Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=2)[NH:10][CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH2:12][CH:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCCC(c2ccccc2)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(NCCC(c2ccccc2)c2ccccc2)c2cccc(N)c2)cc1
Yield: 81 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(3,3-diphenylpropyl)amine (3.53 g) [prepared as described in step (a) above] in ethanol (70 ml), nickel chloride hexahydrate (3.71 g) and sodium borohydride (1.18 g) were reacted, to afford the title compound (2.67 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](I)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>>[C:22](/[CH:23]=[CH:24]/[C:17]1[CH:16]=[N:15][C:9]2[N:10]([CH2:13][CH3:14])[C:11]3[N:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N:6]([CH3:21])[C:7](=[O:20])[C:8]=2[CH:18]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: C=CC(=O)OCC
Product: CCOC(=O)/C=C/c1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Yield: 74.9 %

Procedure:
2-Chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.6 g, 1.45 mmol) was coupled with ethyl acrylate (0.19 mL, 1.75 mmol) by a procedure analogous to that described in Example 1h to give 0.42 g of the title compound as beige crystals, m.p. 192°-193° C. (ethyl acetate/hexanes). Hydrogenation, as described in Example 15, gave 0.22 g of a mixture of reduction products, which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:35][CH2:34][CH:33]([CH:36]([CH3:38])[CH3:37])[C@H:9]1[C:10]([N:12]1[CH2:32][CH2:31][CH2:30][C@H:13]1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH:29]=[N:28][CH:27]=[N:26]1)=[O:15])=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[CH:36]([CH:33]1[CH2:34][CH2:35][NH:8][C@@H:9]1[C:10]([N:12]1[CH2:32][CH2:31][CH2:30][C@H:13]1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH:29]=[N:28][CH:27]=[N:26]1)=[O:15])=[O:11])([CH3:38])[CH3:37]
Reactant: CC(C)C1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C1CCN[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Reaction time: 1 h

Procedure:
To a stirred solution of diastereomer A of 1-(tert-butoxycarbonyl)-3-isopropylprolyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (96 mg, 0.18 mmol) in dioxane (5.0 mL) was added 4.0 N HCl in dioxane in excess. After 1 h, the solvent was removed in vacuo to give the HCl salt of the title compound as a yellow solid. LCMS (M+H): 445.3. 1H NMR (CD3OD, 400 MHz): δ 9.05 (s, 1 H), 8.38 (s, 1 H), 7.71 (s, 1 H), 7.51–7.45 (m, 2 H), 4.48–4.42 (m, 2 H), 4.39 (d, J=16.0 Hz, 1 H), 4.24 (d, J=16.4 Hz, 1 H), 3.79–3.48 (m, 3 H), 3.37–3.31 (m, 1 H), 2.44–2.39 (m, 1 H), 2.38–2.23 (m, 1 H), 2.16–2.11 (m, 1 H), 2.09–1.84 (m, 4 H), 1.79–1.71 (m, 1 H), 1.07 (d, J=6.8 Hz, 3 H), 1.01 (d, J=6.4 Hz, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([CH3:22])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.C(O)C.O.S([O-])(O)(=O)=O.[K+]>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:3]([OH:23])=[O:2])=[CH:13][C:14]=1[CH3:22])(=[O:20])=[O:19]
Reactant: COC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(C)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(CC2CCOCC2)C(=O)O)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
2-(4-Methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (1.30 g, 3.82 mmol) was dissolved in tetrahydrofuran:ethanol:water (6:3:2) reaction (50 mL) and treated with lithium hydroxide monohydrate (800 mg, 19.1 mmol) at 25° C. It was stirred at 25° C. for 2 h. The reaction was then diluted with a 1 M aqueous solution of potassium hydrogen sulfate (100 mL) and then extracted with ethyl acetate (1×200 mL), the organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 10% methanol/ethyl acetate) to afford 2-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (1.15 g, 92%) as a colorless oil.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[CH3:10][C:11]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24](OCC)=[O:25])=S)=[CH:16][C:15]=1[F:29].[NH:35]1[CH:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[N:36]1.C(Cl)Cl>ClCCCl.Cl[Ti](Cl)(Cl)Cl.CCO>[CH3:10][C:11]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]2[C:17](=[CH:16][C:15]=1[F:29])[N:20]=[C:21]([N:35]1[CH:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[N:36]1)[NH:23][C:24]2=[O:25]
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2c(C)cccc2C)c(F)c1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(F)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.3 %

Procedure:
Neat diisopropylcarbodiimide (45.4 g, 290 mmol) was added to a solution of 1-(4-(2,6-dimethylphenoxy)-3-fluorophenyl)-3-ethoxycarbonylthiourea (100 g, 276 mmol), ethyl pyrazole-4-carboxylate (45.4 g, 290 mmol), and DCM (1 L). The solution was maintained at rt for 24 h, then concentrated. The residue was stirred with ether (500 mL) for 3 h in an ice bath, then filtered. The filtrate was concentrated to a thick orange oil (180 g, ca. 70% purity, 97%). A portion of this material (20 g, ca. 30 mmol) was dissolved in DCE (150 mL), then neat TiCl4 was added. The mixture was then heated to reflux for 6 h, then cooled in an ice bath. EtOH (750 mL) was added, and the mixture was stirred for 3 h. The resulting precipitate was collected by filtration, washed with cold EtOH, and dried to provide the titled compound (3.9 g, 31%). 1H NMR (500 MHz, DMSO): 13.03 (s, 1H), 8.95 (d, J=0.6 Hz, 1H), 8.29 (s, 1H), 7.75 (d, J=11.5 Hz, 1H), 7.31-7.24 (m, 2H), 7.22 (dd, J=8.5, 6.4 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.11 (s, 6H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[N:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: COc1ccc2nccc(Br)c2c1
Product: COc1ccc2nccc(N3CC[C@H](N)C3)c2c1

Procedure:
Starting from (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercial) and 4-bromo-6-methoxy-quinoline (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a brown oil (801 mg, 78% over two steps).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[S:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:15]2/[C:14](=[O:16])[NH:13][C:12](=[O:17])[S:11]/2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: CSc1nccc(C=O)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1nccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A 40 mL round-bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80° C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][NH:7][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)(=[O:30])=[O:29])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccccn2)CC1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
Pyridine (1.85 ml) was added to a stirred solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (4.46 g) and pyridine-2-sulphonyl chloride (3.7 g) in dichloromethane (110 ml) at -10° C. under a nitrogen atmosphere. The reaction was then warmed to ambient temperature over 16 hours and poured into water (300 ml). The organic layer was separated and further washed with hydrochloric acid (1 M, 2×200 ml), saturated aqueous sodium bicarbonate solution (200 ml) and brine (200 ml). After drying over anhydrous magnesium sulphate, the solution was evaporated to dryness to afford N-{[1-(tert-butoxycarbonyl)-4-piperidyl]methyl}pyridine-2-sulphonamide (3.5 g) as an oil.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:22]=4[C:23]([CH2:38][CH3:39])=[N:24][N:25]5[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=4)=[O:19])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.[ClH:41]>O.FC(F)(F)C(O)=O.O1CCOCC1.C(OCC)C.ClCCl.CO>[ClH:41].[ClH:41].[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH2:38][CH3:39])=[N:24][N:25]4[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:19])=[CH:16][N:17]=[C:11]2[CH:10]=1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCC5COC(C)(C)O5)ccn34)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCC(O)CO)ccn34)c12
Reaction time: 16 h

Procedure:
A solution of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (77 mg, 0.142 mmol) in water (4 mL), trifluoroacetic acid (4 mL) and 1,4-dioxane (1 mL) was stirred for 1 hour at ambient temperature. The mixture was concentrated under reduced pressure to give a residual oil. The oil was dissolved in a mixture of diethyl ether, dichloromethane and methanol. A solution of hydrogen chloride (0.5 mL; 4M in 1,4-dioxane) was added. The mixture was concentrated under reduced pressure and placed under high vacuum for 16 hours to provide 7-(2,3-dihydroxypropoxy)-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (74 mg) as a beige solid. MS (APCI), positive scan, m/z=501.2 (M+H).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=1.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:16][C:17]1[C:22]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1nc(N)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cccnc2F)n1
Temperature: 100 °C

Procedure:
1,4-Dioxane (6.00 mL, 2927 μmol) was added to a mixture of 4-chloro-6-methyl-1,3,5-triazin-2-amine (423.1 mg, 2927 μmol), 2-fluoropyridin-3-ylboronic acid (619 mg, 4390 μmol), bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (91.0 mg, 146 μmol) and potassium acetate (862 mg, 8780 μmol) and the mixture was heated at 100° C. overnight. After cooling, the mixture was passed through a short plug of Celite® (diatomaceous earth). The filter cake was washed with EtOAc (3×15 mL). The combined organic phases were concentrated to give a crude residue. Flash column chromatographic purification (short column, SiO2, pure DCM to 3% MeOH in DCM) provided the title compound which was washed with MeOH to give 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (454 mg, 76%) as a pale brown powder. LCMS (API-ES) m/z 206 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.48 (ddd, J=9.91, 7.65, 2.01 Hz, 1H) 8.39 (d, J=5.02 Hz, 1H) 7.65 (br. s., 2H) 7.51 (ddd, J=7.15, 5.14, 1.76 Hz, 1H) 2.37 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-:11].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N.O.CCOC(C)=O>[F:11][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CF)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 2-bromoacetophenone (Aldrich Chemical Company) (5.42 g, 27.3 mmol), KF (6.32 g, 0.11 mol) and 18-crown-6 (3.61 g, 13.7 mmol) in CH3CN (150 mL) was heated at 90° C. for 16 h under a N2 atmosphere. Heating was discontinued and the mixture was allowed to cool to room temperature. The mixture was diluted with H2O (300 mL) and EtOAc (400 mL) and transferred to a separatory funnel. The organic solution was separated, washed with H2O (2×300 mL), saturated NaCl (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The resulting crude ketone (3.02 g) was used without further purification (see Gregory et al. J. Med. Chem. 1990, 33 (9), 2569).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27]I>O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[C:17]2=[O:26])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)N(C2CCN(Cc3ccccc3)CC2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g sodium hydride (60% oil dispersion) was added to 7 g 3-(1-benzyl-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one at 0° C. under nitrogen. The reaction was stirred at RT for 1 h and 1.5 mL methyliodide was added. The reaction was stirred 1 h at RT and poured into 600 mL water. The water layer was extracted with ethyl acetate. The organic layer was dried and evaporated to give 7.3 g of the desired product.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:42][CH:41]=4)=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:42][CH:41]=4)=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)OC(C)(C)C)C4)cc3)nc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)O)C4)cc3)nc2)cc1
Reaction time: 4 h
Yield: 97.2 %

Procedure:
Prepared using General Procedure 8: To a stirred solution of tert-butyl (S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (188 mg, 0.26 mmol), in DCM (2 mL) was added TFA (2 mL). The mixture was stirred for 4 h then concentrated. The resulting solid was dissolved in DCM (10 mL) and concentrated (5×) to remove excess TFA, affording 169 mg (98%) of 1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid 798 as a yellow solid. LCMS-ESI (m/z) calculated for C38H44N4O5S: 668.85. found 669.3 [M+H]+, tR=9.121 min (Method 16). 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 2H), 8.12 (d, J=7.8 Hz, 2H), 7.58 (m, 3H), 7.45 (m, 1H), 7.42 (m, 2H), 7.06 (m, 2H), 6.84 (m, 1H), 4.71 (d, J=7.7 Hz, 1H), 4.33-4.14 (m, 2H), 4.08 (dd, J=19.8, 9.1 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 3.30 (dd, J=12.5, 4.2 Hz, 1H), 3.06 (t, J=11.9 Hz, 1H), 2.91 (s, 1H), 1.91-1.76 (m, 2H), 1.64 (dt, J=13.0, 6.6 Hz, 1H), 1.43-1.33 (m, 11H), 0.95 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl>[Pt]=O.CO>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Cc1c(-c2ccncc2)cccc1S(C)(=O)=O
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O

Procedure:
Preparation according to preparation 9: 4-[2-methyl-3-(methylsulfonyl)phenyl]pyridine (0.4 g, 1.6 mmol), methanol (10 ml), platinum oxide (0.10 g), hydrochloric acid (0.1 ml, conc). Yield: 0.41 g. MS m/z (rel. intensity, 70 eV) 247 (M+, 96), 246 (51), 168 (53), 167 (bp), 139 (51).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN(CCCN2CN(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)CC1

Procedure:
The title compound, MS: m/e=612.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-methylpiperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:28][C:29]([S@:32]([NH2:34])=[O:33])([CH3:31])[CH3:30].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)/[CH:5]=[N:34]/[S@@:32]([C:29]([CH3:31])([CH3:30])[CH3:28])=[O:33]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 3,5-difluorobenzaldehyde (1.00 g, 7.04 mmol, 1.00 equiv) in CH2Cl2 (20 mL) were added pyridinium p-toluenesulfonate (0.089 g, 0.35 mmol, 0.05 equiv), (R)-(+)-2-methylpropane-2-sulfinamide (0.852 g, 7.03 mmol, 1.00 equiv), and MgSO4 (4.2 g, 35.00 mmol, 5.00 equiv). The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether) to provide 500 mg (29%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-:30].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23]([OH:30])=[O:24])[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CCO)c12
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of 2-[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol (861 mg, 1.75 mmol) in methanol (5 mL) was added 8N aqueous sodium hydroxide (1.5 mL), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, followed by neutralization with 6N hydrochloric acid. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give 781 mg (1.73 mmol, 99.1%) of the title compound as an amorphous.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][C:26](=[O:37])[NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].CC(O)=O.[Na]>ClCCCl.O>[C:21]([O:25][C:26](=[O:37])[NH:27][C@H:28]1[CH2:29][CH2:30][C@H:31]([CH2:34][CH2:35][N:18]2[CH2:17][CH2:16][N:15]([C:7]3[CH:8]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[N:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=3)[CH2:20][CH2:19]2)[CH2:32][CH2:33]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: COCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)CC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-tert-butyl-4-(2-methoxy-ethyl)-6-piperazin-1-yl-pyrimidine (500 mg, 1.796 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (433 mg, 1.796 mmol) and AcOH (108 mg, 1.796 mmol) in DCE (30 ml) was stirred at room temperature for 10 min. Sodium triacetoxyhydroborate (571 mg, 2.69 mmol) was added. After 4 h, water was added. The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the yellow title compound (900 mg, 1.680 mmol, 94% yield) which was used next step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH:13][NH2:14])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: O
Solvent: CCO
Product: NNc1ncccc1C(F)(F)F

Procedure:
A solution of 200 g of 2-chloro-3-trifluoromethylpyridine in 500 ml of ethanol and 300 ml of hydrazine hydrate is heated under reflux for 6 hours. The solution is then concentrated in vacuo and, after cooling, the crystalline residue is then taken up with water, filtered off, washed with water and dried to give 145 g of 3-trifluoromethyl-2-hydrazinopyridine in the form of crystals melting at 72° C.