Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([OH:17])=O)[N:9]=2)=[CH:4][C:3]=1[C:18](=[O:29])[NH:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.ON1C2C=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=N1.N1CCCC1.CN(C1C=CC=CN=1)C.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15](=[O:17])[N:33]3[CH2:34][CH2:39][CH2:38][CH2:37]3)[N:9]=2)=[CH:4][C:3]=1[C:18]([NH:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:29]
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CC(=O)O
Reactant: On1nnc2ccccc21
Agent: CC[NH+](CC)CC
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
To a solution of (3-{4-chloro-3-[(1-hydroxy-cycloheptylmethyl)-carbamoyl]-phenyl}-5-methyl-pyrazol-1-yl)-acetic acid (41.9 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was added a solution of 1-hydroxybenzotriazole (20.25 mg, 0.15 mmol) in N,N-dimethylformamide (0.5 mL) and carbonyldiimidazole on polystyrene (294 mg, 0.3 mmol). The mixture was shaken at room temperature for 10 minutes. Pyrrolidine (10.65 mg, 0.15 mmol) was added as a solution in N,N-dimethylformamide (1.5 mL). Polystyrene supported dimethylaminopyridine (152 mg, 0.22 mmol) was added and the mixture was shaken at room temperature for 16 h. MP-carbonate resin (139 mg, 0.4 mmol) was added and the mixture was shaken at room temperature for 3 h. The mixture was filtered, washed with methanol and concentrated in vacuo. The residue was purified by reverse phase chromatography to afford the title compound (22 mg). LCMS (m/z) 473.4 M+1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[NH2:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O>>[Cl:27][C:25]1[CH:26]=[C:18]2[C:19]([C:20](=[O:22])[N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[C:15](=[O:16])[NH:17]2)=[CH:23][CH:24]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: COC(=O)c1ccc(S(=O)(=O)N=C=O)cc1
Product: COC(=O)c1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 58.8 %

Procedure:
1.12 g (4.65 mmol) of 4-methoxycarbonylbenzenesulfonylisocyanate and 798 mg (4.65 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.08 g of the above-identified compound (yield 58.9%). Properties: colorless crystal, Melting point: >230° C., PMR (δppm, DMSO-d6): 3.91 (3H,s), 7.13 (1H,s), 7.23 (1H,d), 7.86 (1H,d), 8.20 (2H,d), 8.29 (2H,d), 11.80 (1H,br).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[OH:11].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[OH:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH2:9][NH:8][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: COc1cccc(C(O)CN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCC(O)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (52 ml, 0.37 mol) was added to the amine from example 1 (31.3 g, 0.19 mol) in dichloromethane (400 ml) and reaction mixture stirred under an atmosphere of nitrogen gas at 0° C. for 10 minutes. Propionyl chloride (16.3 ml, 0.19 mol) was added and after stirring for 30 minutes, the reaction temperature was raised to room temperature for a further 5 hours. The reaction mixture was quenched 1 N HCl (aq) (100 ml) and then extracted with dichloromethane (2×50 ml). The organic fractions were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a colourless oil that crystallised on standing to white crystals (28 g, 0.13 mol, 67%). 1H NMR (CDCl3, 400 MHz) δ: 1.18 (t, 3H), 2.22 (q, 2H), 2.51 (bs, 1H), 3.31 (m, 1H), 3.71 (dd, 1H), 3.80 (s, 3H), 4.81 (m, 1H), 5.95 (bs, 1H), 6.80 (d, 1H), 6.90 (d, 1H), 6.91 (s, 1H), 7.22 (t, 1H). LRMS: m/z 224. Mpt: 77-78° C. Analysis found C, 63.86; H, 7.82; N, 6.28%. C12H17NO3.0.1H2O requires C, 64.04; H, 7.70; N, 6.22%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[H][H]>CCO.[Pd]>[F:13][C:2]([F:1])([F:12])[C@H:3]1[CH2:4][CH2:5][NH:6][CH2:7][C@H:8]1[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@@H]1CNCC[C@@H]1C(F)(F)F
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A solution of 4-(trifluoromethyl)nicotinic acid (1.50 g, 7.85 mmol) in EtOH (78 mL) was passed through an H-cube™ equipped with a ThalesNano CatCart® 10 wt % Pd/C catalyst cartridge at about 1.0 mL/min, at about 80° C., under about 1305 psi of hydrogen. After about 3 h, the solvent was removed under reduced pressure to afford cis-4-(trifluoromethyl)piperidine-3-carboxylic acid (1.55 g, 100% crude): LC/MS (Table 1, Method b) Rt=0.54 min; MS m/z: 198 (M+H)+.
Reaction SMILES: Cl.[C:2]([CH2:4][CH:5]1[CH2:13][CH:12]2[CH:8]([CH2:9][NH:10][CH2:11]2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:6]1)#[N:3].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[C:2]([CH2:4][CH:5]1[CH2:13][CH:12]2[CH:8]([CH2:9][N:10]([C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:11]2)[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([OH:14])[CH2:6]1)#[N:3]
Reactant: COc1ccccc1CC(=O)O
Reactant: N#CCC1CC2CNCC2C(O)(c2ccccc2)C1
Agent: Cl
Product: COc1ccccc1CC(=O)N1CC2CC(CC#N)CC(O)(c3ccccc3)C2C1
Yield: 64.3 %

Procedure:
The procedure is as described in Example 14 beloW, starting from 0.63 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenylperhydroisoindol-4-ol hydrochloride and 0.39 g of 2-methoxyphenylacetic acid, and gives 0.56 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenyl-2-(2-methoxyphenylacetyl)perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:38]=[CH:37][C:12]2[N:13]([C:20]3[CH:25]=[N:24][C:23]([NH:26][C:27](=[O:36])[C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])=[CH:22][N:21]=3)[C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:11]=2[CH:10]=1)=[O:8])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[F:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([F:35])[C:28]=1[C:27]([NH:26][C:23]1[CH:22]=[N:21][C:20]([N:13]2[C:12]3[CH:37]=[CH:38][C:9]([C:7]4[O:8][CH:4]=[CH:5][N:6]=4)=[CH:10][C:11]=3[N:15]=[C:14]2[C:16]([F:19])([F:18])[F:17])=[CH:25][N:24]=1)=[O:36]
Reactant: CCOC(CNC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1)OCC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C(Nc1cnc(-n2c(C(F)(F)F)nc3cc(-c4ncco4)ccc32)cn1)c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 3 h

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 0.09 mmol, 1.00 equiv) in CH3SO3H (3 g). To the mixture was added P2O5 (80 mg, 0.56 mmol, 5.00 equiv). The resulting solution was allowed to stir at 130° C. for 3 h, then was diluted with ice water and extracted three times with 150 mL of EtOAc. The organic layers were combined and dried over Na2SO4. After removal of the solvent and volatile components, the residue was purified by eluting through a silica gel column with first a 1:3 and then 1:2 EtOAc/PE solvent system to provide 2,6-difluoro-N-[5-(5-oxazol-2-yl-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide 9 Compound 153) (5 mg, 12% yield) as a white solid. 1H NMR (300 Hz, DMSO-d6): δ 7.12 (t, 2H, J=9), 7.28-7.30 (m, 1H), 7.46 (d, 1H, J=9), 7.54-7.59 (m, 1H), 7.79 (s, 1H), 8.25 (d, 1H, J=9), 8.58 (s, 1H), 8.64 (s, 2H), 9.84 (s, 1H) ppm; ESMS calcd for C22H11F5N6O2: 486; found: 487 (M+H).
Reaction SMILES: CS[C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[NH2:16].Cl.N1C=CC=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:3]2[C:4]3[NH:11][N:10]=[CH:9][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CSc1ncnc2cn[nH]c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Fc1cccc(COc2ccc(Nc3ncnc4cn[nH]c34)cc2Cl)c1
Temperature: 120 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (known compound from literature: J. Am. Chem. Soc., 1956, 78, 2418) (150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridine hydrochloride (156 mg) in 1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 10 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/3→1/10) to give the title compound (220 mg, yield 61%) as a pale-yellow solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1.CO.[H][H]>[OH-].[Pd+2].[OH-].O1CCCC1>[C:23]1([CH2:22][CH2:21][S:18]([N:15]2[CH2:14][CH2:13][CH:12]([CH2:11][NH2:10])[CH2:17][CH2:16]2)(=[O:19])=[O:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: O=C(NCC1CCN(S(=O)(=O)C=Cc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
A mixture of [1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzyl ester (2.5 g), 20% palladium hydroxide (1 g) on carbon, 200 mL of methanol and 50 mL of tetrahydrofuran were shaken under 50 psi of hydrogen for 2 days at room temperature. The catalyst was filtered off and washed with 250 mL of methanol. Concentration under reduced pressure gave C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine as white solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[C:12]=1[B:19]([OH:24])[OH:20]
Reactant: CCCCCc1cc(F)cc(F)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1cc(F)c(B(O)O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of n-butyllithium (10.4M in hexane; 2.70 ml, 0.028 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 13 (5.00 g, 0.027 mol) in dry THF (60 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and a previously cooled solution of tri-isopropyl borate (10.22 g, 0.054 mol) in dry THF (50 ml) was added dropwise at -78° C. The stirred mixture was allowed to warm to room temperature overnight and stirred for 1 h with 10% hydrochloric acid (30 ml). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([CH3:42])[CH3:41])(=O)=O>>[Br:21][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:39][C:40]([F:43])([CH3:42])[CH3:41])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1ncc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(F)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A vial was charged with (S)-2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-3-ol (750 mg, 2.154 mmol), DMF (8617 μL, 2.154 mmol) and cesium carbonate (2106 mg, 6.46 mmol). The mixture was cooled to 0° C. and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (966 mg, 4.31 mmol) was added. The reaction was removed from the ice bath and stirred at RT for 45 minutes. The reaction was diluted with water (250 mL) and poured into a separatory funnel containing ethyl acetate (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a light yellow solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-bromo-3-(2-fluoro-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>[Cu]I.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.C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([C:27]#[C:26][CH2:25][OH:28])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (330 mg, 0.74 mmol), CuI (3 mg, 0.01 mmol) and (Ph3P)2PdCl2 (104 mg, 0.01 mmol) were dissolved dry THF (2 mL) in a flask which was then flushed with nitrogen. A solution of propargyl alcohol (47 mg, 0.81 mmol) in TEA (2 mL) was added to the reaction, which was stirred at R.T. for 15 h. The solvent was removed under reduced pressure, then the residue purified by chromatography on silica gel (10% MeOH/CH2Cl2 as eluant), giving 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a viscous, transparent oil (44%). 1H NMR [(CD3)2SO, 400 MHz] δ 11.50 (v br s, 1H), 9.60 (s, 1H), 8.16 (s, 1H), 7.49 (t, J=8.3 Hz, 1H), 7.40 (dd, J=10.1, 1.9 Hz, 1H), 7.28 (dd, J=8.3, 1.4 Hz, 1H), 5.67 (s, 1H), 5.37 (t, J=5.1 Hz, 1H), 4.73 (br s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.91 (t, J=4.8 Hz, 2H), 3.62 (br t, J=4.8 Hz, 2H), 3.36 (s, 3H). LCMS (APCI+) calcd for C18H19N3O5F 376 (MH+), found 376.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](O)[CH:11]=[C:10]([CH:15]([CH3:17])[CH3:16])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[CH:11]=[C:10]([CH:15]([CH3:17])[CH3:16])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(O)nc(-c2ccc(Cl)cc2)n1
Product: CC(C)c1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C

Procedure:
The mixture of 12 g of 2-(4-chlorophenyl)-4-hydroxy-6-isopropylpyrimidine and 35 ml of phosphorus oxychloride was heated at 90° C. for 3 hours with stirring. Most of the excess of the phosphorus oxychloride was distilled off in vacuo, and the residue was added to 100 ml of ice water and stirred. The solid white precipitate forming was filtered off with suction and dried in vacuo at room temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:11][CH3:12])[C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[C-:16]#[N:17].[Na+]>CN(C)C=O.O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:11][CH3:12])[C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1)#[N:17]
Reactant: CCOC1Oc2ccc(Br)cc2C1(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1Oc2ccc(C#N)cc2C1(C)C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-ethoxybenzofuran (4.7 g, 0.017 mole) was heated under reflux with cuprous cyanide (2.7 g, 0.03 mole) in dimethyl formamide (10 ml) as in example 2 for 3 hours. A warm solution of sodium cyanide (5 g) in water (20 ml) was added with stirring and stirring was continued for 1 hour at ambient temperature. The solution was diluted with water and extracted with ether. The extracts were washed with water, dried over magnesium sulphate and run down yielding 3.6 g crude product. Purification was accomplished by silica gel chromatography in 1:4 ether/petroleum ether (b.p. 40°-60° C.). The yield of pure title product was 2.9 g (79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCI
Reactant: COC(=O)Cc1ccc(O)cc1
Product: CCCCCCCCCCOc1ccc(CC(=O)OC)cc1

Procedure:
First, a dibenzyl ketone having the alkoxy (OC10H21) groups is prepared to produce the polyphenylene (a). Specifically, 4-hydroxybenzeneacetic acid methyl ester is reacted with 1-iododecane to obtain 4-decyloxybenzeneacetic acid methyl ester as shown in the following reaction formula (32).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]2[N:3]=1.N>ClCCl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]2[N:3]=1
Reactant: CC(C)c1nc2nc(Cl)c(-c3ccccc3)c(Cl)n2n1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nc2nc(Cl)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.00 g 5,7-dichloro-2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine is dissolved in 360 ml dichloromethane. 360 ml brine, 120 ml ammonia solution 25% w/w and 6.00 g zinc powder are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is filtrated over kieselgur and is washed with dichloromethane and water. The organic phase is separated and the water phase is extracted with dichloromethane. The combined dichloromethane phase is dried over Na2SO4 and evaporated. The crude product contains 5,7-dichloro-2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine. The crude product is dissolved again in dichloromethane. 360 ml brine, 120 ml ammonia solution 25% w/w and 6.00 g zinc powder are added and the mixture is stirred at room temperature for 2 h. The reaction mixture is filtrated over kieselgur and washed with dichloromethane and water. The organic phase is separated and the water phase is extracted with dichloromethane. The combined organic layers are dried over sodium sulphate and the solvent is evaporated. The product is used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:20]C(=O)C)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1(CCCC2C=C(N)C=C(C(F)(F)F)C=2)CCCCC1>>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1
Agent: Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Product: Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1

Procedure:
3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine was prepared from N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide similar to that described in the preparation of 3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OCCN1CCOCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCN1CCOCC1
Yield: 85.6 %

Procedure:
2-[2-(4-Morpholinyl)ethoxy]benzaldehyde (55.9 g) is reacted with 29 g of phenethylamine in 240 ml of toluene following the procedure described in Example 1A to yield 68.8 g of product as an oil, boiling point 204°-210° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[C:69]([C:70]2[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][CH:71]=2)=[N:68][N:67]=[N:66]1>C(Cl)Cl>[NH:68]1[C:69]([C:70]2[CH:75]=[CH:74][C:73]([NH:76][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]3)=[O:30])=[CH:72][CH:71]=2)=[N:65][N:66]=[N:67]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-(1H-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24 g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.