Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:1].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:26]3[CH2:25][CH2:24][N:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:29])([F:30])[F:15])[CH:18]=4)[CH2:28][CH2:27]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: Fc1ccc2c(CCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)noc2c1
Yield: 35.8 %

Procedure:
A mixture of 6.5 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 5.8 g of N-(α,α,α-trifluoro-m-tolyl)piperazine, 7.0 g of potassium carbonate and a few crystals potassium iodide in 80 ml of dimethylformamide was stirred at 70°-75° C. for seven hrs. The reaction mixture was cooled, filtered and concentrated to an oil, which was stirred with water and extracted with ether-ethyl acetate. The organic extracts were washed with water (2×), saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated to an oil, which was converted to a salt by treatment with ethereal hydrogen chloride. The salt was recystallized from ethyl acetate/methanol to give 4 g (35%) of product mp, 208°-209° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[CH2:16]([O:19][C:20]1([CH3:49])[CH2:25][CH2:24][N:23]([C:26]2[N:31]3[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Br:41])[CH:36]=4)[CH:34]=[C:30]3[N:29]=[C:28]([CH3:42])[C:27]=2[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22][CH2:21]1)[CH:17]=[CH2:18].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[CH2:16]([O:19][C:20]1([CH3:49])[CH2:25][CH2:24][N:23]([C:26]2[N:31]3[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Br:41])[CH:36]=4)[CH:34]=[C:30]3[N:29]=[C:28]([CH3:42])[C:27]=2[CH:43]([OH:14])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22][CH2:21]1)[CH:17]=[CH2:18]
Reactant: C1CCOC1
Reactant: C=CCOC1(C)CCN(c2c(CC(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: C=CCOC1(C)CCN(c2c(C(O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1M KHMDS/THF (49.3 mL, 49.3 mmol) in THF (150 mL) at −78° C. was added dropwise a THF (100 mL) solution of ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (20 g, 37.9 mmol) over 5 min. After 30 min, a THF (100 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (12.88 g, 49.3 mmol) was added and stirred for additional 30 min at −78° C. Then, the resulting dark reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage(5-50% EtOAc/hexane) to afford ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (17 g, 31.3 mmol, 82% yield) as white foam. Impurities were present by NMR. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.16 (t, J=1.7 Hz, 1H), 7.99-7.92 (m, 1H), 7.58-7.50 (m, 2H), 7.34 (t, J=7.9 Hz, 1H), 6.83 (s, 1H), 6.18-6.06 (m, 1H), 5.57 (d, J=5.4 Hz, 1H), 5.48 (d, J=17.0 Hz, 1H), 5.27 (d, J=10.2 Hz, 1H), 4.83 (br. s., 2H), 4.35 (dq, J=10.8, 7.1 Hz, 1H), 4.23 (dq, J=10.9, 7.1 Hz, 1H), 4.06-3.99 (m, 2H), 2.65 (s, 3H), 2.00 (d, J=14.2 Hz, 2H), 1.84 (d, J=13.4 Hz, 2H), 1.36 (s, 3H), 1.29-1.26 (m, 3H). LCMS (M+H)=545.3.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH2:12][C:13]([CH3:15])=[CH2:14])=[CH:3]/[CH2:4][OH:5].[C:17]1(C)C=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.[OH2:28]>O1C=CCCC1>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]/[CH2:4][O:5][CH:21]1[CH2:20][CH2:19][CH2:18][CH2:17][O:28]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: C=C(C)CCC/C(C)=C/CC/C(C)=C\CO
Agent: C1=COCCC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Reaction time: 2 h

Procedure:
A solution of 1 g (0.0045 mol) (2Z,6E)-3,7,11-trimethyl-2,6,11-dodecatrien-1-ol in 32 ml of 3,4-dihydro-2H-pyran is treated at 0° with 91 mg of p-toluenesulfonic acid. The solution is stirred at the same temperature for 2 hours under argon. After the addition of 100 ml of water the mixture is extracted with ether. The organic phase is washed with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained tetrahydro-2-[[(2Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran which has the following bands in the IR spectrum: 1666 cm-1, 1444 cm-1, 1379 cm-1, 1116 cm-1, 1075 cm-1, 1020 cm-1.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[C:44]([F:52])=[C:45]([S:48](Cl)(=[O:50])=[O:49])[CH:46]=[CH:47][C:39]1=2)#[N:27].CO>C1COCC1.CO.O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[C:44]([F:52])=[C:45]([S:48]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])[CH:46]=[CH:47][C:39]1=2)#[N:27]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c1ccc(S(=O)(=O)Cl)c2F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c1ccc(S(=O)(=O)Nc1nccs1)c2F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.036 g, 0.162 mmol) was added THF (0.482 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.177 ml, 0.177 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.062 g, 0.147 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was allowed to warm to rt over 1 hr providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture concentrated under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr, the mixture was concentrated under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid, which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.04 g, 0.083 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83-3.95 (m, 2 H) 4.34-4.46 (m, 2 H) 6.56 (dd, J=8.90, 1.27 Hz, 1 H) 6.84 (d, J=4.60 Hz, 1 H) 7.17 (dd, J=8.85, 7.29 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.76 (d, J=8.61 Hz, 1 H) 8.11 (dd, J=8.80, 2.05 Hz, 1 H) 8.42 (d, J=1.76 Hz, 1 H) 12.80 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:20][OH:21].Cl[C:23](Cl)(Cl)[CH:24]([OH:26])O>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:26])[CH:23]=[N:20][OH:21])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCc1cc(Br)ccc1N
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(Br)ccc1NC(=O)C=NO
Temperature: 90 °C
Yield: 45.9 %

Procedure:
To a suspension of 4-bromo-2-ethylaniline (50.0 g, 250 mmol) in water (1000 mL) was added concentrated hydrochloric acid (25 mL), sodium sulfate (220 g), and hydroxylamine hydrochloride (56.25 g), followed by addition of chloral hydrate (44.0 g). The reaction mixture was heated to 90° C. using an oil bath for 1 hour. After cooling down to room temperature, it was extracted with ethyl acetate. Extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (31.1 g, 46% yield). 1H NMR (DMSO-d6) δ 12.24 (s, 1H), 9.56 (s, 1H), 7.68 (s, 1H), 7.41 (m, 3H), 2.58 (q, 2H), 1.11 (t, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])[CH2:20][CH2:19]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2](=[O:3])[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]3=4)=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethyl-amine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=533.3
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23](C(OCC1C=CC=CC=1)=O)[C@@H:24](C(O)=O)[CH2:25]C1C=CC=CC=1>C(N(CC)CC)C.ClCC#N>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([O:12][CH2:25][C:24]#[N:23])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: N#CCCl
Solvent: CCN(CC)CC
Product: N#CCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 gram of Z-L-Phe-OH or Z-D-Phe-OH was dissolved in 2 mL of triethylamine and 2 mL of chloroacetonitrile. The reaction was stirred for two hours at room temperature. The reaction was concentrated under vacuum and the residue taken up in 5 mL ethyl acetate. The ethyl acetate was then washed with 2% Na2CO3 (3x), water (2x), 1 N HCl (2x), water (2x), and 0.5 M or higher saline (1x). The organic phase was dried over MgSO4, and concentrated to dryness. The residue was recrystallized from CH2Cl2 /hexanes. Yield for Z-L-Phe-OCH2CN was 1.0 g (89%). M.P. 53°-55° C. [α]d (c 2, DMF)+6.6°. 1H-NMR (CDCl3) 3.1 (d, 2H, Phe βH), 4.7 (m, 3H, αH and cyanomethyl), 5.1 (s, 2H, CBZ βH), 5.2 (d, 1H, amide), 7.3 (m, 10 H, Phe and CBZ phenyl). Z-D-Phe-OCH2CH, yield 0.88 g (78%). M.P. 53°-54° C. [α]d (c, 2, DMF)-6.1°.
Reaction SMILES: Br[C:2]1([NH:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[S:6][NH:5][CH:4]=[N:3]1.[C:19]([Cu])#[N:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][C:2]2[S:6][N:5]=[C:4]([C:19]#[N:20])[N:3]=2)=[CH:13][CH:14]=1
Reactant: N#C[Cu]
Reactant: CC(C)(CNC1(Br)N=CNS1)c1ccc(F)cc1
Product: CC(C)(CNc1nc(C#N)ns1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 8.9 %

Procedure:
5-Bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5-amine (635 mg, 1.92 mmol, 1.0 equiv) and CuCN (224 mg, 2.5 mmol, 1.3 equiv) were added to a microwave vial equipped with a stirbar. A septum was affixed to the vial, and the vial was purged with nitrogen for ˜5 min. DMF (2.5 mL) was then added, and the vial was sealed and heated for 20 min at 120° C. in a microwave. The reaction mixture was diluted with EtOAc and washed with sat'd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC provided the title compound (47 mg, 9%). m/z=275.0 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])([F:7])[F:6].[CH:13]1[CH2:17][CH:16]=[CH:15][CH:14]=1>>[F:9][C:4]1([C:5]([F:8])([F:7])[F:6])[C:3]([F:10])([C:2]([F:11])([F:12])[F:1])[CH:16]2[CH2:17][CH:13]1[CH2:14][CH2:15]2
Reactant: C1=CCC=C1
Reactant: FC(=C(F)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)C1(F)C2CCC(C2)C1(F)C(F)(F)F

Procedure:
In a like manner, octafluoro-but-2-ene and cyclopentadiene react to give 2,3-difluoro-2,3-bis(trifluoromethyl) bicyclo [2.2.1] heptane which, after hydrogenation over ruthenium gives 2,3-bis(trifluoromethyl)bicyclo [2.2.1] heptane.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=1>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>[Br:27][C:28]1[N:29]=[C:30]([C:6]2[N:10]3[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]3=[N:8][CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1ccn2c(-c3cccc(Br)n3)cnc2n1

Procedure:
To the degassed solution of 3-tributylstannyl-7-trifluoromethyl-imidazo[1,2-α]pyrimidine was added 2,6-dibromopyridine (1.8 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (218 mg, 0.18 mmol) and the mixture heated at reflux for 3 h. The crude reaction was adsorbed onto silica and purified by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-60%) to give a yellow solid. Crystallisation from ethyl acetate/isohexane afforded 3-(6-bromopyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (702 mg) as a white solid: δH (400 MHz, DMSO) 7.64 (1H, d, J 9), 7.83 (1H, d, J 8), 7.93 (1H, dd, J 9 and 9), 8.20 (1H, d, J 9), 8.92 (1H, s), 10.18 (1H, d, J 9); m/z (ES+) 343, 345 (M++H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[F:17].CCCCCC.CN([CH:27]=[O:28])C>C1COCC1>[F:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[CH:27]=[O:28]
Reactant: Fc1c(Br)ccc2c1ncn2C1CCCCO1
Reactant: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(ncn2C2CCCCO2)c1F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 91.2 %

Procedure:
To a solution of 146 (10 g, 0.034 mol) in dry THF (100 mL) at −78° C. was added dropwise 1.6 M N-butyl lithium solution in hexane (23 mL, 0.0374 mol). After stirring for 45 min at −78° C., a solution of DMF (5 g, 0.068 mol) in THF (20 mL) was added dropwise. After 1 h at −78° C. the reaction mixture was quenched slowly by adding water. The aqueous phase separated was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 15% EtOAc/petroleum ether to afford 7.7 g (93%) of 4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (148) as a yellow solid.
Reaction SMILES: O=CC[CH:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5]1.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19].[C:21]1(C)C=CC=C[CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:16]1([CH2:17][CH:18]([OH:20])[CH3:19])[CH:22]=[CH:21][C:13]2[CH2:4][S:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: Cc1ccccc1
Reactant: CC(O)CN
Reactant: O=CCC1CC(=O)c2ccccc2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1ccccc1SC2
Reaction time: 0.58 h
Yield: 76 %

Procedure:
A solution of 2 g of 2-(2-oxoethyl)-4-thiochromanone and 120 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator, A solution of 2.9 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). There were obtained 1.8 g (76%) of (RS)-1-(1,4-dihydro-[1]benzothiopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol as a pale brown solid which was used in the next reaction without further recrystallization.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.C1COCC1.O>C1COCC1>[I:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(I)c(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Methyl-2-iodobenzoic acid (100 g, 0.38 mol) is dissolved in THF (350 ml) and cooled in an ice bath. Borane-THF complex (380 ml of 1M in THF, 0.38 mol) is added dropwise. After addition is complete, the reaction is warmed to room temperature and stirred for 14 hours. The mixture is transferred to a large erlenmeyer flask, cooled in an ice bath, and carefully quenched with water (250 ml). Evaporation of the THF on a rotovap gives a white suspension which is treated with additional water (1L) and then filtered and dried in a vacuum dessicator over P2O5 to give 2-iodo-5-methylbenzyl alcohol as a white solid, m.p. 82-85°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][NH2:21].O>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:21][CH3:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
2,4-Difluoronitrobenzene (1.00 g, 6.29 mmol), potassium fluoride (0.365 g, 6.29 mmol), potassium carbonate (0.869 g, 6.29 mmol), and 40% methylamine in water (0.58 mL, 7.5 mmol) were added to a vial and heated in a microwave at 90° C. for 10 min. The reaction was then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) δ 8.22 (dd, J=9.4, 6.1 Hz, 1 H), 8.16 (br s, 1 H), 6.48 (dd, J=11.5, 2.6 Hz, 1 H), 6.40-6.36 (m, 1 H), 3.01 (d, J=5.0 Hz, 3 H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.CN(C)C=O>O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:6]3[C:5]4[CH:4]=[CH:3][C:2](=[O:1])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)=[CH:19][CH:18]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)ccc23)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc3[nH]c(=O)ccc23)cc1

Procedure:
N-(4-Fluorophenyl)-N′-{4-[(7-oxo-7,8-dihydro[1,8]naphthyridin-4-yl)oxy]aniline (30 mg), p-fluorophenyl isocyanate (0.016 ml) and dimethylformamide (6 ml) were stirred at 70° C. until disappearance of the starting materials. After returning the reaction solution to room temperature, water was added dropwise and the precipitated solid was filtered out to obtain 22 mg of a light brown solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>CN(C)C=O>[CH2:3]([O:10][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[N:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
The (2RS,3SR)-3-(5-hydroxypryid-5-yl)-3-methoxy-2-methyltetrahydrofuran used as a starting material was obtained as follows: Sodium hydride (50% w/w dispersion in mineral oil, 5 g) was added portionwise to a mixture of benzyl alcohol (12.4 g) and dimethylformamide (150 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for 1 hour. 3,5-Dibromopyridine (25.2 g) was added and the mixture was heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and a dilute aqueous potassium carbonate solution. The organic layer was washed with a dilute aqueous hydrochloric acid solution and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was a red oil which on trituration under petroleum ether (b.p. 60°-80° C.) gave 5-benzyloxy-3-bromopyridine (18.6 g, 67%), m.p. 65°-67° C. A solution of a portion (11.5 g) of this product in diethyl ether (500 ml) was cooled to -50° C. and n-butyl-lithium (1.5M in hexane, 32 ml) was added dropwise. The mixture was stirred at -50° C. for 20 minutes, further cooled to -60° C. and a solution of 2-methyltetrahydrofuran-3-one (5 g) in diethyl ether (50 ml) was added. The mixture was stirred at -60° C. for 1 hour and at -30° C. for 30 minutes. A saturated aqueous ammonium chloride solution (200 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained (2RS,3SR)-3-(5-benzyloxypyrid-3-yl)-3-hydroxy-2-methyltetrahydrofuran (7.8 g, 63%), as an oil; the 2-methyl and 3-hydroxy groups being in a cis-relationship.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[I:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([I:24])[C:18]=1[OH:25].[OH-].[K+]>C(O)C>[I:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[C:19]([I:24])[C:18]=1[O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCBr
Reactant: Oc1c(I)cc(I)cc1I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCCOc1c(I)cc(I)cc1I
Reaction time: 12 h
Yield: 60.8 %

Procedure:
Ethanol (70 mL) was added with 12-bromododecanoic acid (4.8 g) and 2,4,6-triiodophenol (9.1 g) and the mixture was refluxed for dissolution. The solution was added with potassium hydroxide (2.2 g) and stirred for 12 hours. The precipitates obtained were separated by filtration, washed with ethanol and added with chloroform and 1 N hydrochloric acid to conduct extraction with chloroform twice. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the resulting residue was purified by silica gel column chromatography to obtain 12-(2,4,6-triiodophenoxy)dodecanoic acid (7.0 g, yield: 60%). In the same manner as the synthetic method of 12-(2,4,6-triiodophenoxy)dodecanoic acid, 16-(2,4,6-triiodophenoxy)hexadecanoic acid was synthesized from 16-bromohexadecanoic acid.