Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:4].[C:17]1([CH2:23][CH2:24]O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[CH:9]=[C:10]([O:15][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[CH:14]=1)=[O:4]
Reactant: OCCc1ccccc1
Reactant: COC(=O)c1cc2ccc(O)cc2oc1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(OCCc3ccccc3)cc2oc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.6g, 3 mmol) and 2-phenyl ethanol (0.36 mL, 3 mmol) are dissolved in anhydrous tetrahydrofuran (60 mL). Triphenylphosphine (1.2 g, 4.5 mmol) is added, and diethyl azodicarboxylate (0.72 mL, 4.5 mmol) is added dropwise and slowly at 0° C. The resulting solution is stirred for 24 hours at room temperature. After the solvent was removed under reduced pressure, the residue is diluted with methanol and a white solid is separated out. The solid is recrystallized with methanol to give 0.45 g of the captioned compound, yield: 46.3%. m.p. 100-101° C. 1H NMR(CDCl3): δ=3.12(t, J=6.8 Hz, 2H), 3.92(s, 3H), 4.14(t, J=7.1 Hz, 2H), 6.79(d, J=2.4 Hz, 1H), 6.88(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.21-7.35(m, 5H), 7.47(d, J=8.7 Hz, 1H), 8.50(s, 1H); Element Anyalysis, C19H16O5 (324): Calculated C, 70.37; H, 4.94. Found C, 70.25; H, 4.93; IR(KBr) :3045.1, 2952.5, 1751.1, 1693.2, 1610.3, 1554.4, 1506.2, 1436.7, 1375, 1307.5, 1222.7, 1114.7, 1018.2, 835, 749.5, 738.6, 700, 594 cm−1; EI-MS(m/z): 324(24, M+), 105(100).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:16][CH3:17])[CH2:12][C:13]([OH:15])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[C:13]([OH:15])=[O:14])[CH2:16][CH3:17]
Reactant: CCC(C)CC(=O)O
Reactant: CC(=O)c1ccncc1
Product: CCC(C)C(C(=O)O)C(C)(O)c1ccncc1

Procedure:
The reaction of 4-acetylpyridine (24.1 grams, 0.2 mole) with the dianion of 3-methylvaleric acid (from 23.2 grams of acid, 0.2 mole) is carried out as described in Example III.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][O:8]/[N:9]=[C:10](/[C:30]1[N:31]=[C:32]([NH:35]C(OC(C)(C)C)=O)[S:33][CH:34]=1)\[C:11]([NH:13][C@H:14]1[C@@H:17]([CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])[N:16]([S:25]([OH:28])(=[O:27])=[O:26])[C:15]1=[O:29])=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:10](=[N:9]/[O:8][CH2:7][C:6]([OH:43])=[O:5])/[C:11](=[O:12])[NH:13][C@H:14]2[C@@H:17]([CH2:18][N:19]3[CH2:23][CH2:22][O:21][C:20]3=[O:24])[N:16]([S:25]([OH:28])(=[O:26])=[O:27])[C:15]2=[O:29])[N:31]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCOC1=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Yield: 24.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (135 mg, 0.208 mmol), DCM (1.04 mL) and TFA (801 μl, 10.4 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (25 mg, 23%) as a white powder. LCMS: Rt=0.25 min, m/z=493.0 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.41 (d, J=9.1 Hz, 1H) 6.86 (s, 1H) 5.24 (dd, J=9.0, 5.8 Hz, 1H) 4.62 (s, 2H) 4.20-4.11 (m, 3H) 3.72-3.63 (m, 2H) 3.40-3.31 (m, 2H assumed; obscured by water).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11](=[O:23])[CH:10]=1.Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:11](=[O:23])[CH:10]=1
Reactant: BrCc1ccncc1
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cc(Cl)ccc2Br)cc1=O
Agent: Br
Product: CC(C)(C)OC(=O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
1.3 g (purity 94%, 3.0 mmol) of tert-butyl [4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate and 1.2 g (4.5 mmol) of 4-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 1.7 g (purity 89%, quant.)
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[OH-:16].[Na+].OO>O>[C:1]([C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])(=[O:16])[NH2:2]
Reactant: COC(=O)c1ccc(C(C)(C)C#N)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-(1-cyano-1-methylethyl)benzoate (1.0 g), sodium hydroxide (0.4 g), water (2 ml) and IMS (5 ml) was heated to 50° C. with stirring. Hydrogen peroxide (60% w/v, 1.23 ml) was added dropwise and the reaction mixture was stirred at 50° C. for 1 hour. and then at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. Water (10 ml) was added to the residue and this mixture was heated at 95° C. for 1 hour. The mixture was cooled, washed with dichloromethane, acidified with 5M hydrochloric acid and filtered to give 4-(1-carbamoyl-1-methylethyl)benzoic acid, m.p. 218°-219° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12]O.O=P(Cl)(Cl)[Cl:16]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][Cl:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(CCO)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1c(CCCl)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitrophenyl ethyl alcohol (100 g) is added to toluene (500 ml). POCl3 (62 ml) is added to the reaction mixture and refluxed for 2 to 3 hrs. Toluene is distilled off completely to give 2-Methyl-3-nitro phenylethyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[CH:13][CH2:14][OH:15])=[CH:5]2.C(OCC)C.[Na+].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[O:15])=[CH:5]2
Reactant: OCC=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C/C=C/c1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of (E) 3-(5,6-dichloroindol-2-yl)-2-propen-1-ol (23.8 g, 98.3 mmol) in diethyl ether (800 ml) activated MnO2 (71 g, 8.76 mol) and NaCl (60 g) were added and the resulting suspension stirred for one day at RT. It was then filtered on a Celite pad repeatedly washed with AcOEt and the organic phase dried (MgSO4) and evaporated to give 21.0 g of the title compound (87.5 mmol, yield 89.0%) that was used as such in the next step.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([Si:14](Cl)(Cl)Cl)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCCCCCC>[CH2:6]([Si:14]([O:4][C:1](=[O:3])[CH3:2])([O:3][C:1](=[O:4])[CH3:2])[O:3][C:1](=[O:4])[CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCC[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCCCCCC
Product: CCCCCCCC[Si](OC(C)=O)(OC(C)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In a 1-1 round-bottomed flask were placed first 55 g of anhydrous sodium acetate, and then 500 ml of anhydrous heptane. To the white suspension formed was added 50 g of octyltrichlorosilane. The reaction medium was left under stirring at ambient temperature for 2 h, and then filtered under argon to remove the precipitate. The filtrate was concentrated to eliminate the heptane, giving 54 g (88% yield) of octyltriacetoxysilane as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:19](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CN(C)CCCCNc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Product: CCCC/C=C/c1cnc2ccc(NCCCCN(C)C)nn12
Yield: 42 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (51 mg, 42%) as a brown solid; 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=9.5 Hz, 1H), 7.49 (s, 1H), 6.72-6.58 (m, 2H), 6.32 (d, J=9.5 Hz, 1H), 5.60 (br, 1H), 3.39 (q, J=6.2 Hz, 2H), 2.38 (t, J=6.7 Hz, 1H), 2.31-2.22 (m, 8H), 1.78-1.72 (m, 2H), 1.69-1.63 (m, 2H), 1.52-1.36 (m, 4H), 0.94 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.3, 136.9, 131.4, 129.4, 127.2, 125.7, 115.9, 110.5, 59.2, 45.1, 41.8, 33.4, 31.7, 26.9, 25.4, 22.3, 13.9; HPLC tR=11.4 min (Luna), 96.8%; ES-MS: (M+H)=316 m/z.
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: CN(C)CCN(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a 30 L jacketed reactor, dry THF (6 L) and magnesium turnings (243.0 g, 10 mol, 1.5 eq.) were added under N2. In a separate flask, FeCl3 (162 g, 1.0 mol, 0.15 eq.) was dissolved in THF (800 mL) (caution, exothermic) under N2. This dark brown solution was cooled to ambient temperature using an ice bath and then added over 35 min to the 30 L reactor contents under N2 at an internal temperature of 10° C. To this yellow/green mixture, TMEDA (1.2 L) was added keeping the internal temperature below 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at 45° C. for 1 h under N2. The reactor content was allowed to cool below 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (1500 g, 6.67 mol) and bromocyclopentane (1192 g, 8.00 mol, 1.2 eq.) added dropwise under N2 at such a rate as to maintain the internal temperature between 25-30° C. (caution, exothermic). After the addition (3.33 h) and the exotherm subsided, the reaction mixture was stirred at 25° C. under N2 overnight, allowed to cool to an internal temperature of 0° C. and quenched with 6 NHCL (3 L, 1.5 h) at such a rate as to maintain the internal temperature below 15° C. (caution, very exothermic). After the quench, ethyl acetate (4 L) was added and the reactor content stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with ethyl acetate (2.5 L). The combined organic layers were washed with H2O (1 L), brine (1.5 L) and dried (Na2SO4). The solvent was rotary evaporated at 35° C. and the residue fraction distilled under high vacuum (65-70° C., 0.15 Torr) to give 823 g of product (58%, not wt % corrected) as a clear colorless liquid. 1H NMR (Bruker, 400 MHz, DMSO-d6) δ ppm 7.58-7.64 (m, 3H, ArH), 7.34-7.4 (m, 1H, ArH), 3.21-3.29 (m, 1H, —CH), 1.95-2.04 (m, 2H, —CH2), 1.76-1.88 (m, 2H, —CH2), 1.49-1.71 (m, 4H, —CH2).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>[Cu]I>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:45][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: c1ccc(Sc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 120 °C

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.125 g, 0.334 mmol), Sodium tert-butoxide (96.4 mg, 1.00 mmol), Copper(I) iodide (6.4 mg, 0.033 mmol), 1,2-Ethanediol (37.4 uL, 0.671 mmol), N,N-Dimethylformamide (4.7 mL, 6.0E1 mmol), and finally Benzenethiol (51.4 uL, 0.501 mmol). The reaction was heated at 120° C. overnight. The reaction was partitioned with DCM and water. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol) the collected fractions afforded (4-Morpholin-4-yl-phenyl)-(7-phenylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine an orange solid (72 mg, 53%). MP 143-145° C. LCMS (E/I+) 404.17 (M+H). NMR 1H (DSMO-d6)-9.33 (s, 1H), 8.97 (s, 1H), 7.45 (d, 2H, J=9.05 Hz), 7.30 (t, 2H, J=7.57 Hz), 7.18 (t, 1H, J=7.29), 7.12 (d, 2H, J=7.37 Hz), 7.01 (d, 1H, J=4.40 Hz), 6.93 (d, 1H, J=4.60 Hz), 6.75 (d, 2H, J=9.05 Hz), 3.73 (t, 4H, J=4.48 Hz), 3.00 (t, 4H, J=4.72 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:30])[CH2:13][CH2:12]1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[ClH:43]>CN(C)C=O.C(O)C>[ClH:43].[ClH:43].[CH2:41]([O:40][C:38]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[N:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH3:3])[CH2:16][CH2:15]2)[C:20]1=[O:30])=[O:39])[CH3:42]
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CCCCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2ccccc21
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 60% sodium hydride (0.44 g) in dimethylformamide (50 ml), was added 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione (3.80 g) in a small portion under a nitrogen stream, and the mixture was stirred at room temperature for 30 minutes and at 50° C. for 10 minutes. After cooling to room temperature, a solution of ethyl 7-bromoheptanoate (2.37 g) in dimethylformamide (20 ml) was added to the mixture and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under vacuum and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and dried with sodium sulfate. When the solvent was distilled off under vacuum, an oily substance was obtained and upon column chromatography on silica gel (eluted with a chloroformethanol 25:1 mixture), a pale yellow oil of 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H, 3H)quinazolinedione (3.62 g) was obtained. The oil was dissolved in ethanol (50 ml) and hydrogen chloride gas was introduced into the solution for about 5 minutes. After distilling off the solvent, the crystalline residue was recrystallized from a mixture of ethanol and n-hexane to give colorless needles of 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride (3.45 g) having a m.p. of 109°-111° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][N:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:41]([N:38]2[CH2:37][CH2:36][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:40][CH2:39]2)=[O:42])[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Yield: 75.8 %

Procedure:
To a solution of rac-[(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.76 g, 2.46 mmol) in CH2Cl2 (10 ml) was added ethyl-diisopropyl-amine (0.51 ml, 2.95 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (0.61 g, 2.7 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 1:1) afforded 0.87 g (70%) of the title compound as a white solid. ES-MS m/e: 501.4 (M+H+).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16]C(O)=C[CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(=[O:10])[CH3:9].N1C=CC=CC=1>C1COCC1>[C:8]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
Acetic anhydride (50 mL) was added to a mixture of 2-acetyl-7-hydroxyfluorene (50 g), pyridine (200 mL) and THF (200 mL) at 28° C. The temperature was elevated slowly up to 61° C. by exothermic heat to obtain a yellow transparent reaction mixture. An organic layer obtained by extracting the mixture with chloroform was washed well in order with 3M-hydrochloric acid, saturated sodium hydrogencarbonate and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) and recrystallization (ethanol/ethyl acetate) to obtain 2-acetyl-7-acetoxyfluorene (47.3 g) of colorless crystal. Melting point: 125.5-127.6° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31](O)=[C:30]([F:36])[CH:29]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[Br:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([O:1][C@H:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])=[C:30]([F:36])[CH:29]=1
Reactant: Cc1cc(O)c(F)cc1Br
Reactant: O=C1OCC[C@H]1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(O[C@H]2CCOC2=O)c(F)cc1Br
Temperature: 0 °C
Yield: 50 %

Procedure:
(R)-3-hydroxydihydrofuran-2(3H)-one (2.0 g, 20 mmol) was suspended in Toluene (150 mL) and triphenylphosphine (6.2 g, 24 mmol) and 4-bromo-2-fluoro-5-methylphenol (4.8 g, 24 mmol) were added and cooled to 0° C. The solution was degassed with nitrogen bubble for 10 minutes. Di-tert-butyl diazene-1,2-dicarboxylate (5.4 g, 24 mmol) was dissolved in toluene (40 mL) and added to the reaction over 5 minutes. The reaction was allowed to slowly warm to ambient temperature overnight. The toluene was removed and the oily residue was purified over silica gel (20 to 40% EtOAc in hexanes) to afford (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)dihydrofuran-2(3H)-one (2.9 g, 10 mmol, 51% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14]Br>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
To a suspension of 1.53 g (63.8 mmol) of sodium hydride in 50 ml of dry dimethylformamide was added over thirty minutes a solution of 8.23 g (63.8 mmol) of 4-chlorophenol. After stirring for one hour at room temperature, 16 g (77 mmol) of 1,3-dibromopropane was added in one portion. The mixture was stirred for 68 hours, and the solvent removed under reduced pressure. The residue was dissolved in diethyl ether and washed with water. The aqueous layer was then extracted twice with ether. The combined organic extracts were washed three times with water, once with brine, then dried (MgSO4). After filtration, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, using 10% methylene chloride/hexane as the eluent and produced 710 mg of the title compound, which was homogeneous by thin layer chromatography (10% by volume of methylene chloride/hexane on silica gel plates).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[NH2:14])[CH3:2].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]2[N:14]=[C:17]([C:18]([Cl:21])([Cl:20])[Cl:19])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cccc(N)c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: CCOCCOc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
4-(2-Ethoxy-ethoxy)-2-trichloromethyl-1H-benzoimidazole was prepared by a procedure according to example 108 (iii) starting from 345 mg (1.76 mmol) 3-(2-Ethoxy-ethoxy)-benzene-1,2-diamine and 0.30 mL (2.46 mmol) 2,2,2-trichloro-acetimidic acid methyl ester.