Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.Cl.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:1]2[CH2:2][CH2:3][C:4](=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)[CH2:5][CH2:6]2)=[O:31])=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 0.15 g (0.6 m mole) of 10,11-dihydro-5-(4-piperidylidene)-5H-dibenzo[a,d]cycloheptene, 0.096 g (0.55 m mole) of 4-pyridylacetic acid hydrochloride, 0.16 g (0.83 m mole)of DEC and 0.075 g (0.55 m mole) of HOBT in 5 mL of DMF and stir at room temperature for 18 hours under nitrogen. Concentrate under vacuo and partition between 100 mL each of EtOAc and 10% aqueous sodium hydrogenphosphate. Dry the organic layer over MgSO4 and concentrate under vacuo. The resulting residue is chromatographed on silica gel using 98% dichloro methane and 2% MeOH, saturated with ammonia as the solvent, giving the product as a white waxy solid, mp=162.8°-163.4° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:34][C:35]([CH3:39])([CH3:38])[CH2:36]O.O>CN(C)C=O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:34][C:35]([CH3:39])([CH3:38])[CH3:36])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CC(C)(C)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.84 g) was dissolved in dimethylformamide (30 ml) and carbodiimidazole (1.78 g) was added to the solution. After stirring at room temperature for 2 hours, 2,2-dimethyl-propanol (0.88 g) was added. After stirring at 60° C. for 4 hours, water was added and the mixture was extracted with ethyl acetate. The extracted layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.82 g), yield 23%, m.p. 138°-139° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH3:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>[Pd]>[ClH:1].[ClH:1].[OH:21][CH2:20][CH2:19][CH2:18][N:16]([CH3:17])[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: CN(CCCO)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CN(CCCO)C1CCNCC1
Reaction time: 2 h
Yield: 183.4 %

Procedure:
42.8 g of 1-benzyl-4-[(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are dissolved in 450 ml of methaol, combined with 5 g of 5% palladium/charcoal and hydrogenated at about 50° C. with hydrogen at a pressure of 4-5 bar. The catalyst is filtered off, the methanol is distilled off and the residue is stirred into acetone. Ether is added, the mixture is left to stand for about two hours and then the crystals are suction filtered. 28.7 g of 4-[(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are obtained as a solid.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[S:14](Cl)(=[O:16])=[O:15]>[NH4+].[Cl-]>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[S:14]([NH2:2])(=[O:16])=[O:15]
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])ccc1S(N)(=O)=O
Yield: 68.9 %

Procedure:
To a concentrated solution of ammonium hydroxide (28%, 2.5 mL, 20 mmol) was added cautiously 2-methoxy-4-nitrobenzenesulfonyl chloride (0.25 g, 1.0 mmol). After stirring 24h the reaction mixture was added to satd NH4Cl (50 mL) and extracted with DCM (2×50 mL). The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure. The crude residue was chromatographed (silica, MeOH/DCM, 0:100 to 10:90) to yield 2-methoxy-4-nitrobenzenesulfonamide (0.16 g, 68%) as a pale brown solid. 1H-NMR (DMSO-d6) δ 7.99 (1H, d), 7.90-7.95 (2H, m), 7.47 (2H, br s), 4.04 (3H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOC(=O)CCc1ncc[nH]1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CCc1nccn1-c1ccc(C)cc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 92.9 %

Procedure:
1-Fluoro-4-methyl-2-nitrobenzene 239 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 252 mg, potassium carbonate 415 mg and N,N-dimethylacetamide 10 mL were stirred at 100° C. for 11.5 hours, and then at 130° C., for 6 hours. The reaction liquid was diluted with diethyl ether, washed with water and saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was subjected to silica gel chromatography (ethyl acetate) to provide 422 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]OC.CO>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1
Reactant: COCOC
Reactant: Oc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: COCOc1cccc(Cl)c1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
To a solution of 3-chlorophenol (8 ml, 77 mmol, ABCR) in DCM (120 ml) was added dimethoxymethane (32 ml, 362 mmol, Aldrich) and then p-toluenesulphonic acid (0.164 g, 0.952 mmol, Alfa Aesar). The solution was heated to reflux under nitrogen using a Soxhlet apparatus containing 3A activated molecular sieves (approximately 20 g)* for 24 h. *The 3A molecular sieves were replaced after 6 h. Approximately a quarter of the reaction mixture was applied to a 70 g aminopropyl cartridge (prewashed with methanol). The cartridge was eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to give 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (1.66 g). The remaining reaction mixture was applied evenly to 3×70 g aminopropyl cartridges (pre-washed with methanol). The cartridges were eluted with methanol (1-2 column volumes) and several fractions collected. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and the solvent removed in vacuo to leave a colourless mobile oil (first batch). The mixed fractions were combined and the solvent removed in vacuo to leave a colourless mobile oil. The residue from the mixed fractions was applied to a 70 g aminopropyl cartridge (pre-washed with methanol) and eluted with methanol. Appropriate fractions were combined (TLC 50:50 DCM in cyclohexane) and added to the first batch. The solvent was removed in vacuo to give another batch of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene as a colourless mobile oil (5.27 g). To THF (20 ml) under nitrogen at 0° C. was added 1.6 M n-butyllithium in hexanes (18.1 ml, 29.0 mmol, Aldrich). To the solution at −60° C. was added a solution of 2,2,6,6-tetramethylpiperidine (4.90 ml, 29.0 mmol, Alfa Aesar) in THF (5 ml) and then a solution of 1-chloro-3-{[(methyloxy)methyl]oxy}benzene (5.01 g, 29.0 mmol) in THF (10 ml). The temperature was maintained below −50° C. during the addition. The solution was stirred at −60° C. to −70° C. for 1 h. To the solution was added a large excess of freshly ground solid carbon dioxide and the mixture allowed to warm to ambient temperature. The reaction mixture was diluted with water (100 ml) and diethyl ether (130 ml). The phases were separated and aqueous phase carefully acidified to pH1 using concentrated HCl. The suspension was extracted with dichloromethane (3×40 ml). The solvent was removed in vacuo to give the title compound as a white solid (4.36 g);
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH3:30]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19]([CH2:29][CH3:30])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOCc3ccccc3)cc2O1
Reactant: CCI
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1

Procedure:
The title compound was prepared from ethyl 7-(3-benzyloxypropoxy)-chromane-2-carboxylate following the procedure described in Example 2, Step A employing iodoethane instead of iodopropane.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([OH:15])=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]1>O1CCCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:13]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:33]3)=[O:15])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)#[N:31]
Reactant: CCOC(=O)C1CCCNC1
Reactant: N#Cc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)COc2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.35 g of carbonyldiimidazole are added to a solution of 7.6 g of 4-(carboxymethyloxy)-4'-cyano-biphenyl (prepared from 4-cyano-4'-hydroxy-biphenyl and tert.butyl bromoacetate according to Example 13, but with potassium tert.butoxide as base, and subsequent ester cleaving with trifluoroacetic acid) in 30 ml of tetrahydrofuran and the resulting mixture is stirred for 0.5 hours at ambient temperature. 5.1 ml of ethyl piperidine-3-carboxylate are added and the mixture is stirred for 22 hours at ambient temperature. The tetrahydrofuran is evaporated off, the residue is taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution, 0.1N hydrochloric acid and water. After evaporation of the organic phase the residue remains as an oil.
Reaction SMILES: [I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH3:24])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(C(=O)O)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(n1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a suspension of 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.750 g, 1.696 mmol) in DCM (8.5 mL) and a few drops of DMF was added oxalyl chloride (0.259 mL, 2.97 mmol) at RT. After 30 min, the reaction was cooled to 0° C., MeOH was added and the mixture was stirred for 30 min. The mixture was then concentrated. To the yellow solid was added H2O and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give methyl 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.700 g, 1.534 mmol, 90%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 457.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 2.38 (3H, s), 4.01 (3H, s), 7.27-7.32 (2H, m), 7.75-7.81 (2H, m), 8.02 (1H, s), 8.18 (1H, d, J=8.80 Hz), 8.34 (1H, d, J=8.61 Hz).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:46]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=1[F:53])([S:36]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:32][CH2:33][CH2:34][CH3:35])(C(C)(C)C)(C)C>O1CCCC1.C(OCC)C.C(OCC)(=O)C.CCCCCC>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([S:36]([C:31]([C:46]2[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=2[F:53])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:30][CH2:29][CH2:28][CH2:27][OH:26])(=[O:38])=[O:37])=[CH:44][CH:43]=1
Reactant: CCCCC(CCCCO[Si](C)(C)C(C)(C)C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC(CCCCO)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
After addition of tetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 0.532 ml, 0.532 mmol) to a solution of 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-butylpentyl]-1,4-difluorobenzene (154 mg, 0.283 mmol) in tetrahydrofuran (4 ml), the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated. The residue thus obtained was dissolved in diethyl ether, followed by successive washing with water and brine, drying over MgSO4, and concentration. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (50% ethyl acetate-hexane), whereby the title compound (122 mg, 0.283 mmol) was obtained as a colorless oil.
Reaction SMILES: [CH:1]#[CH:2].[SiH:3]([Cl:6])([Cl:5])[Cl:4]>>[Si:3]([CH2:1][CH2:2][Si:3]([Cl:6])([Cl:5])[Cl:4])([Cl:6])([Cl:5])[Cl:4]
Reactant: C#C
Reactant: Cl[SiH](Cl)Cl
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl

Procedure:
An example is the reaction of acetylene with HSiCl3 to give Cl3 SiCH2CH2SiCl3 in the first step of the process. An intermediate produced is CH2 =CHSiCl3, which can be used as starting material in place of acetylene and, when reacted with HSiCl3, leads to the same end product of the first step of the process, Cl3SiCH2CH2SiCl3.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>C(O)C.Cl.[Pd]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCN(C)c1ccc(N)cc1

Procedure:
A solution of N,N,N′-trimethyl-N′-(4-nitrophenyl)ethane-1,2-diamine in ethanol, containing 5 drops of concentrated hydrochloric acid, is hydrogenated overnight at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give N-[2-(dimethylamino)ethyl]-N-methylbenzene-1,4-diamine as a dark maroon oil.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]([F:37])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:11]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:10]1=2)(C(C)(C)C)(C)C.CO.O1CCCC1.C(=O)([O-])O.[Na+]>Cl.C(OCC)(=O)C>[CH:21]1([C:13]2[C:12]([CH:26]([F:37])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[C:11]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:10]3[CH:9]([OH:8])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=3[N:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O)C1

Procedure:
110 g of 5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline were stirred at 40° C. for 2 hours in a mixture of 913 ml of 5 N hydrochloric acid, 1364 ml of methanol and 902 ml of tetrahydrofuran. Working up was carried out by pouring into saturated aqueous sodium hydrogencarbonate solution and extraction with ethyl acetate. The organic phases were dried after fresh washing with saturated aqueous sodium hydrogencarbonate solution. After distilling off the solvent in vacuo, the residue was recrystallized from cyclohexane. After drying in an oil-pump vacuum, a total of 71.1 g of colorless crystals having a purity of 99.4% according to HPLC (e.e. 99.5%) resulted. By chromatography on silica gel, it was possible from the mother liquor of the crystallization, using petroleum ether/ethyl acetate 7:1, to obtain a further 10.8 g of the same quality.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2S[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[N+](C1C=CC2OC(C(O)=O)=CC=2C=1)([O-])=[O:17]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(N)ccc2s1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Product: CCOC(=O)c1cc2cc(N)ccc2o1

Procedure:
The appropriate arylcarboxylic acid is synthesized by the coupling of indole-2-carboxylic acid, benzofuran-2-carboxylic acid or benzothiophene-2-carboxylic acid with ethyl 5-amino-aryl-2-carboxylate in DMF with EDCI, and saponification of the ester. Ethyl 5-aminoindole-2-carboxylate is formed by catalytic hydrogenation of ethyl 5-nitroindole-2-carboxylate (Parmerter, S. M.; Cook, A. G.; Dixon, W. B. J. Am. Chem. Soc. 1958, 80, 4621). Ethyl 5-aminobenzothiophene-2-carboxylate can be synthesized as described in: Zambias, R. A.; Hammond, M. L. J. Syn. Commun. 1991, 21, 959. Ethyl 5-aminobenzofuran-2-carboxylate is prepared from the commercially available 5-nitrobenzofuran-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([F:12])=[C:4]([Cl:13])[N:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([F:12])=[C:4]([Cl:13])[N:3]=1
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: OCc1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
To a solution of methyl 2,6-dichloro-5-fluoro-3-pyridinecarboxylate (3 g, 13.39 mmol) in DCM (12 ml) at 0° C. under N2 was added dropwise DIBAL-H (1.5 M solution in toluene, 19.20 ml, 28.8 mmol). The reaction mixture was stirred at 0° C. for 20 h. TLC (DCM) showed starting material remaining. Then, more DIBAL-H (1.5 M solution in toluene, 10 ml) was added. The reaction was stirred at 0° C. for 20 h. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was treated with 1N HCl solution and extracted 3 times with EtOAc. The combined organic phases were washed with sat. NaCl, dried over Na2SO4 and concentrated to give 1.5 g (53%) of the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:16]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(=[O:18])[CH3:17].C([BH3-])#N.[Na+].C(OCC)(=O)C>CO.O>[ClH:1].[ClH:1].[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([NH:3][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:8][CH:9]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1CCC(Nc2ccc(N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-(4-aminophenyl)piperidine dihydrochloride obtained in Example 17 and 1-acetyl-4-piperidone (0.70 g) in methanol (10 ml) was added sodium cyano borohydride (0.63 g), followed by stirring at room temperature for 5 hours. To the mixture was added ethyl acetate ester (20 ml) and water (30 ml). After the organic layer was dried over anhydrous sodium sulfate, to the solution was added 6N solution of hydrogen chloride in dioxane (2 ml) and the solvent was distilled off. The residue was recrystallized from ethanol to obtain colorless crystals, m.p. 187°-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:13][OH:14].CCCCCC.C(OCC)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:13][OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1cccc(C#CC=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: Cc1cccc(C#CC=NO)c1
Yield: 85 %

Procedure:
130 mg of the resulting aldehyde was dissolved in 20 ml of ethanol, and 5 ml of an aqueous solution of 70 mg of hydroxylamine hydrochloride was added. The solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography column: Lobar column, size A, Lichroprep Si 60 (E. Merck Co.); eluting solvent: hexane/ethyl acetate=-10/1] to give 122 mg (yield 85%) of 3-(3-methylphenyl)-2-propynaldehyde oxime as a pale yellow oil.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[Si]([N:19]=C=O)(C)(C)C.[ClH:22].O1CCOCC1>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6]([NH2:19])=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 5.04 mmol) in DCM (15 mL) is added TMS-isocyanate (2.68 mL, 20.2 mmol) and the reaction stirred at about 25° C. for 72 hours. The reaction is concentrated, and the residue dissolved in DCM (15 mL) and treated with 4M HCl in 1,4-dioxane (5.04 mL, 20.2 mmol). The reaction is stirred overnight, and the solid filtered to afford the title compound (P).
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.[CH:11]1[C:16]([C:17](CBr)=[O:18])=[CH:15][CH:14]=[C:13]([F:21])[CH:12]=1.[ClH:22]>C(Cl)(Cl)Cl.CCO>[ClH:22].[NH2:4][CH2:10][C:17]([C:16]1[CH:15]=[CH:14][C:13]([F:21])=[CH:12][CH:11]=1)=[O:18]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hexamethylenetetramine (1.42 g, 10.1 mmol) was added dropwise over 30 min to a solution of 2-bromo-4-fluoroacetophenone (2.0 g, 9.2 mmol) in dry CHCl3 (40 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction the solid precipitate formed was collected by filtration and washed with CHCl3. The solid obtained was suspended in EtOH (40 mL) and conc. HCl (4 mL) was added. The mixture was heated to 80° C. for 3 h, cooled to room temperature, and the solid formed was filtered off. The clear filtrate was concentrated to afford 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (1.5 g, crude) as yellow solid. MS (ESI) m/z: Calculated for C8H8FNO: 153.06. found: 153.9 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: COCCC(N)=NO
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 134 mg (0.910 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 185 mg (49% of theory)