Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([CH3:13])[CH:12]=1.CN([CH:19]=[O:20])C.[Cl-].[Na+]>C1COCC1>[CH3:15][O:14][C:10]1[CH:9]=[CH:8][C:7]([CH:19]=[O:20])=[CH:12][C:11]=1[CH3:13]
Reactant: COc1ccc(Br)cc1C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C
Reaction time: 1.17 h
Yield: 91.4 %

Procedure:
A stirred solution of 180 mL (1.6 Molar in hexane: 0.29 mole) of n-butyllithium in 250 mL of THF was cooled to below −60° C., and a solution of 50 grams (0.26 mole) of 5-bromo-2-methoxytoluene (commercially available) was added at a rate to maintain the reaction mixture temperature below −55° C. Upon completion of addition, the reaction mixture was cooled to about −60° C. to −70° C. where it stirred for 70 minutes. After this time, 80 mL (0.99 mole) of DMF was added to the reaction mixture at a rate to maintain the reaction mixture temperature below −50° C. Upon completion of addition, the reaction mixture was poured into an aqueous dilute sodium chloride solution, and then it was extracted with two portions of diethyl ether. The combined extracts were washed with one portion of an aqueous dilute sodium chloride solution, with one portion of an aqueous saturated sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 35.7 grams of a residual oil. The oil was purified by column chromatography on silica gel using mixtures of hexane and ethyl acetate as eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 23.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][O:13][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])c1cnc(NCCO)cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)OCCNc1cnc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A solution of 2-(5-nitro-pyrazin-2-ylamino)-ethanol (370 mg, 2.01 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was treated with chlorotriethylsilane (371 μL, 2.21 mmol) and imidazole (342 mg, 5.02 mmol). The reaction mixture was then allowed to warm up to 25° C. where it was stirred overnight for 16 h. After this time, the reaction was diluted with ethyl acetate (20 mL) and a saturated aqueous sodium chloride solution (10 mL) and then further extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded (5-nitro-pyrazin-2-yl)-(2-triethylsilanyloxy-ethyl)-amine (531 mg, 89%) as a light yellow solid: (ES)+-HRMS m/e calcd for C12H22N4O3Si (M+H)+ 299.1534, found 299.1538.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[N:3]=1.[Cl-].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][Zn+])=[CH:19][CH:18]=1>C1COCC1.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>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:13][CH3:14])[N:3]=2)=[CH:19][CH:18]=1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Reactant: Fc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1nc(Cc2ccc(F)cc2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 68.2 %

Procedure:
(26) A solution of compound (25) (1.2 g, 5.5 mmol), 4-fluorobenzylzinc chloride (13.1 mL, 0.5 M in THF, 6.6 mmol), tetrakis(triphenylphosphine)palladium (0.13 g, 0.1 mmol) in THF (50 mL) was heated to refluxed for 3 hours under nitrogen. After it cooled to room temperature, the THF was removed in vacuo. The residue was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4. After concentrated, the residue was purified by a column chromatography on silica gel eluting with 5% ethyl acetate in hexane to yield 2-(4-fluoro-benzyl)-4,6-dimethoxy-5-nitro-pyrimidine (26) (1.1 g, 63%). 1H NMR (CDCl3)
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1cccc2c1ncn2C1CCCCO1
Yield: 81.3 %

Procedure:
A mixture of 4-bromo-1H-benzo[d]imidazole (1.5 g, 7 mmol), TsOH.H2O (0.1 g, 0.7 mmol), and 3,4-dihydro-2H-pyran (2.9 g, 35 mmol) in THF (10 mL) was heated at reflux overnight. The reaction mixture was concentrated in vacuo. To the residue was added water and the mixture was extracted with EtOAc. The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using a petroleum ether/EtOAc gradient (10:1 to 3:1) to afford 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a gray solid (1.6 g, 75%). MS (ESI): m/z=281 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH3:22][NH:23][CH3:24].O1CCCC1>O>[CH3:22][N:23]([CH3:24])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N(C)C)c12
Temperature: 100 °C
Yield: 97 %

Procedure:
4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.00 g, 3.39 mmol) was added to a 2M dimethylamine in tetrahydrofuran solution (5.00 mL, 10.0 mmol), and the solution was heated under reflux overnight at 100° C. in a sealed tube. The solution was cooled to room temperature and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (1.00 g, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>>[CH2:23]([O:22][C:20](=[O:21])[C:19]1[CH:25]=[CH:26][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([C:12](=[O:13])[NH2:14])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[CH:17][CH:18]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C(N)=O)ccc2OC)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and ethyl 4-amino-benzoate by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:44][CH2:43][C:42]3([CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]3)[C:41]2=[O:51])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:44][CH2:43][C:42]3([CH2:49][CH2:48][C:47](=[CH:2][O:3][CH3:4])[CH2:46][CH2:45]3)[C:41]2=[O:51])=[CH:38][CH:39]=1)([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C1CCC2(CC1)CCN(c1ccc(C(C)(C)C)cc1)C2=O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
(Methoxymethyl)triphenyl phosphonium chloride (3.05 g, 8.9 mmol) in THF was cooled to −78° C. under argon and a solution of potassium tert-butoxide (832 mg, 7.41 mmol) in THF was added at −78° C. To the resulting red solution was added a solution of 2-(4-tert-butyl-phenyl)-2-aza-spiro[4.5]decane-1,8-dione (described in example 343 step 2, 888 mg, 2.97 mmol) in THF was added dropwise at −78° C. The reaction was allowed to warm to room temperature and the reaction was monitored by TLC. After disappearance of starting material, the reaction was quenched with sat NaHCO3 (aq), and extracted with EtOAc. The organic layers were combined washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (0% to 50% EtOAc in heptane) to yield the title compound as a white solid (793 mg, 82%). MS (m/e): 328.3 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=O)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18]([O:27][CH3:28])=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:22]=1)[CH:23]=[O:24]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Ex-32B: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-1-carboxylic acid tert-butyl ester (Ex-32A, 2.0 g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu4NF (6.86 g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No significant reaction occurred under these conditions by HPLC. Then, additional Bu4NF (6.86 g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction reached about 50% completion (HPLC). The reaction mixture was poured into CH2Cl2, and washed with water and brine. The organic phase was dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc/hexanes, 2:1) to give 0.45 g (30%) of 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehyde. 1H-NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 9.25 (br, 1H), 8.28 (s, 1H), 7.63(d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.08–7.20 (m, 2H), 6.92(d, J=2 Hz, 1H), 6.56 (s, 1H) 4.11(s, 3H), 4.00 (s, 3H). HMRS (EI) calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1049.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH:13]([Br:15])[CH3:14])[N:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(Cl)ccnc1CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)ccnc1C(C)Br

Procedure:
A mixture of the above ethylnicotinate (5.45 g), N-bromosuccinimide (NBS) (5.50 g) and 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.40 g) in carbon tetrachloride (50 ml) is heated under reflux for 2 hours, then cooled, filtered and concentrated in vacuo to give ethyl 4-chloro-2-(1-bromoethyl)-nicotinate.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: Cc1ccccc1
Product: COCCCOc1ccnc(CCl)c1C
Yield: 112.6 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise into the solution in a temperature that did not exceed 25° C. Stirring was carried out at room temperature, and then after it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g (yield: 97.3%)).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH2:20])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH:20][C:28](=[O:31])[CH2:29][CH3:30])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Temperature: 25 °C

Procedure:
0.3 g (1.1 mmol) of the compound obtained in Example 71 are suspended in 15 ml dichloromethane, combined with 0.4 ml (2.5 mmol) triethylamine and gently refluxed. 0.2 ml (2.3 mmol) propionic acid chloride are added and the mixture is refluxed for 5 hours with stirring. After cooling to ambient temperature the reaction solution is washed with sodium hydrogen carbonate and water, dried and evaporated to dryness. The residue is stirred with diethyl ether and suction filtered. Yield: 0.2 g (m.p.: 274-275° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14]([O:16][C:17]1[C:18](=O)[C:19](=[O:24])[C:20]=1[O:21]CC)[CH3:15]>>[CH3:13][O:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][C:18]3[C:19](=[O:24])[C:20](=[O:21])[C:17]=3[O:16][CH2:14][CH3:15])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Product: CCOc1c(Nc2cc(OC)cc3cccnc23)c(=O)c1=O
Yield: 28.9 %

Procedure:
In a procedure identical to Example 10, Step 1, 8-amino-6-methoxyquinoline (2.00 g, 11.48 mmol) was reacted with 3,4-diethoxy-3-cyclobutene-1,2-dione (1.70 mL, 11.48 mmol) to give 0.99 g (29%) of product: 1H NMR (DMSO-d6) δ10.21 (s, 1H), 8.75 (dd, 1H), 8.29 (dd, 1H), 7.61 (m, 2H), 7.17 (d, 1H), 4.76 (q, 2H), 3.90 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[CH2:11][Cl:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(Cl)c1ccccc1CCl
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1CCl
Yield: 44 %

Procedure:
A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0° C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0° C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0° C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (1H, d, J=7.5 Hz), 7.58-7.67 (2H, m), 7.49-7.57 (2H, m), 7.20-7.25 (1H, m), 7.15 (1H, t, J=7.9 Hz), 4.72 (2H, s), 2.31 (3H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)([O-:17])=[O:16]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc([N+](=O)[O-])c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-nitroaniline (34 mg, 0.243 mmol) similar to Example 11 as a yellow solid (65 mg, 87%). 1H NMR (DMSO-d6): 10.17 (s, 1H), 9.18 (s, 1H), 8.77 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.98 (t, J=6.9 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.63 (t, J=8.3 Hz, 1H), 7.55–7.51 (m, 1H), 6.74 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: O.[C:2]([NH:9][C:10](=[NH:19])[NH:11]C(OC(C)(C)C)=O)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]>CC(OC)(C)C>[C:5]([O:4][C:2]([NH:9][C:10]([NH2:19])=[NH:11])=[O:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC(=N)N
Temperature: 57.5 °C

Procedure:
After addition of water (200.00 g) the resultant mixture was evaporated to yield a solid comprising the crude product together with inorganic salts and a small amount of bis-Boc-guanidine. The solids were suspended in 2-Me-THF (344.00 g), the suspension was stirred and heated to reflux and maintained at reflux for about 1 h. The suspension was then cooled to about 55-60° C. and filtered warm to remove the inorganic salts. Evaporation of the 2-MeTHF yielded a solid. This solid was re-suspended in MTBE (37.00 g) and the resultant suspension was stirred at ambient temperature for ˜1 h. The suspension was filtered, and the solid was washed with MTBE (18.5 g). The MTBE treatment was repeated again and the resultant product was air dried for several hours at ambient temperature. The product —N-(t-butyloxycarbonyl)-guanidine—was isolated as a solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#N>C(#N)C1C=CC=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#Cc1ccncc1
Reactant: C#CCCCCCC
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccncc1
Reaction time: 21 h
Yield: 80 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 21 h at room temperature showed the presence of 1.60 mmol (80% yield) of 4-(1-octynyl)pyridine and no remaining 4-cyanopyridine in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([C:6]1[NH:10][N:9]=[C:8]([N+:11]([O-])=O)[CH:7]=1)=[O:5]>[Pd].CO>[NH2:11][C:8]1[CH:7]=[C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:5])[NH:10][N:9]=1
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])n[nH]1
Agent: [Pd]
Solvent: CO
Product: CON(C)C(=O)c1cc(N)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A 250-mL single-neck round-bottomed flask was purged with nitrogen and charged with 287a (16.0 g, 1.0 eq., 80.0 mmol), 10% palladium on carbon (50% wet, 800 mg), and methanol (100 mL). The mixture was evacuated, charged with hydrogen gas, and stirred under hydrogen atmosphere at room temperature overnight. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE®. The filtrate was concentrated under reduced pressure to afford 287b (11.0 g, 81%) as white solid. MS-ESI: [M+H]+ 171.1
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([F:27])[CH:17]=2)[CH:15]=1)[CH2:5][CH:6]([CH2:8][CH3:9])[CH3:7].[Li+].[OH-]>CO.O>[F:27][C:18]1[CH:17]=[C:16]([C:14]2[CH:15]=[C:10]([CH:4]([CH2:5][CH:6]([CH2:8][CH3:9])[CH3:7])[C:3]([OH:38])=[O:2])[CH:11]=[C:12]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)[CH:13]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]([F:25])([F:24])[F:26]
Reactant: CCC(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 564.6 %

Procedure:
A mixture of 2-(3-fluoro-4-trifluoromethoxy-4″-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-ethyl-pentanoic acid methyl ester (2 mg) THF (1 mL), 10% LiOH in MeOH (0.3 mL) and H2O (0.3 mL) was stirred at 30° C. for 3 h. The solution was concentrated in vacuo and the residue was diluted with H2O and then acidified with concentrated HCl. The aqueous solution was extracted with DCM and filtered through polytetrafluoroethylene filter. The solution was concentrated in vacuo to give a solid residue. The solid was purified using reverse phase preparative HPLC (MeCN, H2O) to give the title product (11 mg, 44%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]([CH:45]=O)=[CH:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1CCCCC1>CO>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38](/[CH:45]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])=[CH:37]2)(=[O:34])=[O:35])=[CH:31][CH:32]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(Cl)cc4)c4ccccc24)C3=O)CC1
Yield: 86.3 %

Procedure:
tert-Butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 and 1-(4-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.0918 g, 0.287 mmol) were stirred overnight at room temperature in methanol (1.2 mL) in the presence of piperidine (0.00244 g, 0.0287 mmol). The reaction mixture was further added with methanol (1 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(4-chlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.161 g, 86%).