ethanol (10 ml) was refluxed for 1 hour. After cooling, 1N hydrochloric acid (40 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless oily substance was dissolved in pyridine (50 ml), and stirred at 110° C. for 2 hours. After pyridine was removed under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid (4.02 g, yield: 80%). This was recrystallized from acetone-hexane. Melting point: 172˜173° C.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1>CO.[Pd]>[CH:1]1([O:5][C:6]2[N:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(OC2CCC2)nc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ccc(OC2CCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask containing 10% w/w Pd/C (485 mg) was gently flushed with argon while slowly adding MeOH (50 mL) along the sides of the flask, followed by the addition in ˜5 mL portions of a solution of 2-cyclobutoxy-5-nitro-pyridine (4.85 g, 25 mmol), as prepared in the previous step, in MeOH (30 mL). (Caution: Large scale addition of volatile organics to Pd/C in the presence of air can cause fire.) The flask was then evacuated one time and stirred under H2 balloon pressure for 2 h at rt. The reaction was then filtered, and the clear amber filtrate was concentrated, taken up in toluene (2×50 mL) to remove residual MeOH, and concentrated under reduced pressure to provide the crude title compound as a translucent dark brown oil with a faint toluene smell (4.41 g, “108%” crude yield). 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=3.0 Hz, 1H), 7.04 (dd, J=8.71 and 2.96 Hz, 1H), 6.55 (d, J=8.74 Hz, 1H), 5.04 (m, 1H), 2.42 (m, 2H), 2.10 (m, 2H), 1.80 (m, 1H), 1.66 (m, 1H). LC-MS (ESI): calcd mass 164.1, found 165.2 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.N1C=CC=CC=1.Cl[C:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:50]>ClCCl>[C:49](=[O:50])([O:51][C:52]1[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=1)[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:25][C:26]([O:27][C@@H:28]2[C@H:35]3[C@H:31]([O:32][CH2:33][CH2:34]3)[O:30][CH2:29]2)=[O:36])[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:19][CH:20]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (0.5 g, 0.84 mmol) in dichloromethane (4 mL) at 0° C. was added pyridine (0.16 mL, 0.158 g, 2.0 mmol) and 4-nitrophenyl chloroformate (0.22 g, 1.09 mmol) and the mixture was stirred at ambient temperature for 1 h. Dichloromethane was added and the mixture was washed with 15% citric acid/water (2×), saturated sodium bicarbonate/water, dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, dichloromethane/methanol, 49:1) to provide the title compound as a solid foam (0.5 g, 79% yield). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.16 (1H, dd), 1.3-1.4 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.65-2.80 (3H, m), 3.0 (2H, dd), 3.3-3.4 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.1 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 7.05 (1H, d), 7.2-7.4 (7H, m), 7.7 (2H, d), 8.35 (2H, d)
Reaction SMILES: C1C=CC(CC(NC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=O)=CC=1.[CH3:23][C:24]1([CH3:46])[S:28][C@@H:27]2[C@H:29]([NH:32]C(COC3C=CC=CC=3)=O)[C:30](=[O:31])[N:26]2[C@H:25]1[C:43]([O-:45])=[O:44].[K+].O>C(N(CC)CC)C>[CH3:23][C:24]1([CH3:46])[S:28][C@@H:27]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:26]2[C@H:25]1[C:43]([OH:45])=[O:44]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 38 °C
Reaction time: 9 h
Yield: 83.7 %

Procedure:
290 g of carrier-bound penicillinacylase according to Example 4, having an enzymatic activity of 2,803 U (NIPAB test) and 138 g of potassium penicillin V are added to 2,000 ml of water and stirred for 9 hours at 38°C. The pH value is kept constant at 7.8 by continuous addition of triethylamine. The mixture is worked up as described in Example 1. Yields of 6-APA 64.3 g (86.1% of theory); purity 97.4%.
Reaction SMILES: [N:1]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O-:11].[Na+]>CO>[N:1]1([C:8](=[NH:9])[O:11][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: N#CN1CCCCCC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCCCCC1

Procedure:
In the manner given in Example 2, 1-hexahydroazepinecarbonitrile is treated with sodium methoxide in methanol to give methyl 1-hexahydrazepinecarboximidate.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[N:18]=1>>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][S:25][C:19]1[N:18]=[C:17]([NH:15][S:12]([N:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:22]=[C:21]([O:23][CH3:24])[N:20]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CCS(=O)(=O)N1CCN(S(N)(=O)=O)CC1
Product: CCS(=O)(=O)N1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1

Procedure:
The title compound was prepared from 4-ethanesulfonylpiperazine-1-sulfonamide (the product of step i) (0.31 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent. Yield: 0.37 g
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.Br[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:15][CH2:14][CH2:13][CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: C1=CC2(CCC1)CCCNC2
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCC1NCCCC12C=CCCC2
Yield: 72 %

Procedure:
A mixture of 2-azaspiro-[5.5]-undec-7-ene (30.2 g.; 0.20 mole), 2-bromoethanol (25 g.; 0.20 mole) and triethylamine (20.2 g.) in toluene (250 ml.) is heated under reflux for 5 hours. The solution is cooled, filtered to removed triethylamine hydrobromide and the filtrate concentrated under reduced pressure. The residual liquid is distilled under reduced pressure to afford 28 g. (72% yield) of 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene, b.p. 90°-91° C./0.45 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O.CCO.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=1
Reactant: CCCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCNC(=O)c1ccc(N)cc1
Yield: 91 %

Procedure:
4-Nitro-N-propylbenzamide (3.31 g, 15.9 mmol) was dissolved in EtOAc (125 mL) and EtOH (125 mL) and passed through the H-Cube® at 1 mL/min equipped with a 10% Pd/C catcart (ThalesNano), at full hydrogen and temperature set to about 50° C. The solvent was stripped off and the solid was dried overnight in a vacuum oven set at about 50° C. to provide 4-amino-N-propylbenzamide (2.58 g, 91%): 1H NMR (DMSO-d6) δ 7.93 (t, J=5.48 Hz, 1H); 7.54 (d, J=8.57 Hz, 2H); 6.51 (d, J=8.67 Hz, 2H) 5.54 (br s, 2H) 3.13 (m, 2H) 1.47 (sextet, J=7.29 Hz, 2H) 0.85 (t, J=8.49 Hz, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O.O>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1([CH2:12][CH2:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCC1(CCO)CCCCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCC1(CCOCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (881 mg) in N,N-dimethylformamide (20 mL) was added 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (2.92 g) under ice cooling. To the solution was further added benzyl bromide (2.83 mL) under ice cooling, and it was stirred at room temperature for 63 hours. Water and 3N hydrochloric acid were added to the solution, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=6:4) to give the title compound (2.93 g).
Reaction SMILES: Cl.[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:37]1([P:43](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.Cl>[Si:2]([O:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C@@H:24]([NH:29][P:43]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:44])[CH2:25][CH:26]([CH3:27])[CH3:28])([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C[C@H](N)/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NP(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.6 %

Procedure:
To a solution of the amine 7 (400 mg, 1.01 mmol) in dry DCM (7 mL) were added Et3N (0.44 mL, 3.13 mmol), and then a solution of diphenylphosphinic chloride (Ph2POCl, 0.22 mL, 1.11 mmol) in dry DCM (3 mL) at 0° C. After being stirred at 0° C. for 15 min, the reaction mixture was allowed to warm to rt and stirred for 4 h, then diluted with DCM and 10% HCl. The aqueous phase was extracted with DCM and the combined organic layers were washed with sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford 720 mg of the crude title compound as a pale yellow solidified oil, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Reactant: C#Cc1ccc(N)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4ccc(N)nc4)on3)cc2)o1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 11.4 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (38 mg, 0.14 mmol) described in Manufacturing Example 46-1-6 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (15 mg, 0.13 mmol) described in Manufacturing Example 28-1-3 and triethylamine (35 μL, 0.25 mmol), which was stirred for 3.5 hours at 50° C. The reaction mixture was allowed to room temperature, and water was added to the system at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid), after which triethylamine was added to a mixture of the resulting target product and the mobile phase, thereby rendering the mobile phase basic, and the eluate was concentrated under a reduced pressure. The residue thus obtained was washed with water to obtain the title compound (5.1 mg, 12%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18](#[N:22])[CH2:19][C:20]#[N:21]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:18]#[N:22])[C:20]#[N:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: N#CCC#N
Reactant: O=C(C=Cc1ccccc1)c1ccc(I)cc1
Product: N#CC(C#N)C(CC(=O)c1ccc(I)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-iodophenyl)-3-phenylprop-2-en-1-one and malononitrile, 2-(3-(4-iodophenyl)-3-oxo-1-phenylpropyl)malononitrile was obtained as colourless solid.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH2:19][CH2:20][CH:21]=O)[C:3]1=[O:23].Cl.[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1.C(N(CC)CC)C>CCO.C(Cl)Cl.N1C=CC=CC=1>[OH:33][C@@H:28]1[CH2:29][N:30]([CH2:21][CH2:20][CH2:19][N:4]2[CH2:5][CH2:6][N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=3)[CH:2]([CH3:1])[C:3]2=[O:23])[CH2:31][CH2:32][C:27]21[CH2:26][CH2:25]2
Reactant: CC1C(=O)N(CCC=O)CCN1c1cccc(OC(F)(F)F)c1
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(OC(F)(F)F)c1
Yield: 58.2 %

Procedure:
To a solution of 3-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-propionaldehyde (117 mg, 0.35 mmol) in EtOH (1.6 mL) and CH2Cl2 (1.6 mL) were added (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 70 mg, 0.43 mmol) triethylamine (43 mg, 0.43 mmol), borane pyridine complex solution (8 M in pyridine, 0.093 mL, 0.74 mmol), then after 1 h the reaction mixture was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; CH2Cl2, then CH2Cl2/MeOH 4:1) afforded the title compound (90 mg, 58%). Light yellow oil, MS: 442.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:19][CH2:18]1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:21][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
A suspension of 3.8 g of 6-[4-(4-(5-nitroindol-3-yl)butyl)piperazino]-1,4-benzodioxane in 45 ml of methanol is hydrogenated with stirring on 0.1% Pd-C at 20° and 1 bar until absorption of H2 is complete. The mixture is poured into ice-water, worked up in the conventional manner and gives 6-[4-(4-(5-aminoindol-3-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[NH:11][C:10]([CH3:12])=[N:9][CH:8]=1)=[O:6].[CH3:14]N(C(OC)OC)C>>[CH3:13][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH3:14])[C:10]([CH3:12])=[N:9][CH:8]=1)=[O:6]
Reactant: COC(OC)N(C)C
Reactant: Cc1ncc(C(=O)C=CN(C)C)[nH]1
Product: Cc1ncc(C(=O)C=CN(C)C)n1C
Temperature: 100 °C
Yield: 29 %

Procedure:
5-(3-Dimethylaminoprop-2-enoyl)-2-methylimidazole (350 mg, 1.95 mmol) was suspended in DMFDMA (14 ml) and the mixture stirred and heated at 100° C. for 56 hours. The excess DMFDMA was removed by evaporation and the residue purified by chromatography eluting with DCM/MeOH (94:6) to give the title compound 111 mg, (29%) as a solid. NMR (CDCl3): 2.40 (s, 3H), 3.00 (s, 6H), 3.88 (s, 3H), 5.50 (d, 1H), 7.47 (s, 1H), 7.65 (d, 1H); m/z 194.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[C:11]#[N:12])([CH3:3])[CH3:2].[OH:13]O.[OH-].[Na+]>CS(C)=O.O>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[C:11]([NH2:12])=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C#N
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.105 g (0.634 mmol) of (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarbonitrile in 4.9 mL of dimethyl sulfoxide was placed in a 10 mL flask with a magnetic stir bar. After adding 0.60 mL of 35% hydrogen peroxide and 0.097 g (1.2 mmol) of 50% sodium hydroxide solutions the flask was capped and stirred at room temperature for 20 h. The reaction mixture was diluted with 10 mL of water, extracted twice with 10 mL of methylene chloride. The combined methylene chloride layers were back extracted with 3×20 mL of water, dried over magnesium sulfate, and concentrated in vacuo to provide an off-white solid that was further purified by column chromatography (silica gel, 75:25 hexane:ethyl acetate) to provide (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc2ccccc12)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cccc2ccccc12)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.344 mmol) of (2R*,4S*)-2-benzyl-1-(1-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 52 mg (1.37 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR32## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.35, FD-MS: M+ =485.