Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>CCOCC>[Cl:1][CH2:2][C:3]([NH:19][CH2:18][C:14]1([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH2:17][CH2:16][CH2:15]1)=[O:4]
Reactant: NCC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)NCC1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 4 h

Procedure:
A solution of chloroacetylchloride (3 g) in dry ether was added dropwise to a stirred solution of [1-(3,4-dichlorophenyl)cyclobutyl]methylamine (6.2 g prepared from the hydrochloride salt described above) and triethylamine (2.9 g) in dry ether (20 ml) at a temperature of 5° to 10° C. The mixture was stirred for four hours, filtered and the filtrate washed with water, dried and evaporated to give N-(2-chloroacetyl)[1-(3,4-dichlorophenyl)cyclobutyl]methylamine (m.p. 104°-105° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]2)[CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:26][CH2:25][CH2:24][NH2:27]
Reactant: Clc1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Reactant: NCCN
Product: NCCNc1cc(N2CCSc3ccccc3C2)nc2ccc(Cl)cc12

Procedure:
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to the one in Example 4-1) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, CD3OD) δ ppm 7.901 (s, 1 H), 7.70-7.60 (m, 1 H), 7.55-7.42 (m, 2 H), 7.378-3.350 (dd, J=8.8, 2.4 Hz, 1 H), 7.28-7.16 (m, 1 H), 7.14-7.12 (m, 1 H), 6.05 (s, 1 H), 5.51 (s, 1 H), 4.97 (s, 2 H), 4.38 (s, 2 H), 3.43-3.39 (t, J=6.4 Hz, 2 H), 2.99-2.95 (m, 4 H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:4]=2[S:3]1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:11])[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:4]=2[S:3]1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2s1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a mixture of 2-oxo-5-chlorobenzothiazoline (465 g) in conc.sulfuric acid (500 ml) was added dropwise a solution of nitric acid (d=1.42, 275 g) in conc.sulfuric acid (500 ml) with stirring at 10° C. during an hour. After the stirring was continued for an hour under ice-cooling, to the resultant mixture was added ice-water (10 liters) to give crystals, which were separated by filtration, washed with water and dried to give 2-oxo-5-chloro-6-nitrobenzothiazoline (539 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=O.C([BH3-])#N.[Na+]>C(O)C.CO>[CH:7]1([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)CN
Reactant: O=C1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)CNC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glycine methyl ester (0.053 moles, 6.64 g) is dissolved in absolute ethanol (420 ml) and methanol (42 ml), added with 2-indanone (0.053 moles, 7 g), and with sodium cyanoborohydride (0.058 moles, 3.7 g) under stirring, in 40 minutes. The mixture is left under stirring at r.t. overnight, evaporated to dryness under vacuum and the residue is taken up with water (500 ml) and ethyl acetate (500 ml). The phases are separated and the organic phase is extracted with a 0.1N HCl solution (3×200 ml). The acidic solution is adjusted to pH 8.5-9 with a sodium bicarbonate saturated solution and 20 extracted with ethyl acetate (3×250 ml). The organic solution is separated, dried over sodium sulfate and evaporated under vacuum. The resulting product is dried under vacuum at r.t. Yield: 5.8 g (53.4%)
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH2:5][CH2:6][CH3:7])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[C:3]([C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:5][CH2:6][CH3:7])[CH3:8])#[N:4]
Reactant: CCCC(C)(N)C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(C)(C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
20 g (178.3 mmol) of rac-2-amino-2-methylpentanonitrile (described in: Deng, S L. et al., Synthesis 2001, 2445-2449; Freifelder, M. et al., J. Am. Chem. Soc. 1960, 696-698) were initially charged in 2.63 l of THF/water (8/1), and 76.4 g (552.7 mmol) of potassium carbonate were added. Then 27.6 ml (196.1 mmol) of benzyl chloroformate were slowly added dropwise at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was concentrated, and the residue was admixed with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=4/1). 43.84 g of the target compound were obtained (76% of theory, 76% purity).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.CN1CCOCC1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CN(C=O)C>[S:12]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:1][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:3]2)([OH:15])(=[O:13])=[O:14]
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(O)CCC(=O)Nc1ccc2c(S(=O)(=O)O)cccc2c1

Procedure:
6-Amino-1-naphtalenesulfonic acid (Dahl's acid) (1 eq, 0.5 mmol,) was dissolved in DMF containing N-methylmorpholine (NMM) (2 eq), and succinic anhydride (10 eq) was then added. After over night reaction the solvent was removed under reduced pressure and the product was purified by preparative RP-HPLC (Reversed Phase HPLC). The column (Phenomenex Luna C18 10μ, 22×250 mm) was eluted at 10 ml/min with a gradient of 5 to 15% acetonitrile (ACN) in 0.1% aq TFA over 40 min. The desired peak fractions collected from six consecutive runs were pooled and lyophilized affording 146 mg of pure N-(−5-Sulfo-naphthalen-2-yl)-succinamic acid 2. Analytical RP-HPLC: tR=16.7 min, (Phenomenex Luna 5μ, 4.6×250 mm, 5-15% ACN in 0.1% aq TFA over 20 min at 1 ml/min, λ=214 nm). Electrospray MS: [M+H]+ of product expected at 324.0 m/z, found at 324.0 m/z.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:50][CH3:51])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]([NH:39][C:34]2[C:33]([CH2:50][CH3:51])=[N:32][C:31]([C:54]3[CH:55]=[CH:56][C:57]([CH3:59])=[CH:58][C:53]=3[CH3:52])=[C:36]([CH2:37][CH3:38])[N:35]=2)[CH2:41][CH2:42]1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Agent: [Pd]
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(C)cc2C)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether, 2,4-dimethyl phenyl boronic acid and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.38, 7.22, 7.11–6.90, 5.38, 4.58, 4.31, 2.68, 2.53, 2.37, 2.26, 2.14, 1.25–1.15; HRMS (FAB) calcd for C25H29N3O+H 388.2389, found 388.2383.
Reaction SMILES: [N+:1]([C:4]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:5]=1[CH:6]=[CH:7][C:8]1[CH2:9][S:10][C@@H:11]2[C@H:22]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:33])[N:12]2[C:13]=1[C:14]([O:16]C(C)(C)C)=[O:15])([O-:3])=[O:2].Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:5]=1[CH:6]=[CH:7][C:8]1[CH2:9][S:10][C@@H:11]2[C@H:22]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:33])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)C1=C(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12
Temperature: 20 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylate (67.41 g, purity 8% E-isomer, 81% Z-isomer, 105.9 mmol) in dichloromethane (1685 ml) was cooled to -25° C. Titanium tetrachloride (53 ml, 482 mmol) was added in 10 min and the temperature was brought to 0° C. After 105 min a chilled 2 M solution of hydrochloric acid in water was added at such a rate that the temperature remained under 10° C. The organic phase was separated and extracted with a 2 M solution of hydrochloric acid in water (2×1685 ml) and brine (1685 ml). The organic phase was concentrated under reduced pressure to give an orange foam. Crude product thus obtained was crystallized by dissolving in acetone (1350 ml) at 65° C. and adding water (675 ml). Crystallization was allowed to proceed for 16 h at 0° C. and the crystals were collected by filtration. Recrystallization of the product was performed by dissolving the material in acetone/acetic acid (2:1) at 53° C., removing solvent (1700 ml) by evaporation under reduced pressure and stirring for 16 h at 20° C. Crystals were collected by filtration, washed with acetic acid (300 ml) and ether (250 ml), and dried under vacuum at 45° C. to give 34.33 g (purity 99% E-isomer, 66.6 mmol; yield 63%) of (6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylic acid as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][OH:15])[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][C:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][O:12][CH2:11]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(COCc2ccccc2)COC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(COCc2ccccc2)COC1
Temperature: 25 °C
Yield: 523.8 %

Procedure:
An ice cooled solution of (3-(benzyloxymethyl)oxetan-3-yl)methanol (Example 44E, 1.00 g, 4.80 mmol) in DCM (5.14 mL) was treated with triethylamine (1.31 mL, 9.43 mmol) and methanesulfonyl chloride (0.438 mL, 5.66 mmol) and gradually allowed to warm up to rt over 16 hrs. The mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution (1×), brine (2×), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to a solid to afford 7.2 g of the title compound (100%). The crude product was used in next step without further purification. 1H NMR (400 MHz, CD3OD) δ 7.23-7.38 (m, 5H), 4.58 (s, 2H), 4.46-4.54 (m, 6H), 3.74 (s, 2H), 3.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CCCO)cc2c1O
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxy-1-propynyl)-thieno[2,3-b]pyridine-5-carboxamide (Example No.5) (0.300 g) in 1/1 CH2Cl2/CH3OH (70 mL) is hydrogenated over 10% Pd/C (90 mg) at 35 psi. After 3 h, an additional 90 mg of 10% Pd/C is added, and the solution is hydrogenated at 35 psi for 1 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale orange solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield and off-white solid which is recrystallized from ethanol to yield 0.083 g (27%) of the title compound as a white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.Cl[O-].[Na+]>>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COC(=O)C1CC(Cl)=NN1C
Agent: [Na+]
Agent: [O-]Cl
Product: COC(=O)c1cc(Cl)nn1C
Reaction time: 72 h
Yield: 28.9 %

Procedure:
Methyl 3-chloro-1-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (21 g, 119 mmol) was added drop wise to sodium hypochlorite (95 ml, 155 mmol) under ice cooling. Then, the ice bath was removed and stirring continued for 72 h. The organic phase was separated, washed with Na2S2O3 (10% aqueous solution) and water, dried over Na2SO4 and the solvent removed under reduced pressure. The resulting oil was purified by distillation (bp 35° C., 0.2 mbar) followed by column chromatography (eluent 80% hexane in EtOAc) to yield 6.0 g (29%) of the title compound. [1H-NMR (DMSO-d6, 360 MHz) δ 6.96 (s, 1H), 6.80 (s, 1H), 4.07 (s, 3H), 3.86 (s, 3H)]
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 18 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2,2-dimethylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.51–7.41 (s, 1H), 7.34–7.10 (m, 13H), 6.99–6.80 (m, 2H), 4.81 (s, 1H), 3.40–3.26 (m, 2H), 2.96–2.78 (m, 2H), 2.50–2.25 (m, 3H), 1.98–1.82 (m, 2H), 1.79–1.68 (m, 2H), 1.68–1.45 (m, 4H), 1.23 (s, 9H); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]#[N:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1nc(-c2ccccc2)n[nH]1
Solvent: C1CCOC1
Product: NCCc1nc(-c2ccccc2)n[nH]1
Yield: 127.9 %

Procedure:
Borane dimethyl sulfide complex (0.2 mL, 2.16 mmol) was added to a solution of compound 2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetonitrile (100 mg, 0.54 mmol) in dry THF (5 mL) at room temperature. The reaction mixture was refluxed for 1 h, then quenched carefully with methanol and again heated to reflux for 0.5 h. The reaction mixture was concentrated under reduced pressure and then diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethanamine (130 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C10H12N4: 188.11. found: 189.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: COc1cccc(CBr)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COc1cccc(Cn2c(Sc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 49.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (203 mg, yield: 49.4%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1)[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>CCO>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1)[CH:13]=[CH:12]2
Reactant: CCOC(=O)C1CCCN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCCN(Cc2ccc3cc(O)ccc3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-((6-((tert-butyldimethylsilyl)oxy)quinolin-2-yl)methyl)piperidine-3-carboxylate (240 mg, 0.56 mmol) in EtOH (30 mL) was added HCl (3 N, 1 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h. The mixture was neutralized with sat. NaHCO3 and the organic solvent were removed. Then the mixture was extracted with DCM (3×10 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated to give ethyl 1-((6-hydroxyquinolin-2-yl)methyl)piperidine-3-carboxylate as a white solid, 120 mg, Y: 60%, ESI-MS (M+H)+: 315.2. 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.29 (dd, J=9.2, 2.4 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 4.09 (q, J=6.4 Hz, 2H), 3.90 (ABq, J=21.6, 13.6 Hz, 2H), 3.12-3.09 (m, 1H), 2.89-2.86 (m, 1H), 2.70-2.68 (m, 1H), 2.49-2.44 (m, 1H), 2.31-2.26 (m, 1H), 1.95-1.92 (m, 1H), 1.75-1.70 (m, 2H), 1.50-1.48 (m, 1H), 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: F[C:2]1[C:3](=[CH:17][C:18]([F:24])(C)[CH:19]([F:22])[C:20]=1[F:21])[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:25]C(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:14]1([N:13]2[C:2]3[C:3](=[C:17]([CH3:25])[C:18]([F:24])=[C:19]([F:22])[C:20]=3[F:21])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)C1=CC(C)(F)C(F)C(F)=C1F
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
To a mixture of 9.05 g (26.3 mmol) of ethyl 2-(2,3,4,5-tetrafluoro-5-methylbenzoyl)-3-cyclopropylaminoacrylate in 100 ml of dry t-butanol was added a slurry of 3.25 g (29.0 mmol) of potassium t-butoxide in 20 ml of dry t-butanol, and the mixture was stirred at 60° C. for four hours. The suspension was cooled to room temperature and concentrated to a paste which was partitioned between dichloromethane and 1N hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, and concentrated. Recrystallization from ethyl acetate:hexane gave 4.70 g of the title compound, mp 176°-177° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]([OH:11])[CH2:8][CH2:9][CH:10]=1)/[CH:2]=[CH:3]\[CH2:4][CH3:5].[C:12](OC)(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>>[C:14]([O:16][CH3:17])(=[O:15])[CH2:13][C:12]([O:11][C@@H:7]1[CH2:8][CH2:9][CH:10]=[C:6]1[CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH3:5])=[O:18]
Reactant: COC(=O)CC(=O)OC
Reactant: CC/C=C\CC1=CCCC1O
Product: CC/C=C\CC1=CCC[C@H]1OC(=O)CC(=O)OC
Reaction time: 1.33 h

Procedure:
A mixture of (Z)-2-(2-pentenyl)-2-cyclopenten-1-ol (17.8 g; 117 mmol), dimethyl malonate (17.8 g; 135 mmol), ground KHCO3 (0.58 g; 5.8 mmol) and Novozym 435® (immobilized Candida antarctica from Novo Nordisk; 1.80 g) was gently swirled in a 100 ml flask connected to a Büchi rotavapor at 40° C. and 10 hPa. After 80 min., the reaction mixture was filtered, washed (sat. aq. NaHCO3, sat. aq. NaCl), dried (Na2SO4) and concentrated (30.8 g). Bulb-to-bulb distillation afforded 15.5 g of volatiles (oven temp. 70° C./10-0.1 hPa) and ca. 11.14 g (95% pure, 36%, 97% ee) of the desired product which is isolated at an oven temperature of 80-130° C./0.06 hPa.
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]([C:12]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:13]=1[CH2:14][N:15]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[CH2:10][CH3:11])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:26]=1)[CH2:22][N:15]([CH2:14][C:13]1[CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=[CH:40][C:12]=1[CH:9]([NH:8][CH3:1])[CH2:10][CH3:11])[C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1
Reactant: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N(C)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC(NC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 109 %

Procedure:
To a Parr flask was added 20% Pd(OH)2 on carbon (23.2 mg) followed by addition of methanol (22 mL). To this suspension was added a solution N-[2-{1-[benzyl(methyl)amino]-propyl}-5-(trifluoromethyl)benzyl]-N-[3,5-bis(trifluoromethyl)-benzyl]-2-methyl-2H-tetrazol-5-amine (298.7 mg, 0.463 mmoles) in methanol. The reaction mixture was stirred under hydrogen (pressure =14.7 psi) at room temperature for 9 hours. The reaction mixture was filtered through Celite, washed with methanol, concentrated under vacuo to give 279.8 mg (100%) of the title compound as yellow oil. MS (ES+) Calc: 608.5, Found: 609.1 (M+1).