Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:63][C:64]([C@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)=[O:65]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@@H:66]1[C:64]([NH2:63])=[O:65])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: NC(=O)[C@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3C(N)=O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-(aminocarbonyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH:33]([OH:41])[CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: OC1CNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12)N1CC(O)C1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (30 mg, 0.090 mmol) was added CDI (29 mg, 0.18 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (20 mg, 0.18 mmol) was added in one portion, followed by addition of DIEA (0.047 mL, 0.27 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 85% yield). MS (apci) m/z=431.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1.COCCOC>CCOC(C)=O.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>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:19]2[CH:20]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:7][C:6]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(C)cc(-c2cncnc2)nc1C
Temperature: 90 °C
Yield: 85 %

Procedure:
To a solution of 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester (0.30 g, 1.40 mmol) and 5-pyrimidine boronic acid (0.522 g, 4.21 mmol) in argon-degassed DME/2 M Na2CO3 (4:1, 12.5 ml) was added Pd(PPh3)4 (162 mg, 0.14 mmol) and the mixture heated to 90° C. overnight. The reaction was cooled, diluted with EtOAc (25 ml) and H2O (15 ml). The aqueous layer was extracted with EtOAc (2×10 ml) and the combined organic extracts were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 3:2) to afford 2,4-dimethyl-6-pyrimidin-5-yl-nicotinic acid ethyl ester (306 mg, 85%). 1H NMR (CDCl3) δ 1.43 (t, 3H, J=6 Hz), 2.44 (s, 3H), 2.64 (s, 3H), 4.47 (q, 2H, J=6 Hz), 7.44 (s, 1H), 9.26 (s, 1H), 9.32 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]2[NH:21][C:26](=[O:27])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 5-chloro-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-trifluoromethyl-1,2-benzenediamine (D52) (0.34 g, 0.9 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with carbonyl diimidazole (0.29 g, 1.80 mmol)—added in portion over 5 minutes. The mixture was stirred at room temperature under argon for 4 hours. The mixture was warmed to a gentle reflux. After 18 hours, a further 0.29 g, 1.8 mmole of carbonyl diimidazole was added and the mixture maintained at reflux for another 24 hours. The mixture was cooled to room temperature and was treated with ethyl acetate (40 ml) and washed with water and brine then dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 1 to 10% methanol in dichloromethane to afford 6-chloro-5-trifluoromethyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was subsequently converted to the hydrochloride salt and isolated as a cream powder. 0.25 g, 73%. MH+=404 and 406
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2Br)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:44][S:45]([C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][CH:53]=1)(=[O:47])=[O:46].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[C:52]2[CH:51]=[CH:50][CH:49]=[C:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH:53]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Cl)ccc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Cl)ccc4-c4cccc(S(C)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-5-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (285 mg, 1.43 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol) and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction was heated to 90° C. for 2 h, then cooled to RT, concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.N>Br>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: Br
Agent: N
Solvent: O
Product: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 95.6 %

Procedure:
The product from step (i) (1.5 g) in concentrated hydrobromic acid (30 ml) was heated under argon at 130°-135° C. for 2 1/2 hours. The solution was cooled, poured into water (150 ml) and basified with aqueous ammonia. The precipitate was filtered, washed with water and dried to give 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.36 g) as a solid: m.p. 310°-312° C.; NMR(d6DMSO) δ 8.2(2H,d); 6.8(4H,m); 6.66(2H,d); 3.45(4H,m); 3.08(4H,m).
Reaction SMILES: [ClH:1].Cl.N([C:11]([C:14](=[NH:16])N)([CH3:13])C)=N[C:5]([C:8](=N)[NH2:9])(C)[CH3:6].[CH3:17][C:18]([CH3:20])=O>>[ClH:1].[CH:18]([CH:13]=[CH:11][CH2:14][NH2:16])([CH3:20])[CH3:17].[ClH:1].[CH2:17]([NH:9][CH2:8][CH:5]=[CH2:6])[CH:18]=[CH2:20]
Reactant: CC(C)=O
Reactant: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: Cl
Product: C=CCNCC=C
Product: CC(C)C=CCN
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A 66.7% aqueous solution of N-iso-propylallylamine hydrochloride (hereinafter, abbreviated as i-PAA.HCl) was prepared by adding 52.1 g of 35% hydrochloric acid to 49.6 g (0.5 mole) of N-iso-propylallylamine while cooling the reaction mixture. On the other hand, 48.58 g (0.5 mole) of diallylamine was neutralized with 52.1 g of 35% hydrochloric acid while cooling the reaction mixture to obtain a 66.4% aqueous solution of diallylamine hydrochloride (hereinafter, abbreviated as DAA.HCl). Then, 20.34 g (0.1 mole) of the aqueous solution of i-PAA.HCl and 20.14 g (0.1 mole) of the aqueous solution of DAA.HCl, obtained above, were mixed together and heated to 60° C. Then, as a polymerization initiator, 0.809 g 2,2'-azobis(2-amidinopropane) dihydrochloride was added, and a polymerization was carried out at that temperature for 48 hours. After the reaction, the reaction mixture (a solution) was poured into a large amount of acetone to precipitate the reaction product. The precipitate was collected by filtration using a glass filter and dried under reduced pressure. Thus, a copolymer of N-isopropylallylamine hydrochloride and diallylamine hydrochloride was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1
Reactant: C=COC(=O)Cl
Reactant: CC(C)(C)C1CCC(O)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)OC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, thermometer, ice water bath, dropping funnel, was added 10.0 g (64.0 mmol) of 4-t-butylcyclohexanol, 5.6 g (70.3 mmol) of pyridine and 100 mL of chloroform. The reaction mixture was cooled to less than 10° C. and 6.8 g (64.0 mmol) of vinyl chloroformate was added so that the temperature remained below 15° C. The reaction mixture was stirred at room temperature for 20 hours, then washed with 100 mL 2N HCl, 100 mL distilled water and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil chromatographed (silica gel, methylene chloride) to afford 7.3 g (32.28 mmol, 50.4%) of an oil. FTIR (neat, capillary) 2949.85, 2867.24, 1753.81, 1650.71, 1478.96, 1468.77, 1452.57, 1393.73, 1385.90, 1361.15, 1325.03, 1296.75, 1246.94, 1193.82, 1178.29, 1155.10, 1118.52, 1106.53, 1083.32, 1041.01, 1016.58, 1005.94, 946.14, 923.71, 902.63, 867.23, 843.74, 804.43, 783.98, 758.83, 696.74, 668.14. NMR (CDCl3) δ 6.86-7.22 (1H,m), 4.37-4.97 (2H,m), 1.00-2.30 (10H,m), 0.85 (9H,S). ##STR42##
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([OH:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23]([O:25]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:28]>C1COCC1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([OH:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23](=[O:25])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Yield: 44 %

Procedure:
A solution of the 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (470 mg, 1.36 mM) in 20 ml THF and 80 mL concentrated aqueous ammonium hydroxide was sonicated for 6 hours at 30-40° C. The precipitated solid was filtered and triturated with Et2O to afford 200 mg (44%) of 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.25 (m, 3H), 7.1 (m, 2H), 6.95 (s, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 314, 331.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[F:27][C:22]1[C:21]2[NH:20][CH:19]=[C:18]3[C:28](=[O:29])[N:15]([C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][CH3:7])=[CH:10][CH:11]=4)[N:16]=[C:17]3[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCC(C)C(=O)Cl
Reactant: Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(=O)Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
(±)-2-Methylbutyryl chloride (13.6 μl, 0.11 mmol) was added dropwise over 30 sec to a stirred solution of 2-(4-amino-phenyl)-6-fluoro-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (Intermediate 2) (30 mg, 0.10 mmol), triethylamine (14 μl, 0.11 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) in dichloromethane (1 ml) at room temperature. The mixture was stirred at room temperature for 16 h. The yellow solid was then filtered and purified by washing sequentially with a saturated solution of sodium bicarbonate (1 ml), ethyl acetate (1 ml) and ethyl alcohol (0.5 ml) and finally dried under suction to give the title compound (10 mg, 26%) as a bright yellow solid, LCMS m/z 379.36 [M+H]+ @ RT 1.18 min. δH(400 MHz, (CD3)2SO) 9.89 (1H, s), 8.52 (1H, s), 8.15 (2H, d J 9.0 Hz), 8.01 (1H, d J 7.0 Hz), 7.69 (2H, d J 9.0 Hz) 7.57-7.46 (2H, m), 2.46-2.39 (1H, m), 1.69-1.36 (2H, m), 1.11 (3H, d J 6.8 Hz), 0.91(3H, t J 7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH3:15])[N:5]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10]C=1)C=O.[C:17](Cl)(=O)C(Cl)=O.Cl.Cl[CH2:25][Cl:26]>>[Cl:26][C:25]1[CH:17]=[C:13]2[C:12]([CH:15]=[C:4]([C:3]([O:2][CH3:1])=[O:16])[N:5]=[CH:8]2)=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](C)N(C=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Agent: Cl
Product: COC(=O)c1cc2ccc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-N-Formyl-(4-chlorophenyl)alanine methyl ester (1.45 g) was dissolved in dichloromethane (40 ml), and oxalyl chloride (0.57 ml) was added dropwise. After the mixture was stirred at room temperature for 30 minutes, ferric chloride (1.17 g) was added at an ambient temperature of about −10° C. to stir the mixture at room temperature for 4 days. 1N Hydrochloric acid was added, and the resultant mixture was diluted with dichloromethane to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (38 ml), and concentrated sulfuric acid (2 ml) was added to heat the mixture for 20 hours under reflux. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, the resultant mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→ethyl acetate) to obtain the title compound (0.25 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
4-Chlorobenzaldehyde (1x, 1.00 g, 7.1 mmol) and acetone (19, 0.26 ml, 3.5 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 3 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.75 g (70%) of yellow crystals: mp 187-189° C. [expected mp 191-193° C.]; 1H NMR: δ 7.00 (d, 2H, J=15.9 Hz), 7.37 (d, 4H, J=8.5 Hz), 7.52 (d, 4H, J=8.5 Hz), 7.66 (d, 2H, J=15.9 Hz); 13C NMR: δ 125.7, 129.2, 129.5, 133.2, 136.4, 141.9, 188.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[CH:4]1.Cl[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[CH3:18][Si:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[CH:4]1
Reactant: COC(=O)c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred suspension of sodium hydride (572 mg, 23.8 mmol, 94%) in dry DMF (50 mL) at 0° C. was added methyl 1H-imidazole-4-carboxylate (3.0 g, 23.8 mmol) in DMF (90 mL) and was allowed to warm up to room temperature over 30 min. The reaction mixture was cooled to 0° C. and was treated dropwise with (2-(chloromethoxy)ethyl)trimethylsilane (Aldrich, 4.77 g, 28.6 mmol). The cold bath was removed and the mixture was stirred for 16 h. The reaction mixture was quenched by the addition of ice-flakes and then by water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 2 to 5% MeOH/CH2Cl2) to provide the title compound (4.46 g, 73%). 1H NMR (CDCl3) δ 7.72 (s, 1H), 7.61 (s, 1H), 5.29 (s, 2H), 3.90 (s, 3H), 3.49 (t, J=8.0 Hz, 2H), 0.90 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 257.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:5][C:6]=1[CH3:7].[Cu](C#N)[C:15]#[N:16].[C-]#N.[Na+]>CN(C)C=O>[C:15]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:5][C:6]=1[CH3:7])#[N:16]
Reactant: N#C[Cu]C#N
Reactant: Cc1sc(C(=O)OC(C)C)cc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc(C(=O)OC(C)C)cc1C#N
Yield: 62.8 %

Procedure:
Isopropyl 4-cyano-5-methylthiiophene-2-carboxylate: A stirred solution of 1.9 g (7.3 mmol) of isopropyl 4-bromo-5-methylthiophene-2-carboxylate was dissolved in dry dimethylformamide (30 mL) and refluxed with copper cyanide (785 mg, 8.8 mmol) for 16 hours. The cooled solution was poured into 0.1 M aqueous sodium cyanide solution (300 mL) and extracted with diethyl ether (4×40 mL). The organic layers were washed with brine (2×40 mL), dried over anhydrous sodium sulfate, and the solvents removed in vacuo. Column chromatography on silica gel eluting with hexanes:ethyl acetate 9/1 (v:v), gave isopropyl 4-cyano-5-methylthiophene-2-carboxylate (960 mg, 63%) as a yellow crystalline solid 1H-NMR (DMSO-d6; 300 MHz) δ 8.01 (s, 1H), 5.09 (septet, 1H, J=6.2 Hz), 2.67 (s, 31H), 1.29 (d, 6H, J=6.2 Hz).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14]Br)[CH2:5]3)[CH2:2]1)[CH2:9]2.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14][N:28]4[CH2:27][CH2:26][N:25]([C:21]5[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=5)[CH2:30][CH2:29]4)[CH2:5]3)[CH2:2]1)[CH2:9]2
Reactant: O=C(CCBr)N1CC2CC3CC(C2)CC1C3
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CCN1CCN(c2cccc(Cl)c2)CC1)N1CC2CC3CC(C2)CC1C3
Yield: 51.2 %

Procedure:
A solution of 1-(4-azatricyclo[4.3.1.1(3,8)]undec-4-yl)-3-bromo-1-propanone (1.96 g, 6.8 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (1.60 g, 6.8 mmol) and diisopropylethylamine (2.4 mL, 14 mmol) in anhydrous dimethylformamide (100 mL) was heated at 60° C. for 19 hours. The reaction mixture was poured into water (700 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried, preadsorbed onto silica gel, and purified by flash chromatography (8 cm diameter, gradient elution with 2-5% methanol in dichloromethane). The resulting solid was recrystallized from ethyl acetate in hexane to yield a light tan solid (1.4 g, 51%, m.p. 110°-112° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: NCc1ccccc1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and heated to reflux with stirring for 2 hours. After cooling to room temperature, a light brown solid was collected by filtration. (33.4 g, 77%): 1H NMR (DMSO-d6/300 MHz) δ: 10.5 (s, 1H), 7.4-7.1 (m, 5H), 5.8-5.6 (m, 2H), 5.2 (s, 2H), 5.1 (s, 2H), 2.2 (s, 3H). ES HRMS m/z 216.100 (M+H, C12H13NO2 requires 216.102).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].CCCCC.[CH3:17][C:18]([CH:21]=O)([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>FC(F)(F)S(O)(=O)=O>[C:18]([C@H:21]1[O:10][C:1](=[O:11])[C@@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:3]1)([CH3:20])([CH3:19])[CH3:17]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC(C)(C)C=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCCCC
Product: CC(C)(C)[C@H]1OC(=O)[C@@H](c2ccccc2)O1
Temperature: 36 °C
Reaction time: 5.5 h
Yield: 83.1 %

Procedure:
(R)-Mandelic acid (20 g, 130 mmol) was dissolved in anhydrous pentane (200 mL, 1.7 mol). Pivaldehyde (13.6 g, 153 mmol) was added followed by trifluoromethanesulfonic acid (488 μL, 5.4 mmol). The mixture was allowed to reflux at 36° C. under nitrogen. After 5.5 hours, the mixture was allowed to cool to room temperature before stirring with 200 mL of an 8 wt % NaHCO3 solution for 10 minutes. Excess pentane was removed by rotary evaporation. The solids were collected by filtration and rinsed (100 mL water) while under vacuum filtration. The solids were dried overnight under high vacuum to yield 23.8 grams of intermediate (1a) as a white solid (88% purity).