Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+]>C(#N)C>[F:16][CH:12]([F:17])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC(F)F)nc1
Yield: 6.7 %

Procedure:
To a solution of 2-hydroxy-5-nitro pyridine (10 g, 0.071 mol) in acetonitrile (100 mL) was added sodium chlorodifluoroacetate (11.5 g, 0.075 mol). The reaction mass was refluxed for 72 h. The excess of solvent was removed under vacuum and the reaction mass was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): δ 7.05 (d, J=8.7 Hz, 1H), 7.53 (d, J=71.4 Hz, 1H), 8.54 (dd, J=8.1 Hz & 5.4 Hz, 1H), 7.91 (s, 1H); MS [M]−: 190.83.
Reaction SMILES: O[CH:2]([CH2:7][CH:8]([S:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)C)[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([S:10][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:16][CH:15]=1
Reactant: CC(=O)CC(O)CC(C)Sc1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C)cc1
Yield: 66.7 %

Procedure:
1.00 Gram of 4-hydroxy-6-(4-methylphenylthio)-2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.74 g of 6-(4-methylphenylthio)-3-hexen-2-one. (trans : cis =5.5 : 1) (purity: 83.5%). The yield was 66.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:13]2[NH:14][C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[I-].[Li+].CS([CH2:29]/[CH:30]=[CH:31]/[CH3:32])(=O)=O>CN(C=O)C.CCOCC>[CH2:29]([N:14]1[C:13]([N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:10](=[O:12])[CH3:11])=[C:18]([CH2:19][CH3:20])[C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:30]=[CH:31][CH3:32]
Reactant: CCc1c(N(C(C)=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: C/C=C/CS(C)(=O)=O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC=CCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 13 h
Yield: 40.9 %

Procedure:
To a stirred solution of N-(3,5-dimethyl-phenyl)-N-(5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (109) (602 mg, 2 mmol) anhydrous powdered K2CO3 (276 mg, 2 mmol), and lithium iodide (268 mg, 2 mmol) in DMF (6 mL), was added 1-methanesulfonyl-trans-2-butene (283 μL, 2.4 mmol). After stirring for 13 hr., the reaction mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 291 mg (40%) of a white solid. m.p. 218-220° C.; m/z (EI) 355(M+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:18]2[C:17](=[O:19])[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[O:14][C:13]=2[C:12]([CH2:23][CH2:24][CH3:25])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:2]=[CH2:3]>C(O)C.[Pd]>[O:19]=[C:17]1[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[O:14][C:13]2[C:12]([CH2:23][CH2:24][CH3:25])=[C:11]3[C:6](=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:18]1=2)[CH2:7][CH2:8][CH2:9][CH2:10]3
Reactant: C=CCOc1c2c(c(CCC)c3oc(C(=O)O)cc(=O)c13)CCCC2
Agent: [Pd]
Solvent: CCO
Product: CCCOc1c2c(c(CCC)c3oc(C(=O)O)cc(=O)c13)CCCC2

Procedure:
A solution of the product of Example 23 (1.4 g) in ethanol (25 ml) was treated with a 5% palladium on charcoal catalyst (50 mg) and hydrogenated at 45 psi/room temperature for 5 hours. Catalyst was filtered off and the ethanolic filtrate was evaporated to low bulk, treated with sodium bicarbonate (0.8 g) and water (30 ml), and heated under reflux for 1 hour. The solution was evaporated, diluted with water and filtered and the filtrate was acidified. The precipitated acid was filtered off, washed with water, dried and the title compound recovered as a pale yellow powder (1.4 g), mp 208° (decomp).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)C(=O)CCl
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[NH:12]=[C:13]1[NH:15][C:3](=[O:4])[CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[S:14]1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Product: N=C1NC(=O)C(c2ccccc2)S1
Yield: 157.2 %

Procedure:
A mixture of 100 g (0.47 mole) of α-bromophenylacetic acid (Aldrich) and 41.0 g (0.54 mole) of thiourea (Baker) in 600 mL of ethanol was stirred and heated on a steam bath for 4 hr. The solvent was evaporated under reduced pressure to give 142.0 g crude title compound as a white solid. An analytical sample of title compound, mp 249°-252° C., was prepared from 95% ethanol as white flakes.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:7])=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:16][CH2:15]1)=[O:13]>CS(C)=O>[CH3:1][C:2]1[N:6]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=3[C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:18][CH2:19]2)=[O:13])[CH:5]=[C:4]([CH3:7])[N:3]=1
Reactant: Cc1cnc(C)[nH]1
Reactant: O=C(Nc1ccccc1)c1ccccc1N1CCN(C(=O)CCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cn(CC(=O)N2CCN(c3ccccc3C(=O)Nc3ccccc3)CC2)c(C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To 2,5-dimethyl imidazole (0.060 g, 0.630 mmol) in 1 mL of DMSO in a reaction tube is added 60% NaH (0.030 g, 0.730 mmol). The mixture bubbles as deprotonation occurs. The mixture is stirred for 0.5 h and then 0.5 mL of a DMSO solution containing 2-[4-(2-chloro-acetyl)-piperazin-1-yl]-N-phenyl-benzamide (0.075 g, 0.210 mmol) is added. The flask is sealed and heated at 80° C. for 60 h. The product is purified via Prep HPLC (20-100% CH3CN/H2O) to give 74.7 mg of 2-{4-[2-(2,4-dimethyl-imidazol-1-yl)-acetyl]-piperazin-1-yl}-N-phenyl-benzamide in 85% yield. MS: MH+=418.9
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:9](/[CH:10]=[CH:11]/[C@@H:12]([OH:24])[CH2:13][C@@H:14]([OH:23])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:7]=[C:6]([N:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:33])[N:5]=1)[CH3:3].[OH-].[Na+:39]>C1COCC1.O>[CH3:3][CH:2]([C:4]1[C:9]([CH:10]=[CH:11][CH:12]([OH:24])[CH2:13][CH:14]([OH:23])[CH2:15][C:16]([O-:18])=[O:17])=[C:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:7]=[C:6]([N:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH3:33])[N:5]=1)[CH3:1].[Na+:39]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC(O)CC(O)CC(=O)[O-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Rosuvastatin tert-butyl ester (3.0 g, 5.6 mmol) is dissolved in 25 mL of a 4:1 mixture of THF/water. The clear solution is warmed to 30° C. and 8.0 M NaOH (0.75 mL, 6.0 mmol) was added portionwise. The reaction mixture is stirred at 30° C. for 2 hours giving a clear yellow solution. Then THF is removed completely under the reduced pressure (20 mbar) at 40° C. The remaining aqueous solution is diluted with water to 25 mL and washed with AcOEt (2×10 mL). After separation from the organic layer aqueous phase is distilled under the reduced pressure (20 mbar) at 40° C. to completely remove the dissolved AcOEt. The remaining clear solution of sodium rosuvastatinate is diluted with water to 25 mL and liophylized to afford 2.81 g (100%) of rosuvastatin sodium salt as white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:14]([C@H:15]2[CH2:20][C@H:19]3[CH2:21][C@@H:16]2[CH2:17][CH2:18]3)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH:35]2[CH2:36][CH2:37][CH:31]1[CH2:32][N:33]([C:38]([C:40]1[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=1)=[O:39])[CH2:34]2)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH:31]2[CH2:37][CH2:36][CH:35]1[CH2:34][N:33]([C:38]([C:40]1[CH:41]=[N:42][C:43]([NH:46][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:22])[CH3:1])[N:14]([C@H:15]5[CH2:20][C@H:19]6[CH2:21][C@@H:16]5[CH2:17][CH2:18]6)[C:8]=4[N:9]=3)=[CH:44][CH:45]=1)=[O:39])[CH2:32]2)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1[C@H]1C[C@@H]2CC[C@H]1C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1[C@H]1C[C@@H]2CC[C@H]1C2

Procedure:
Following general N—C coupling procedure 1 as in example 76, 7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (90 mg, 0.28 mmol) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester which gave 3-[6-((1S,2S,4R)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and was used as is without further characterization.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[C:25]2[CH2:29][CH2:28][CH2:27][CH:26]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:25]1([C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[CH2:7]2)=[O:30])[CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1C1=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
The mixture of 2-(2-cyclopent-1-enyl-3-methyl-benzoylamino)-5-fluoro-indan-2-carboxylic acid ethyl ester (151) (190 mg, 0.47 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (152) as white solid (182 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH3:32][CH:33]([CH3:38])[CH:34]([OH:37])[C:35]#[CH:36]>>[CH3:32][CH:33]([CH3:38])[CH:34]([OH:37])[C:35]#[C:36][C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:29])([F:30])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: C#CC(O)C(C)C
Product: CC(C)C(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (Example 69) was coupled to 4-methyl-1-pentyn-3-ol (Aldrich, St. Louis, Mo.) to afford 4-methyl-1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol as a mixture of enantiomers.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][N:37]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([C:33]4[O:34][CH:35]=[CH:36][N:37]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-c4ncco4)cc3)CC2)nc1
Temperature: 90 °C

Procedure:
The product of step A (100 mg, 0.2 mmol), Pd(PPh3)2Cl2 (16 mg, 0.02 mmol), and 2-(tributylstannyl)oxazole (125 mg, 0.35 mmol) were dissolved in toluene (2.5 mL), and the solution was heated at 90° C. for 18 h. Silica gel was added, and the slurry was subjected to silica gel column chromatography (2/1 EtOAc/hexanes) to provide the title compound. MS (ESI) m/z 419 [M+H]+. GPR119 Human EC50: 12 nM
Reaction SMILES: [CH:1]1([N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21].C(NC(C)C)(C)C>CN(C)C=O>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:8]3[CH2:9][CH2:10][CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[F:18])[CH2:6][CH2:7]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: Fc1ccccc1CN(C1CCNCC1)C1CC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2ccccc2F)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-(2-fluoro-benzyl)-piperidin-4-yl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (60%, colourless oil). HPLC-MS m/z=(M+1), Rt: 3.02 min.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[Li]CCCC>C1COCC1>[CH3:5][C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]#[CH:2]
Reactant: C[C@H](C=C(Br)Br)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#C[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
A solution of zinc (135 g, 2.08 mol), PPh3 (545 g, 2.08 mol) and CBr4 (682 g, 4.08 mol) in CH2Cl2 (2 L) was stirred at 0° C. for 1.5 hr. A solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (114 g, 0.66 mol) in DCM was added in one portion, and the reaction mixture was stirred at 0° C. for another 3 hr. The mixture was quickly passed though a silica gel, and the solvent was evaporated to give the crude (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate. To a cooled (−78° C.) solution of the crude compound (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate in THF (2 L) was added dropwise 2.5 M BuLi (0.75 L, 1.88 mol) under nitrogen. The reaction was quenched with water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered and concentrated to give the crude compound N.2, (R)-tert-butyl but-3-yn-2-ylcarbamate, which was used without further purification. 1H NMR (CDCl3) δ 4.47 (br s, 1H), 2.24 (s, 1H), 1.49 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(F)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(c1cccc(F)c1)CC2

Procedure:
The title compound was synthesized from methyl 6-(3-fluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (116 mg, 0.45 mmol) and lithium hydroxide (188 mg, 4.50 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography. eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.28-2.39 (m, J=12.87, 8.60, 6.35, 6.35 Hz, 1H), 2.64-2.74 (m, 1H), 2.74-2.85 (m, 1H), 2.90-3.01 (m, J=12.83, 8.48, 8.48, 4.32 Hz, 1H), 4.23-4.31 (m, 1H), 6.80-6.87 (m, 2H), 6.89-6.97 (m, 2H), 7.23-7.32 (m, 1H), 8.74 (br. s, 1H). LCMS m/e 246 (M+H). Purity>98% (HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>C(OCC)(=O)C>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:16]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCCCCBr
Solvent: CCOC(C)=O
Product: O=C(CCCCCBr)Nc1ccccc1O
Yield: 73 %

Procedure:
was prepared in 73% yield from 34.7 g (0.23 mol) of 2-aminophenol and 32 g (0.15 mol) of 6-bromohexanoyl chloride according to the procedure of Example 1, part a, except that the addition was made at room temperature and the crude product was dissolved in ethyl acetate and washed with 1N HCl. The 6-bromo-N-(2-hydroxyphenyl)hexanamide was recrystallized from ethyl acetate-hexane, mp 88°-90° C.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:30][CH2:31][O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(O)(=O)C>[CH3:33][O:32][CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:8])[CH2:14][CH2:13]3)=[CH:17][CH:18]=2)[CH2:24][CH2:25]1
Reactant: O=C(c1ccccc1)N1CCN(Cc2ccc(OC3CCNCC3)cc2)CC1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: COCCN1CCC(Oc2ccc(CN3CCN(C(=O)c4ccccc4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
1-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone (E32) (150 mg, 0.40 mmol) was dissolved in 2-butanone and treated with 1-chloro-2-methoxy-ethane (0.08 ml, 0.80 mmol), potassium carbonate (132 mg, 0.96 mmol) and potassium iodide (159 mg, 0.96 mmol). The reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool to room temperature, acidified by the addition of glacial acetic acid and passed down an SCX ion exchange column (2 g) eluting with methanol followed by ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (76 mg). MS(ES+) m/e 438 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([NH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:16][CH3:17])#[N:13]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:15]([NH:16][CH3:17])=[N:14][C:12]#[N:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CN=C(NC#N)NCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CNC(=NC#N)NCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 40 h
Yield: 42.9 %

Procedure:
A solution of p-toluenesulphonyl chloride (9.11 g) in pyridine (40 ml) was added in portions to a stirred solution of N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (8.0 g) in pyridine (40 ml) at -10°. The mixture was stirred at 2° for 40 hours and was poured into ice-water. The aqueous mixture was extracted with chloroform, and the extracts were washed with dilute hydrochloric acid and evaporated to give 5-(N'-cyano-N"-methylguanidino)pentyl p-toluenesulphonate (6.3 g) as an orange oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using 5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 118.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.06 min, m/z=459.1-460.1 [M+H]+, m/z=457.2-458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.38 (m, 2H) 1.53-1.61 (m, 1H) 1.79-1.86 (m, 1H) 2.59 (dd, J=12.23, 9.05 Hz, 1H) 2.69-2.78 (m, 1H) 3.35-3.41 (m, 1H) 3.43-3.50 (m, 1H) 3.56-3.62 (m, 1H) 4.73 (d, J=4.40 Hz, 1H) 7.37 (d, J=8.80 Hz, 2H) 7.50-7.54 (m, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.02 (dt, J=8.01, 1.86 Hz, 1H) 8.11 (d, J=2.45 Hz, 1H) 8.57-8.61 (m, 1H) 8.77 (d, J=2.20 Hz, 1H) 8.81 (d, J=1.71 Hz, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3]1=[O:13].[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3]1=[O:13]
Reactant: CN1C(=O)C2(CC2)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-methyl-spiro[cyclopropane-1,3′-indoline]-2′-one (8 g) in acetic acid (150 ml) is added nitric acid (fuming, 5.5 ml) over a period of 15 min at 15° C. The mixture is stirred at RT for 3 h and then poured into water. The precipitate is collected by filtration and washed with water, 2-propanol and tertbutyl-methyl-ether to give the title compound (8.80 g).