Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][C:19](=[O:21])[CH3:20])=[CH:10]2)=[CH:5][CH:4]=1.COC1C=CC(I)=CC=1.[H][H]>C(O)C.[Ni].C(O)(=O)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][CH:19]([OH:21])[CH3:20])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2cc(CC(C)=O)c3ccccc32)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: COc1ccc(I)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-n2cc(CC(C)O)c3ccccc32)cc1
Reaction time: 8 h

Procedure:
5.6 G (0.02 mole) of 1-(4-methoxyphenyl)-3-(2-oxopropyl)indole, prepared as described in example 1 but using 4-methoxyiodobenzene instead of iodobenzene are dissolved in 50 ml of anhydrous ethanol in a 200 ml autoclave. 2 g of Raney nickel are added. The autoclave is brought to a pressure of 50 kg of hydrogen and heat is applied at 100° for 8 hours at this pressure. The reaction medium is taken to dryness and the residue dissolved in normal acetic acid in the presence of diethyl ether. The organic phase is dried and the solvents are removed. The residue is then distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C([Li])CCC.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH4+].[Cl-]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([O:9][CH3:10])=[CH:5][CH:6]=[CH:7][C:8]=1[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccccc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cccc(OC)c1OC
Temperature: -40 °C
Reaction time: 24 h

Procedure:
A mixture of 27.6 g of 1,2-dimethoxybenzene in 160 ml of ether is cooled to −40° C., 250 ml of 1.6 M solution of n-butyllithium in hexane are added dropwise and the mixture is then stirred for 24 hours while allowing the temperature to return to RT. The reaction mixture is cooled to −20° C., 136 ml of diethyl oxalate are added quickly and the mixture is stirred while allowing the temperature to return to RT. After stirring for 30 minutes at RT, the reaction mixture is poured into saturated NH4Cl solution, the phases are separated by settling, the aqueous phase is extracted with ether, the combined organic phases are washed twice with water and dried over Na2SO4, and the solvents are evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=90° C. at 2400 Pa). The resulting crude product is chromatographed on silica gel, eluting with a heptane/iso-ether mixture (90/10; v/v). 25 g of the expected product are obtained and are used in the next step without further purification.
Reaction SMILES: F[C:2]1[C:3](CC#N)=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:18][C:14]1[N:13]=[C:12]([C:2]2([C:3]#[N:4])[CH2:7][CH2:6][CH2:5]2)[CH:17]=[CH:16][CH:15]=1
Reactant: N#CCc1ncccc1F
Reactant: Fc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(F)n2)CCC1
Yield: 64 %

Procedure:
Following the same procedure as above for 2-(3-fluoropyridin-2-yl)acetonitrile with 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0 equiv) and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene (100 mL) gave the desired product (4.9 g, 64%) as a colorless oil following purification over silica gel using 25% EtOAc/hexanes as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH:39]1([NH:42][C:43]([C:45]2[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=2)=[O:44])[CH2:41][CH2:40]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:39]1([NH:42][C:43]([C:45]2[CH:50]=[C:49]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=[C:5]4[C:17]3[N:22]=[C:21]([O:23][C@H:24]4[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]54[CH2:27][CH2:26]5)[CH:20]=[N:19][CH:18]=3)[CH:48]=[CH:47][CH:46]=2)=[O:44])[CH2:40][CH2:41]1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cccc(C(=O)NC6CC6)c5)cc34)n2)C1
Temperature: 120 °C
Yield: 80 %

Procedure:
A glass microwave reaction vessel was charged with (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (115 mg, 0.20 mmol), 3-(cyclopropylcarbamoyl)phenylboronic acid (81 mg, 0.39 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol) and Na2CO3 (104 mg, 0.98 mmol) in dioxane (0.8 mL) and water (0.2 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. The layers were separated and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-75% EtOAc in hexanes, to provide (4R)-tert-butyl 4-(6-(5-(3-(cyclopropylcarbamoyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (107 mg, 0.16 mmol, 82% yield) as a clear, colorless oil. MS (ESI, pos. ion) m/z: 665.3 (M+1).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:13]C(C(OC)=O)C=C)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:36][C:37]1([CH3:49])[S:41][C@@H:40]2[C@H:42]([NH2:45])[C:43](=[O:44])[N:39]2[C@H:38]1[C:46]([OH:48])=[O:47]>C(Cl)Cl.C(N(CC)CC)C.CC(N(C)C)=O>[CH3:36][C:37]1([CH3:49])[S:41][C@@H:40]2[C@H:42]([NH:45][C:10]([C@H:9]([NH2:13])[C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[O:12])[C:43](=[O:44])[N:39]2[C@H:38]1[C:46]([OH:48])=[O:47]
Reactant: C=CC(NC(C(=O)O)c1ccc(O)cc1)C(=O)OC
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Temperature: 22.5 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
A suspension of the potassium salt of D(-) p-hydroxy-N(1-methoxycarbonyl-2-propenyl)-alpha-aminophenylacetic acid (3.607 g, 1.19 cmoles), methylene chloride (25 ml), dimethylacetamide (2.5 ml) and TMSO (1.82 ml) was stirred at room temperature (20-25° C.) for 45 minutes. Thereafter triethylamine hydrochloride (1.63 g; 1.19 cmoles) was added and after 15 minutes the result was a translucid solution which was cooled to -20° C. Pivalyl chloride (1.45 ml; 1.2 cmoles) in methylene chloride (1.25 ml) and a drop of triethylamine were added. The reaction mixture was stirred for 60 minutes at a temperature of from -10 to -7° C. Thereafter a solution of 6-APA (1 cmole) prepared according to Example 1 was added under the conditions specified in that Example. Then, in a like manner, 3.25 g of amoxicillin (ratio of 1:1,50 with respect to 6-APA) were obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C)C=O>[C:15]1([CH2:14][CH2:13][N:12]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc(CCNc2nc(-c3ccccc3)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of 4-phenyl-N-(2-phenylethyl)-1,3-thiazole-2-amine (4.63 g, 16.5 mmol) in N,N-dimethylformamide (50 mL) was added 60% sodium hydride (990 mg, 24.8 mmol) and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (4.54 g, 19.8 mmol) was added and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.39 g, yield 48%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]12[CH2:14]C[CH:10]([CH2:11][CH2:12]1)[C@@H:9](C(O)=O)[CH2:8]2>C1(C)C=CC=CC=1>[ClH:4].[N:7]12[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8]1)[C@@H:1]([C:2]([Cl:4])=[O:3])[CH2:14]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Cl)[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8.18 g (64.43 mmol) of oxalyl chloride are added dropwise to a solution of 2.0 g (12.89 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid (Example 3A) in 10 ml of toluene. After stirring at room temperature for 18 h, the reaction mixture is concentrated in vacuo and codistilled with toluene twice. Drying under high vacuum results in 2.31 g (85.2% of theory) of the title compound, which is reacted further without further purification.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]2[O:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH3:23])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:28]C(OC(Cl)C)=O.CCO>C(Cl)Cl>[ClH:28].[CH3:23][C:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][C:18]=1[CH:16]1[CH2:15][NH:14][CH2:17]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1c(C2CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C2CNC2)oc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a cooled (0° C.) solution of 1-benzhydryl-3-(3-methylbenzofuran-2-yl)azetidine (52.0 mg, 0.147 mmol) in DCM (4 mL) under N2 was added 1-chloroethyl chloroformate (18.0 μL, 0.167 mmol) and the reaction was stirred at rt under N2 for 4 h. Next, EtOH was added and the mixture was stirred under nitrogen at 50° C. for 21 h. The mixture was concentrated in vacuo and the residue triturated with Et2O (3×5 mL), yielding the title product (20.4 mg, 62%) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]([C:12]1[CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[C:14]([C:20]([O:22]C)=O)=C(C)[NH:16][C:17]=1[CH3:18])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH3:2][O:9][C:10]([CH2:12][C:20](/[CH:14]=[CH:13]/[C:24]1[C:25]([N+:30]([O-:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22])=[O:11].[CH3:1][CH:2]([O:9][C:10](=[O:11])/[CH:12]=[C:17](\[NH2:16])/[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)c2ccccc2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C/C(N)=C/C(=O)OC(C)c1ccccc1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid α-methylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid α-methylbenzyl ester of melting point 154° C (from ethanol).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)SC)#[N:2].[CH2:9]([N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1)[CH3:12])[CH3:10].CNC(=N)S.[CH2:29]([NH2:32])[C:30]#[CH:31]>C(O)(C)C>[C:1]([NH:3][C:4]([NH:32][CH2:29][C:30]#[CH:31])=[N:23][CH2:22][CH2:21][S:20][CH2:19][C:17]1[O:18][C:14]([CH2:13][N:11]([CH2:9][CH3:10])[CH3:12])=[CH:15][CH:16]=1)#[N:2]
Reactant: CCN(C)Cc1ccc(CSCCN)o1
Reactant: C#CCN
Reactant: CSC(=NC#N)SC
Agent: CNC(=N)S
Solvent: CC(C)O
Product: C#CCNC(=NCCSCc1ccc(CN(C)CC)o1)NC#N

Procedure:
When an isopropyl alcohol solution of dimethyl cyanodithioimidocarbonate [prepared according to the procedure described in J. Org. Chem., 32, 1566 (1967)] is reacted with 2-[(5-{[N-ethyl-N-methylamino]methyl}-2-furyl)methylthio]ethylamine and the resultant N-cyano-N'-2-[(5-{[N-ethyl-N-methylamino]methyl}-2-furyl)methylthio]-ethyl}-S-methylisothiourea treated with propargylamine in the procedure of Example 2, there is produced N-cyano-N'-(2-propyn-1-yl)-N"-{2-[(5-{[N-ethyl-N-methylamino]methyl}-2-furyl)methylthio]ethyl}guanidine.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[CH:27]=[N:28][N:29]([CH2:30][CH2:31][O:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=3)[C:3]1=2.[OH-].[Na+].C1COCC1.CO>O>[O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[CH:27]=[N:28][N:29]([CH2:30][CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:41][CH:42]=3)[C:3]1=2
Reactant: COC(=O)c1ccc(OCCn2ncc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCCn2ncc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of methyl 4-({2-[7-oxo-5-({[(3-{[2-(1H-1,2,4-triazol-3-yloxy)ethyl]oxy}phenyl)methyl]amino}carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl}oxy)benzoate obtained in Example 47 (164 mg, 0.285 mmol), 4N aqueous sodium hydroxide solution (0.250 mL), THF (2 mL), methanol (2 mL) and water (2 mL) was stirred at 90° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (20 mL), and acidified with 1N hydrochloric acid (1.5 mL). The precipitated solid was collected by filtration, and washed with water (4 mL×2) and methanol (4 mL). The obtained solid was recrystallized from methanol to give the title compound as a white powder (120 mg, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:24])[CH2:26][CH:27]3[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNC(Cc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)C(Cc2ccccc2)C1

Procedure:
Following the procedure of steps 2 and 4 of Example 1, 5-bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.48 g, 1.6 mmol) was coupled with 3-benzyl-piperazine-1-carboxylic acid tert-butyl ester to give 5-(2-benzyl-4-tert-butoxycarbonyl-piperazin-1-yl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester, which was then deprotected by reaction with TFA to afford 5-(2-benzyl-piperazin-1-yl)-2,3-dihydro-1H-indole (0.16 g) as a yellow foam; 1H NMR (300, MHz, CDCl3) δ 7.24-7.10 (m, 3H), 7.17-1.01 (m, 2H), 6.96 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.2, 2.2 Hz, 1H), 3.61-3.46 (m, 3H), 3.20-2.69 (m, 7H), 2.84-2.72 (m, 2H), 2.56 (dd, J=10.5, 13.6 Hz, 1H); MS (M+H)=294.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[C:6]1([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[C:18]#[N:19])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20]1COC[CH2:21]1>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:20][CH2:21][C:13]1([C:18]#[N:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: C1CCOC1
Reactant: N#CC1CCCCC1c1ccccc1
Product: CN(C)CCCC1(C#N)CCCCC1c1ccccc1
Reaction time: 3 h

Procedure:
In a 500 ml flask was added 0.88 g of freshly washed (with hexane) KH (2.2 eq, 22 mmoles). To this was added 100 ml THF, 50 ml DMF, and 10 mmoles of 2-phenylcyclohexane carbonitrile and the contents were heated at reflux under N2 for 3 hours. After 3 hours, a solution of 1.5 eq of freshly distilled 3-N,N-dimethylaminopropyl chloride (9.83 g) dissolved in 25 ml THF was added dropwise and the reaction then heated at reflux overnight.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C)C=O>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:2]=3[F:1])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A solution of 2-fluoro-4-bromobenzoic acid (0.24 g) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g) and stirred for 30 minutes at ambient temperature under argon. A solution of 1-(4-pyridyl)piperazine (1.6 g) in dry dimethylformamide (3 ml) was added to the mixture and the mixture cooled to 50° C. The reaction was then allowed to warm to room temperature and stirred overnight. The solution was poured into water and then extracted into diethyl ether, washed with aqueous sodium hydrogen carbonate solution, water, brine. dried (Na2SO4) and evaporated to yield a colourless oil. This oil was then triturated with diethyl ether and recrystallised from ethyl acetate/isohexane to give 1-(4-pyridyl)-4-(2-fluoro-4-bromobenzoyl)piperazine (0.14 g) as a solid, m.p. 125-126° C.: microanalysis, found: C, 52.6; H, 4.1; N, 11.2%; C16H15BrFN3O requires: C, 52.8; H, 4.15; N, 11.5%; NMR: (CDCl3) 3.32(t,2H), 3.46(t,4H), 3.94(t,2H), 6.68(dd,2H), 7.29-7.43(m,3H), 8.33(d,2H); MS: m/z 364 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](OC(OCC)OCC)(=O)C>>[CH:12](=[N:11][C:4]1[N:3]=[C:2]2[N:1]=[CH:10][N:9]([CH3:19])[C:7](=[S:8])[N:6]2[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CNC(=S)n1nc(N=Cc2ccccc2)nc1N
Product: Cn1cnc2nc(N=Cc3ccccc3)nn2c1=S
Yield: 93 %

Procedure:
The synthesis method of Example 55 was applied. The compound (783 mg) obtained in Example 37 and diethoxymethyl acetate (5 ml) were used as reagents. The mixture was reacted at 90° C. for 1.5 hours to give 757 mg of white powdery crystals (yield 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[NH:14][N:13]=[N:12][N:8]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Temperature: 130 °C
Yield: 93.1 %

Procedure:
A mixture of 3-nitrobenzonitrile (3.70 g, 25 mmol), sodium azide (4.88 g, 75 mmol) and triethylamine hydrochloride (10.32 g, 75 mniol) in N-methylpyrrolidone (55 ml) was heated at 130° C. for 2 hours under stirring. The reaction mixture was poured into ice-water, to which was dropwise added 6N hydrochloric acid in order to acidify. The resultant precipitates were collected by filtration, washed with water and dried to afford 5-(3-nitrophenyl)-1H-tetrazole (4.45 g, 93.1%), which was used in a following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[S:16](N)([NH2:19])(=[O:18])=[O:17]>C(COC)OC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:10]2)=[CH:14][CH:15]=1
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(CO[C@H]2CCNC2)cc1
Solvent: COCCOC
Product: COc1ccc(CO[C@H]2CCN(S(N)(=O)=O)C2)cc1
Yield: 61.2 %

Procedure:
A mixture of (S)-3-((4-methoxybenzyl)oxy)pyrrolidine (4.50 g, 21.7 mmol) and sulfamide (2.50 g, 26.0 mmol) in dimethoxyethane (100 mL) was refluxed for 72 h. The reaction was concentrated in vacuo. Purification of the residue by column chromatography (30% to 100% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (3.80 g, 61%): 1H NMR (300 MHz, DMSO-d6) δ 7.27-7.24 (m, 2H), 6.91-6.88 (m, 2H), 6.74 (s, 2H), 4.39 (s, 2H), 4.16-4.11 (m, 1H), 3.74 (s, 3H), 3.30-3.25 (m, 1H), 3.18-3.10 (m, 3H), 2.00-1.88 (m, 2H); MS (ES+) m/z 287.2 (M+1); MS (ES−) m/z 285.3 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10](CC(O)=O)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1CCC[CH2:27]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:27][OH:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1C(=O)N(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Reactant: C1CCOC1
Product: OC[C@@H]1CN(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of trans (4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one (1.97 g) in tetrahydrofuran (20 ml) was treated with borane-tetrahydrofuran complex (19.6 ml, 1 molar) and heated at reflux for 6 hours. After cooling, the reaction was quenched with 1 molar hydrochloric acid, then stirred and heated at reflux for a further 1 hour. The mixture was cooled to ambient temperature, the pH adjusted to 9 with 1 molar sodium hydroxide, and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with saturated sodium chloride and evaporated to give trans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (1.59 g, 92%).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[CH:4]=[CH2:5]>CC(C)=O>[I-:2].[CH2:3]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N+:14]([CH3:1])[CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C=CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.4 ml, 6 mmol ) and 3-(4-(2propenyloxy)-1,2,5-thiadiazol-3-yl )pyridine (3 mmol ) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitiated from the solution and was collected by filtration to give 0.96 g (88%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1.[CH2:13]([Mg]Br)CCCCC>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCCCCC[Mg]Br
Reactant: CCCCCc1cc(C)ccn1
Product: CCCCCCc1cc(C)ccn1

Procedure:
This compound was obtained using the same experimental procedure as per 4-methyl-2-pentyl-pyridine (see above), using hexyl magnesium bromide instead of pentyl magnesium bromide. The product was obtained with similar yield and purified in the same way.