Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9](OC1C=CC([N+]([O-])=O)=CC=1)=[O:10].C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>ClCCl.CCOC(C)=O>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][N:44]([C:9]([NH:1][C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[O:10])[CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccncc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccncc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 0° C. under nitrogen, to a solution of 4-aminopyridine (114 mg, 1.21 mmol) and 4-nitrophenyl chloroformate (244 mg, 1.21 mmol) in dichloromethane (5 mL) is added diisopropyl(ethyl)amine dropwise (391 mg, 3.03 mmol). After 10 min, the ice bath is removed, and the reaction mixture is stirred at rt. for an additional hour. After removal of solvent under vacuum, EtOAc (5 mL), diisopropyl(ethyl)amine (261 mg, 2.02 mmol) and 7-chloro-4-(piperazin-1-yl)quinoline (250 mg, 1.01 mmol) are added. The resulting mixture is kept at reflux for about 5 hr, then cooled to rt, diluted with EtOAc (10 mL), and quenched with saturated sodium bicarbonate (5 mL). The aqueous solution is extracted with EtOAc (2×10 mL), and the combined organic phase is washed with brine (10 mL) and dried over sodium sulfate. Removal of solvent followed by purification through flash chromatography with CH2Cl2-MeOH affords the title product.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]([CH2:16][C:17](O)=O)#[N:15].C=O.[C:22](=O)=O>CCOCC.O1CCOCC1>[N:1]1([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][C:16](=[CH2:17])[C:14]#[N:15])[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C=O
Reactant: C1CCN(CC2CCNCC2)CC1
Reactant: N#CCC(=O)O
Agent: C=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCC(CN2CCCCC2)CC1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
4-(1-Piperidylmethyl)piperidine (0.05 mole) was dissolved in 17 ml. of dioxane containing cyanoacetic acid (4.25 g., 0.05 mole) by warming and the solution then cooled to 22° C. Over a 9 minute period, 37% aqueous formaldehyde (8.5 g., 0.1 mole) was dripped in. The temperature throughout the addition was 25°-28° C. It was then warmed to 35°-40° C. for carbon dioxide evolution and maintained then for 2 hours. The mixture was stripped at a bath temperature of 60° C./15 mm. to leave approximately 12 g. of an oil. Most dissolved in 150 ml. of ether; the solution was washed twice with water, dried over anhydrous sodium sulfate and the solvent stripped. A nearly colorless oil was obtained, 8.6 g., which gradually solidified on standing at room temperature.
Reaction SMILES: [F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:23][C:24]([F:29])([F:28])[CH:25]1[O:27][CH2:26]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>C(#N)C>[F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: FC(F)(F)C1CO1
Reactant: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: Oc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Yield: 54.1 %

Procedure:
A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (11.0 g, 34.9 mmol), 3,3,3-trifluoro-1,2-epoxypropane (4.5 mL, 52.4 mmol) and ytterbium trifluoromethanesulfonate (2.2 g, 10 mol %) in 20 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 16 h. The reaction mixture was cooled, water was added, and the reaction mixture was extracted with ether. The ether layer was washed with saturated aqueous sodium bicarbonate and brine and dried over MgSO4. The dried organic layer was evaporated to give 8.07 g (89%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2hydroxypropyl)amino]phenol product as a yellow oil. HRMS calcd. for C18H17F7NO3: 428.1097 [M+H]+, found: 428.1104. 1H NMR (CDCl3) δ3.58 (dd, 1H), 3.88 (dd, 1H), 4.39 (m, 1H), 4.68 (s, 2H), 5.91 (tt, 1H), 6.25-6.37 (m, 3H), 7.07-7.14 (m, 4H), 7.35 (t, 1H).
Reaction SMILES: COC(=O)/C=C/C1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1.[C-:20]#N.[Na+].[C:23]([OH:26])(=[O:25])[CH3:24]>[O-2].[O-2].[Mn+4].CO>[CH3:20][O:25][C:23](=[O:26])[C:24]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: [C-]#N
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CO
Product: COC(=O)c1ccc(Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 300 mg of the aldehyde (prepared as described in Reference Example 1), 370 mg of sodium cyanide, 3.0 g of manganese dioxide, 0.18 ml of acetic acid and 15 ml of methanol was stirred overnight at room temperature, filtered through a pad of infusorial earth, and the filtrate was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The extract was washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:2) as eluent to give 255 mg of the title compound having the following physical characteristics:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C.[N-:18]=[C:19]=[O:20].[K+]>O>[NH:1]([CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:19]([NH2:18])=[O:20]
Reactant: [N-]=C=O
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1
Yield: 73.6 %

Procedure:
37 g (0.2 mole) of para-[N-(β-amino-ethyl)]amino nitrobenzene is dissolved in 200 cm3 of water at 30° C, to which 15 cm3 (0.26 mole) of acetic acid had been added. 17 g (0.21 mole) of potassium isocyanate is then rapidly added. The desired product precipitates immediately in a form which is very difficult to dry. 150 cm3 of acetic acid is added to the reaction mixture and it is heated until the urein is completely dissolved. After slow cooling, drying yields 33 g of para-[N-(β-ureidoethyl)]amino nitrobenzene in a well crystallized form, which is practically prue and melts at 187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([C:16]#[C:17][CH2:18][OH:19])[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][CH2:17][CH2:18][OH:19])[CH:3]=1
Reactant: COc1nc2cc(Cl)cc(C#CCO)c2nc1OC
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)cc(CCCO)c2nc1OC
Yield: 98 %

Procedure:
2.05 g (7.36 mmol) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-prop-2-yn-1-ol are hydrogenated at normal pressure in 20 ml of tetrahydrofuran with approximately 0.4 g of Raney nickel until twice the molar amount of hydrogen has been absorbed. The hydrogenated mixture is filtered with suction over a glass fiber filter and the filtrate is concentrated. 2.04 g (98%) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-propan-1-ol are obtained in the form of beige crystals having a melting point of 104-105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1.O>CN(C)C=O>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][S:6][C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
A solution of tert-butyl {3-[(3-aminobenzyl)thio]phenyl}carbamate (0.55 g, 1.7 mmol) in N,N-dimethylformamide (5.0 mL) was treated with potassium carbonate (0.30 g, 2.2 mmol) and stirred at 25° C. for 5 min. The reaction mixture was treated with 2,4,5-trichloropyrimidine (0.25 mL, 2.2 mmol) and stirred at 25° C. for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude gum. This material was purified by flash column chromatography to give the desired product (0.67 g, 84%) as a solid. LCMS for C22H22Cl2N4O2SNa (M+Na)+: m/z=499.0, 501.0.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C:33]([CH:36]2[O:40][CH2:39][CH2:38][O:37]2)=[CH:34][CH:35]=1)CCC>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[O:32][C:33]([CH:36]5[O:40][CH2:39][CH2:38][O:37]5)=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Yield: 68.1 %

Procedure:
(4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) and tetrakis(triphenylphosphine)palladium(0) (0.26 g) in dimethylacetamide (20 ml) in accordance with Procedure B. Purification via column chromatography, eluting with ethyl acetate, followed by trituration with diethylether afforded a yellow solid (1.4 g); δH [2H6] DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)([OH:3])=O.ClC(OCC(C)C)=O.[OH:27][CH2:28][CH2:29][NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[OH:27][CH2:28][CH2:29][N:30]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)=[O:3]
Reactant: OCCNC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCC(=O)N2
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(OCCCC(=O)N(CCO)C3CCCCC3)ccc2N1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Into 100 ml of chloroform were added 2.5 g of 6-(3-carboxypropoxy)-3,4-dihydrocarbostyril and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 1.5 ml of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation, stirring was continued for 30 minutes and 2.0 g of N-(2-hydroxyethyl)cyclohexylamine was added to the reaction mixture and further stirred at a room temperature for 2 hours. After the reaction was completed, the chloroform solution of the reaction product was washed with a diluted NaHCO3 aqueous solution, a diluted hydrochloric acid and water in this order. The chloroform solution was dried with anhydrous Na2SO4, then the chloroform was removed by distillation and the residue thus obtained was recrystallized from chloroform-petroleum ether to obtain 2.1 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 139°-141.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]nc(I)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (0.219 mL, 1.61 mmol) was added to tert-butyl 4-(3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.575 g, 1.34 mmol) and K2CO3 (0.222 g, 1.61 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 2 hours. Ether (30 mL) and water (10 mL) were added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.59 g, 80%) as a solid. MS APCI (+) m/z 549.7 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.37 (d, J=5.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.53 (s, 2H), 3.70 (s, 3H), 3.62 (m, 4H), 3.19 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[ClH:15].Cl.[Cl:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:17].[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 55.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.1 g of 4-ethoxycarbonylphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-ethoxycarbonylphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 231°-233° C.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[CH3:22][C:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.O>O1CCCC1>[CH3:22][C:23]([NH:26][C:27]([N:15]1[CH2:16][CH:13]([O:12][C:11]2[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)[CH2:14]1)=[O:28])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CC(C)(C)N=C=O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 2 g (0.02 mole) of 1,1-dimethylethyl isocyanate followed in 30 min with 5 ml of triethylamine. The clear solution which developed was stirred for 18 hr. The reaction mixture was treated with 10 ml of water and after 20 min, the tetrahydrofuran portion was separated, dried over magnesium sulfate, and concentrated on a rotary evaporator. The solid residue was recrystallized from ethanol/water, yielding 5.8 g (91.7%) of fine white crystals, m.p. 105°-107° C.
Reaction SMILES: COC(C1SC(C#CC(C)(C)C)=CC=1NC1CC(OCC2C=CC=CC=2)C1)=O.C(N(CC)C(C)C)(C)C.C[C@H]1CC[C@H](C(Cl)=O)CC1.[CH3:48][O:49][C:50]([C:52]1[S:53][C:54]([C:79]#[C:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[CH:55][C:56]=1[N:57]([CH:67]1[CH2:70][CH:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:68]1)[C:58]([C@H:60]1[CH2:65][CH2:64][C@H:63]([CH3:66])[CH2:62][CH2:61]1)=[O:59])=[O:51]>ClCCCl>[CH3:48][O:49][C:50]([C:52]1[S:53][C:54]([C:79]#[C:80][C:81]([CH3:82])([CH3:84])[CH3:83])=[CH:55][C:56]=1[N:57]([CH:67]1[CH2:70][CH:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[CH2:68]1)[C:58]([C@H:60]1[CH2:65][CH2:64][C@@H:63]([CH3:66])[CH2:62][CH2:61]1)=[O:59])=[O:51]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CC(OCc2ccccc2)C1
Agent: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CC(OCc2ccccc2)C1
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@@H](C)CC1)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(3-benzyloxy-cyclobutylamino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.26 g, 3.17 mmol) and N,N-diisopropylethylamine (2.4 mL, 13.8 mmol) in DCE (8 mL) was treated with trans-4-methyl-cyclohexanecarbonyl chloride and heated to 100 deg C. for 5 hours. The reaction mixture was cooled to room temperature, adsorbed onto silica, and purified by silica gel chromatography (0-30% ethyl acetate:hexanes). This resulted in 590 mg (36% yield) of cis-cyclobutyl isomer (cis-3-[(3-benzyloxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester) and 230 mg (14% yield) of the trans-cyclobutyl isomer (trans-3-[(3-benzyloxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C(C)=CC=CC=1.[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Cl)[CH:24]=1)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=1)(=[O:20])[CH3:19]
Reactant: Oc1ccccc1
Reactant: CC(=O)OCc1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 73 %

Procedure:
18.07 g. (0.192 mole) of phenol, 8.42 g. (0.15 mole) of potassium hydroxide and 20 cm3 of xylene are weighed together. The water is azeotropically distilled with stirring and boiling then the xylene is also distilled. To the reaction mixture 1.0 g. of copper(I) chloride and 1.0 g. of activated copper are added and in oil bath of 160° C. 18.07 g. (0.1 mole) of 3-chlorobenzyl acetate are dropped during 70 minutes then stirred at the same temperature for four hours. After cooling 25 cm3. of toluene are added to the reaction mixture, then the reaction mixture is filtered off and washed with 25 cm3. of toluene. The filtrate is washed with a mixture of 30 cm3. 15% sodium chloride solution and 2 cm3. 40% sodium hydroxide solution. The organic phase is evaporated and the residue is distilled in vacuo. 17.68 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 138°-144° C./40 Pa, nD20 : 1.562, yield 73%.
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[CH2:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>COCCO.O>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(N)cc1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Solvent: O
Solvent: COCCO
Product: CCCCc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cc1
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
A stirred solution of 2-bromohypoxanthine (10.8 g, 50 mmol) and p-n-butylaniline (23.5 mL, 150 mmol) in a mixture of 2-methoxyethanol (300 mL) and water (100 mL) was heated at reflux. After 2.5 h, the mixture was chilled in an ice bath, and the fine precipitate was filtered, washed with concentrated aqueous ammonia (80 mL) and methanol (3×25 mL). The product was purified by dissolving the slightly yellow precipitate in hot N sodium hydroxide (300 mL) and treatment with activated charcoal. The hot mixture was filtered, acidified with glacial acetic acid and chilled. The product was isolated by filtration, washed with methanol and dried over phosphorus pentoxide to yield 12.0 g (85%) of fine colorless crystals, identical with an authentic sample. NMR (250 MHz; Me2SO-d6) 10.45 δ(s, 1-H), 8.60 δ(s, 2-NH), 8.00 δ(s, 8-H), 7.50 δ(d, J+8.5 Hz, 2',6'-H), 7.14 δ(d, J=8.5 Hz, 3',5'-H), 2.55 δ(t, CH2), 1.56 δ(quin, CH2), 1.33 δ(sext, CH2), 0190 δ(t, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:40][C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[NH2:43]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[F:40])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Nc1ccccc1F
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccccc4F)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (8 mL) was added 2-fluoroaniline (68.4 mg, 0.615 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (191 mg) as a yellow solid. LC-MS (ES) m/z=435 [M+H]+.