Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36]CC4C=CC=CC=4)=[C:32]([F:44])[CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CCOC(C)=O.CC(O)=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:44])[CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(OCc3ccccc3)c(F)c2)c1)C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(F)c2)c1)C1CCCC1
Reaction time: 4 h

Procedure:
To an evacuated flask containing palladium on carbon [50% water by weight] was added a solution of (1R)-2-{[6-({4-[3-(cyclopentylsulfonyl)phenyl]butyl}oxy)hexyl]amino)-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}ethanol (37 mg) in EtOAc (8 ml) and AcOH (2 ml). The reaction mixture was hydrogenated for 4 h. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound. LCMS RT=2.60 min 535(M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C(C(O)=O)=CON=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1conc1-c1ccc(Cl)cc1
Agent: O=C(O)c1conc1-c1ccc(F)cc1
Product: OCc1conc1-c1ccc(Cl)cc1
Yield: 46.1 %

Procedure:
As described for example 323e, 3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid (40.0 g, 178.9 mmol) was converted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid, to the title compound (17.3 g, 46%) which was obtained as a light green solid. MS: m/e=210.1 [M+H]|.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19][C:20]([CH3:22])=O.[C:32]1(C)C=CC=CC=1>C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH2:25]([O:24][C:18](=[O:23])/[CH:19]=[C:20](/[NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[CH:11][C:12]=1[CH3:32])\[CH3:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: Cc1ccccc1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Product: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1C
Yield: 71 %

Procedure:
[2-(4-Amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.76 mmol), benzyl acetoacetate (0.796 g, 4.14 mmol) and toluenesulfonic acid (0.026 g, 0.138 mmol) were refluxed in toluene at 125° C. 3 hours. The reaction was then cooled, evaporated to dryness, the crude redissolved in EtOAc and dried over anhydrous Na2SO4. Filtration under vacuum followed by purification on SiO2 (30% EtOAc/hexane) gave 1.055 g (71%) of the desired (E)-3-[4-(2-tert-butoxycarbonylamino-ethyl)-2-methyl-phenylamino]-but-2-enoicacid benzyl ester. 1HNMR (400 MHz, DMSO): δ 1.32 (s, 9H), 1.81 (s, 3H, olefineCH3),2.63 (t, J=2.96 Hz, 2H), 3.12 (q, J=6.03 Hz, 2H), 4.77 (s, 1H, olefineH), 5.07 (s, 2H), 6.83 (b, ArH), 7.20-7.35 (m, 6H, ArH), 7.70 (s, 1H, ArH), 10.05 (s, ArNH). MS(APCI−) m/z 535.2(M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1>CO.C1(C=O)CC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([C:33](=[CH:39][CH:40]3[CH2:42][CH2:41]3)[C:34]#[N:35])=[O:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.20 mmol, 1.00 equiv) in methanol (3 mL), cyclopropanecarbaldehyde (1 mL), and piperidine (1 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with 10 mL of dichloromethane, washed with saturated aqueous NH4Cl, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum and the residue was purified via column chromatograpy using dichloromethane/methanol (20/1) to give 26 mg (23%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1.[CH3:19][C:20]1([CH3:29])[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=O)[CH2:21]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:13]1([C:11](=[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21]2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCO)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a stirred suspension of Zn (0.65 g, 9.91 mmol) in THF (10 mL) was added TiCl4 (0.55 mL, 4.95 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. After cooling to room temperature, a solution of 5 (0.30 g, 1.24 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.59 g, 3.71 mmol) in THF (17 mL) was added at once. The reaction mixture was refluxed for another 2.5 h. Following cooling to room temperature, the reaction was quenched with 10% K2CO3 (40 mL). The quenched reaction mixture was filtered through a pad of celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated to give a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give 6 as a white solid (0.35 g, 78%). mp 131-132° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.99 (s, 2H), 3.80-3.85 (m, 2H), 4.00-4.05 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 7.10-7.20 (m, 3H), 7.20-7.25 (m, 2H). LRMS (ESI): m/z 365 (M+H)+. Anal. Calcd for C25H32O2: C, 82.37; H, 8.85. Found: C, 82.11; H, 9.03.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1>Cl.O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:10]1[N:9]=[C:8]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=12
Reactant: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: O
Product: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Yield: 101.8 %

Procedure:
A solution of benzyl 4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]piperidine-1-carboxylate (3.61 g, 0.00774 mol) in conc. HCl (100 ml) was stirred at rt overnight. The mixture was then diluted with water (200 mL), washed with Et2O (2×30 mL) then the aqueous layer concentrated in vacuo yielding 2.62 g of desired product as the trihydrochloride salt. 1H NMR (400 MHz, MeOD): δ 2.19-2.32 (m, 4H), 3.26-3.30 (m, 2H), 3.53-3.36 (m, 2H), 3.70 (m, 1H), 7.06 (d, J=5.6 Hz, 1H), 7.10-7.14 (m, 1H), 7.23-7.26 (m, 2H), 7.50-7.52 (m, 1H), 7.67 (m, 1H), 7.93 (m, 1H), MS (ES+): m/z 333.27 [MH+].
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1.C(O)C.O.C(O)(=O)C>[OH-].[Na+]>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Yield: 69.5 %

Procedure:
Ethyl 7,8-methylenedioxy-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a) quinoline-4-carboxylate (1.38 grams, 4.3 mmol) was suspended in a mixture of 2.0 grams of sodium hydroxide, 40 ml of ethanol and 30 ml of water and the whole mixture was heated to reflux for thirty minutes. Then it was acidified with acetic acid when the solution was still hot, the crystals separated out were collected by filtration, washed with water and air dried and the resulting crude crystals were recrystallized from dimethyl formamide to give 870 mg (69.0 percent) of the title compound, melting point 315° to 320° C. (decomposition). Elementary analysis calculated as C13H9NO5S: C 53.61, H 3.11, N 4.81; Found: C 53.68, H 2.92, N 4.66.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH:11]1([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][N:22]=3)[C:17]([C:24](Cl)=[O:25])=[CH:16]2)[CH2:13][CH2:12]1.C(OCC)(=O)C>C1COCC1.O>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][C:24]([C:17]2[C:18]3[C:23](=[N:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH2:14][CH:11]3[CH2:13][CH2:12]3)[CH:16]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)c1cn(CC2CC2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccncc1)c1cn(CC2CC2)c2ncccc12
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60%, 1.14 g) is suspended in 21 mL of THF. While stirring at about 10° C., a solution of 0.93 g of 4-aminomethylpyridine (8.6 mmoles) in 21 mL of THF is added dropwise. After about 15 minutes, the previously prepared solution of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid chloride is added dropwise to the reaction mixture. Subsequently, the whole is refluxed for 3 hours. After cooling, the reaction mixture is mixed with 36 mL of ethyl acetate and 36 mL of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off and the residue recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Br:17][CH2:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]>>[Br-:17].[NH2:1][C:2]1[N:6]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:4]=2[N+:3]=1[CH2:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: Clc1ccc(SCBr)c(Cl)c1
Reactant: Nc1nc2cc(-c3ccccc3)ccc2[nH]1
Product: Nc1n(CSc2ccc(Cl)cc2Cl)c2cc(-c3ccccc3)ccc2[n+]1CSc1ccc(Cl)cc1Cl
Product: [Br-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-6-phenylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2,4-dichlorophenyl bromomethyl sulfide, the title compound is obtained.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1>>[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:20]([CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:21])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][N:11]1[C:20]([CH:16]1[CH2:19][CH2:18]1)=[O:21])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)C1CCC1
Reactant: C(=C/c1ccccc1)\CC1CCCCN1
Product: O=C(C1CC1)N1CCCC1C/C=C/c1ccccc1
Product: O=C(C1CCC1)N1CCCCC1C/C=C/c1ccccc1

Procedure:
Stage a) The method is the same as that of Example 1.1, Stage a), the initial reactants being (E)-2-(cinnamyl)piperidine and cyclobutanecarboxylic acid chloride, which furnish (E)-2-cinnamyl-1-(cyclobutanecarbonyl)piperidine (formula II; Ar=C6 H5, m=1, n=2, R=cyclobutyl). Yield: 99%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C([O:18][C:19]([C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:29][C:24]=2[O:23][N:22]=1)=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[C:25]3[CH:26]=[CH:27][C:28]([O:30][Si:31]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[CH:32]([CH3:33])[CH3:34])=[CH:29][C:24]=3[O:23][N:22]=2)=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1noc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc2c(C(=O)Nc3cccc(C(F)(F)F)c3)noc2c1)(C(C)C)C(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 207 μl (1.66 mMol) 3-trifluoromethyl-aniline are dissolved in 28 ml toluene and cooled to 10° C. Then 2.5 ml Me3Al (2 M in toluene; 5.0 mMol) are added via syringe. After 1 h at rt, a solution of 602 mg (1.66 mMol) 6-triisopropylsilanyloxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 6 ml THF is added and the reaction mixture stirred for 30 min in an oil bath at 110° C. The solution is cooled in ice and hydrolyzed with 70 ml of a sat. NH4Cl. After 15 min stirring, EtOAc and Celite are added. The mixture is filtered through Celite, the solid washed with EtOAc and water, the aq. phase separated from the filtrate and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound as an oil: MS: [M−1]=477; TLC(hexane/EtOAc 19:1): Rf=0.30.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:11][C:12]([NH2:14])=[S:13].[I:15]I>>[IH:15].[S:13]1[C:2]2[CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:1]=2[N:11]=[C:12]1[NH2:14]
Reactant: NC(N)=S
Reactant: II
Reactant: O=C1CCc2ccccc21
Product: I
Product: Nc1nc2c(s1)Cc1ccccc1-2
Temperature: 95 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of 1-indanone (6.00 g; 45.4 mmol), thiourea (6.92 g; 90.8 mmol) and iodine (11.52 g; 45.4 mmol) was heated to 95° C. with stirring. After 3 hours, the mixture was allowed to cool to room temperature. The crude solid was triturated with absolute ethanol and filtered. The light yellow solid was washed twice with absolute ethanol then allowed to air dry to provide 9.13 g of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9](N(OC)C)=[O:10]>C1COCC1.C(OCC)C>[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9]([CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1ccc(C)cc1Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added to 1.09 g (5.10 mmol) of the compound from Example 121A in 19 ml of diethyl ether, and the mixture was stirred at RT overnight. A further 7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water and extracted with dichloromethane, the organic phase was dried over magnesium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 326 mg (33% of theory) of the title compound.
Reaction SMILES: [C:1]([Cl:5])(=[O:4])[CH2:2][CH3:3].[CH:6](=[O:10])[CH:7](C)[CH3:8].[CH2:11](Cl)Cl>>[C:6]([O:4][CH:1]([Cl:5])[CH:2]([CH3:11])[CH3:3])(=[O:10])[CH2:7][CH3:8]
Reactant: CC(C)C=O
Reactant: CCC(=O)Cl
Reactant: ClCCl
Product: CCC(=O)OC(Cl)C(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To freshly fused zinc chloride (41 mg) in methylene chloride (10 ml) was added propionyl chloride (5.0 g, 54.0mmol). The reaction was cooled to 10° C. and isobutyraldehyde (3.89 g, 54.0 mmol) was added dropwise maintaining the temperature at 25° C. Once the addition was complete, the reaction Was Stirred for one hour at room temperature. The reaction mixture was washed with 20% NaOAc and the organic phase was concentrated in vacuo to provide the title A compound.
Reaction SMILES: CC(N([C@H](C)C(NC1C=NC(OC2C3C(C)(C)COC=3C=CC=2)=CC=1)=O)C(=O)[O-])(C)C.[CH3:32][C:33]1([CH3:63])[C:37]2[C:38]([O:42][C:43]3[N:48]=[CH:47][C:46]([NH:49][C:50]([C@H:52]([NH:55]C(=O)OC(C)(C)C)[CH2:53][CH3:54])=[O:51])=[CH:45][CH:44]=3)=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH2:34]1>>[NH2:55][C@H:52]([CH2:53][CH3:54])[C:50]([NH:49][C:46]1[CH:47]=[N:48][C:43]([O:42][C:38]2[C:37]3[C:33]([CH3:32])([CH3:63])[CH2:34][O:35][C:36]=3[CH:41]=[CH:40][CH:39]=2)=[CH:44][CH:45]=1)=[O:51]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Agent: C[C@H](C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1

Procedure:
The title compound was made in a similar fashion to the preparation of Intermediate 61 replacing 1,1-dimethylethyl[(1R)-2-({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate with 1,1-dimethylethyl {(1R)-1-[({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate
Reaction SMILES: [N:1]1C=CC=C(OC2C=C(C=C(C#N)C=2)N)C=1.N1C=CC=CC=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:1])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N#Cc1cc(N)cc(Oc2cccnc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1ccc(F)cc1

Procedure:
Formula I where R1 is Pyridin-3-yl, R2 is CN, and R3 is 4-Fluorophenyl To a solution of 1 eq. (0.1 g, 0.473 mmol) of 3-(pyridin-3-yloxy)-5-cyano-aniline in 0.47 M in CH2Cl2 (1 mL) and 1.6 eq. of pyridine (0.56 g, 0.71 mmol) was added 3 eq. of 4-fluorobenzoyl chloride (0.225 g, 1.42 mmol) and the resultant mixture stirred at rt overnight. The reaction mixture was diluted with CH2Cl2, washed with sat. NaHCO3, dried (Na2SO4) and concentrated in vacuo. The resultant residue was diluted with toluene and concentrated in vacuo (5 times). Purification by chromatography over silica with 5% MeOH/CH2Cl2 as the eluant afforded 134 mg of a the desired title compound of Formula I, N-[3-cyano-5-(pyridin-3-yloxy)-phenyl]]-4-fluoro-benzamide, as a solid (85% yield). Mpt 169-172° C. MS (M−1) 332.3.
Reaction SMILES: ClC1C=CC([C@@H]2[C@@H]([C@@H](OC3C=CC(Cl)=C(Cl)C=3)C)CCN(C(C3CCN(C4C=CC(C#N)=CN=4)CC3)=O)C2)=CC=1.N1CCCCC1.C([N:54]1[CH2:59][CH2:58][C@H:57]([C@H:60]([OH:62])[CH3:61])[C@@H:56]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[C:65]([F:70])[CH:64]=2)[CH2:55]1)C1C=CC=CC=1.[Cl:71][C:72]1[CH:73]=[CH:74][C:75](O)=[N:76][CH:77]=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[Cl:71][C:72]1[CH:73]=[CH:74][C:75]([O:62][C@H:60]([C@H:57]2[CH2:58][CH2:59][NH:54][CH2:55][C@@H:56]2[C:63]2[CH:68]=[CH:67][C:66]([F:69])=[C:65]([F:70])[CH:64]=2)[CH3:61])=[N:76][CH:77]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Agent: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CCNC[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanol and 5-Chloro-2-hydroxy-pyridine via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol to yield 5-Chloro-2-{(S)-1-[(3S,4S)-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethoxy}-pyridine. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as off-white solid. MS (m/e): 566.4 [(M+H)+].
Reaction SMILES: [BrH:1].CN([C:5]1[C:10]2[C:11](N(C)C)=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7][CH:6]=1)C.[CH2:18](O)[CH3:19]>>[Br:1][C@@H:18]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1)[CH3:19]
Reactant: CCO
Reactant: Br
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Product: C[C@@H](Br)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
A 5 mm NMR tube was charged with 4.7 mg (0.010 mmol) of crystals of salt (S)-5. This readily dissolved in CDCl3 to 5 cm depth. NMR spectra (1H and 19F) showed 5 with a low level (7 mole %) of ethanol impurity. This was mixed with 2 mg of crystals of (R)-7a ([α]D≈+23°). Note that excess 5 is necessary to assure complete reaction of 7a, thus avoiding kinetic sorting at the end. NMR (1H and 19F) of this solution showed 5 and 7a in 1:0.82 mole ratio. After 30 min. at 20° C., the spectra showed 30% conversion of 7a cleanly to (S,S) and (S,R) diastereomers in ˜2.5:1 ratio. At 18 h, NMR showed 97% conversion to 3:1 mixture of the diastereomers (de≈50%). No more 7a was detected after an additional 24 h at 25° C. The final integration ratio of the two singlets at −69.42 and −69.28 ppm in the 19F NMR spectrum was 2.8 (de≧47%)* for the major (S,S)-6a and minor (S,R)-6a diastereomers. Proton NMR assignments for these are, respectively: 3.54 and 3.49 (q, CH3O, 5JHF=1.7 Hz), 1.76 and 1.71 (d, CH3CH, 3JHH=7 Hz), 4.89 and 4.91 (overlapping q, CH3CH) and 7.18-7.95 ppm (m, 12 aryl H, not resolved). Note that large crystals of the HBr salt of PROTON SPONGE (12-HBr) separated in the course of this reaction but did not interfere with NMR acquisitions and integrations.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[S:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:27])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Product: COc1ccc(Oc2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 4-methoxy-7-phenoxy-benzothiazol-2-ylamine and 5-methyl-thiophene-2-carboxylic acid chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (1:1), to afford the pure title compound as a pale yellow solid (76% yield), MS: m/e=396.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 2-amino-5-bromo-3-methylbenzoic acid (3.0 g, 13 mmol) from Step A above in DMF was added cesium carbonate (6.4 g, 20 mmol) followed by iodomethane (0.8 ml, 13 mmol). The reaction was stirred at ambient temperature overnight. The mixture was washed with water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo to afford methyl 2-amino-5-bromo-3-methylbenzoate (3.2 g, 100%) as a grey solid: 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=2.4 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 5.84 (brs, 2H), 3.87 (s, 3H), 2.15 (s, 3H); MS (ESI+) m/z 245 (M+H).