Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([F:17])[CH:8]=1)[CH2:3][C:4]([NH2:6])=[O:5].[NH2:25][C:26](N)=[O:27]>>[NH2:6][C:4](=[O:5])[CH2:3][C@@:2]([NH:1][C:26]([NH:25][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:17])[CH:8]=1)=[O:27])([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)[C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([F:17])[CH:8]=1
Reactant: NC(=O)C[C@](N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: NC(N)=O
Product: NC(=O)C[C@](NC(=O)Nc1cccc(F)c1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Yield: 56 %

Procedure:
(S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl) propanamide (0.031 g, 0.085 mmol) was converted to the urea as described in Procedure 2. (S)-1-(3-amino-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-oxopropyl)-3-(3-fluorophenyl)urea (0.023 g, 56% yield) was isolated after purification by reverse phase prep HPLC: YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 min, flow rate 20 mL/min eluting at a retention time of 10.3 min. LCMS: 1.98 min [M+1] 499.1 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:26][CH3:27]>CN(C=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 2A (1 g, 3.6 mmol) in DMF (15 mL) was added with an. K2CO3 (1.4 mol eq, 0.7 g) and, after few minutes, 2-iodoethane (1.2 mol eq, 0.45 ml) was added and the mixture heated at 50° C. for 5 h. The solvent was removed under reduced pressure, water was added to the residue (80 mL) and the aqueous phase extracted with EtOAc (3×30 mL). The combined organic phases were dried using Na2SO4 and evaporated under reduced pressure to obtain 3B as a pale yellow oil (1.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.13 (t, 3H, J=8), 3.29 (q, 2H), 3.41 (s, 3H), 3.79 (m, 2H), 4.53 (t, 1H), 5.14 (t, 1H), 7.41 (t, 2H, J=10), 7.86 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:43])[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1.CO.[OH-].[Li+]>O1CCCC1>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:32]=1)[C:28]([NH:27][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:44])=[O:2])=[O:43]
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)ccc1C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 25.2 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.22 g, 0.35 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.26 mL). The crude material was triturated with hot hexanes and filtered. The product was then crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid (0.055 g, 26%) as a white solid. mp=218-219° C. (dec). 1H NMR (500 MHz, DMSO-d6); δ 13.50 (bs, 1H), 12.72 (s, 1H), 8.49 (s, 2H), 8.44 (s, 1H), 8.38 (s, 1H), 8.31 (d, 1H), 7.99 (d, 1H), 7.80-7.71 (AA′BB′, 4H), 6.82 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 2.18 (m, 2H). Mass spec (MW 622.44); (ES+) m/z 623.05, (ES−) m/z 621.50. Elemental analysis; Calculated for C27H19F9N2O5: C, 52.10; H, 3.08; N, 4.50. Found: C, 51.78; H, 3.03; N, 4.26.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:21].C1C(=O)N([Cl:29])C(=O)C1>C(#N)C>[Cl:29][C:9]1[C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]([NH2:21])=[C:2]([CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)ccc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)cc(Cl)c32)cc1
Temperature: 50 °C

Procedure:
To a solution of 5-methyl-1-tosyl-1H-indol-4-amine (0.52 g, 1.731 mmol) in acetonitrile (17.31 mL) was added NCS (0.231 g, 1.731 mmol), and the mixture was stirred at 50° C. After 2 hours the reaction was cooled to room temperature, quenched with sat. aq. NaHCO3, and with sat. sodium thiosulfate. The layers were separated and the aqueous layer extracted with EtOAc (twice), dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 335.0 (M+H).
Reaction SMILES: Cl.[C:2]1([C:8]2([OH:29])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([N+:25]([O-])=O)=[CH:20][CH:21]=4)[C:16]3=[O:28])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:2]1([C:8]2([OH:29])[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([NH2:25])=[CH:20][CH:21]=4)[C:16]3=[O:28])[CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CCC1CN1CCC(O)(c2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)C(CN1CCC(O)(c3ccccc3)CC1)CC2

Procedure:
4.15 g. of 2-(4-phenyl-4-hydroxypiperidinomethyl)-7-nitro-1-tetralone hydrochloride are dissolved in 30 ml. of methanol and are reduced at 20° and 1 atmosphere over 0.3 g. of pre-reduced platinum oxide. After the calculated quantity of hydrogen has been absorbed, the mixture is filtered, evaporated and worked up in the customary manner to give 2-(4-phenyl-4-hydroxypiperidinomethyl)-7-amino-1-tetralone.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH3:13])=[N:7]2.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([NH2:21])[CH:20]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:21][C:19]3[CH:20]=[C:15]([CH3:14])[CH:16]=[CH:17][C:18]=3[S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: CCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Product: CCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 8f (88 mg, 0.46 mmol) was reacted with the product from Example 7f (100 mg, 0.46 mmol) for 24 h following the procedure from Example 7f giving the title compound as a hydrochloride salt which was triturated with ether giving (134 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J=7.35 Hz, 3 H) 3.02 (q, J=7.35 Hz, 2 H) 6.69 (d, J=6.99 Hz, 1 H) 6.97 (d, J=8.82 Hz, 2 H) 7.10 (dd, J=7.35 Hz, 1 H) 7.15 (d, J=8.82 Hz, 2 H) 7.30 (dd, J=8.09 Hz, J=7.72 Hz, 2 H) 7.56 (dd, J=2.94 Hz, J=9.19 Hz, 1 H) 7.71 (d, J=2.57 Hz, 1 H) 7.88 (d, J=8.82 Hz, 1 H) 8.52 (d, J=6.99 Hz, 1 H) 9.02 (d, J=8.45 Hz, 1 H) 11.16 (br s, 1 H) 14.56 (br s, 1 H); MS (ESI+) m/z 376 (M-Cl)+; (ESI−) m/z 374 (M−HCl)−.
Reaction SMILES: CO[C:3]1[CH2:12][C:11]([O:13]C)=[C:10]2[CH:5]([CH2:6][CH2:7][N:8]([CH3:15])[CH2:9]2)[CH:4]=1.CN1CCC2C(C(=O)CC(=O)C2)C1.[CH3:29][CH2:30][C:31](/[C:33](/[CH3:36])=[N:34]/O)=O>C(O)(=O)C.[Zn]>[CH2:30]([C:31]1[C:12]2[C:11](=[O:13])[CH:10]3[CH:5]([CH2:6][CH2:7][N:8]([CH3:15])[CH2:9]3)[CH2:4][C:3]=2[NH:34][C:33]=1[CH3:36])[CH3:29]
Reactant: CCC(=O)/C(C)=N/O
Reactant: COC1=CC2CCN(C)CC2=C(OC)C1
Agent: CN1CCC2CC(=O)CC(=O)C2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCc1c(C)[nH]c2c1C(=O)C1CN(C)CCC1C2
Yield: 28.8 %

Procedure:
1,2,3,4,4a,7-Hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.56 g, 2.68 mmol) was heated to 90°-100° in 70% aqueous acetic acid (10 ml) to hydrolyze the bis(enolether) to the octahydro-2-methylisoquinolin-6,8-dione. To the hot solution was added zinc dust (0.6 g, 9.25 mmol) and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol). The mixture was refluxed for 3 hours, cooled and filtered to remove zinc and zinc acetate. The filtrate was concentrated to dryness on a rotary evaporator and the residue was dissolved in dichloromethane. To the solution was added ammonium hydroxide and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated to give the crude product. Chromatography of the crude product on Alumina III afforded 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinolin-4-one as a white solid (0.19 g, 29% yield).
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)C.[I:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26]CCI>>[I:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=1
Reactant: ICCOCCOCCI
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(=O)c1ccc(OCCOCCOCCI)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 21 except that 1,2-bis-(2-iodoethyloxy)ethane was used instead of 2-(diethylamino)ethyl chloride hydrochloride. This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:1 hexanes/ethyl acetate to give 43 (3.85 g, 52%) as a clear oil: MS (ES+) m/z 407.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][C:32](=[O:50])[C:33]3[CH:38]=[CH:37][C:36]([NH:39]C(OCC4C=CC=CC=4)=O)=[CH:35][CH:34]=3)=[O:27])[C:15]([O:17]CC3C=CC=CC=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C)C>[Pd].C1COCC1>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([O:31][CH2:30][CH2:29][O:28][C:26](=[O:27])[CH2:25][C@H:14]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:15]([OH:17])=[O:16])=[O:50])=[CH:38][CH:37]=1
Reactant: O=C(C[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Reaction time: 6 h
Yield: 90.4 %

Procedure:
10% Palladium on charcoal (0.040 g) was added in one portion to a stirred solution of 18 (0.360 g, 0.57 mmol) in a 1:1 mixture of isopropanol (4 mL) and THF (4 mL) under nitrogen atmosphere. The suspension was then stirred under hydrogen atmosphere for 6 h. The solution was filtered through celite and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography CH3OH:CH2Cl2 (5:95) to afford to obtain (S)-4-(2-(4-aminobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-4-oxobutanoic acid 19 (0.230 g, 96%) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:22]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[CH:22]=2)[N:14]=1)([CH3:8])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2cnn(-c3cccc(C(F)(F)F)c3)c2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2cnn(-c3cccc(C(F)(F)F)c3)c2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
2-Methyl-2-({4-[2-({1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}oxy)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (400 mg) obtained in Example 158-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (290 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[N:9]([CH3:14])[N:10]=[CH:11][C:12]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([C:12]4[CH:11]=[N:10][N:9]([CH3:14])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: Cn1ncc(Br)c1NC(=O)OC(C)(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: (4-bromo-2-methyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:19]=[C:18]2[C:13]([N:14]=[C:15]([NH:24][CH:25]([CH3:27])[CH3:26])[C:16]3[N:17]2[C:20](=[O:23])[NH:21][N:22]=3)=[CH:12][CH:11]=1)=O)([CH3:3])[CH3:2].[BH4-].[Na+].B(F)(F)F.CCOCC.Cl>C1COCC1.C(Cl)Cl.[OH-].[Na+]>[CH:1]([O:4][CH2:5][CH2:6][NH:7][CH2:8][C:10]1[CH:19]=[C:18]2[C:13]([N:14]=[C:15]([NH:24][CH:25]([CH3:27])[CH3:26])[C:16]3[N:17]2[C:20](=[O:23])[NH:21][N:22]=3)=[CH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc2ccc(C(=O)NCCOC(C)C)cc2n2c(=O)[nH]nc12
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Nc1nc2ccc(CNCCOC(C)C)cc2n2c(=O)[nH]nc12
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A suspension of 30 mg of 4-isopropylamino-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid-(2-isopropoxy-ethyl)-amide in THF (5.0 mL) was stirred as sodium borohydride (30 mg) was added. This mixture was heated to reflux and then boron trifluoride etherate (0.15 mL) was added dropwise. The mixture was refluxed for two hr. and then cooled to 23° C. and acidified to pH 3.0 with 3N HCl. After stirring for 30 min., the reaction was diluted with methylene chloride and basified to pH 14 with 6N sodium hydroxide. The layers were separated and the aqueous was extracted with methylene chloride and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography provided the product as a white solid. MS (M+H)+=359.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:19][O:18][C:16]([N:7]1[CH2:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11][CH:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:22]([F:23])=[C:21]([F:24])[CH:20]=1)=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)c(F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Dimethyl 2-(3,4,5-trifluorobenzyl)piperidine-1,4-dicarboxylate (4.01 g, 11.61 mmol) was dissolved in acetonitrile (40 mL) and water (0.8 mL). Lithium bromide (2.329 mL, 92.90 mmol) was added followed by triethylamine (6.44 mL, 46.45 mmol). The reaction was refluxed for 2 h. The reaction was cooled to room temperature. Water (200 mL) and MTBE (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (2×150 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and then extracted with MTBE (2×400 mL). The combined organic phases were dried with Na2SO4, filtered and evaporated in vacuo to yield 1-(methoxycarbonyl)-2-(3,4,5-trifluoro-benzyl)piperidine-4-carboxylic acid (3.42 g, 89%) as a light brown foam. MS m/z 330 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([NH:20][C:14]([C:12]2[CH:11]=[N:10][C:9]([CH:17]3[CH2:19][CH2:18]3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (Example 3a) and 1-amino-piperidine as starting materials, and isolated (29 mg, 40%) as white solid; LC-MS (UV peak area, ESI) 100%, 357.1485 (M+H).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[S:9][C:10](Cl)=[N:11][N:12]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:14]([SH:16])[CH3:15]>O1CCOCC1>[CH2:14]([S:16][C:10]1[S:9][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[N:12][N:11]=1)[CH3:15]
Reactant: CCCCS(=O)(=O)c1nnc(Cl)s1
Reactant: CCS
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)c1nnc(SCC)s1
Temperature: 0 °C

Procedure:
114.5 g 2-butylsulfonyl-5-chloro-1,3,4-thiadiazole and 36 ml ethylmercaptan are dissolved in 400 ml dioxane. Then under agitation 70 ml triethylamine are added to this drop by drop and the solution is heated to boiling under reflux for about one hour. After cooling the reaction mixture is introduced into ice water, the separating oil is extracted with dichloromethane, the methylenechloride phase is dried with magnesiumsulfate and the solvent is completely distilled off, finally in vacuo. 125.3 g of a colorless oil, that is 99 percent of theory, are obtained with an index of refraction of nD20 =1.5552.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.Cl.[NH:16]1[CH2:21][CH2:20][C:19]2([C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH2:23][O:22]2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:16]3[CH2:17][CH2:18][C:19]4([C:25]5=[N:26][CH:27]=[CH:28][CH:29]=[C:24]5[CH2:23][O:22]4)[CH2:20][CH2:21]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1cnc2c(c1)COC21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)OCc3cccnc34)nn2)n1

Procedure:
The object product (72 mg, 28%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), 5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] dihydrochloride (86 mg) and potassium carbonate (290 mg).
Reaction SMILES: BrC1C=NN(CC2C=C(O)C=CC=2)C=1.BrC1C=NN(CC2C=CC=C(OC)C=2)C=1.[CH3:30][C:31]1[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([N:39]1[C:48]2[C:43](=[C:44]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([O:61]C)[CH:56]=4)[CH:53]=3)[CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH2:40]1)=[O:38]>>[CH3:30][C:31]1[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([N:39]1[C:48]2[C:43](=[C:44]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=4)[CH:53]=3)[CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH2:40]1)=[O:38]
Reactant: COc1cccc(Cn2cc(-c3cccc4c3CCCN4C(=O)CCCOc3cccc(C)c3C)cn2)c1
Agent: COc1cccc(Cn2cc(Br)cn2)c1
Agent: Oc1cccc(Cn2cc(Br)cn2)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(O)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 3-((4-bromo-1H-pyrazol-1-yl)methyl)phenol except that 4-bromo-1-(3-methoxybenzyl)-1H-pyrazole was replaced with 4-(2,3-dimethylphenoxy)-1-(5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one. LCMS, [M+H]+=496.4.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[CH:11]([N-]C(C)C)(C)C.[Li+].IC.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:11][CH:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1
Reactant: O=C1CCCc2sccc21
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCc2sccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 6,7-dihydro-1-benzothiophen-4(5H)-one (1.63 g) in tetrahydrofuran (90 ml) at −78° C. under N2 was added lithium diisopropyl amide (5.89 ml, 2 M). After 30 min, iodomethane (0.732 ml) was added and the reaction was allowed to warm to ambient temperature. After 2 h, the reaction mixture was poured into saturated sodium bicarbonate (100 ml), extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated. MPLC was run on a biotage 40M column with 4–6% ethyl acetate/heptane to provide the title compound as an oil (560 mg, 32%): 1H NMR (300 MHz, CDCl3) δ) 7.41, 7.08, 3.15–2.99, 2.61–2.53, 2.33–2.25, 2.06–1.92, 1.28; HRMS (FAB) calcd for C9H10OS+H 167.0531, found 167.0527.
Reaction SMILES: II.[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.C[O-].[Na+]>CO>[CH3:9][N:8]1[C:4]([S:3][S:3][C:4]2[N:8]([CH3:9])[N:7]=[N:6][N:5]=2)=[N:5][N:6]=[N:7]1
Reactant: Cn1nnnc1S
Agent: C[O-]
Agent: II
Agent: [Na+]
Solvent: CO
Product: Cn1nnnc1SSc1nnnn1C
Temperature: -60 °C
Reaction time: 3 h

Procedure:
Iodine of 5 mmol is solved in methanol of 30 ml in an argon atmosphere. Into the solution thus formed, a solution of 5-mercapto-1-methyltetrazole of 10 mmol and sodium methoxide of 5 mmol dissolved in methanol is dropped slowly. Thereafter, the solution thus formed is stirred for three hours, and cooled to -60° C. Then, the precipitate thus created is separated by filtration. The precipitate is dried in a decompressing atmosphere, and recrystallized three times by ethanol to provide 5,5'-dithiobis (1-methyltetrazole).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC(C(=O)OC(C)(C)C)CC1
Reaction time: 5 h

Procedure:
Next, 20.3 g of piperidine-4-carboxylic acid t-butyl ester is dissolved in 100 ml of CH2Cl2 and cooled in an ice bath. Under a nitrogen atmosphere, 12 ml of triethylamine and then, 8.2 ml of acryloyl chloride solution in CH2Cl2 are added dropwise to the ester solution. This mixture is completely mixed by stirring for 5 hrs. Thereafter, this mixture is washed three times with 20 ml of 1 N HCl, washed another three times with 20 ml of NaHCO3 and then washed once with 25 ml of brine water, and dried over MgSO4 to obtain N-acryloyl-piperidine-4-carboxylic acid t-butyl ester.