Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:29])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: OCCCCO
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1CCc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCCCCO)(c2ccc(Cl)cc2)N1CCc1ccc([N+](=O)[O-])cc1
Yield: 46.4 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (562 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (306 mg, 63%). 1H NMR (300 MHz, CDCl3): 8.11-8.08 (m, 2H, O2N—C—CH), 7.91-7.88 (m, 1H, C(O)═C═CH), 7.55-7.53 (m, 2H, Ar—H), 7.30-7.14 (m, 7H, Ar—H), 3.66 (m, 2H, N—CH2), 3.45 (t, J=8.1 Hz, 2H, HO—CH2), 3.16-3.11 and 3.03-2.99 (m, 2H, OCH2), 3.00-2.89 and 2.73-2.66 (m, 2H, NCH2CH2), 1.75-1.63 (m, 5H, CH2 and OH). 13C NMR (75 MHz, CDCl3): 168.23, 147.02, 146.62, 145.32, 137.69, 134.84, 132.74, 131.98, 129.99, 129.48, 128.74, 127.87, 123.65, 123.51, 123.10, 94.54, 62.79, 62.43, 40.51, 34.21, 29.60, 26.07. HPLC: Rt=3.45 min. Anal.: calc. for C26H25ClN2O5: C, 64.93; H, 5.24; N, 5.82. Found: C, 64.82; H, 5.18; N, 5.68.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])[O:27]C2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.O.[OH-].[Li+]>C1COCC1.CO>[C:35]([NH:34][C:26](=[O:27])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=1)[CH2:37][CH3:38])#[N:36]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NC#N
Temperature: 25 °C

Procedure:
[2′-(3-Cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.100 g, 0.19 mmol) in THF (2 mL), MeOH (0.5 mL), and H2O (0.5 mL) was treated with lithium hydroxide (0.030 g, 0.71 mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[C:39]([O:43][C:44](=[O:65])[NH:45][CH2:46][C:47]1[CH:64]=[CH:63][C:50]2[N:51]([CH2:56][CH2:57][CH2:58][S:59]([CH3:62])(=[O:61])=[O:60])[C:52]([CH2:54]Cl)=[N:53][C:49]=2[CH:48]=1)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:65])[NH:45][CH2:46][C:47]1[CH:64]=[CH:63][C:50]2[N:51]([CH2:56][CH2:57][CH2:58][S:59]([CH3:62])(=[O:60])=[O:61])[C:52]([CH2:54][N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13](=[O:14])[N:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[C:5]3=[O:15])=[N:53][C:49]=2[CH:48]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(CCl)n2CCCS(C)(=O)=O
Reactant: O=c1[nH]c2ccccc2c(=O)n1CC(F)(F)F
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCS(C)(=O)=O
Temperature: 23 °C
Reaction time: 12 h
Yield: 17.8 %

Procedure:
A slurry of 3-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione (88 mg, 0.36 mmol) in THF (20 ml) was treated with BTPP (0.33 ml, 1.08 mmol) and stirred for 15 min at 23° C. [2-Chloromethyl-1-(3-methanesulfonyl-propyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (150 mg, 0.36 mmol) was added and the mixture stirred at 23° C. for 12 h. The solvent was removed and the residue triturated with water. The residue was chromatographed to give 40 mg (18%) of [2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-1-(3-methanesulfonyl-propyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A slurry of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (10 g, 29.2 mmol) and 2-amino-4,6-difluorobenzoic acid (source: Buttpark Ltd.) (5.06 g, 29.2 mmol) in iPrOH (250 ml) and DIPEA (25.5 ml, 146 mmol) was heated at 95° C. overnight, then distilled 180 mL of solvent off over 4 h, then heated for another 2 h. After allowing to cool to rt, the reaction mixture was diluted with EtOAc (300 mL), washed with a 1N HCl solution (400 mL), a saturated NaHCO3 solution (200 mL), a saturated NaCl solution (200 mL). The organic layer was diluted with Et2O (200 mL). The resulting slurry was filtered, the solid dried in vacuum oven overnight at 80° C. to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzoic acid as a pale yellow solid (5.3 g, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3H), 6.60-6.78 (m, 2H), 7.48 (d, J=8.06 Hz, 2H), 7.77 (d, J=3.85 Hz, 1H), 7.98 (d, J=8.42 Hz, 2H), 8.23-8.36 (m, 1H); ESIMS (M+H)+=478.94.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[NH2:13].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:22](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[N:13]=[CH:22][NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: COC(OC)OC
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Clc1cc2[nH]cnc2c(Cl)c1Cl
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of 2,3,4-trichloro-6-nitro-phenylamine (0.250 g, 1.04 mmol), sodium dithionite (0.907 g, 5.21 mmol), trimethyl orthoformate (4 ml), DMF (4 mL), and acetic acid (0.5 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was collected and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to yield the titled compound (0.098 g, 43%). MS (ESI/CI): mass calcd. for C7H3Cl3N2, 219.9; m/z found, 221.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.16 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](CC([O-])=O)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[O-:16]CC.[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:16])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1ccc(CC(=O)[O-])cc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methoxy-3-nitrophenylacetate (2.46 g, 11.7 mmol) was dissolved in anhydrous ethanol (80 ml) and sodium ethoxide (1.19 g, 17.5 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The dark red solution was acidified with 2M HCl and concentrated under reduced pressure. The residue was taken up into water and extracted with dichloromethane. The combined organics were washed with 2M HCl and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1.C(Cl)(=O)C([Cl:19])=O>ClCCCl>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:19])=[O:10])=[CH:7][N:6]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102 %

Procedure:
To 6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (100 mg, 0.45 mmol) was added DCE (5 mL) and oxalyl chloride (60 ul, 0.68 mmol) under an atmosphere of nitrogen. The mixture was stirred at rt for 1.5 h then heated at 80 C for 2 h and after cooling to room temperature, evaporated to give the title compound as a pale yellow oil (110 mg, 100%). Method C HPLC-MS (in MeOH, identifying the methyl ester): MH+ requires m/z=236. Found: m/z=236, Rt=1.41 min (95%).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.CS(C)=O.[NH2:25][C@H:26]([CH2:29][CH3:30])[CH2:27][OH:28]>C(Cl)(Cl)Cl.CO>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:25][C@H:26]([CH2:29][CH3:30])[CH2:27][OH:28])=[N:3][C:4]=2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(Nc3ccccn3)nc(F)nc21
Reactant: CC[C@@H](N)CO
Solvent: CO
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC[C@H](CO)Nc1nc(Nc2ccccn2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.6 %

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-yl-amine (0.25 g, 0.87 mmol) in BunOH/DMSO (5 mL, 4:1) at RT under Ar was added Pri2NEt (1.5 mL, 8.61 mmol) followed by. (R)-(−)-2-aminobutan-1-ol (0.82 mL, 8.71 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The reaction mixture was allowed to cool to RT and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and H2O (150 mL), the aqueous, phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3/MeOH (100:0→97:3), to afford the title compound as a white solid (0.29 g, 95%). Mp 30-35° C. 1H-NMR (d6-DMSO, 250 MHz): δ 0.77 (m, 3H, —NHCH(CH2CH3)CH2OH), 1.24-1.48 (m, 8H, —NHCH(CH2CH3)CH2OH+CH(CH3)2), 3.38 (m, 2H, —NHCH(CH2CH3)CH2OH), 3.70 (m, 1H, —NHCH(CH2CH3)CH2OH), 4.52 (m, 2H, —NHCH2-Pyr), 4.75 (m, 2H, OH+CH(CH3)2), 5.81 (d, 2H, J=8.33 Hz, —NHCH(CH2CH3)CH2OH), 7.24, 7.67, 8.48 (3×m, 4H, Pyr), 7.79 (bs, 2H, —N═CH—N+—HNCH2-Pyr). FAB-MS m′z (relative intensity): 356 ([M+H]+, 100), 324 (28), 154 (26), 136 (22). Accurate Mass (M+H: Actual: 356.2199, Measured: 356.2208. Microanalysis (Expected:Measured) C18H25N7O: C, 60.83:61.81; H, 7.09:7.29; N, 27.58:27.09.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:31][CH2:32][CH2:33][OH:34])[C:24]([O:26]C(C)(C)C)=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([O:19][C:20]([NH:22][C@H:23]1[CH2:31][CH2:32][CH2:33][O:34][C:24]1=[O:26])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(N[C@H]1CCCOC1=O)OCc1ccccc1
Yield: 51 %

Procedure:
In benzene (100 ml) was dissolved tert-butyl (S)-2-(N-benzyloxycarbonylamino)-5-hydroxyvalerate [synthesized by the method described in the Journal of Organic Chemistry, 55, 1711 (1990)](5.1 g) and following addition of p-toluenesulfonic acid (0.05 g), the mixture was stirred under reflux for 1 hour. This reaction mixture was diluted with ethyl acetate (100 ml) and washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in the order mentioned. After drying (MgSO4), the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with ethyl acetate-hexane (1:2, v/v). From the eluate was obtained (S)-3-(N-benzyloxycarbonylamino)-2-oxotetrahydropyran (2.0 g, 51%) as an oil. NMR (δ ppm in CDCl3): 1.54-1.74 (1H, m), 1.96-2.10 (2H, m), 2.55-2.72 (1H, m), 4.36 (2H, t, J=6.2 Hz), 4.37-4.50 (1H, m), 5.13 (2H, s), 5.62 (1H, broad), 7.34-7.40 (5H, m). Optical rotation [α]D +51.5° (C=0.98, CHCl3)
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C@@H:5]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C(C)=O)cc1
Solvent: CO
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 22 h
Yield: 13.1 %

Procedure:
A 500 ml autoclave was loaded in a glove box with 15.0 g (50.4 mmol) of (Z)-2-acetyl-1-(p-methoxybenzylidene)-1,2,3,4,5,6,7,8-octahydroisoquinoline, 170 ml of methanol and the catalyst solution prepared according to a). The hydrogenation was carried out at 100° and 35 bar for 22 hours. The conversion was 98.5%. A 2 g product-containing aliquot of the hydrogenation solution was evaporated and the residue was dissolved in diethyl ether. The ether solution was filtered through a silica gel pad in order to separate the catalyst. Evaporation of the filtrate gave 1.97 g of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline as yellowish crystals of 95.9% e.e.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:12])=[C:6]([CH2:10][CH3:11])[C:7]=1[CH2:8][Cl:9])[CH3:2].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl-:9].[CH2:1]([C:3]1[S:4][C:5]([CH3:12])=[C:6]([CH2:10][CH3:11])[C:7]=1[CH2:8][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCc1sc(C)c(CC)c1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1sc(C)c(CC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 115 °C

Procedure:
19.7 G. of 2,4-diethyl-5-methyl-3-chloromethylthiophene and 39.5 g. of triphenylphosphine were dissolved in 400 ml. of toluene. The resulting solution was heated at 115° C. overnight under argon and then cooled to room temperature. The white phosphonium salt which precipitated was collected by filtration, washed with toluene and dried at 100° C. under high vacuum to yield (2,4-diethyl-5-methyl-3-thenyl)triphenylphosphonium chloride, m.p. 192°-194° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[CH:33]=[C:34]([O:38][C:39]2[N:44]=[CH:43][C:42]3[N:45]=[C:46]([C:50]4[C:51]([NH2:55])=[N:52][O:53][N:54]=4)[N:47]([CH2:48][CH3:49])[C:41]=3[CH:40]=2)[CH:35]=[CH:36][CH:37]=1>CN(C=O)C.O.CCOC(C)=O>[NH2:55][C:51]1[C:50]([C:46]2[N:47]([CH2:48][CH3:49])[C:41]3[CH:40]=[C:39]([O:38][C:34]4[CH:33]=[C:32]([NH:31][C:1]([C:2]5[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=5)=[O:9])[CH:37]=[CH:36][CH:35]=4)[N:44]=[CH:43][C:42]=3[N:45]=2)=[N:54][O:53][N:52]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4cccnc4)c3)cc21
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a room temperature suspension of 0.036 g of nicotinic acid (0.30 mmols) and 0.061 g of EDCI (0.32 mmols) in dry DMF (2.0 mL) was added 0.043 g of HOBt (0.32 mmols). After stirring for 10 min., 0.10 g of the product of Example 3 (0.3 mmols) was added to the reaction mixture. After stirring for 1 h, the reaction was treated with an additional 0.061 g of EDCI (0.32 mmols). The mixture was allowed to stir for 27 h at rt. The reaction mixture was diluted with 2 mL of water and 10 mL of EtOAc. The layers were separated, and the organic layer was washed with water. The organics were dried over MgSO4, filtered, and concentrated. The yellow residue was washed with methanol to yield an off-white solid (73 mg, 57%). MS (ES+) m/e 444 [M+H]+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N+:7]1[CH2:11][CH2:10][C:9]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:19].Cl[CH2:21]Cl.[N+](=C)=[N-]>C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N+:7]12[CH2:19][C:8]1([CH3:21])[C:9]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH2:11]2
Reactant: ClCCl
Reactant: CC1=[N+](C)CCC1(C)c1ccccc1
Agent: C=[N+]=[N-]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Product: CC1(c2ccccc2)CC[N+]2(C)CC12C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 17 g. of 1,2,3-trimethyl-3-phenyl-1-pyrrolinium tetrafluoroborate in 400 cc. of dichloromethane was stirred and cooled to 0° C. in an ice-water bath. A solution of diazomethane in diethyl ether was added dropwise to the reaction mixture over 21/2 hours. The reaction mixture was warmed to 25° C. and stirred for 12 hours. The solvent was evaporated from the reaction mixture under reduced pressure to provide 1,2,3-trimethyl-3-phenyl-1,2-methylene pyrrolidinium tetrafluoroborate as a solid. M.P. 151°-155° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:32](=[O:35])[CH2:33][Br:34].CC#N>C(Cl)(Cl)Cl.CS(C)=O>[Br-:34].[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:32](=[O:35])[CH2:33][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: O=C(CBr)c1cc2ccccc2o1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(C[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2)c1cc2ccccc2o1
Product: [Br-]
Temperature: 60 °C
Yield: 55.1 %

Procedure:
1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.022 g, 0.075 mmol) was diluted in CHCl3 (1.8 mL) and dispensed directly into a 1 dram vial containing 1-(1-benzofuran-2-yl)-2-bromoethanone (0.027 g, 0.112 mmol). Added CH3CN (1.2 mL), the vial was fitted with stirring bar and capped. The reaction was stirred and heated at 60° C. for 24 h and then concentrated under vacuum to give a white solid. This residue was dissolved in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.022 g, 57.4%). LC/MS ESI RT 1.98 min, M+ 452
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH2:17])[CH:9]=[CH:8]1.C(N(CC)CC)C>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH:17][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[CH:9]=[CH:8]1
Reactant: NCc1cccc2cc[nH]c12
Reactant: CC(Br)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Add 2-bromopropionyl chloride to a solution of (indol-7-yl)methylamine and triethylamine (0.49 g, 47.6 mmol) in tetrahydrofuran (20 ml) at 0° C. Stir for 1 hour at room temperature and quench with saturated aqueous sodium bicarbonate. Extract with ethyl acetate, concentrate under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound (0.62 g, 46%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15]([CH2:17]O)=[N:16][C:12]=2[CH:11]=1.C(Cl)(=O)C(Cl)=O.[I-].[Na+].[CH3:35][NH:36][CH3:37]>CN(C)C=O.O1CCCC1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:15]([CH2:17][N:36]([CH3:37])[CH3:35])=[N:16][C:12]=2[CH:11]=1
Reactant: CNC
Reactant: OCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Yield: 43 %

Procedure:
An eggplant flask (50 mL) equipped with a reflux condenser was charged with 5-(benzoxazol-2-yl)-2-hydroxymethyl-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 13) (0.055 g, 0.16 mmol), oxalyl chloride (0.024 g, 0.19 mmol), and anhydrous dichloromethane (3 mL), and after the addition of anhydrous N,N-dimethylformamide (5 drops) at room temperature, this was refluxed for 3.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. To the yellow residue was added anhydrous tetrahydrofuran (5 mL) and anhydrous sodium iodide (0.036 g, 0.24 mmol), followed by a tetrahydrofuran solution of dimethylamine (2.0 M, 3 mL), and this was refluxed for 14 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure. The yellow residue (0.70 g) was purified by silica gel column chromatography (silica gel: 2.6 g; MeOH/CHCl3=1/5) to yield the title compound (0.026 g, 43% yield) as a pale yellow powder.
Reaction SMILES: C(O[CH2:4][CH3:5])=O.[H-].[Na+].[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].[CH3:14][C:15](=O)[CH2:16]C>>[C:8]([C:10]1[C:11]([OH:12])=[N:13][C:4]([CH3:5])=[C:15]([CH3:16])[CH:14]=1)#[N:9]
Reactant: CCOC=O
Reactant: N#CCC(N)=O
Reactant: CCC(C)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)c(O)nc1C

Procedure:
Ethyl formate and 2-butanone are added to sodium hydride and cyanoacetamide is added to give 3-cyano-5, 6-dimethyl-2-hydroxypyridine, which is reacted with phosphorus pentachloride and the product reduced with hydrogen and Raney nickel in the presence of semicarbazide, and formaldehyde is added to the mixture to give 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde m.p. 69°-70°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1nccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (190 mg, 1.37 mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (189 mg, 0.66 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diethyl ether and the desired compound was obtained as a white solid (190 mg, 76%), MS: m/e=364.1 (M+H+).