Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[C:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:25]Br.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[C:6]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:24])[CH:22]([Br:25])[CH3:23])=[CH:19][CH:20]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(Br)C(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a tetrahydrofuran solution (30 mL) of 3.00 g (11.9 mmol) of the p-(benzoyloxy)propiophenone, a hexane solution (5 mL) of 2.07 g (1.1 equivalents) of bromine was added at 5° C. The temperature of the mixture was elevated to room temperature, followed by 1 hour of stirring. To the resulting mixture, 30 mL of a saturated sodium hydrogen carbonate solution and 40 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 30 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. An yellow oily substance (5.54 g) was obtained as a result. This substance was crystallized from 5 mL of ethyl acetate and 30 mL of hexane. White crystals of 1-[4-(benzoyloxy)phenyl]-2-bromo-1-propanone were obtained as a result (3.147 g, isolation yield: 80%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=2[O:21][CH3:22])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=2[O:21][CH3:22])[NH2:18])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CNC(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N)cc1-c1cccc(CNC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
2-(3-(N-Isopropylamino)methylphenyl)-4-nitroanisole (120 mg, 0.39 mmol) was dissolved in MeOH/THF (5 mL:5 mL), and 10% Pd/C (20 mg) was added. The slurry was stirred at room temperature under an atmosphere of H2 for 16 h. The slurry was then filtered and evaporated to afford 3-[3-(N-isopropylamino)methylphenyl]-4-methoxyaniline as a brown oil (101 mg, 0.37 mmol, 96%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[CH2:11][CH2:12][N:13]([CH2:36][CH2:37]Cl)[C:14]1[CH:34]=[C:33]([Cl:35])[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=3[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=2[CH:15]=1.[CH3:39]O>>[CH3:39][O:32][C:30]([C:26]1[CH:27]=[C:28]([CH3:29])[C:19]2[O:18][C:17]3[C:33]([Cl:35])=[CH:34][C:14]([N:13]4[CH2:12][CH2:11][N:1]([CH2:2][CH2:3][N:4]5[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]5)[CH2:37][CH2:36]4)=[CH:15][C:16]=3[CH2:22][S:21](=[O:23])(=[O:24])[C:20]=2[CH:25]=1)=[O:31]
Reactant: CO
Reactant: NCCN1CCNCC1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(CCN4CCNCC4)CC3)cc(Cl)c1O2
Temperature: 70 °C

Procedure:
N-Aminoethyl piperazine (0.6 mL, 5.2 mmol) was added to a solution of Example 102j (0.5 g, 1.04 mmol) in methanol (5 mL), followed by the addition of n-tetrabutylammonium iodide (0.075 g, 0.20 mmol) in an atmosphere of nitrogen, in a pressure reactor vessel at 120° C. for 5 h. The reaction mixture was brought to room temperature, concentrated and treated with water. The solid that separated was washed with water, dried, treated with methanolic HCl solution, and refluxed at 70° C. for 2 h. The reaction mixture was concentrated, treated with aqueous sodium bicarbonate solution to neutral pH and extracted with n-butanol. The organic layer was washed with water, dried, concentrated and purified using flash chromatography (silica gel, 20% methanol/chloroform) to obtain the title compound. Yield: 0.075 g, (13%); 1H NMR (DMSO-d6): δ 2.50-2.60 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.00-3.40 (m, 14H, 7CH2), 3.70 (s, 1H, OH), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (EI+) 459 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC=C[C@H]1C#N)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)N1CC=C[C@H]1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
(140 mg, 0.46 mmol) of (3) was dissolved in 0.5 ml of dichloromethane and the mixture was cooled to 0° C. 0.5 ml of trifluoroacetic acid was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was evaporated and the crude product was purified by preparative HPLC, using acetonitrile /water as the eluent. Fractions containing the product were collected and the solvent was evaporated, to afford 25 mg of the title compound (1) as the trifluoroacetic acid salt. Oil, 17% yield. 1H-NMR (MeOH, 200 MHz) δ: 1.20 (s, 9H); 4.08 (s, 1H); 4.46-4.70 (m, 2H); 5.56-5.62 (m, 1H); 5.95-6.02 (m, 1H); 6.22-6.29 (m, 1H). LC-MS, m/z: 208.4 (M+1)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1)(=[O:3])[CH3:2].BrBr.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.O1CCCC1>[Br-:10].[Br:10][C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH2:2][N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: c1ccncc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(C[n+]1ccccc1)c1cccc(Br)n1
Product: [Br-]
Temperature: 25 °C
Yield: 73 %

Procedure:
2-Acetyl-6-bromopyridine from example 1 (20.0 g, 100 mmol) was treated with bromine (6.2 mL, 0.12 mol) at reflux in 200 mL of CHCl3 for 45 min. The solution was cooled to room temperature then washed with dilute aqueous NaHCO3 /Na2S2O3. The organic phase was dried over Na2SO4, filtered, and evaporated to give an oil. The oil was dissolved in 200 mL of tetrahydrofuran (THF) and 30 mL of pyridine was added. The resulting solution was refluxed for 30 min. The mixture was cooled and filtered to give 26.1 g of off-white powder (73% yield); mp 256° C. (decomposition; discolors at 245° C.). The nuclear magnetic resonance (NMR) and infrared (IR) spectra were consistent with the assigned structure and the product was homogeneous by TLC.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18].CCO.CCN(C(C)C)C(C)C>O>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:17]([CH2:13][CH2:14][OH:18])[C:16](=[O:15])[N:11]=1
Reactant: O=C1OCCC1Br
Reactant: NC(=S)N[C@H]1C[C@@H]2CC[C@H]1C2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCO

Procedure:
1-((1S,2S,4R)-Bicyclo[2.2.1]heptan-2-yl)thiourea (887 mg, 5.25 mmol), 3-bromo-dihydrofuran-2(3 H)-one (1.65 g, 5 mmol), EtOH (10 mL) and DIEA (5.0 mL) were placed in a microwave reaction vessel. The mixture was placed in a microwave synthesizer and was irradiated at 150° C. for 30 min. The resulting mixture was poured into water and extracted with EtOAc and dried over MgSO4. After being filtered and concentrated in vacuo, the title compound was obtained a brown solid. MS (ES+): 255 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12]Cl.[OH:14][C:15]1([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][N:18]1[CH2:19][CH2:20][C:15]([OH:14])([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]1
Reactant: Cc1ccc(OCCCCl)c(C)c1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Product: Cc1ccc(OCCCN2CCC(O)(c3cnc4ccccc4c3)CC2)c(C)c1
Yield: 44.6 %

Procedure:
Beginning with 0.235 gm (1.2 mMol) 3-chloropropyl 2,4-dimethylphenyl ether and 0.270 gm (1.2 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.209 gm (45%) of the title compound were recovered as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC([C:38](C2C=C([N+]([O-])=O)C=CC=2C)=[O:39])=C(Cl)C=1.COC1C=CC=CC=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:39][CH3:38])[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Solvent: COc1ccccc1N
Product: COc1ccccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.56 mmol) and 2-methoxy-phenylamine (0.56 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C@H:8]1(C(O)=O)[CH2:13][CH2:12][C@H:11]([C:14](O)=O)[CH2:10][CH2:9]1.C[N:21](C=O)C>ClCCl>[C@H:8]1([C:6]#[N:5])[CH2:13][CH2:12][C@H:11]([C:14]#[N:21])[CH2:10][CH2:9]1
Reactant: CN(C)C=O
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](C#N)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
50.4 g (357 mmol) of chlorosulfonyl isocyanate in 30 ml of dichloromethane are added dropwise to 30 g (174 mmol) of trans-cyclohexane-l,4-dicarboxylic acid in 90 ml of dichloromethane under reflux. When the evolution of gas is completed, the mixture is stirred for a further 1.5 hours under reflux. 40 ml (715 mmol) of DMF are subsequently added dropwise at from -15 to -20° C., and the mixture is stirred for a further 15 minutes and hydrolyzed using 300 ml of ice water. The phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed four times with water, dried over MgSO4 and evaporated in vacuo. Crystallization from DMF gives 8.74 g (37.4%) of trans-cyclohexane-l,4-dinitrile.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:26]2[N:27]=[N:28][S:29][C:30]=2[C:31]2[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[N+:23]([C:13]1[CH:12]=[C:11]([C:26]2[N:27]=[N:28][S:29][C:30]=2[C:31]2[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=[C:9]([OH:8])[C:14]=1[OH:15])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(-c2nnsc2-c2cccnc2C(F)(F)F)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nnsc2-c2cccnc2C(F)(F)F)cc(O)c1O
Temperature: -40 °C

Procedure:
4-(3,4-bis(benzyloxy)-5-nitrophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,2,3-thiadiazole (0.147 g, 0.26 mmol) in dichloromethane (10 mL) was cooled to −78° C. with stirring and treated under argon with boron tribromide (0.26 g, 1.03 mmol). The resulting deep purple suspension was then allowed to stir at room temperature for one hour before cooling again to −40° C. The mixture was quenched by the careful addition of methanol. After stifling at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give 3-nitro-5-(5-(2-(trifluoromethyl)pyridin-3-yl)-1,2,3-thiadiazol-4-yl)benzene-1,2-diol as a yellow solid, 0.089 g (89%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([O:21]C)=[O:20])=[N:8]1.[OH-].[Li+]>CO.C1COCC1.O.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([OH:21])=[O:20])=[N:8]1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)n(C2CCCCO2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)nn2C2CCCCO2)cc1
Reaction time: 16 h
Yield: 102.3 %

Procedure:
Methyl 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylate (363 mg, 0.70 mmol) was dissolved in a mixture of MeOH/THF/H2O (1:2:1, 4 mL). Lithium hydroxide was added and the reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with water and washed with DCM. The aqueous phase was evaporated. 1-(Tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylic acid (205 mg, quantitative) was obtained as a white solid which was used without further purification in the next step.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C=O.[C:23](=O)=O>O.O1CCOCC1>[C:1]1([S:7]([C:10](=[CH2:11])[CH2:23][N:18]2[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: O=C=O
Agent: C=O
Solvent: C1COCCO1
Solvent: O
Product: C=C(CN1CCC(O)CC1)S(=O)(=O)c1ccccc1
Temperature: 42 °C

Procedure:
4.0 g. (0.02 mole) of phenylsulfonylacetic acid was dissolved in 15 ml. of dioxane followed by a solution of 2.0 g. (0.02 mole) of 4-hydroxypiperidine in 20 ml. of dioxane and 2 ml. of water. At 30° C. 3.5 g. (0.04 mole) of 37% aqueous formaldehyde was added rapidly and the reaction mixture agitated thoroughly. The temperature was gradually raised by means of an oil bath to 42° C. and carbon dioxide evolution was initiated. The mixture was maintained at approximately 42° C. for an additional 2 hours. The solvent was removed under reduced pressure and the product was obtained as a residue.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:16]([N:17]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]3)[C:11]=2[N:10]=[N:9]1)[C:2]1C=CC=CC=1.C(C1N=C(N2CC[C@@H](O)C2)C2N=NNC=2N=1)(C)(C)C.C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.ClC[C:70]1[N:74](C)[N:73]=[N:72][N:71]=1>[Pd]>[C:23]([C:14]1[N:15]=[C:16]([N:17]2[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]2)[C:11]2[N:10]=[N:9][N:8]([CH2:1][C:2]3[N:71]([CH3:70])[N:72]=[N:73][N:74]=3)[C:12]=2[N:13]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)c1nc(N2CC[C@@H](O)C2)c2nnn(Cc3ccccc3)c2n1
Reactant: Cn1nnnc1CCl
Agent: [Pd]
Agent: CC(C)(C)c1nc(N2CC[C@@H](O)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cn1nnnc1Cn1nnc2c(N3CC[C@@H](O)C3)nc(C(C)(C)C)nc21

Procedure:
(R)-1-(3-Benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was hydrogenated over Pd/C and the resulting (R)-1-(5-tert-Butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was reacted in analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b) with 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 359.3 (MH+)
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].O.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:31](=[S:33])=[S:32]>CS(C)=O>[CH2:20]([S:33][C:31]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: S=C=S
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Yield: 55 %

Procedure:
In the same manner as described in Example 6, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), NaOH (1.65 g), water (2 ml), dimethylsulfoxide (24 ml), carbon disulfide (1.2 ml) and n-decyl bromide (5.31 g) are reacted and treated. The residue thus obtained is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=98:1:0.5) and then crystallized from n-hexane to give the title compound (4.8 g, 55%), m.p. 152.5°-154° C. (decomp.).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1([Cl:24])[CH2:19][C:18]1([CH3:23])[C:20](O)=[O:21].[F:25][C:26]([F:37])([F:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[Cl:16][C:17]1([Cl:24])[CH2:19][C:18]1([CH3:23])[C:20]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:35]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH2:27][C:26]([F:25])([F:36])[F:37])=[CH:30][CH:31]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:21]
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC1(C(=O)N2CCC3(CC2)CCN(c2ccc(OCC(F)(F)F)cc2)C3=O)CC1(Cl)Cl

Procedure:
Brown crystalline solid. MS (ESI): 480.2 (MH+). This example was prepared in analogy to example 13 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2,2-dichloro-1-methyl-cyclopropanecarboxylic acid, 4-(2,2,2-trifluoro-ethoxy)-phenylamine.
Reaction SMILES: C([O-])(=O)C.[Na+].[C:6]([O:12]C)(=[O:11])[CH2:7][C:8]([CH3:10])=O.C[N:15]([CH:17]([O:20]C)[O:18][CH3:19])C.Cl.[C:23]([NH:27][NH2:28])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([N:27]1[C:8]([CH3:10])=[C:7]([C:6]([OH:12])=[O:11])[CH:17]=[N:15]1)([CH3:26])([CH3:25])[CH3:24].[C:23]([N:27]1[C:8]([CH3:10])=[C:7]([C:17]([O:18][CH3:19])=[O:20])[CH:6]=[N:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)NN
Reactant: COC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn(C(C)(C)C)c1C
Product: Cc1c(C(=O)O)cnn1C(C)(C)C

Procedure:
The title compound was prepared according to the procedure as described in Anderson, K. W., et al., PCT Publication, WO 2007/107470, published Sep. 27, 2007, as described in Example 54, Steps 2 and 3, pages 97-98, and substituting triethylamine for the sodium acetate reagent in Step 2) from methyl acetoacetate (1.14 mL, 10.6 mmol), DMFDMA (1.48 mL, 11.1 mmol), tert-butylhydrazine hydrochloride (1.32 g, 10.6 mmol), and TEA (4.43 mL, 31.8 mmol) to yield methyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate after chromatography using a 80-g SiO2 pre-packed column eluting with 0:1-3:7 EtOAc/heptane. Said product was used directly in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 3.80 (s, 3H), 2.75 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ncsc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1ccccc1
Yield: 60.1 %

Procedure:
4.8 g (20.58 mmol) of ethyl 5-phenyl-4-thiazolecarboxylate and 4.0 g (25.0 mmol) of t-butyl (2-aminoethyl)carbamate were heated under reduced pressure for 21 hours at a bath temperature of 100°, whereby the ethanol formed was distilled off continuously. Subsequently, the mixture was cooled, dissolved in 50 ml of methylene chloride and chromatographed on 150 g of silica gel. Elution was first carried out with methylene chloride, then with a 9:1, 8:2 and finally 7:3 mixture of methylene chloride and ethyl acetate. The fractions which were pure according to the thin-layer chromatogram were combined and recrystallized from ethyl acetate/hexane. In this manner there were obtained 4.3 g (60.1% of t-butyl [2-(5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as white crystals, melting point 139°-140°.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:32]([O:34]CC)=O)[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12.[Cl-].[NH4+].O>C1COCC1>[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:32](=[O:34])[CH3:1])[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(C)=O)ccc1-c1cnc(C)o1

Procedure:
Methylmagnesium bromide (12% THF solution, 13 mL) was added to a mixture of ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.60 g) in THF (16 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and methylmagnesium bromide (12% THF solution, 13 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (121 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([Sn:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)C>[CH2:2]([Sn:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
In a three-necked flask, a solution of 1-bromobutane (34.25 g, 250 mmol) in diethyl oxide was added on magnesium (7.3 g, 300 mmol) covered with dry diethyl oxide. When the addition was completed, the mixture was refluxed during one hour. This solution was then added to triphenyltin chloride (42.6 g, 110 mmol) in 150 mL of diethyl oxide and refluxed for 3 hours. The mixture was hydrolysed with a minimum of water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated. Crystallization of the crude product in methanol gave a white solid (32.3 g, 93 mmol).