Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+]([O-])=O)[NH:16][C:17](=[O:31])[CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)=[O:3].[OH2:43].O.[Sn](Cl)Cl>C(O)=O>[NH2:1][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:41])[NH:16][C:17](=[O:31])[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH:7]=1)=[O:3].[C:17]([O-:31])(=[O:43])[CH3:18]
Reactant: NC(=O)OCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: O
Agent: Cl[Sn]Cl
Solvent: O=CO
Product: CC(=O)[O-]
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(COC(N)=O)cc1

Procedure:
0.7 g (1.216 mMol) of (R)-N-[[4-(Aminocarbonyloxymethyl)-phenyl]methyl]-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)ornithinamide were dissolved in 50 ml of 60% aqueous formic acid, mixed with 2.7 g (11.97 mMol) of tin(II)-chloride-dihydrate and heated to +50° C. for 10 minutes. 20 ml of formic acid were added and the mixture was maintained at +50° C. for a further 72 hours. It was evaporated down in vacuo. the residue was taken up in methanol and filtered to remove the insoluble matter. It was evaporated down once more, the residue remaining was taken up in saturated aqueous soda solution and suction filtered. The crystals were treated once more with methanol, then filtered, the filtrate was evaporated down and carefully freed from any accompanying matter by column chromatography on silica gel (Baker; 0.03-0.06 mm) using ethyl acetate/methanol/glacial acetic acid=70/30/1 (v/v/v) as eluant. 40 mg (5.6% of theory) of a colourless, glassy-amorphous substance were obtained.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([Cl:16])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].[CH3:21][O-:22].[Na+]>CN(C)C=O>[Cl-:16].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([O:22][CH3:21])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNc1cc(N)[n+](CCCC)c(OC)c1C#N
Yield: 32 %

Procedure:
3.2 gms (.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano-pyridinium chloride (compound 6 - Table 1) was dissolved in dry dimethylformamide, 0.06 gms (0.01 mole) of sodium methoxide added, and the mixture refluxed for 60 minutes, filtered and solvent evaporated off. The solid was recrystallised from acetone to give 1.0 gm (30% yield) of 2-amino-1-n-butyl-4-n-butylamino-5-cyano-6-methoxy pyridinium chloride (MPt 187° - 189°C.)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1.C(OCC)(=O)C>ClCCl>[CH:16]12[O:9][CH:15]1[CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH2:18][CH2:17]2
Reactant: O=C(OCc1ccccc1)N1CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC2OC2CC1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
18 g m-chloroperbenzoic acid was added to 10 g benzyl 2,3,6,7-tetrahydro-1H-azepine-1-carboxylate in 250 ml dichloromethane at 0° C. in several portions. The mixture was allowed to warm to RT over 2 h. 1 L ethyl acetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. The organic layer was evaporated and the residue was purified by chromatographie on silica gel (ethyl acetae/hexanes 1:5) to yield 10.4 g of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][N:35](C(OCC2C=CC=CC=2)=O)[CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)C.C(#N)C.[Pd]>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][NH:35][CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-hydroxypropanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (108 mg, 0.159 mmol) in degassed ethanol (3 mL, 0.05 M solution) was added Pd/C (17.2 mg) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 30 min. The reaction mixture was filtered through Celite® pad that was washed with methanol and EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product obtained was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 75% yield (66 mg, over 2 steps) as the free amine. 1H NMR (CD3Cl, 400 MHz): δ 7.87 (1H, m), 7.33-7.27 (4H, m), 7.22-7.14 (2H, m), 7.08 (1H, m), 6.08 (1H, s), 4.71-4.62 (1H, m), 4.60-4.40 (1H, m), 4.23 (2H, s), 3.95 (1H, m), 3.63 (2H, m), 3.01-2.86 (1H, m), 2.70-2.46 (2H, m), 2.14-2.06 (2H, m), 1.45 (3H, m), 1.03 (9H, s). LC/MS (uplc): MH+ 546.4, 1.00 min.
Reaction SMILES: [CH2:1]([N:17]([CH3:19])[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:20]([Br:29])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>C(O)C>[Br-:29].[CH2:1]([N+:17]([CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22])([CH3:19])[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN(C)C
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CC(=O)c1ccccc1
Product: [Br-]

Procedure:
A mixture of hexadecyldimethylamine (0.1 mol) and phenacyl bromide (0.1 mol) in ethanol was refluxed for 5 hours. Ethanol was removed under reduced pressure and the product was crystallised from acetone.
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18]Cl.CC(C)=O>C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCNC1c1ccccc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NCCN(Cc2ccc(Cl)c(Cl)c2)C1c1ccccc1

Procedure:
140 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 163 g. of 3,4-dichloro benzylchloride in 1600 cc. of acetone for 6 hours while 330 cc. of triethylamine are added. The hot reaction mixture is filtered to remove precipitated triethyl ammonium chloride and is concentrated by fractional distillation. The resulting crystal fractions are twice recrystallized from 4 l. of 96 % ethanol.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[C:4]([NH:7][C@H:8]([C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])(=[O:6])[CH3:5].CC(C)[O-].[Al+3:24].CC(C)[O-].CC(C)[O-]>O.C(O)(C)C>[Mg:2].[Al:24].[C:4]([NH:7][C@H:8]([C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])(=[O:6])[CH3:5]
Reactant: [Al+3]
Reactant: [Mg+2]
Agent: CC(=O)NCCCC[C@H](NC(C)=O)C(=O)O
Agent: CC(C)[O-]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: [Al]
Product: [Mg]
Reaction time: 0.5 h

Procedure:
Magnesium hydroxide (3.5 g.) in water (6 cc.) is added to a solution, heated to 60° C, of N,N'-diacetyl-L-lysine (55.2 g.) and water (360 cc.), and then the reaction mixture is kept at 60° C for 30 minutes with stirring. A suspension of aluminium isopropoxide (24.5 g.) in isopropanol (30 cc.) is then added with stirring and while keeping the temperature at 60° C. The isopropanol is removed by distillation under reduced pressure (25 mm Hg). The reaction mixture is then filtered in order to remove insoluble material and the filtrate concentrated to dryness under reduced pressure (25 mm Hg) at 50° C. The paste-like residue obtained is triturated three times in acetone and then dried under reduced pressure (25 mm Hg). A solid is thus obtained which is washed by filtration using acetone (3 × 150 cc.). After drying, a mixed aluminium magnesium salt of N,N'-diacetyl-L-lysine (60.35 g.) corresponding to the formula: ##EQU11## is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([OH:19])=O)[S:11]3)=[CH:4][CH:3]=1.[Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:33]OC(N(C)C)=[N+](C)C)=O.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([NH2:33])=[O:19])[S:11]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2nc(-c3ccc(F)cc3)cn12
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(N)=O)sc2nc(-c3ccc(F)cc3)cn12
Yield: 28.3 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid (example 7, 50 mg, 0.18 mmol), ammonium chloride (19.4 mg, 0.36 mmol), TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol) in 3 ml DMF were stirred at RT for 8 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 14 mg (28%) of the desired product. MS: M+H+=276.03.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OC(C)(C)C)=[O:9])=[CH:4][CH:3]=1.[CH2:30]([NH:32][C:33]([N:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1)=[O:34])[CH3:31].CCN(CC)CC>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([N:42]2[CH2:41][CH2:40][C:39]3([N:35]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:36][CH2:37][CH2:38]3)[CH2:44][CH2:43]2)=[N:7][CH:6]=1)=[O:9]
Reactant: CCNC(=O)N1CCCC12CCNCC2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCCC12CCN(c1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cn1)CC2
Reaction time: 1 h

Procedure:
A solution of intermediate F (82 mg, 0.19 mmol), N-ethyl-1,8-diazaspiro[4.5]-decane-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 mL of DMSO was stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (MgSO4), filtered and concentrated. The residue was stirred in 2 mL of TFA and 2 mL of CH2Cl2 for 1 h at room temperature and concentrated. Reverse-phase chromatography (10 to 100% MeCN/water with 0.05% TFA) followed by neutralization with EtOAc/saturated NaHCO3 extraction and drying with MgSO4 gave the title compound: MS (ESI+): cal'd [M+H]+ 505.2, obs'd 505.2.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1)=[O:2].[Cl-].[NH4+].[CH2:40]1COCC1>>[OH:2][CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:4]1)[CH3:40]
Reactant: C1CCOC1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (150 mg) in THF (10 ml) was added 3M-methyl magnesium bromide-ether solution (0.3 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.ClCCl.CO>C(O)C>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:15][CH:14]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(CN2CCCC2)cc1
Yield: 36.9 %

Procedure:
To a solution of 1-(4-nitro-benzyl)-pyrrolidine (1.37 g) in ethanol (66 mL) tin(II)-chloride dihydrate (9.0 g) was added portionwise and the resulting mixture refluxed for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (432 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)(=O)C.[Br:14]Br>>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1
Yield: 40.7 %

Procedure:
Reaction of acetophenone (5.0 g, 42.00 mmol), acetic acid (2.4 mL, 42.00 mmol), and bromine (2.5 mL, 48.00 mmol) followed by recrystallisation from cold EtOAc/Hexane gave the title compound (3.4 g, 41%) as a white crystal. 1H NMR (300 MHz, CDCl3) δ 4.47 (s, 2H), 7.51 (d, 2H, J=7.5 Hz), 7.63 (t, 1H, J=7.5 Hz), 8.00 (d, 2H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:34]=[CH:33][C:19]([CH2:20][N:21]4[CH:25]=[C:24]([CH:26]=O)[C:23]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)=[N:22]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OP([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(OCC)=O)C.O>CN(C)C=O>[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]4[CH:25]=[C:24](/[CH:26]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:23]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)=[N:22]4)=[CH:33][CH:34]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Sodium hydride (60%, oily, 150 mg) was added to a solution of 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.54 g) and ethyl diethylphosphonoacetate (0.82 g) in N,N-dimethylformamide (15 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl(E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoate (1.65 g, yield: 93%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 104˜105° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O>[C:34]1([CH2:40][CH2:41][NH:42][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(CCNc2cccc3ccccc23)cc1
Yield: 97 %

Procedure:
288 parts of β-naphthol, 9 parts of triphenyl phosphite and 270 parts of 2-phenylethylamine are heated to 180° C whilst stirring. The elimination of water commences at this temperature and has ended after 5 hours at an internal temperature of 240° C. 36 parts of water are collected in the water separator. After distilling off excess β-naphthol and amine under reduced pressure, 2-phenylethyl-naphthylamine distils, at a boiling point of 230° - 231° C/5 mm Hg. 479 parts of 2-phenylethyl-naphthylamine are obtained, corresponding to a yield of 97% of theory.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23]OS(C)(=O)=O)[N:11]=1)=[O:9].C(Cl)Cl.[CH3:42][NH:43][CH3:44]>O>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23][N:43]([CH3:44])[CH3:42])[N:11]=1)=[O:9]
Reactant: CNC
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(COS(C)(=O)=O)ncc1-c1ccccc1Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1ncc(-c2ccccc2Cl)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 0.62 g (1.07 mmol) methanesulfonic acid 4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-5-(2-chloro-phenyl)-pyrimidin-2-ylmethyl ester in 10 ml CH2Cl2 1.53 ml (8.52 mmol) of a 5.6 M solution of dimethylamine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 200:10:1) to give 0.40 g (70%) 5-(2-chloro-phenyl)-2-dimethylaminomethyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (ISP): 531.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C=CC=CC.[Br:19]N1C(=O)CCC1=O>>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1cccc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C=CC=CC
Product: BrCc1cccc(-c2ccccc2)n1

Procedure:
2-Methyl-6-phenylpyridine, obtainable from 1,3-pentadiene and benzonitirle via the procedure of Janz and McColloch [J. Am. Chem. Soc., 77 (1955), 3413] is treated with N-bromosuccinimide to give 2-bromomethyl-6-phenylpyridine. The bromomethyl compound is treated with 1-methyl-2-cyanopyrrolidine, and the resulting salt is rearranged using sodium amide in liquid ammonia and decyanated with sodium borohydride in ethanol according to the procedures described in Example 1. The product can be purified by distillation.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]#N)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([OH:20])C.[OH-:21].[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([OH:20])=[O:21])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CC1(c2ccc(CN3CCCC3)cc2)CC1
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(c2ccc(CN3CCCC3)cc2)CC1

Procedure:
A solution of 1-[4-(pyrrolidin-1-ylmethyl)phenyl]cyclopropanecarbonitrile (100 mg, 0.0004 mol) in ethanol (5 mL, 0.08 mol) and 50% NaOH (aq. 4 ml) and water (2 ml) was stirred at 100 celsius overnight. The mixture was then carefully adjusted to be slightly acidic (pH=6) and the precipitate formed was filtered and dried to afford the product. LC-MS: 246.1 (M+H)+
Reaction SMILES: CN1CCOCC1.Cl.[C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH:17]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[CH3:18])=[CH:13][CH:12]=1)#[N:10].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](OC)[CH:34]=1)=[O:31].O>C(Cl)Cl>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH:17]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:24])[CH3:25])[NH:22][C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])[CH3:18])=[CH:27][CH:28]=1)#[N:10]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: COc1cccc(OC(=O)Cl)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 13.1 %

Procedure:
1.0 g of N-methylmorpholine was added to a solution containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide hydrochloride dissolved in 100 ml of methylene chloride, at -20° C. After 0.9 g of 3-methoxyphenyl chloroformate was added to the mixture at -20° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred. The whole mixture was stirred for 2 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus yielding 0.25 g of the desired product in the form of a white plated crystal (yield: 12%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:8](=[O:20])[CH2:7][CH2:6]1)=O.[NH3:21]>CO>[O:20]=[C:8]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]([C:3]([NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: N
Reactant: COC(=O)C1CCC(=O)N1CC#CCN1CCCCC1
Solvent: CO
Product: NC(=O)C1CCC(=O)N1CC#CCN1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-[4-(1-piperidinyl)-2-butynyl]-2-pyrrolidinone (5.44 g) in sieve dried methanol (175 ml) was treaed with anhydrous ammonia for fifteen minutes and was allowed to stand at ambient temperature overnight. The solution was concentrated to a brown solid (5.00 g). The solid was recrystallized from toluene (125 mL) to give 3.85 g of slightly brown crystals, mp 143°-145° C.