Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1O2
Reactant: O=C1OCCN1CCCl
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Br)ccc3Oc3ccccc32)CC1

Procedure:
In an analogous manner to that described in Example 6, from 1-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]piperazine and 3-(2-chloro-ethyl)-2-oxazolidinone, there is obtained 3-[2-{4-[2-bromo-10,11-dihydro-dibenz[b,f]-oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 150°-152° C. The dihydrochloride, prepared in ethanol, melts at 175°-176° C.
Reaction SMILES: CCN(CC)CC.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:31][NH:30][CH2:29]2)[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:29][N:30]([C:8](=[O:10])[CH3:9])[CH2:31]2)[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=[O:15]
Reactant: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC2CN(C(C)=O)C2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Et3N (400 uL, 2.87 mmol) and acetyl chloride (70 uL, 0.99 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (300 mg, 0.96 mmol) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 4 hr, then quenched with 1 N aqueous HCl (80 mL), and extracted with CH2Cl2 (80 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 80% EtOAc in hexanes to give a colorless oil (239 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.12 (br. s., 1 H) 6.76 (br. s., 1 H) 5.03 (br. s., 1 H) 4.55 (br. s., 1 H) 4.43 (br. s., 1 H) 4.03-4.19 (m, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.92 (s, 3 H) 1.51 (br. s., 6 H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Cc1cccc(Cl)c1N=C=O
Product: Cc1cccc(Cl)c1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 29 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.31 g, 29%). EI-MS m/z 322(M+H)+
Reaction SMILES: [N+:1]([O-])([O-:3])=[O:2].[K+].[OH:6][C:7]1[C:8]([OH:24])=[N:9][C:10]2[CH:11]=[CH:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:14]=3[C:15]=2[N:16]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:8]([OH:24])=[N:9][C:10]2[CH:11]=[C:12]([N+:1]([O-:3])=[O:2])[C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:14]=3[C:15]=2[N:16]=1
Reactant: O=[N+]([O-])c1cccc2ccc3nc(O)c(O)nc3c12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c([N+](=O)[O-])cccc12
Temperature: 25 °C

Procedure:
Finely powdered potassium nitrate (81 mg, 0.8 mmol) was added during a few minutes to a stirred solution of 2,3-dihydroxy-10-nitrobenzo(f)quinoxaline (0.21 g, 0.B mmol) in 3 ml of conc. sulfuric acid at 0° C. After stirring over night at room temperature, the solution was poured into 50 ml of ice/water. The yellow precipitate was isolated, washed with water, dried and recrystallized from 96% ethanol affording 0.12 g (50%) of the dinitro compound, m.p.> 300° C., IR (KBr): 700 cm-1 (C=0),1H-NMR (DMSO-d6): 7.72 (t,J=8 Hz,1H,H-8), 8.10 (dd,J7-8 =8Hz,J7-91Hz, 1H, H-7), 8.23 (s,1H,H-5), 8.55 (dd,J9-8 =8 Hz, J9-7 =1Hz, 1H,H-9), 12.9 (broad s, 1H, OH, only one exchangeable proton could be seen).
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[S:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:30])[CH:11]2[CH:14]([O:16]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:15])[C:8]=1[C:31]([O:33]CC1C=CC([N+]([O-])=O)=CC=1)=[O:32])(=[O:3])[NH2:2].C(=O)([O-])O.[Na+:48]>[Pd].O1CCOCC1.O>[C:1](/[CH:4]=[CH:5]/[S:6][C:7]1[CH2:13][CH:12]2[N:9]([C:10](=[O:30])[CH:11]2[CH:14]([OH:16])[CH3:15])[C:8]=1[C:31]([O-:33])=[O:32])(=[O:3])[NH2:2].[Na+:48]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C/C(N)=O)CC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(S/C=C/C(N)=O)CC12
Reaction time: 0.33 h

Procedure:
10% Palladium/charcoal catalyst (15 mg), suspended in 50% aqueous dioxan (4 ml) was pre-hydrogenolysed for 20 mins. To this was then added a solution of p-nitrobenzyl 3-[E-2-carbamoylethenyl thio]-6-[1-p-nitrobenzyloxycarbonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (11 mg) in 50% aqueous dioxan (6 ml). After hydrogenolysis for 21/2 hr., sodium hydrogen carbonate (1.5 mg) in water (1 ml) was added. The dioxan was removed in vacuo and the aqueous phase extracted with ethyl acetate. The aqueous solution was shown to contain 3.75 mgs; (65%), of sodium 3-[E-2-carbamoylethenylthio]-6-[1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, νmax. (H2O) 316 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:37]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1.CO.[ClH:40]>O1CCOCC1>[ClH:1].[ClH:40].[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:37]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1cnc2nc1Nc1ccc(OCC3CCNC3)c(c1)CCc1cncc(c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into the reaction was added tert-butyl 3-({[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)pyrrolidine-1-carboxylate (0.024 g, 0.046 mmol), methanol (0.5 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (0.5 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product (19 mg, 92%). LCMS for C22H24ClN6O (M+H)+: m/z=423.2.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([C:16]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:24]3[C@@H:20]([CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23]3)[C@@:19]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])(O)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([C:16]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:24]3[C@@H:20]([CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23]3)[C@:19]([F:7])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1[C@]1(F)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 3 h

Procedure:
A solution of 4.3 cm3 of diethylaminosulphur trifluoride in 20 cm3 of dry methylene chloride is added dropwise to a solution, cooled to 0° C., of 6.48 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindol-4-ol in 70 cm3 of dry methylene chloride. The reaction mixture is stirred at this temperature for 3 hours, washed with 100 cm3 of an aqueous saturated solution of sodium bicarbonate and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 26 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (95/5 by volume) and collecting fractions of 50 cm3. Fractions 34 to 63 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.2 g of (3aS,4S,7aS)-7,7-diphenyl-4-fluoro-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindole are obtained in the form of a white foam.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)[CH2:3]Br.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(O)C.C1C=CC=CC=1>[OH:1][CH:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)[CH2:3][N:20]1[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]1
Reactant: OC(CBr)c1cc(-c2ccccc2)on1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
A mixture of 3-(1-hydroxy-2-bromoethyl)-5-phenylisoxazole (268 mg) and 4-hydroxypiperidine (121 mg) is dissolved in a mixture (4 ml) of 99% ethanol and benzene (1:1). To the solution is added sodium hydrogen carbonate (168 mg) and stirred at 70°C for 5 hours. After removal of the solvent, the residue is subjected to a column chromatography (silica gel,) eluted with a mixture of methylene chloride and methanol, and the crude crystals collected are recrystallized from ethyl acetate to give 3-[1-hydroxy-2-(4-hydroxypiperidino)ethyl]-5-phenylisoxazole (180 mg) as colorless prisms melting at 117-119°C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:23]3[C:22]4[C:26](=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=4)[NH:25][C:24]3=[O:29])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A stirred solution of 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (67 mg, 0.267 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with ethanol (1 ml×3) and purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-dimethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33]([O:35][CH2:36][C:37](O)=[O:38])[CH3:34].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:38])[CH3:34]
Reactant: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCOCC(=O)O
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOCC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 35.5 %

Procedure:
To a solution of 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (889 mg) and ethoxyacetic acid (250 mg) in pyridine (25 ml) is added N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1527 mg) under ice-cooling, and the mixture is stirred at room temperature for 19 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is stirred. The organic layer is collected, washed with water, dried, and evaporated to remove the solvent. The residue is dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), and thereto is added triethylamine (202 mg). The mixture is stirred at 50° C. for 40 minutes, and evaporated to remove the solvent. The residue is dissolved in ethyl acetate, and the mixture is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 2'-(6-O-ethoxyacetyl-β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (377 mg).
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CO)CN1C(=O)CSc2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CI)CN1C(=O)CSc2ccccc21
Yield: 75.4 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM34-31) (2.33 g, 9.82 mmol), triphenylphosphine (5.15 g, 19.7 mmol), imidazole (1.67 g, 24.6 mmol) and iodine (7.48 g, 29.5 mmol) in CHCl3 (30 mL) were reacted according to GP4 to give the title compound (108LM37-34) (2.57 g, 75%). 1H NMR (CDCl3) δ 7.37 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 4.02 (d, J=6.8 Hz, CH2), 3.37 (s, CH2), 3.15-3.05 (m, CH2), 1.95 (m, 1H), 0.97 (d, J=6.2 Hz, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and morpholine (0.24 ml, 2.78 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (398 mg, 93%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (R)-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 30 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). 1.5 g (63%) of (R)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 75°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:14][CH:15]=1)=[O:9])([O-])=O.[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([C:43]3[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=3)=[O:42])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:12]=[CH:11][C:10]([C:8]([NH:7][C:6]3[CH:22]=[CH:23][C:24]4[NH:25][C:47]([C:46]5[CH:49]=[CH:50][C:43]([C:41](=[O:42])[NH:40][C:37]6[CH:38]=[CH:39][C:34]([N:28]7[CH2:29][CH2:30][O:31][CH2:32][CH2:33]7)=[CH:35][CH:36]=6)=[CH:44][CH:45]=5)=[N:1][C:4]=4[CH:5]=3)=[O:9])=[CH:15][N:14]=2)[CH2:17][CH2:18]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)nc1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCOCC5)nc4)ccc3[nH]2)cc1

Procedure:
Compound 253 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(2-morpholinyl-5-pyridinecarbonyl)aniline and 4-(4-morpholinylphenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C34H33N7O4: 604.26; found: 604.10.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[C:16]#[C:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)Cn1c(Br)nc(Cl)c1Cl
Product: CCOC(=O)Cn1c(C#Cc2ccccc2)nc(Cl)c1Cl

Procedure:
The title compound, MS: m/e=323.0 (M+H+) was prepared in accordance with the general method of example 1b from ethyl (2-bromo-4,5-dichloroimidazole-1-yl)acetate and ethynylbenzene.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][OH:14]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Nc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
A solution of methane sulfonyl chloride (10.2 ml, 0.13 mol) in chloroform (100 mL) was added dropwise to a solution of (2-aminophenyl)methanol (15.0 g, 0.12 mol) in pyridine (100 mL) and chloroform (150 mL) under nitrogen over 1 h at 0° C. The reaction mixture was stirred for 12 h at ambient temperature and then washed with hydrochloric acid (2N, 200 ml×2). The organic phase was dried over anhydrous MgSO4 and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:3) to afford N-[2-(hydroxymethyl)phenyl]methanesulfonamide (13.0 g, 53% yield) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][O:23]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O-].[Na+].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][O:23][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
18.1 To a stirred solution of 200 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (example 17.2) at r.t. in 5 ml THF under an argon atmosphere were added 78 mg sodium methylate. The resulting suspension was heated to reflux for 4 hrs, then treated again with 78 mg sodium methylate and 1.5 ml MeOH and refluxed overnight. The reaction mixture was cooled to r.t. and concentrated. The crude product was purified by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 35:65) to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless gum. MS 375.0 ([M+H]+)