Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][NH:2]1.C([Li])CCC.[S:17](=[O:19])=[O:18].O.O.O.C([O-])(=O)C.[Na+].[NH2:28]OS(O)(=O)=O>C1COCC1.O>[S:1]1(=[O:11])(=[O:10])[C:6]2[S:7][C:8]([S:17]([NH2:28])(=[O:19])=[O:18])=[CH:9][C:5]=2[CH:4]=[N:3][NH:2]1
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Reactant: O=S1(=O)NN=Cc2ccsc21
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NN=C2
Temperature: -78 °C
Reaction time: 18 h

Procedure:
The product from step B (0.1 g, 5.3 mmol) was dissolved in dry THF (4 mL) and cooled to -78° C. under nitrogen. n-Butyllithium (0.7 mL of a 2.5 M solution in hexanes, 1.75 mmol) was added dropwise, the mixture stirred for 1h at -78° C. A stream of sulfur dioxide gas was passed through the surface of the mixture for 15 min. and then the mixture was allowed to warm to room temperature. Evaporation of the reaction mixture provided a residue which was dissolved in water (5 mL) to which was added sodium acetate trihydrate (0.21 g, 1.39 mmol); this solution was cooled to 0° C. and hydroxylamine-O-sulfonic acid (0.18 g, 1.39 mmol) was added followed by stirring for 18 h. The reaction mixture was extracted with ethyl acetate (2×5 mL). The combined extracts were dried over MgSO4 and concentrated to a crude oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give a white solid. (0.021 g, 15%). decomposition:t>183° C. Cl-MS m/e 268 (m+H)+. 1HNMR (DMSO-d6): δ:7.90 (1H, 1s, CH); 8.22 (2H, S, NH2 exchangeable); 8.34 (1H, 1s, CH=N).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-trifluoromethoxy-benzene (0.306 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.125 g, 81%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.82 (s, 2H), 7.16 (d, 2H), 7.32-7.52 (m, 5H), 7.90 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:17][C@@H:18]([C@@H:26]1[C@@:30]2([CH3:47])[CH2:31][CH2:32][C@@:33]34[CH2:39][C@:38]53[CH2:40][CH2:41][C@H:42]([OH:46])[C:43]([CH3:45])([CH3:44])[C@@H:37]5[CH2:36][CH2:35][C@H:34]4[C@:29]2([CH3:48])[CH2:28][CH2:27]1)[CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([CH3:24])[CH3:23]>O1CCOCC1>[CH3:17][C@@H:18]([C@@H:26]1[C@@:30]2([CH3:47])[CH2:31][CH2:32][C@@:33]34[CH2:39][C@:38]53[CH2:40][CH2:41][C@H:42]([OH:46])[C:43]([CH3:45])([CH3:44])[C@@H:37]5[CH2:36][CH2:35][C@H:34]4[C@:29]2([CH3:48])[CH2:28][CH2:27]1)[CH2:19][CH2:20][C:21]([CH3:25])=[C:22]([CH3:23])[CH3:24].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O-:10])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)=C(C)CC[C@@H](C)[C@H]1CC[C@@]2(C)[C@@H]3CC[C@H]4C(C)(C)[C@@H](O)CC[C@@]45C[C@@]35CC[C@]12C
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C([O-])c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To p-nitrobenzoic acid (1 g, 0.006 mole) dissolved in dioxane (20 ml) was added thionyl chloride (3 ml, 7 equivalents) and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was evaporated under reduced pressure, then dioxane (20 ml) and pyridine (3 ml) were added to the resulting residue. Cyclobranol (2 g, 0.0045 mole) was added to the solution and the mixture was stirred at 60° C. for 2 hours to complete the reaction. The mixture was evaporated under reduced pressure, and the residue was extracted with chloroform (30 ml). The extract was washed successively with 3% aqueous sodium carbonate, water, and saturated brine, dried, and evaporated to dryness under reduced pressure. The crude crystals were washed with ethanol (50 ml), and recrystallized from ethyl acetate, giving cyclobranol-p-nitrobenzoate (2.28 g) in a 90% yield. m.p. 244°-245° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]([O-:15])(=[O:14])C.[Na+].[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]([O:15][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)[O-]
Reactant: Brc1ccc2cnccc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 267.1 %

Procedure:
To a solution of 6-bromoisoquinoline (10 g, 48 mmol), purchased from Gateway Chemical Technology, Inc., in 200 mL of 1:1 DMF:MeOH was added sodium acetate (5.0 g, 61 mmol), triphenylphosphine (3.8 g, 14 mmol), and palladium(II) acetate (2.8 g, 12 mmol). The vessel was charged with 300 kPa of carbon monoxide. The vessel was then purged. This charging purging sequence was repeated three times, then the vessel was charged with 300 kPa of CO and heated to 100° C. After 15 hours, the reaction was judged to be complete by LC/MS. The reaction was filtered through Celite (eluting with EtAOc) and the resulting mixture was concentrated under reduced pressure. The residue was taken up in 250 mL of EtOAc and washed three times with water and once with brine. The mixture was then dried over MgSO4, filtered, and concentrated under reduced pressure. Flash chromatography on silica gel (10% to 35% EtOAc/hexanes) afforded methyl isoquinoline-6-carboxylate as a white powder (7.0 g, 78% yield): LCMS (API ES) m/z 188 [M+1+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:22])([CH3:23])[C:19]([O:1][CH2:2][C:3]2[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: COC(=O)c1cnc(CO)s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(COC(=O)C(C)(C)Oc2ccc(Cl)cc2)s1

Procedure:
Using the procedure of Example 3, methyl 2-hydroxymethyl-thiazole-5-carboxylate and p-chlorophenoxy-isobutyric acid chloride were reacted in toluene and triethylamine to obtain methyl 2-[α-(p-chlorophenoxy)-α,α-dimethylacetoxymethyl]-thiazole-5-carboxylate melting at 80° C.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([CH2:11][CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(Cl)Cl.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([CH2:11][CH2:12][O:13][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:8]=[CH:9][CH:10]=2)[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccc(C2COC2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C3COC3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
4.9 g of 2-(3-Oxetan-3-yl-phenyl)-ethanol were dissolved using 30 ml of CH2Cl2 and 9.5 ml of pyridine added. Then, 6.3 g of p-toluenesulfonyl chloride was added at 0° C. and the reaction mixture stirred for 6 h at room temperature. The reaction mixture was then evaporated, re-dissolved using 100 ml of EA and washed using 100 ml of a saturated aqueous NaHCO3-solution. The aqueous layer was then extracted twice using 100 ml of EA each. The combined organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 2.0 g of the title compound, colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:12]2=[N:13][C:14]3[CH:15]=[C:16]([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:16]2[CH:17]=[CH:18][C:19]3[C:20](=[O:21])[N:11]4[CH2:10][CH2:9][NH:8][CH2:32][CH2:31][C:12]4=[N:13][C:14]=3[CH:15]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-8-(2-(3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carboxylate (1.3 g, 3.0 mmol) in DCM (30 mL) was added trifluoroacetic acid (15 mL). The mixture was stirred for 1 h at room temperature. Then the reaction mixture was concentrated and purified by silica gel chromatography to give the desired product. MS (ESI): 334 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.26-8.23 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.59-7.55 (d, J=8.3 Hz, 1.5 Hz, 1H), 7.38-7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.14-7.09 (m, 1H), 4.53-4.50 (t, J=3.6 Hz, 2H), 3.24-3.17 (m, 4H), 3.11-3.10 (t, J=4.5 Hz, 2H). mGluR5 PAM EC50: ++.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[CH3:25][C:26]([N-:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:27].[Na+].C(Cl)(Cl)Cl.CS(C)=O>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[CH3:25][C:26]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:27]
Reactant: CC(=O)[N-]S(=O)(=O)c1ccc(N)cc1
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and a yellowish gel was obtained in 76.99% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=35-40° C. Thermal data determined by thermalgravimetric analysis (TGA): Tonset5%=164° C. and Tonset=181° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[N:3]1[CH2:24][CH2:23][C:6]2([N:10]([CH3:11])[C:9](=[O:12])[CH:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>O1CCCC1>[CH2:37]([O:36][C:34](=[O:35])[O:22][C:7]1[C:6]2([CH2:5][CH2:4][N:3]([N:2]([CH3:1])[CH3:25])[CH2:24][CH2:23]2)[N:10]([CH3:11])[C:9](=[O:12])[C:8]=1[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])[CH3:38]
Reactant: Cc1cc(C)c(C2C(=O)N(C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(C)C12CCN(N(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
105 mg 8-Dimethylamino-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (from Step 4) and 62 mg triethylamine are dissolved in 5 ml tetrahydrofuran, and the mixture cooled in an ice bath. Then, 40 mg ethyl chloroformate is added at 0° C. The mixture is allowed to warm to room temperature, and stirred for 2 hours. Then water is added and the mixture extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and the solvent evaporated. The crude product is purified by chromatography on silica gel, with acetone as a solvent, yielding 110 mg Carbonic acid 8-dimethylamino-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester as an oil. 1H-NMR (CDCl3): 6.85 ppm (s, 2H), 4.03 ppm (q, 2H), 3.00 ppm (m, 2H), 2.96 ppm (s, 3H), 2.85 ppm (m, 2H), 2.42 ppm (s, 6H), 2.27 ppm (m, 2H), 2.24 ppm (s, 3H), 2.16 ppm (s, 2H), 1.83 ppm (m, 2H), 1.09 ppm (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Reactant: c1cn[nH]c1
Product: c1cnn(-c2nc(NCCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:44]([O:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=[O:57])=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[C@H:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=1)[C@@H:56]([C:55]1[CH:58]=[CH:59][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:53][CH:54]=1)[OH:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)c1ccc(OCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(O[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 75.6 %

Procedure:
In a similar manner to that described in Reference example 29(b), a reaction was carried out using (R)-4-benzyl-3-[(4isopropylphenoxy)acetyl]oxazolidine-2-one (10.0 g), which is the product of Reference example 30(a), solution of dibutylboron triflate in dichloromethane (1M, 34.0 ml), triethylamine (5.11 ml) and 4-benzyloxybenzaldehyde (6.60 g) and the reaction mixture was treated to afford the desired compound (12.1 g) as a mass of foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1Br)=[O:4].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:20][CH:17]1[CH2:19][CH2:18]1)=[O:4]
Reactant: NC1CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
To a solution of 3-Bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (250 mg, 0.89 mmol) in toluene (25 ml) was added cyclopropylamine (57 mg, 1.0 mmol), cesium carbonate (382 mg, 1.2 mmol), BINAP (50 mg, 0.08 mmol) and tris(dibenzylidenacetone)dipaladium (0) (38 mg, 0.04 mmol). The reaction mixture was stirred for 16 h at 110° C. in a sealed tube. The mixture was partitioned between toluene (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with toluene (2×10 mL) and the combined toluene layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% EtOAc/Hexane) to obtain 52 mg (22%) of 3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.67-7.62 ppm (m, 2H, Haro); 7.43-7.32 ppm (m, 3H, Haro); 7.16 ppm (s, 1H, Haro); 3.82 ppm (s, 3H); 2.65 ppm (m, 1H); 0.62 ppm (m, 2H); 0.35 ppm (m, 2H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]([O:17][C:18](=[O:36])[CH2:19][C@H:20]([NH:29][CH2:30][CH:31](OC)OC)[C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.[N:44]1[C:49]2[NH:50][CH2:51][CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=[CH:46][C:45]=1[CH2:55][CH2:56][CH2:57][NH2:58].OS(O)(=O)=O>C1COCC1>[C:13]([O:17][C:18](=[O:36])[CH2:19][C@@H:20]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[N:29]1[CH:30]=[CH:31][N:58]([CH2:57][CH2:56][CH2:55][C:45]2[CH:46]=[CH:47][C:48]3[CH2:54][CH2:53][CH2:52][CH2:51][NH:50][C:49]=3[N:44]=2)[C:5]1=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: NCCCc1ccc2c(n1)NCCCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc([C@H](CC(=O)OC(C)(C)C)NCC(OC)OC)cn1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](CC(=O)OC(C)(C)C)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 208.3 %

Procedure:
To a solution of triphosgene (0.246 g, 0.804 mmol) in THF (5 mL) at 0° C. was added a mixture of 1-6 (0.78 g, 2.29 mmol), triethylamine (0.36 mL, 3.09 mmol) and THF (1 mL) over 10 minutes. After 30 minutes, the reaction was allowed to warm to ambient temperature and stir for 1 hour. The mixture was then purged with argon for 30 minutes, and to it was added a mixture of 3-6 (0.435 g, 2.52 mmol), triethylamine (0.36 mL, 3.09 mmol) and THF (5 mL). The mixture was then heated at 0° C. for 2 hours, allowed to cool to ambient temperature. 2M H2SO4 (2.5 mL) was then added, and the mixture stirred for 15 hours. The reaction was then quenched with a 10% w/v solution of K2CO3 (10 mL), diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to give 850 mg of 3-7 as a yellow oil, used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:26][CH2:27]2)=[CH:19][CH:20]=1
Reactant: Clc1c(-c2ccc(CN3CCNCC3)cc2)ccc2c1nnn2CC1CC1
Reactant: N#CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCC(=O)N1CCN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-chloro-1-(cyclopropylmethyl)-5-[4-(piperazin-1-ylmethyl)phenyl]-1H-benzotriazole (Example 71, 15 mg, 0.039 mmol) in dichloromethane (530 uL) was added cyanoacetic acid (6.7 mg, 0.079 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (31 mg, 0.059 mmol) and diisopropylethylamine (34 uL, 0.20 mmol). After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (95:5 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid) to afford the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.01 (1H, d, J=8.5 Hz), 7.66 (2H, d, J=7.7 Hz), 7.62 (2H, d, J=7.7 Hz), 7.60 (1H, d, J=8.6 Hz), 4.68 (2H, d, J=7.4 Hz), 4.39 (1H, br s), 2.57-2.46 (10H, m), 1.75-1.72 (2H, m), 1.49-1.38 (1H, m), 0.60-0.56 (2H, m), 0.52-0.49 (2H, m) ppm high resolution mass spectrometry (ES+) m/z 449.1862 [(M+H)+; calculated for C24H26ClN6O: 449.1851].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([CH2:16][C:17]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])#[N:15]>>[C:14]([C:16](=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:17]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])#[N:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)COC(=O)CC#N
Product: CC(C)(C)COC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 67 %

Procedure:
The procedure described in Example 4 was repeated using 3,4-dihydroxy-5-nitrobenzaldehyde and neopentyl cyanoacetate. Yield 67%, m.p. 173°-179° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])/[CH:5]=[CH:12]/[C:11]([OH:14])=[O:13]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C=O)cc1C
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(/C=C/C(=O)O)cc1C
Yield: 69.8 %

Procedure:
A 1 L single-neck round bottom flask equipped with a condenser, magnetic stir bar, and a nitrogen inlet was charged with 3,4-dimethylbenzaldehyde (Lancaster 97%, 70.0 g, 0.52 mol), sodium acetate (anhydrous, 47.1 g, 0.57 mol), and acetic anhydride (300 mL, 3.2 mol). The mixture was stirred and heated to reflux. After 48 hours heating was discontinued and the reaction mixture was quenched, while still hot, by the cautious addition of water (300 mL). Ice-water was added to double the volume and the mixture was extracted with diethyl ether (700 mL); the organic phase was separated, washed with water (4×1 L), dried over anhydrous magnesium sulfate, and evaporated to dryness. Recrystallization of the crude product from methanol gave trans-3,4-dimethylcinnamic acid (64.0 g, 97% purity by GC) as yellow crystals. 1HNMR (CD2Cl2, 500 MHz) δ7.74 (d, JAB=16 Hz, 1H); 7.36 (br s, 1H); 7.32 (d, JAB=8 Hz, 1H); 7.18 (d, JAB=8 Hz, 1H); 6.41 (d, JAB=16 Hz, 1H); 2.29 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CS(O[CH2:34][CH:35]1[CH2:38][C:37]([F:40])([F:39])[CH2:36]1)(=O)=O>>[F:39][C:37]1([F:40])[CH2:38][CH:35]([CH2:34][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([C:9]4[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH3:18])=[CH:11][CH:10]=4)[O:8][C:4]=3[CH:3]=2)[CH2:36]1
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Reactant: C[C@@H](COc1ccc(-c2nc3ccc(O)cc3o2)nc1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ccc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)nc1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl [(1S)-2-{[6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate and (3,3-difluorocyclobutyl)methyl methanesulfonate, and in the same manner as in Example 2, step E, the title compound was obtained.