Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][C:9]2[CH:14]=[C:13]([NH:15]C(=O)C(F)(F)F)[CH:12]=[CH:11][C:10]=2[S:22](Cl)(=[O:24])=[O:23])=[N:5][N:4]=1)[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[CH2:34][O:33][B:32]([OH:35])[C:31]=2[CH:36]=1.N1C=CC=CC=1>C(#N)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:22]([NH:26][C:27]2[CH:28]=[CH:29][C:30]3[CH2:34][O:33][B:32]([OH:35])[C:31]=3[CH:36]=2)(=[O:23])=[O:24])=[C:9]([CH2:8][C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:14]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.1 %

Procedure:
To a stirred solution of 2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (335 mg, 0.84 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (125 mg, 0.84 mmol) in 5 mL of ACN was added pyridine (205 uL, 2.53 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (390 mg, yield 91%).
Reaction SMILES: C([Si]([O:8][CH2:9][CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:12]=2[O:11]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH3:20][O:19][C:18]1[C:12]2[O:11][CH:10]([CH2:9][OH:8])[CH2:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc2c1OC(CO[Si](C)(C)C(C)(C)C)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CO)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0° C. was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. Rf=0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103° C.; Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[CH:10]=2)[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](N)=[O:29])=[CH:23][CH:22]=1>>[ClH:2].[Cl:15][C:13]1[CH:14]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:17][CH2:18][CH2:19][C:4]3=[C:3]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][CH:22]=3)[CH:8]=2)[CH:10]=[CH:11][C:12]=1[Cl:1]
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(Cl)cc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3ccc(Cl)c(Cl)c3)nc3c2CCC3)cc1
Yield: 16.7 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.060 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.024 g, 18%) as a tan solid. MW=448.77. 1H NMR (DMSO-d6, 500 MHz) δ 14.12 (s, 1H), 9.53 (s, 1H), 7.89 (d, J=2.0 Hz, 2H), 7.81 (s, 1H), 7.36 (s, 4H), 7.13 (s, 1H), 3.73 (s, 2H), 3.63 (s, 2H), 3.11 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.30-2.14 (m, 2H); APCI MS m/z 412 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][C:13]([CH3:15])=O.N1CCCC1>CO>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2[C:2](=[O:3])[CH2:1][C:13]([CH3:15])([CH3:12])[O:11][C:5]=2[CH:6]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(Cl)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccc(Cl)cc2O1

Procedure:
A solution of 4-chloro-2-hydroxyacetophenone (20 g, 0.1176 mol), acetone (13.3 mL, 0.1811 mol) and pyrrolidine (15 mL, 0.18 mol) in methanol (475 mL) was stirred at 25° C. overnight. The mixture was then concentrated to a red oil. Water was added and the solution was adjusted to pH 1 with concentrated hydrochloric acid. The product was extracted with diethylether. The organic layer was dried over magnesium sulfate and diethylether was evaporated under reduced pressure. The residue was dissolved in a small volume of methanol. The solution was treated with charcoal, filtered and water was added to the filtrate. The resulting precipitate was collected by filtration, washed with water and dried (79%). mp: 63-66° C., IR (KBr): υ: 3086 (C—H aromatic), 2976, 2931 (C—H aliphatic), 1693 (C=0) cm−1, Anal. (C11H11O2Cl) C, H.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH:26]=[CH:25][CH2:24]3)[C:9]=2[CH:8]=1)=S)[CH:2]=[CH2:3].C(O)(=[O:31])C>>[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH:26]=[CH:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:31])[CH:2]=[CH2:3]
Reactant: C=CCNC(=S)c1ccc2c(c1)N(C(C)CN1CC=CC1)c1ccccc1S2
Reactant: CC(=O)O
Product: C=CCNC(=O)c1ccc2c(c1)N(C(C)CN1CC=CC1)c1ccccc1S2

Procedure:
The procedure is as described in Example 17, but starting with N-allyl-10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (1.49 g), in acetic acid (25 cc) and a solution of mercuric acetate (1.16 g) in acetic acid (25 cc). The yellow meringue-like residue (1.27 g) is purified by chromatography on a column (height: 23 cm; diameter: 2.6 cm) of silica gel (0.04-0.63 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (1.5 liters) and collecting 25-cc fractions. Fractions 10 to 58 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-allyl-10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazine-carboxamide, L series (0.45 g), in the form of a yellow resin.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22]O)=[N:11][CH:10]=1.ClCCl.[H-].[Na+].[CH3:40][C:41]1[NH:42][CH:43]=[CH:44][N:45]=1>CN(C)C=O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][N:42]2[CH:43]=[CH:44][N:45]=[C:41]2[CH3:40])=[N:11][CH:10]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(Cn2ccnc2C)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 100 mg (0.207 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7) in 1 ml dichloromethane 0.03 ml (0.4 mmol) thionyl chloride were added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated and the light yellow residue was dried in high vacuo. The residue was dissolved in 1 ml dry N,N-dimethylformamide and added to a suspension of 2-methylimidazole sodium salt that had previously been prepared by addition of 54 mg (1.2 mmol) sodium hydride (55% dispersion in mineral oil) to a solution of 52 mg (0.62 mmol) 2-methylimidazole in 3 ml dry N,N-dimethylformamide under argon at room temperature. After stirring for 3 h the reaction was quenched by addition of excess water, followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 52 mg (46%) of the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[Cl:20]N1C(=O)CCC1=O.O.[OH-].[Na+]>CC(O)=O>[Cl:20][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:18][CH3:19])=[CH:4][C:5]=1[N:8]1[CH2:9][CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH2:17]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(N2CCC3(CC2)OCCO3)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCC3(CC2)OCCO3)c(Cl)cc1Cl
Temperature: 60 °C
Yield: 90.7 %

Procedure:
A mixture of 8-(4-chloro-3-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.67 g, 5.89 mmol, Example 13, step 1) and 1-chloropyrrolidine-2,5-dione (0.786 g, 5.89 mmol) in AcOH (15 mL) was heated at 60° C. overnight. The mixture was cooled and water was added. Upon completion of addition, the mixture was neutralized with 1N NaOH, extracted with EtOAc, dried (Na2SO4), and concentrated to give 8-(2,4-dichloro-5-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 5.34 mmol, 91% yield) as a yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:11]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1ccc(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-chlorophenyl)isothiazol-4-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J=8.5, 4.2 Hz, 4H), 6.88 (t, J=7.5 Hz, 1H), 6.77 (t, J=7.5 Hz, 1H), 4.98 (s, 2H), 3.71 (t, J=8.5 Hz, 2H), 2.73 (t, J=8.5 Hz, 2H), 1.88 (m, 2H), 1.75 (br, s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22](ON2C(=O)CCC2=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(#N)C.O>[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22]([NH:1][CH:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: CC(C)C(OC(=O)NC(CO)C(=O)O)OC(=O)C1CCCCC1
Yield: 9.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (0.40 g, 3.80 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl cyclohexanecarboxylate (1.0 g, 2.93 mmol) were reacted in the acetonitrile/water mixture to provide 0.091 g (10% yield) of the title compound (34) as a white wax after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.58 (dd, 1H), 6.11 (dd, 1H), 4.42-4.31 (m, 1H), 4.11-3.92 (br dd, 2H), 2.38 (m, 1H), 2.11 (m, 1H), 1.97 (br d, 2H), 1.77 (br d, 2H), 1.6 (br d, 1H), 1.4 (q, 2H), 1.2 (br m, 3H), 0.99 (dd, 6H). MS (ESI) m/z 354.22 (M+Na)+; 330.21 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([OH:9])=O.CN(C)CCCN=C=NCC.Cl.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[C:27]([C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:45][CH:44]=1)=[O:41])=[CH:26]2>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:7](=[O:9])[CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:31][CH:30]=2)[CH:26]=[C:27]1[C:40]([NH:42][C:43]1[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:48]=1)=[O:41]
Reactant: O=C(O)CC1CCCO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2cc3cc(N)ccc3n2Cc2ccccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2cc3cc(NC(=O)CC4CCCO4)ccc3n2Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
49 mg (0.38 mmol) of tetrahydro-2-furanylacetic acid, 19.3 mg (0.16 mmol) of 4-dimethylaminopyridine and 91 mg (0.47 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl are added to 3 ml of DMF. 150 mg (0.32 mmol) of tert-butyl 4-({[5-amino-1-(2-fluorobenzyl)-1H-indol-2-yl]carbonyl}amino)phenyl-carbamate from Example XXIX are added. The mixture is stirred at RT for 5 hours. For work-up, the mixture is diluted and extracted with dichloromethane and aqueous hydrochloric acid. The organic phase is washed with sat. sodium bicarbonate solution, dried with sodium sulphate, filtered and concentrated under reduced pressure using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:4]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCCCC(=O)CCl
Solvent: CCO
Product: COC(=O)CCCCc1csc(N)n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 70.2 %

Procedure:
Thiourea (15.7 g) and methyl 7-chloro-6-oxoheptanoate (39.7 g) are mixed in ethanol (200 cc). The mixture is stirred for 20 hours at a temperature of about 20° C.; gradual dissolution of the reactants is observed. The solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is stirred in a mixture of methylene chloride (250 cc) and N sodium hydroxide solution (250 cc). The insoluble product is filtered off, washed with water and recrystallised by dissolving it in boiling water (350 cc) and cooling to 5° C. The resulting crystals are washed with water (3×30 cc), ethanol (3×30 cc) and diethyl ether (2×50 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield methyl 5-(2-aminothiazol-4-yl)valerate (31 g), as a white solid, m.p.=131° C.
Reaction SMILES: CC(N[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[O:14])(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][C:33]4[CH:32]=[C:31]([O:30][CH3:29])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=4)[CH2:44][CH2:45]3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12
Reactant: COc1cc(CCN2CCNCC2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCN2CCN(CCCCOc3ccccc3C(=O)Nc3cccc4[nH]ccc34)CC2)cc(OC)c1OC
Yield: 90.8 %

Procedure:
2.5 g of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide of Example 33, 2.71 g of 1-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazine [German Patent No. 3,347,173] and 0.683 g of sodium carbonate in 25 ml of ethanol were heated to 60° C. for 10 hours and the mixture is cooled and poured into ater and extracted with ethyl acetate. The extract was washed with water and dried and the solvents were evaporated under reduced pressure. The residue was chromatographed over silica (eluant:chloroform/acetone/triethylamine 6:3:1) to obtain 3.51 g of N-(1H-indol-4-yl)-2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]butoxy]benzamide.
Reaction SMILES: Br[C:2]1[N:6](S(C2C=NC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:2]1[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1c[nH]c(-c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 301 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,5-difluorophenyl)boronic acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 135 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(Cl)ccc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(Cl)ccc1C=NO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Chloro-2-methylnicotinaldehyde (1 g, 6.43 mmol), hydroxylamine hydrochloride (0.45 g, 6.43 mmol), and sodium acetate (0.53 g, 6.43 mmol) were dissolved in dry ethanol (32 ml) and transferred to a flame-dried round bottom flask. The reaction was allowed to stir at room temperature for 20 minutes. It was then concentrated under reduced pressure, re-dissolved in ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate two times. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (0-100% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:7][C:6]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])=[CH:7][C:6]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(/C=C/CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1N
Yield: 84.9 %

Procedure:
A solution of 16.0 g of 2-t-butyl-5-[(1E)-3-(t-butyldimethylsilyloxy)-propenyl]-1-nitrobenzene [prepared as described in step (iv) above] in 800 ml of diethyl ether was stirred at room temperature for 3 hours in the presence of 8.0 g of 10% palladium-on-charcoal under a stream of hydrogen. At the end of this time, the reaction mixture was filtered and the filtrate was freed from the solvent by distillation under reduced pressure . The residue was purified by column chromatography through silica gel, using a 1:10 by volume mixture of ethyl acetate and hexane as the eluent, to give 12.5 g of the title compound as an oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)nc3)cc2)n(C)c1=O
Yield: 96.4 %

Procedure:
A solution of 1,3-dimethylxanthine (712 mg), potassium carbonate (578 mg) and 4-(6-chloronicotinoyl)benzyl bromide (1515 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and. concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:3) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (1562 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:14][O:15][C:16](OC)([O:21]C)[C:17](OC)=O>>[C:16]([C:17]1[O:13][C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2]([Cl:1])=[CH:11][C:10]=2[N:12]=1)([O:15][CH3:14])=[O:21]
Reactant: COC(=O)C(OC)(OC)OC
Reactant: Nc1cc(Cl)c2cccnc2c1O
Product: COC(=O)c1nc2cc(Cl)c3cccnc3c2o1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A mixture of 5-chloro-7-amino-8-hydroxyquinoline (6 g, 30.8 mol) and methyl trimethoxyacetate (16.3 g, 123.2 mol) was heated at 100° C. overnight. The reaction was cooled in an ice bath and filtered. The precipitate was dissolved in acetone (250 ml). The resulting solution was treated with charcoal at reflux, filtered through a pad of silica gel and celite and partially concentrated. Crystals formed which were filtered and dried giving 4.1 g (51% yield) of solid. M.P. 217°-218° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:17])[CH:10]=3.Br[CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:17][CH2:30][CH2:31][CH2:32][OH:33])[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(O)cc1c32
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
The compound (47 mg) obtained in Example 33 was suspended in DMF (2 mL) and to the suspension was added 3-bromopropanol (11 μL) and potassium carbonate(19 mg) The mixture was stirred at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride:methanol=100:0˜10:1) to obtain the title compound (27 mg; 51%).