Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OC(=O)C)C.O>[C:24]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
5-nitroindole (50 mg, 0.31 mmol) and potassium carbonate (128 mg, 0.93 mmol) were suspended in. dimethylformamide (1.0 ml). Then, benzoyl chloride (0.04 ml, 0.345 mmol) was added and stirred at room temperature for 2 hours. After completing the reaction, water and ethylacetate (respectively 5 ml) were added to extract, washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified through a flash column chromatography (an eluent: ethyl acetate/n-hexane=1/1, v/v). As a result, the present compound (35 mg, productive yield 43%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2ccncc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccncc2)c1CBr
Yield: 21.9 %

Procedure:
Ethyl 4-methyl-3-(pyridin-4-yl)isoxazole-5-carboxylate (5.1 g, 22.0 mmol), NBS (4.7 g, 26.4 mmol), and benzoyl peroxide (0.53 g, 2.2 mmol) were added to 140 mL of carbon tetrachloride and the mixture was refluxed for 16 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography (10-60% EtOAc/hexanes) to afford 1.5 g of the title compound. MS: (+) m/z 311, 313 (M+1, 79Br/81Br).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].O1CCCC1.[NH3:16]>CCOCC>[C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(=[O:2])[NH2:16]
Reactant: O=C(O)Cn1nnnc1S
Reactant: N
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)Cn1nnnc1S
Reaction time: 2.5 h

Procedure:
1-Carboxymethyltetrazole-5-thiol and 1,1-carbonyldiimidazole were reacted as described in Example 4. To the reaction mixture was added tetrahydrofuran saturated with dry ammonia gas. The resulting suspension was stirred for 2.5 hours and the solid which formed was collected by filtration, washed with tetrahydrofuran and dissolved in methanol. Amberlite IR-120 ion-exchange resin (50 g.) was added and the suspension was stirred for 15 minutes. The resin was then removed and washed with absolute methanol. The methanol solution was concentrated to give a residue which was dissolved in ether and triturated with acetone to give 1-carbamoylmethyltetrazole-5-thiol, m.p. 200° (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) was dissolved in tetrahydrofuran (2 mL). Dimethylsulfamoyl chloride (18 mg, 0.122 mmol) was added to the reaction mixture followed by triethylamine (34 uL, 0.244 mmol). The suspension was stirred at rt overnight. The reaction was concentrated under vacuum. The compound was triturated with 1:1 ether-hexanes to yield desired product (22 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.92 (1s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.20 (m, 3H), 7.35-7.25 (m, 4 H), 7.12 (d, 1 H), 5.64 (s, 2 H), 3.90-3.20 (m, 5H), 2.70-2.05 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:34][C:35]([NH2:37])=[O:36].C1CCN2C(=NCCC2)CC1.O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:34][C:35]([NH2:37])=[O:36])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(O)cc23)cc1
Reactant: NC(=O)CI
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(OCC(N)=O)cc23)cc1
Yield: 36.5 %

Procedure:
A solution of tert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.30 ml, 2 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.18 g, 36.7%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: Fc1ccc(C=CCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 1-(3-chloro-1-propenyl)-4-fluorobenzene (0.85 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. Crystallization from diethyl ether-hexane provided 0.9 g of (E)-4-[[3-(4-fluorophenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9][OH:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ClN1C(=O)CCC1=O.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2([C:32]([F:35])([F:33])[F:34])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=3)[CH2:31]2)[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: O=[N+]([O-])c1cc(C=NO)ccc1Cl
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
In dimethylformamide (30 mL), 2-chloro-5-hydroxyiminomethylnitrobenzene (2.92 g) and N-chlorosuccinimide (1.94 g) were dissolved, and the mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature, and thereto was added 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-propene (3.50 g), followed by triethylamine (1.46 g), and then the mixture was stirred for 6 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloronitrobenzene (4.42 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:47][CH2:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][C:50]=1[C:57]([F:60])([F:59])[F:58]>ClCCl>[C:53]([C:52]1[CH:55]=[CH:56][C:49]([CH2:48][NH:47][C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:15][CH2:14]2)=[O:18])=[C:50]([C:57]([F:58])([F:60])[F:59])[CH:51]=1)#[N:54]
Reactant: CNc1nc(C)nc(N2CCC(C(=O)O)CC2)n1
Reactant: N#Cc1ccc(CN)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNc1nc(C)nc(N2CCC(C(=O)NCc3ccc(C#N)cc3C(F)(F)F)CC2)n1
Yield: 3.1 %

Procedure:
1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (163 mg, 0.65 mmol) was dissolved in 10 mL of dichloromethane and treated with EDCI (150 mg, 0.72 mmol), HOBt (88 mg, 0.65 mmol), N-methylmorpholine (0.2 mL, 1.5 mmol), and 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (130 mg, 0.65 mmol) at room temperature for 12 hours. The reaction mixture was concentrated and purified by preparative HPLC to provide N-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxamide (7 mg, 0.02 mmol, 2%) as a white solid. MS (ES+): m/e 434 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[C:21]1[S:25][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[N:28]=2)=[C:23]([C:35]([NH2:37])=[O:36])[CH:22]=1>>[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:14]=[CH:13][C:12]=1[C:21]1[S:25][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH:1][CH2:2][CH:3]3[CH2:4][CH2:5][C:6](=[O:9])[N:7]3[CH3:8])[N:28]=2)=[C:23]([C:35]([NH2:37])=[O:36])[CH:22]=1
Reactant: CN1C(=O)CCC1CN
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Product: CN1C(=O)CCC1CNCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 106, Step 2 using the oxalate salt of 5-(aminomethyl)-1-methylpyrrolidin-2-one (21 mg, 0.096 mmol) and 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-formylpyridin-2-yl)amino]thiophene-3-carboxamide (39 mg, 0.096 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23](N)=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[OH-:26].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([OH:26])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: COc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1

Procedure:
A mixture of 100 parts of 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 49.5 parts of potassium hydroxide and 974 parts of 1,2-ethanediol is stirred and refluxed for 24 hours. After cooling, the reaction mixture is poured onto 1500 parts of water and acidified with a concentrated hydrochloric acid solution. The whole is strongly alkalized with a sodium hydroxide solution and the layers are separated. The aqueous phase is concentrated, whereupon the product is separated as an oil. The supernatant aqueous phase is decanted and the residual oil is taken up in a sodium hydroxide solution. The precipitated product is filtered off and dissolved in water. The solution is acidified with acetic acid till pH=6. The precipitated product is filtered off and warmed in ethanol. It is filtered off again, washed with ethanol and 2,2'-oxybispropane and dissolved in boiling N,N-dimethylformamide. The solution is filtered and the product is allowed to crystallized from the filtrate. It is filtered off, washed successively with N,N-dimethylformamide, water and ethanol, and dried, yielding 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)- 4-piperidinecarboxylic acid; mp. 211.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:10]1=[NH:22].[CH3:23]C(CC)=O.C(=O)([O-])O.[K+].C[I:34]>O>[IH:34].[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[N:11]1[CH2:12][CH2:13][N:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:10]1=[N:22][CH3:23]
Reactant: CI
Reactant: CCC(C)=O
Reactant: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=N
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CN=C1N(c2c(C)cccc2C)CCN1c1c(C)cccc1C
Product: I
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of 8.3 g (28.3 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine, prepared as described in Example 1, Method (a), 150 ml of methyl-ethyl-ketone, 10.0 g (0.1 moles) of potassium hydrogencarbonate and 1.85 ml (4.26 g, 30 mmoles) of methyl iodide is stirred at room temperature for 8 hours. The separated precipitate is filtered off, and the filtrate is evaporated in vacuo. The residue is combined with the precipitate obtained with the previous operation, suspended in 150 ml of water, allowed to stand for 2 hours, and then the insolubles are filtered off. 10.15 g (82.4%) of crude 1,3-bis(2',6'-dimethylphenyl)-2-methylimino-imidazolidine hydroiodide are obtained.
Reaction SMILES: B.C1COCC1.[CH2:7]([N:14]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[C:22]#[N:23])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:29]>C1COCC1.CCOCC>[ClH:28].[ClH:29].[CH2:7]([N:14]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][NH2:23])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCCOc1cccc(Cl)c1C#N)Cc1ccccc1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CCCOc1cccc(Cl)c1CN)Cc1ccccc1
Temperature: 25 °C

Procedure:
Borane/THF (165 ml of a 1M solution) was added with stirring to a solution of 2-[3-(N-benzyl-N-methylamino)propoxy]-6-chlorobenzonitrile (13.01 g) in dry THF (100 ml) under nitrogen at ambient temperature. The mixture was boiled under reflux for 5 hours and then evaporated to dryness. The residue was heated on a steam bath under nitrogen for 2 hours, then cooled to ambient temperature. 1M Hydrochloric acid (100 ml) was added and the mixture was heated on a steam bath for 2 hours. The mixture was cooled in ice and basified with concentrated sodium hydroxide solution and then extracted with dichloromethane to give an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give a solid which was collected by filtration and recrystallised from propan-2-ol/IMS (2:1) to give 2-[3-(N-benzyl-N-methylamino)propoxy]-6-chlorobenzylamine dihydrochloride, m.p. 226°-228° C.
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH3:13][O:14][CH2:15][C:16]#[N:17]>>[CH3:12][N:10]([CH3:11])[CH:6]([N:7]([CH3:8])[CH3:9])[CH:15]([O:14][CH3:13])[C:16]#[N:17]
Reactant: COCC#N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COC(C#N)C(N(C)C)N(C)C
Yield: 33.2 %

Procedure:
360.4 g of 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (Bredereck's reagent) (2068 mmol, 1 eq.) and 150.0 g of methoxyacetonitrile (2068 mmol, 1 eq.) were stirred for 18 hours at 80° C. The reaction mixture was concentrated in vacuo. The residue was purified by vacuum distillation to yield 117 g (687 mmol, 33.0%) of the analytical pure target compound as a yellowish liquid.
Reaction SMILES: [NH:1]1[CH2:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][C@@H:2]1[C:11]([O:13]C)=[O:12].C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[CH3:10][O:9][C:7]([C@H:5]1[CH2:6][NH:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]1)=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)OC)NC1
Solvent: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC[C@H](C(=O)O)NC1
Temperature: 100 °C

Procedure:
Dimethyl cis-piperidine-2,5-dicarboxylate (112 g, 0.56 mol), salicylaldehyde (3 ml, 0.056 mol) and glacial acetic acid (600 ml) were combined and the resulting mixture heated at about 100° C. for 60 hours. The mixture was cooled, than stripped in vacuo to a thick oil from which 61.7 g (59%) of title products crystallized upon stirring with 800 ml of isopropyl alcohol. Product ratio was determined by 1H-NMR (D2O, 300 MHz), a peak at 3.13 ppm (t, 1H, J=14.5 Hz) being diagnostic of trans, and a peak at 3.33 ppm (dd, 1H) being diagnostic of cis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].[C:14]([Cl:19])(=O)[C:15](Cl)=O>CN(C)C=O.O1CCCC1>[Cl:19][C:14]1[CH:15]=[CH:7][C:6]([C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 196.8 %

Procedure:
N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](#[N:17])[CH:15]=[CH2:16].CO>O.C(O)(=O)C>[NH2:17][CH2:14][CH2:15][CH2:16][N:13]([CH2:3][CH2:2][CH2:1][NH2:13])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: C=CC#N
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCN(CCCN)CCCN
Yield: 373.1 %

Procedure:
670 g of laurylamine (C12 -fraction: 73 mole %, and C14 -fraction: 23 mole %) were reacted in the manner already described in Example 1 with 373 g of acrylonitrile in 68 g of water, 34 g of methanol and 14 g of concentrated acetic acid, and the product was then hydrogenated. 2,020 g of bis-(3-aminopropyl)-laurylamine were obtained after the hydrogenation. 954 g of this triamine were condensed with 640 g of ethylene oxide. 1,590 g of bis-(3-aminopropyl)-laurylamine ethoxylate (99%) were obtained. 257 g of this ethoxylate and 538 g of water were reacted with 146 g of 70% by weight strength H2O2. The triamine-trioxide was obtained in 935 g of a 30% by weight strength aqueous solution.
Reaction SMILES: [C:1]([O:5][C:6](N=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC.[CH3:16][NH:17][CH:18]([NH:24][CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([C:18]([NH:24][CH3:25])([NH:17][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(NC)NC
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(NC)(NC)C(=O)OC(C)(C)C

Procedure:
Tert-butoxycarbonyl azide in ether ("Organic Synthesis V", p. 157-158) (2.9 g, 20 mmol, 5.2 ml) was added dropwise to a stirred solution of N,N'-dimethyl-hexane diamine (Aldrich Cat. No. D16110-1) (Beilstein 4(1), p. 422) (2.92 g, 20 mmol) in dimethyl sulphoxide (DMSO) (30 ml). The temperature was kept at 20° C. with external cooling. After the addition was complete (30 minutes), stirring was continued at room temperature for 1 hour, whereupon water (30 ml) was added. The solution was acidified (pH 5) with 2N HCl and extracted with ether (2 ×200 ml). The DMSO/water-mixture was made alkaline (pH 11) with 6N NaOH and extracted with ether (4×200 ml). Evaporation of the ether gave the title compound (1) (1.2 g) as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:41][CH3:42])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:37]([F:38])([F:40])[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=1)[CH2:26][N:13]([C@H:11]1[CH2:10][C@@H:9]([CH2:41][CH3:42])[NH:8][CH2:12]1)[C:14]1[N:15]=[CH:16][C:17]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)=[CH:18][N:19]=1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2 mmol) in CH2Cl2 (20 mL) is added trifluoroacetic acid (7 mL) at room temperature. The reaction mixture is stirred at room temperature for 1.5 hours. The mixture is quenched with saturated aqueous NaHCO3 solution, then extracted with CH2Cl2. The combined organic layer is washed by saturated aqueous NaHCO3 solution, then dried over Na2SO4 and concentrated under reduced pressure to give (3,5-bis-trifluoromethyl-benzyl)-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a yellow oil (1.01 g, quant.). ESI-MS m/z: 499 [M+1]+, Retention time 1.84 min (condition A).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(CC)CC.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([NH:38][C:39]([NH:13][C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reactant: O=C=NCc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-[(2-thiophen-2-yl)thiazol-4-yl)ethan-amine hydrobromide salt, 8, and Et3N (0.42 mL, 3 mmol) in 10 mL DCM is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.445 g (96% yield) of the desired product which is used without further purification.