Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:29]=[CH:28][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:42][CH2:43][OH:44]>O.C(OCC)(=O)C>[F:27][C:24]([F:26])([F:25])[CH2:23][N:19]1[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:42][CH2:43][OH:44])[CH:5]=5)[CH:29]=[CH:28][C:9]=4[C:10]=3[N:11]=2)=[N:22][CH:21]=[N:20]1
Reactant: OCCBr
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
A solution of 8-(1H-Pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.30 g, 0.00072 mol) and Cesium Carbonate (0.28 g, 0.00086 mol) in N,N-Dimethylformamide (1.5 mL, 0.019 mol) was stirred at room temperature for 5 minutes. 2-Bromoethanol (0.061 mL, 0.00086 mol) was added and the reaction was stirred at 70° C. overnight. The mixture was cooled to room temperature and ethyl acetate and water were added to the reaction. The aqueous layer was extracted 3 times with ethyl acetate and the combined organics were washed with water, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 150 (48.4 mg) as a colorless solid. MS (ESI+) 463.1. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.27 (d, J=8.3, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.6, 1H), 7.31 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.91 (t, J=5.3, 1H), 4.40 (t, J=4.9, 2H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.6, 2H), 3.47 (t, J=4.9, 2H)
Reaction SMILES: C([O:8][C:9](=[O:30])[C@@H:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:11]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:24]([O:23][C:21]([CH2:20][CH2:19][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[C@@H:10]([C:9]([OH:30])=[O:8])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:22])[CH3:25]
Reactant: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CC(C)C)C(=O)O
Yield: 93 %

Procedure:
N-[2-(ethoxycarbonyl)ethyl]-N-t-butyloxycarbonyl-D-leucine benzyl ester (837 mg) was dissolved in methanol (25 ml), and 10% palladium-carbon (90 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless oil (612 mg, 93%), which was directly used for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([B:10]([OH:12])[OH:11])=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(B(O)O)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(B(O)O)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 3-amino-4-methoxyphenylboronic acid (1 eq, 2.10 mmol, 0.35 g) in CH2Cl2 (5 mL) at −78° C. was added Et3N (6 eq, 13.0 mmol, 1.7 mL). The reaction was stirred for 30 minutes then methanesulfonyl chloride (1.1 eq, 2.30 mmol, 0.26 g) was added. The reaction was then stirred at −78° C. for 1 hour. The reaction was allowed to warm to room temperature and diluted with CH2Cl2. The reaction washed with 1.0N aqueous HCl and the organic phase was extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 4-methoxy-3-(methylsulfonamido)phenylboronic acid (1.92 mmol, 0.49 g, 96%) as a white solid.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12]O)=[CH:9][CH:8]=1)#[N:6]>C(Cl)(Cl)(Cl)Cl>[C:5]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][Br:2])=[CH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
A solution of phosphorus tribromide (5 g) in carbon tetrachloride (10 ml) was added, dropwise, to a solution of 4-cyanophenethyl alcohol (8.06 g) in carbon tetrachloride (60 ml). The mixture was heated under reflux for 4 hours. On cooling to room temperature, the mixture was poured onto ice (200 g). The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to give a colourless oil which solidified on standing. The solid was chromatographed on silica eluting with ethyl acetate containing hexane (20%). The fractions containing the less polar (higher Rf) product were combined and concentrated in vacuo to give 4-cyanophenethyl bromide as a yellow oil which solidified on standing, yield 8.9 g. The fractions containing the more polar (lower Rf) product were combined and concentrated in vacuo to give the title compound as a colourless solid, yield 0.47 g, m.p. 152°-153° .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](Cl)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[S:30][CH:34]=[CH:33][N:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(Cl)c1nccs1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nccs2)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 20 mg, 50 μmol) and 1,3-thiazole-2carbonyl chloride (23 mg, 150 μmol). Yield 25 mg (97%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18](=[O:20])[CH3:19])=[CH:16][C:5]2[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:4]=2[CH:3]=1.C[O-].[Na+].[CH:24](OCC)=O>COCCOC.O>[NH:1]1[C:2]2[CH:3]=[C:4]3[O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][C:5]3=[CH:16][C:17]=2[C:18](=[O:20])[CH:19]=[CH:24]1
Reactant: CCOC=O
Reactant: CC(=O)c1cc2c(cc1N)OCCOCCOCCO2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1cc[nH]c2cc3c(cc12)OCCOCCOCCO3
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-(3-Amino-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HC 1. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7,8,10,11,13,14-Hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-one. 1HNMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 7.12 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+292.3. found 292.5.
Reaction SMILES: N1C=CN=C1.Cl[Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].CN(C=O)C.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[C:33]([OH:35])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1>C(OCC)(=O)C.O>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[C:33]([O:35][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:34]=[C:25]([C:24]([O:23][CH3:22])=[O:36])[CH:26]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 5.1 g of imidazole and 12.9 ml of chlorotriisopropylsilane to a 100 ml DMF solution containing 10.5 g of 5-hydroxyisophthalic acid dimethyl ester, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (21.53 g) as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32]([N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46](O)=[O:47])[CH:43]=3)[CH2:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])=[C:27]([CH3:49])[CH:26]=1.[CH2:50]1[C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52][N:51]1[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH3:49])[C:28]([S:32]([N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46]([N:57]4[CH2:56][CH2:55][C:54]5([CH2:50][N:51]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:52][CH2:53]5)[CH2:59][CH2:58]4)=[O:47])[CH:43]=3)[CH2:38][CH2:37][CH2:36]2)(=[O:33])=[O:34])=[C:29]([CH3:31])[CH:30]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)O)cc32)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)N4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)cc32)c(C)c1
Yield: 53 %

Procedure:
The target compound was prepared according to general working procedure GWP X (TBTU coupling) from the starting materials 2-(1-(4-methoxy-2,6-dimethylphenyl-sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)acetic acid (E-10) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (F-26). Yield: 53%
Reaction SMILES: [C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C(=O)N([Br:30])C(=O)C1>C(#N)C.C(O)(=O)C>[Br:30][C:16]1[CH:17]=[CH:18][C:11]2[N:12]([CH:15]=1)[C:13](=[O:14])[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:9]([C:19]([O:21][CH3:22])=[O:20])[N:10]=2
Reactant: COC(=O)c1nc2ccccn2c(=O)c1OC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1nc2ccc(Br)cn2c(=O)c1OC(=O)C(C)(C)C
Reaction time: 96 h

Procedure:
Methyl 3-[(pivaloyl)oxy]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (see Example 1, Step 2a) and NBS (5 eqs.) were dissolved in a 3:1 mixture of acetonitrile and acetic acid. The solution was left standing at 5° C. with occasional shaking for 4 days. The solvents were removed under reduced pressure and the residue was suspended in chloroform. The precipitate was removed by filtration and the solution concentrated under vacuum. The residue was dissolved in dichloromethane, and triethylamine (7 eqs.) was added. The mixture was stirred for 1.5 hours at room temperature, the solvent removed under vacuum, and the residue partitioned between EtOAc and 1N aqueous HCl. The organic phase was washed with 1N aqueous HCl and the combined aqueous phases extracted with EtOAc. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was isolated by flash chromatography (SiO2, eluant: PE/EtOAc, 4.5:5.5). The product was obtained as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12](S(C2C=CC=CC=2)(=O)=O)[CH:11]=1)([CH3:3])[CH3:2].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-c1c[nH]c2ccccc12
Yield: 89.8 %

Procedure:
3-Bromo-1-(phenylsulfonyl)-1H-indole (7.45 g, 22.2 mmol), 2-isopropylbenzene boronic acid (4.00 g, 24.4 mmol), tetrakis(triphenylphosphine)palladium (0) (769 mg, 0.67 mmol) and sodium carbonate (7.05 g, 66.5 mmol) were combined in a round bottomed flask and placed under an argon atmosphere. Degassed solvent (3:1:1 toluene/ethanol/water) (100 mL) was added and the contents were heated to 80° C. for 14 h. Upon completion of the reaction, as determined by TLC, the phases were separated, the aqueous phase was extracted three times with 20 mL ethyl acetate and all the organic phases were combined, washed once with water (20 mL) and once with brine (20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to yield a dark residue which was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexanes to yield 3-(2-isopropylphenyl)-1-(phenylsulfonyl)-1H-indole (6.79 g, 82%) as a glassine solid. LC/MS (ESI+) 376.2 (M+H)+. 3-(2-Isopropylphenyl)-1-(phenylsulfonyl)-1H-indole (119 mg, 0.317 mmol) was combined with anhydrous tetrahydrofuran (2 mL) and tetra-n-butylammonium fluoride (1 M in THF, 1.3 mL) and heated to reflux for 14 h. Upon completion as observed by analysis by LC/MS the reaction was diluted with methanol (1 mL) and the solvent was evaporated under reduced pressure to yield a residue which was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexanes to yield 3-(2-isopropylphenyl)-1H-indole (67 mg, 90%) as a colorless glassine solid. LC/MS (ESI+) 236.23 (M+H)+. To 3-(2-isopropylphenyl)-1H-indole (23 mg, 0.10 mmol) in anhydrous tetrahydrofuran (1 mL) was added sodium bis(trimethylsilyl) amide solution (0.1 mL, 0.1 mmol, 1 M in tetrahydrofuran) and stirred for 15 min at ambient temperature. Isocyanatobenzene (0.1 mmol, 1.0 eq.) in THF (1 mL) was added and the reaction was stirred at ambient temperature. Upon completion as observed by analysis by LC/MS the reaction was diluted with methanol (1 mL) and the solvent was evaporated under reduced pressure to yield a residue which was purified by reverse phase HPLC chromatography eluting with a gradient of methanol/water to yield Example 1 (7.8 mg, 22%) as a colorless solid. LC/MS (ESI+) 355.23 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=[O:9])[CH2:3][CH2:2]1
Reactant: OCCC1CCOCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCC1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.7 %

Procedure:
To a solution of 2-(tetrahydro-pyran-4-yl)-ethanol (13 g, 0.1 mol) in dichloromethane (150 mL) was added pyridinium chlorochromate (43 g, 0.2 mol) portion-wise at room temperature. The dark suspension was stirred at room temperature for 5 h. The reaction mixture was filtered through a short pad of silica gel. The filtrate was concentrated in vacuo to afford (tetrahydro-pyran-4-yl)-acetaldehyde (6.5 g, 50%) as a yellow oil which was used in the next step without purification.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[CH2:8][C@@H:7]1[OH:21])(=O)C.Cl.[OH-].[Na+]>CO>[C@@H:9]1([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:5][OH:4])[C@@H:7]([OH:21])[CH2:8]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)C[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 24 h

Procedure:
Dissolve 5'-O-acetyl-2'-deoxyadenosine (0.200 gms.) in methanol (15 ml.), add dilute hydrochloric acid (10 ml., 1 N) and allow the reaction mixture to stand at room temperature for 24 hours. Bring the solution to a neutral pH by the careful addition of dilute sodium hydroxide (2%). Filter any precipitated salts and wash the filtrate with pyridine. Concentrate the combined filtrate and pyridine washings in vacuo and recrystallize the resultant residue from methanol:water to give 2'-deoxyadenosine; m.p. 183°-188° C; [α]D22 -25° (water, c=0.4).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH:2]([CH3:4])[CH3:3].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)Cc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using 4.16 g (25 mM) of 4-isobutylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of toluene. 5-Isobutyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 4.69 g (23 mM) as colorless transparent liquid having a boiling point of 79°-83° C./2 mmHg.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][C:19]([OH:21])=O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][C:19]([N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:8])=[O:21]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)C#Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To a solution of sarcosine ethyl ester hydrochloride (1.14 g, 7.44 mmol) and 3-(2-fluorophenyl)prop-2-ynoic acid (1.22 g, 7.44 mmol) in anhyd. CH2Cl2 was added NMM (10 mL, 8.93 mmol), followed by EDCI.HCl (1.86 g, 9.67 mmol) and DMAP (0.99 g, 8.2 mmol). The reaction mixture was stirred for 5 h at room temperature and diluted with CH2Cl2. The resulting solution was washed with a 0.5N HCl solution (2×25 mL), a 0.5N NaOH solution (2×25 mL) and a saturated NaCl solution. The organic layer was dried (MgSO4), concentrated onto silica gel under reduced pressure and purified by flash chromatography (30% EtOAc/hex) to yield ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (1.50 g, 77%) as a yellow oil: TLC (50% EtOAc/hex) Rf 0.54; HPLC ES-MS m/z (rel abundance) 264 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OC(=O)C)(=O)[CH3:10]>>[CH3:9][C:10]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccncc1N
Product: Cc1nc2cnccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3,4-diaminopyridine (20.0 g, 183 mmol) and acetic anhydride (360 ml) was heated at 100° C. for 16 hours. The excess reagent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate:methanol, 3:1. The product was a brown solid, (15.5 g, 64%).
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:18]=[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:12]3=[N:11]2)=[N:8][CH:9]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].O>ClCCl>[Cl:28][CH2:29][C:30]([N:15]1[CH2:16][CH2:17][C:12]2=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:19])([F:2])[F:20])=[CH:9][N:8]=3)[CH:18]=[C:13]2[CH2:14]1)=[O:31]
Reactant: FC(F)(F)c1ccc(-n2cc3c(n2)CCNC3)nc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CCc2nn(-c3ccc(C(F)(F)F)cn3)cc2C1

Procedure:
1 g of 2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride is suspended in 12 ml of dichloromethane, in a round-bottomed flask equipped with a magnetic stirrer. 0.95 ml of triethylamine is added and the mixture is brought to 0° C. At 0° C., 0.33 ml of chloroacetyl chloride, i.e. the compound of general formula (V) in which Hal=Hal′=Cl and n=1, is run in dropwise. The mixture is left to react for 1 and a half hours and is poured into water. Extraction is carried out with dichloromethane. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. The residue is purified by flash chromatography on a Biotage® column, elution being carried out with 9 cyclohexane/1 ethyl acetate. 1.08 g of the title compound are obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13](I)=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+]>CN(C)C=O>[C:20]([C:13]1[N:12]=[C:11]2[S:18][C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:10]2[C:15](=[O:16])[CH:14]=1)#[N:21]
Reactant: N#C[Cu]C#N
Reactant: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCSc1nn2c(=O)cc(C#N)nc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
In 100 ml of dimethylformamide, 6 g of 2-hexylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 1.77 g of copper cyanide and 0.97 g of sodium cyanide were added and the solution was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was extracted with chloroform and water. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the organic layer and it was shaken. The solvent was distilled off, and 2.3 g of 7-cyano-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 51%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
Dissolve (5-fluoro-2-nitrophenyl)methanol (13.92 g, 81.08 mmol) in dichloromethane (284 mL). Add 4 Å molecular sieves (73 g) and pyridinium dichromate (36.58 g, 97.3 mmol). Stir the mixture at 20° C. for 6 hours. Filter the crude reaction mixture through a short silica gel column. Remove the solvent under reduced pressure and purify the residue by flash chromatography (silica gel, 10-20% ethyl acetate/hexane) to obtain 9.43 g (69%) of title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[NH:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1Br
Reactant: Nc1ccccc1
Solvent: CCO
Product: Cc1ccccc1Nc1ccccc1

Procedure:
2-Bromotoluene (2 mmol) is heated to 230° C. for 6 hours with aniline (20 mmol) in the presence of [(C6H5)2PCH2]2Ni(CO)2 (0.2 mmol) using ethanol (1.2 mL) as the solvent in a sealed tube to form 2-anilinotoluene. 2-Anilinotoluene is oxidized with potassium permaganate in water to form 2-anilinobenzoic acid. (See Cramer, et al., J. Org. Chem. (1975), 40:2267).