Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C2N=C(N)SC=2C([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=CC=1.ClC(OC1C=CC=CC=1)=O.C(O[C:37](=[O:56])[NH:38][C:39]1[S:40][C:41]2[C:47](C3C=CC=CC=3)=[CH:46][CH:45]=[C:44]([O:54][CH3:55])[C:42]=2[N:43]=1)C1C=CC=CC=1.[CH3:57][NH:58][CH:59]1[CH2:64][CH2:63][CH:62]([C:65]([F:68])([F:67])[F:66])[CH2:61][CH2:60]1>>[CH3:55][O:54][C:44]1[C:42]2[N:43]=[C:39]([NH:38][C:37](=[O:56])[N:58]([CH3:57])[CH:59]3[CH2:60][CH2:61][CH:62]([C:65]([F:66])([F:67])[F:68])[CH2:63][CH2:64]3)[S:40][C:41]=2[C:47]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:46][CH:45]=1
Reactant: CNC1CCC(C(F)(F)F)CC1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)nc12
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Agent: O=C(Cl)Oc1ccccc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N(C)C3CCC(C(F)(F)F)CC3)nc12
Yield: 96 %

Procedure:
4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine was first reacted with phenyl chloroformate as described for (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid benzyl ester in WO01/97786 and then with methyl-(4-trifluoromethyl-cyclohexyl)-amine. Usual workup, flash-chromatography (silica, eluent dichloromethane/methanol) and final evaporation of the solvent afforded the title compound as white crystals (96% yield), mp 157-167° C. MS: m/e=473(M+H+). Following the general method of example 1 the compounds of examples 2 to 12 were prepared.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=O)[O:22]C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Reactant: O=C1Cc2ccccc2S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1cccc(Cl)c1)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 18.2 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 60 ml of hexamethylphosphoric acid triamide is added dropwise to a suspension of 5.9 g of a 50% strength sodium hydride/mineral oil suspension in 180 ml of hexamethylphosphoric acid triamide whilst cooling, the reaction temperature being kept below 15°. After stirring for one hour at room temperature, 30.4 g of phenyl N-(3-chlorophenyl)-carbamate are added in portions, with external cooling. The mixture is stirred for a further 16 hours at room temperature and poured onto a mixture of 100 ml of 2 N hydrochloric acid and 1,000 g of ice, whereupon an oil separates out; this oil crystallises on leaving to stand for several hours. The crystals are collected and dissolved in 300 ml of diethyl ether. The solution is washed with water and the organic phase is separated off, dried over sodium sulphate and evaporated to dryness. The residue is recrystallised from ether and gives N-(3-chlorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide with a melting point of 175°-177°.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]([CH3:20])=[CH2:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]([CH3:20])([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C=C(C)OCc1ccccc1
Reactant: C#Cc1ccc(O)cc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)(C)OCc2ccccc2)cc1
Yield: 62.3 %

Procedure:
Using poly(p-hydroxystyrene) (4.0 g) [available from Maruzen Petrochemical Co., Ltd.: Mw ca. 20000] and benzylisopropenylether (4.2 g) [purchased from Tokyo Chemical Industry Co., Ltd.], the reaction and treatment were carried out in the same manner as described in Synthesis Example 2, to give 4.1 g of the desired product as a slightly yellow powder. The polymer was found to have p-(1-benzyloxy-1-methylethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of 4:6 based on 1HNMR.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CC(C)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2-methyl-propan-1-one was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with isobutyryl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, 6H, J=6.9 Hz), 1.95-2.06 (m, 4H), 2.80-2.86 (m, 1H), 2.92-2.99 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.10-4.14 (m, 1H), 4.54-4.57 (m, 1H), 5.08-5.12 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=444.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccc1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Product: c1ccc(CN2CC[C@H](Nc3ccccc3)C2)cc1

Procedure:
((S)-1-benzylpyrrolidin-3-yl)-phenylamine was synthesized using (S)-1-benzylpyrrolidin-3-ylamine and bromobenzene in the same manner as in Reference Example 3.
Reaction SMILES: Cl.Cl.C(C1C([O:11]C)=C(OC)C=CC=1CCN[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[C:28]([O:34]C)[C:27]=1[CH2:36][CH3:37])C.[BrH:38]>>[OH2:11].[BrH:38].[BrH:38].[CH2:22]([NH:23][CH2:24][CH2:25][C:26]1[C:27]([CH2:36][CH3:37])=[C:28]([OH:34])[C:29]([OH:32])=[CH:30][CH:31]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:22][NH:23][CH2:24][CH2:25][C:26]1[C:27]([CH2:36][CH3:37])=[C:28]([OH:34])[C:29]([OH:32])=[CH:30][CH:31]=1
Reactant: CCc1c(CCNCCCCCNCCc2ccc(OC)c(OC)c2CC)ccc(OC)c1OC
Agent: Br
Agent: Cl
Product: CCc1c(CCNCCCCCCNCCc2ccc(O)c(O)c2CC)ccc(O)c1O
Product: O

Procedure:
A suspension of Example 4 (i) (400 mg) in deoxygenated 48% hydrobromic acid (10 ml) was heated and stirred under reflux stirred for 24 h. A slow stream of nitrogen was passed through the mixture. The resulting solution was cooled and evaporated in vacuo. The solid obtained was recrystallised from methanol-ethyl acetate to give the title compound as a tan solid (300 mg), m.p. 200°-202°.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7]>>[C@@H:2]([O:5][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[C:11]#[N:12])([CH2:3][CH3:4])[CH3:1]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC[C@H](C)O
Product: CC[C@H](C)Oc1cccc([N+](=O)[O-])c1C#N
Yield: 85.2 %

Procedure:
Prepared as in Example 111c from (S)-butan-2-ol and 2,6-dinitrobenzonitrile in 85.2% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (t, J=7.6 Hz, 3H), 1.29 (d, J=6.4 Hz, 1H), 1.69 (m, 2H), 4.72 (m, 1H), 7.74 (dd, J=6.8, 2.4 Hz, 1H), 7.86 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[CH2:23]([O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O.O>[CH2:23]([O:25][C:26]1[C:31]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[N:7][C:6]=23)=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:24]
Reactant: CCOc1ncccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1ncccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Temperature: 85 °C
Yield: 68.1 %

Procedure:
To a 1 liter round bottom flask was added 15.00 g (40.76 mmol) of isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate, 8.85 g (52.99 mmol) of (2-ethoxypyridin-3-yl)boronic acid, 14.06 g (101.90 mmol) of K2CO3, 1.41 g (1.22 mmol) of P(PPh3)4, and a stirring rod. After adding all the solids, 200 ml of MeCN was added, followed by the addition of 100 mL of water. The reaction flask was plunged into an oil bath pre-heated to 85° C., and stirred vigorously. This reaction was setup to reflux. After stirring at 85° C. for about 16 hr, it was allowed to cool to RT and diluted with 200 mL of EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with 80 mL portions of EtOAc. The combined organic layers was washed with brine, dried over MgSO4, and concentrated. A small volume of DCM was used to dissolve the crude mixture, and then loaded directly onto a 750 g silica gel column for separation on the ISCO-XL. A gradient of 50% EtOAc/hex to 100% EtOAc was run for the first 35 minutes. The desired product did not elute, only some impurities eluted. However, about 10 minutes into running with 100% EtOAc, the desbromo side product starts eluting together with the desired product. Even though the desbromo compound is spread through all the fractions containing the desired product, the percentage of the desbromo compound seem to decrease with time. Therefore, the initial fractions containing the highest percentages of the desbromo were discarded, and the remaining fractions were concentrated to obtain 13.46 g of about 86% purity at 254 nm. (with about 14% desbromo compound). This material was recrystallized twice, using IPAC and heptanes, to obtain 11.4 g (68%) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 1.53 (t, J=7.07 Hz, 3 H) 3.59-3.70 (m, 4 H) 3.70-3.81 (m, 4 H) 4.53 (q, J=7.07 Hz, 2 H) 5.00 (dt, J=12.44, 6.28 Hz, 1 H) 6.38 (d, J=7.83 Hz, 1 H) 6.98 (dd, J=7.45, 4.93 Hz, 1 H) 8.01 (dd, J=4.93, 1.89 Hz, 1 H) 8.37 (d, J=7.83 Hz, 1 H) 8.70 (s, 1 H) 8.76 (dd, J=7.45, 1.89 Hz, 1 H). LRMS (ESI) m/e 411 [(M+H)+, calcd for C21H26N6O3 410].
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])(O)=O.[Na+]>ClC(Cl)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][N:4]2[CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL of dichloroethane, N-boc-4-formylpiperidine (750 mg) was added to the mixture, followed by 2 g NaHB(OAc)3 and 1 mL of glacial ACOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290 (M−99). Calc'd. for C21H31N3O4−389.5.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.CN(C)CCCN=C=NCC.[C:22]([OH:28])(=O)[CH2:23][CH2:24][C:25]#[CH:26]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:22](=[O:28])[CH2:23][CH2:24][C:25]#[CH:26]
Reactant: CNC
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethylamine (2 M solution in tetrahydrofuran, 8.53 ml), triethylamine (2.59 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3221 mg), were added to a solution of 4-pentynoic acid (552 mg) in methylene chloride (150 ml) and this reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed successively with 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to give the title compound (129 mg). The obtained compound was used in the following reaction without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[S:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>C(O)(=O)C.ClCCCl>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[S:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:41])[CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCNCC3)c2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (3 drops) was added to a mixture of N-cyclopropyl-3-[2-(cyclopropylmethyl)-1-oxo-4-(piperazin-1-ylsulfonyl)-1,2-dihydroisoquinolin-6-yl]-5-fluoro-4-methylbenzamide (Example 47d, 0.047 g) and paraformaldehyde (7.9 mg) in 1,2-dichloroethane (1 mL). The mixture was stirred at room temperature overnight then sodium triacetoxyborohydride (18.5 mg) was added and the reaction stirred at room temperature for 1 h. DCM (10 mL) was added and the solution washed with water (3×10 mL). The organics were dried (MgSO4), filtered and concentrated under reduced pressure then purified by preparative HPLC (Xbridge column using a 95-5% gradient of aqueous trifluoroacetic acid in acetonitrile) then evaporated to dryness. The product was passed through an ion exchange column (StratoSpheres TM SPE PL-HCO3 MP SPE by Polymer Laboratories, eluting with methanol), to give, after triturating with diethyl ether, the title compound (0.032 g) as a white solid.
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]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[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]=[C:15]1[CH2:16][CH2:17][C:18](=[CH:5][C:4]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=2)[C:14]1=[O:19]
Reactant: O=C1CCCC1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C1C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)CCC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 8 was repeated using 5.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.0 g of cyclopentanone. Yield 4.4 g (78%), m.p. 300° C. (decomp.).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].C1(N=C=O)C=CC=CC=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=2[CH2:32][CH2:33][CH2:34][N+:35]([O-])=[O:36])=[CH:20][C:19]=1[CH3:38].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=2[CH2:32][CH2:33][C:34]2[CH2:4][CH:3]([CH2:2][C:1]([O:6][CH3:7])=[O:5])[O:36][N:35]=2)=[CH:20][C:19]=1[CH3:38]
Reactant: C=CCC(=O)OC
Reactant: Cc1cc(C)c(CCC[N+](=O)[O-])c(-c2ccc(F)c(C)c2)c1
Solvent: Cc1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC1CC(CCc2c(C)cc(C)cc2-c2ccc(F)c(C)c2)=NO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A solution of 0.1 g (1.0 mmol) of methyl 3-butenoate and 0.174 ml (1.6 mmol) of phenyl isocyanate in 1 ml of toluene was added with stirring to a solution of 0.240 g (0.8 mmol) of the nitropropyl compound from Step D and 2 drops of triethylamine in 1 ml of toluene. The resulting mixture was stirred at room temperature for 3 hours. Additional quantities of methyl 3-butenoate (0.1 ml), triethylamine (0.1 ml) and phenyl isocyanate (0.15 ml) were added successively and stirring was continued overnight (18 hours). The mixture was filtered and the filtrate was concentrated in vacuo to a residue which was purified by flash chromatography on silica gel (230-400 mesh), first being eluted with methylene chloride to remove the impurities. Continued elution with acetone/methylene chloride (1:50, v/v) gave the desired product (0.218 g, 0.57 mmol, 71%) as a pale viscous oil. nmr (CDCl3) δ: 2.28 (6H, s), 2.32 (3H, s), 2.2-3.0 (6H, m), 3.70 (3H, s), 4.6-5.0 (H, m), 6.85 (H, bs), 7.0-7.2 (4H, m). IR (neat) 1735 cm-1
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].ClC1C=CC2[O:30][CH2:29]CC(CC(OCC)=O)C=2C=1>O1CCCC1>[CH3:29][O:30][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:14]=1
Reactant: OCCC1CCOc2ccc(Cl)cc21
Reactant: CCOC(=O)CC1CCOc2ccc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCO)CCO2

Procedure:
2-(6-Chloro-3,4-dihydro-1(2H)-benzopyran-4-yl)ethanol may be prepared by proceeding as in Example 1, but starting with lithium aluminium hydride (1.97 g), and ethyl (6-chloro-3,4-dihydro-1(2H)-benzopyran-4-yl)ethanoate (6.6 g) in tetrahydrofuran (120 cc). 2-(6-methoxy-3,4-dihydro-1(2H)-benzopyran-4-yl)ethanol (5.5 g) is thus obtained in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: CCI
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(F)cc(F)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2,4,6-trifluorophenylacetic acid (570 mg, 3.0 mmol), iodoethane (1.56 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) in 5 mL of dimethylsulfoxide is stirred at 50° C. for 3 h, and cooled to room temperature. The mixture is partitioned between diethyl ether and water. The organic layer is washed with water, and saturated sodium chloride, dried over magnesium sulfate, and filtered through hydrous magnesium silicate. The filtrate is concentrated to give ethyl 2,4,6-trifluorophenylacetate as a light yellow oil (581 mg, 2.66 mmol).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1C[O:12][C:13](=O)[CH2:14][CH2:15][C:16]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)=[CH:38][CH:37]=1)([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:20][CH:19]=1)[CH3:17].[BH4-].[Na+].CO.O>C1COCC1>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:53]=[CH:52][C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:45]=3)=[CH:38][CH:37]=2)([CH3:17])[CH2:15][CH2:14][CH2:13][OH:12])=[CH:19][CH:20]=1
Reactant: CC(CCC(=O)OCc1ccc2ccccc2n1)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a mixture in THF (50 mL) of 4.4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid 2-quinolylmethyl ester (2.1 g, 3 mmol), prepared as in Example 1, and sodium borohydride (380 mg, 10 mmol) was added dropwise methanol at 50°-55° C. and the mixture was stirred for 30 minutes. The mixture was cooled to room temperature, poured into water (50 mL) and acidified to pH 4. The resulting mixture was extracted with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 3:1) to afford 1.46 g (88%) of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol: 1H NMR (300 MHz, DMSO-d6) d 1.18 (m, 2H), 1.48 (s, 3H), 2.00 (m, 2H), 3.34 (m, 2H), 4.34 (t, 1H, J=6 Hz), 5.30 (s, 4H), 6.96 (d, 4H, J=9 Hz), 7.09 (d, 4H, J=9 Hz), 7.64 (m, 4H), 7.79 (m, 2H), 8.00 (t, 4H, J=8 Hz), 8.41 (d, 2H, J=8 Hz); MS (DCl--NH3) m/e 555 (M+H)+. Anal. Calc'd. for C37H34N2O3.0.5 H2O: C, 78.84; H, 6.44; N, 4.97. Found: C, 78.67; H, 5.95; N, 4.70.
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][Cl:16])[CH2:7][CH:8]([CH3:10])[CH3:9].ClCCl.ClC1C=CC=CC=1>ClC(Cl)C>[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[N:13]([CH2:14][CH2:15][Cl:16])[N:1]=[O:2])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=N[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CC(Cl)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Dinitrogen trioxide gas (1.5 g) was introduced into a solution of the thus prepared 3-isopentyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (4.68 g, 11.38 mmol) in a mixture of dichloroethane (50 ml), dichloromethane (10 ml), and monochlorobenzene (10 ml) with thorough stirring at 10°-18° C., and stirring was continued for further one hour at the same temperature. The reaction mixture was vacuum-concentrated at 28° C. or below and purified by column chromatography (packing silica gel; eluent: octane/isopropyl acetate 4:1) to obtain 3-isopentyl-3-(n-butyl-α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea (3.82 g, 8.68 mmol); yield 76.3%; m.p. 66°-68° C.; [α]D20 +65.3° (C 1.0, methanol).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][S:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1
Reactant: Sc1ccc(Br)cc1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CCSc1ccc(Br)cc1
Temperature: 40 °C
Yield: 95.4 %

Procedure:
3-Bromo-1,1,1-trifluoropropane (640 μL, 6 mmol) was added to a mixture of 4-bromothiophenol (945 mg, 5 mmol) and potassium carbonate (760 mg, 5.5 mmol) in DMF (5 ml) and the reaction mixture heated at 40° C. for 1 hour. The mixture was allowed to cool to ambient temperature and poured into water (50 ml) and extracted with EtOAc (2×30 ml). The extracts were combined, washed with brine (3×30 ml), dried (Chemelut column 1010) and evaporated to give the title compound (1.36 g, 95%) as a pale yellow oil. NMR 2.56 (m, 2H), 3.13 (t, 2H, 7.31 (d, 2H), 7.51 (d, 2H), m/z 285 (M+).