Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]([CH3:22])[C:16]([CH3:21])([C:18]([OH:20])=O)[CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:54][O:55][C@@H:56]([C@@H:73]1[CH2:77][CH2:76][CH2:75][N:74]1[C:78](=[O:97])[CH2:79][C@@H:80]([O:95][CH3:96])[C@@H:81]([N:86]([CH3:94])[C:87](=[O:93])[C@H:88]([CH:90]([CH3:92])[CH3:91])[NH2:89])[C@@H:82]([CH3:85])[CH2:83][CH3:84])[C@@H:57]([CH3:72])[C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:59]>ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]([CH3:22])[C:16]([CH3:17])([C:18]([NH:89][C@H:88]([C:87]([N:86]([C@@H:81]([C@@H:82]([CH3:85])[CH2:83][CH3:84])[C@H:80]([O:95][CH3:96])[CH2:79][C:78]([N:74]1[CH2:75][CH2:76][CH2:77][C@H:73]1[C@H:56]([O:55][CH3:54])[C@@H:57]([CH3:72])[C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:59])=[O:97])[CH3:94])=[O:93])[CH:90]([CH3:91])[CH3:92])=[O:20])[CH3:21])=[O:14]
Reactant: CN(C(=O)CCCCCN1C(=O)C=CC1=O)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of #249 (382 mg, 1.23 mM) in 5 mL of dichloromethane, HATU (482 mg, 1.23 mM) was added followed by triethylamine (0.52 mL, 1.23 mM). The reaction was allowed to stir for 1 hour at room temperature followed by the addition of #250 (762 mg, 1.23 mM). The reaction was allowed to stir for 3 hours. Reaction was concentrated in vacuo. Reverse phase purification (MethodL) followed by lyophilization yielded a white solid mc#120 (124 mg, 11%). HPLC (Protocol A at 45° C.;) m/z 911.5 [M+H+], retention time=9.676 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1Br.C([Li])CCC.[I-].[CH3:18][N+:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(OCC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:24]1[CH:23]=[C:22]([CH3:25])[CH:21]=[CH:20][N:19]1[CH3:18]
Reactant: Cc1cc[n+](C)cc1
Reactant: COc1ccc(Br)c(OC)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2C=C(C)C=CN2C)c(OC)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2,4-dimethoxybromobenzene (1) (0.5 g, 2.3 mmol) in diethyl ether (10 ml) cooled at −78° C. under nitrogen was added a solution of n-butyl lithium (1.0 ml, 2.5 mmol of 2.5M solution in hexane) drop wise. The mixture was stirred at −78° C. for 2 hours and then 1,4-dimethylpyridinium iodide (2) (0.54 g, 2.5 mmol) was added as a solid. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml) and extracted with diethyl ether (2×15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated to yield 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine (4) (0.5 g, 93%) as a brown oil, 1H NMR CDCl3 ?? 1.7 (s, 3H), 2.7 (s, 3H), 3.8 (s, 6H), 4.45 (dd, 1H, J=2.7) 4.85 (m, 1H), 5.4 (d, 1H, J=4), 6.05 (d, 1H, J=7), 6.45 (d, 1H, J=3), 6.55 (m, 1H), 7.5 (d, 1H, J=9).
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5].C([O-])(=O)C.[NH4+:23]>CN(C)C=O>[NH2:23]/[C:3](/[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])=[C:2](\[Cl:1])/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13]
Reactant: CCCCOC(=O)/C(Cl)=C(/Cl)C(=O)OCCCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C(N)=C(/Cl)C(=O)OCCCC
Yield: 99.2 %

Procedure:
29.7 g (0.1 mol) of dibutyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. 27.55 g (88.7% yield) of dibutyl aminochloromaleate were obtained as a reddish, viscous liquid (purity according to GC analysis 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7](=[O:19])[CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([O:15]CC)=[CH:11][C:10]1=O.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1COCC1.CCCCCCC.O>[CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7](=[O:19])[CH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]1
Reactant: CCOC1=CC(=O)C(CC(=O)NCc2ccc(OC)cc2OC)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)CC2C=CC(=O)CC2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of N-(2,4-Dimethoxy-benzyl)-2-(4-ethoxy-2-oxo-cyclohex-3-enyl)-acetamide (549 mg, 1.58 mmol) in THF (10 mL) at −78° C. was added 1.0M of diisobutylaluminum hydride in heptane (2.0 mL). The reaction mixture was then stirred at 0° C. for one hour. 5 M of hydrogen chloride in water (2.0 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was then partitioned between water and ethyl acetate, and the organic layer dried with brine and magnesium sulfate, filtered, and evaporated in vacuo to yield 471.8 mg (98%) of N-(2,4-Dimethoxy-benzyl)-2-(4-oxo-cyclohex-2-enyl)-acetamide which was carried forward without purification. LCMS (Method E, ESI): RT=1.23 min, m+H=304.2; 1H NMR (400 MHz, CDCl3) δ: 7.19 (d, J=8.1 Hz, 1H), 6.84 (ddd, J=10.2, 2.6, 1.3 Hz, 1H), 6.45 (dt, J=8.2, 2.2 Hz, 2H), 5.97 (dd, J=10.2, 2.1 Hz, 1H), 5.88 (s, 1H), 4.38 (d, J=5.7 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.02 (s, 1H), 2.51-2.36 (m, 2H), 2.36-2.27 (m, 1H), 2.23 (dd, J=14.5, 7.6 Hz, 1H), 2.19-2.08 (m, 1H), 1.76-1.62 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@H:3]([OH:7])[CH2:4][CH2:5]I.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([CH2:5][CH2:4][C@@H:3]([OH:7])[C:2]([F:9])([F:8])[F:1])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H](CCI)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC[C@@H](O)C(F)(F)F
Temperature: 50 °C
Yield: 100.1 %

Procedure:
A solution of (R)-1,1,1-trifluoro-4-iodo-2-butanol (3.30 g, 13.0 mmol) in DMSO (22 mL) was treated with sodium azide (0.930 g, 14.3 mmol) at ambient temperature, followed by heating at 50° C. for 20 h. The mixture was diluted with cold water (250 mL) and extracted with diethyl ether. The combined organic extracts were washed (brine), dried, and evaporated without heat to give the product as a pale yellow oil (2.20 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[N:12]1([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[NH:11][CH2:10]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CNC(=O)N3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1NCc2cc(N3CCNCC3)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.7 %

Procedure:
To a solution of compound 10 (0.7 g, 2.11 mmol) in a mixture of CH2Cl2 (15 mL) and THF (5 mL) at 0° C. was added TFA (5 mL) and the mixture was stirred at room temperature for 6 h. The solvent was evaporated under vacuum to afford 0.66 g (96%) of compound 6 as a dark brown gum. 1H NMR (500 MHz, DMSO-d6) δ=3.17 (m, 4H, 2CH2), 3.40 (m, 4H, 2CH2), 4.28 (s, 2H, CH2), 6.70 (m, 2H, aromatic-H), 6.73 (m, 1H, aromatic-H), 8.81 (br. s, 1H, NH), 8.86 (br. s, 1H, NH). 13C NMR (125.7 MHz, DMSO-d6) δ=46.11 (CH2), 46.70 (CH2), 48.68 (CH2), 112.21 (aromatic-C), 112.27 (aromatic-C), 117.31 (aromatic-C), 130.28 (aromatic-C), 134.99 (aromatic-C), 143.38 (aromatic-C), 154.82 (C═O). Calculated (%) for C14H16F3N4O2 (329.12); C, 51.06; H, 4.90; N, 17.01. found (%); C, 51.01; H, 4.95; N, 16.95.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+].I[CH:34]([CH3:36])[CH3:35]>O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH:34]([CH3:36])[CH3:35])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Nc1c(C(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformnamide (4 ml) at room temperature was added potassium carbonate (0.7 g), then 2-iodopropane (190 μl). The mixture was stirred at room temperature for 48 hours. Water (50 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (50 ml), dried (Na2SO4) filtered and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a very pale yellow solid, m.p 136-137° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([CH:21]([OH:24])[C:22]#[CH:23])=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1.I[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>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.[Cu](I)I>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([CH:21]([OH:24])[C:22]#[C:23][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(N(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1ccc(C2=CCC(C)(C)c3cc(C(O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 16b, by reacting 0.81 g (2.4 mmol) of 1-[5-(4-dimethylaminophenyl)-8,8-dimethyl-7,8-dihydro-2-naphthyl]prop-2-yn-1-ol with 0.496 g (2 mmol) of 4-iodobenzoic acid, 0.035 g (0.05 mmol) of trans-dichlorobis(triphenylphosphine)palladium and 0.019 g (b.1 mmol) of copper iodide, a beige-colored solid is obtained (0.65 g; yield=72%; m.p.=91° C.).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].O[CH2:31][CH2:32][C:33]1[CH:42]=[CH:41][C:36]([NH:37][C:38](=[O:40])[CH3:39])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC>[N+:13]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[C:25](=[O:26])[N:24]([CH2:31][CH2:32][C:33]3[CH:42]=[CH:41][C:36]([NH:37][C:38](=[O:40])[CH3:39])=[CH:35][CH:34]=3)[C:23](=[O:27])[NH:22]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CC(=O)Nc1ccc(CCO)cc1
Reactant: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(=O)Nc1ccc(CCN2C(=O)NC(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.8 %

Procedure:
A solution of diethylazodicarboxylate (7.8 g) in DME (40 ml) was added dropwise under N2 to a stirred mixture of the product from step (a) (10.5 g), the product from step (c) (8.0 g) and triphenylphosphine (11.7 g) in DME (400 ml). When addition was complete, the mixture was stirred at room temperature for 17 hours, then evaporated in vacuo and the residue crystallised from ethanol/ether (1:4 v/v) to give the desired product as a pale yellow solid (12.7 g), [α]D25 -97.8° (c=0.50, MeOH).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.CC#N>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:14]=[CH:13]/[CH2:12][CH2:11][C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1ccccc1I
Reactant: C=CCCC(=O)OCC
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC/C=C/c1ccccc1OC
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a 200-mL RB-flask was added 2-iodoanisole (5.00 g, 21.4 mmol), ethyl 4-pentenoate (3.30 g, 25.6 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.740 g, 0.600 mmol), triethylamine (6.00 mL, 42.7 mmol) and a mixture of CH3CN (45.0 mL) and THF (15.0 mL). The reaction mixture was refluxed for overnight and then cooled to room temperature. After solvents were removed in vacuo, the resulted dark brown residue was dissolved in 5% HCl (aq) and extracted with CH2Cl2 three times. The combined extracts were washed by saturated NaHCO3 solution, dried over MgSO4, concentrated in vacuo. The dark brown oil was purified by chromatography (silica gel, EtOAc/Hexanes 1:10) to afford the product as light yellow oil (3.40 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[C:11]1([CH2:17][C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>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.[Cu](I)I.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:19]#[C:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N)c1C#CCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.3 %

Procedure:
A reaction vessel containing 0.8 gram (0.0032 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 0.5 mL (0.0042 mole) of 3-phenyl-1-propyne, 0.2 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, 0.05 gram (catalyst) of copper iodide, and 8 mL of triethylamine is evacuated and refilled with dry nitrogen gas three times. The reaction mixture is then stirred at ambient temperature for about 60 hours. After this time, the reaction mixture is diluted with 100 mL of water. The mixture is then extracted with three 75 mL portions of ethyl acetate. The combined extracts are washed with three 75 mL portions of an aqueous 5% lithium chloride solution. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5-15% methanol methylene chloride mixtures as eluants. The appropriate product-containing fractions are combined and concentrated under reduced pressure, yielding 0.3 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine. The NMR spectrum is consistent with the proposed structure. Other fractions containing less pure product are combined and concentrated under reduced pressure to a residue. This residue is subjected to column chromatography on neutral alumina, using 2.5-10% methanol in methylene Chloride mixtures as eluants. The product-containing fractions are combined and concentrated under reduced pressure, yielding an additional 0.2 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine. The NMR spectrum is consistent with the proposed structure. The two solids are combined, yielding about 0.5 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine, mp 145°-149° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:17])SC2C=CC(C)=CC=2)=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.[CH:24]([C:26]1[CH:30]=[CH:29][O:28][C:27]=1B(O)O)=[O:25].C(Cl)(Cl)Cl.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:1][C:2]1[C:7]([C:8]([C:27]2[O:28][CH:29]=[CH:30][C:26]=2[CH:24]=[O:25])=[O:17])=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccoc1B(O)O
Reactant: Cc1ccc(SC(=O)c2cc(-c3ccccc3)cnc2C)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccccc2)cc1C(=O)c1occc1C=O
Temperature: 50 °C

Procedure:
To a mixture of S-(4-methylphenyl) 2-methyl-5-phenylpyridine-3-carbothioate (66 mg, 0.20 mmol), Cu(I) thiophene-2-carboxylate (59 mg, 0.31 mmol), 3-formylfuran-2-boronic acid (31 mg, 0.22 mmol), Pd2dba3.CHCl3 (2 mg, 0.002 mmol), and tri-2-furylphosphine (1.4 mg, 0.006 mmol) was added THF (2.5 mL). The reaction mixture was heated to 50° C. for 15 h, cooled to room temperature, diluted with EtOAc, and washed with 1 N HCl and brine. The organic layer was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.60 (s, 1H); 8.91 (s, 1H); 8.02 (s, 1H); 7.40-7.61 (series of m, 6H); 7.05 (s, 1H); 2.66 (s, 3H). LRMS (ESI) calc'd for C18H13NO3 [M+H]+, 292.1. found 292.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1.[ClH:21]>>[ClH:21].[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1
Reactant: CC(=O)Nc1ccc(-n2c(N)nc3ccccc32)cc1
Agent: Cl
Product: Nc1ccc(-n2c(N)nc3ccccc32)cc1

Procedure:
2-Amino-1-(4-acetamidophenyl)benzimidazole (1.78 g, 6.68 mmol) was refluxed in hydrochloric acid (25 ml) overnight. The crude mixture was evaporated and triturated with diethyl ether. Yield 1.68 g, 96%, M.p. 258-260° C.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15](Cl)(=[O:17])=[O:16].[OH-].[Na+]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15]([OH:17])=[O:16]
Reactant: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Br)c(S(=O)O)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
37.6 g of sodium sulfite are dissolved in 500 ml of water and heated to 70° C. 62 g of 2-bromo-5-methylbenzenesulfonyl chloride are added in portions at this temperature. A 10N aqueous NaOH solution is simultaneously added dropwise here such that the pH of the solution is kept between pH=9 and pH=10. The mixture is stirred at 70° C. for 1.5 hours, and the solution is filtered off and then adjusted to pH=0 in an ice bath using a saturated aqueous HCI solution. It is subsequently stirred for 30 minutes, then the product is filtered off, washed with a little water and dried. 49.6 g of white crystals are obtained,
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[C:3](OC)=[O:4]>C1COCC1>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2-methyl-2-(4-nitrophenyl)propionate (5.32 g, 23.8 mmol, Step A) in THF (200 mL) at 0° C. was added a solution of BH3 1M in THF (25.8 mL, 45.8 mmol). The reaction was stirred at RT overnight and quenched with MeOH. THF was evaporated under reduced pressure and the residue was diluted in EtOAc and aqueous 1M HCl was added. The mixture was extracted with EtOAc, the organic layer was dried over MgSO4 and evaporated under reduced pressure. The product was purified by flash chromatography using 40% EtOAc-hexane to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1([NH2:35])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1)[C:3]([NH:35][C:28]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]1)=[O:4]
Reactant: NC1(c2ccccc2F)CCC(=O)CC1
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(C(=O)NC1(c2ccccc2F)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 1-(2-fluorophenyl)-4-oxocyclohexylamine hydrochloride (Description 180) according to the method of Example 1. 1H NMR (360 MHz, CDCl3) δ 7.79 (1H, s), 7.68 (2H, s), 7.40–7.35 (1H, m), 7.27–7.21 (1H, m), 7.14–7.10 (1H, m), 6.93–6.86 (1H, m), 5.95 (1H, s), 3.71 (1H, q J 7.0 Hz), 3.08–3.00 (1H, m), 2.86–2.78 (1H, m), 2.56–2.20 (6H, m), and 1.49 (3H, d, J 7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[NH2:17][C:18]1[C:19]([I:29])=[C:20]([O:26][CH2:27][CH3:28])[CH:21]=[C:22]([CH:25]=1)[CH:23]=O>>[NH2:17][C:18]1[C:19]([I:29])=[C:20]([O:26][CH2:27][CH3:28])[CH:21]=[C:22]([CH:25]=1)[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(N)c1I
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(N)c1I
Yield: 8 %

Procedure:
The title compound (4 mg, 8%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 5-amino-3-ethoxy-4-iodo-benzaldehyde. MS: 495.4 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C:12]1([OH:25])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26]I.[Cl-].[NH4+]>CCOC(C)=O.CN(C=O)C>[CH2:3]([O:10][CH2:11][C:12]1([O:25][CH3:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(COCc2ccccc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
55% sodium hydride (4.06 g) was added under ice-cooling to a DMF (100 ml) solution of tert-butyl 4-[(benzyloxy)methyl]-4-hydroxypiperidine-1-carboxylate (9.96 g), and stirring was performed at 50° C. for 40 minutes. Under ice-cooling, methyl iodide (22.0 g) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding a saturated ammonium chloride aqueous solution and purified water to the reaction liquid, extraction was performed with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[(benzyloxy)methyl]-4-methoxypiperidine-1-carboxylate (9.27 g).