Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1>O1CCOCC1.[Pd]>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: CNc1ncccc1N
Yield: 96.2 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 5.00 g of 2-methylamino-3-nitropyridine (prepared as described in Preparation 104) were hydrogenated in 80 ml of 1,4-dioxane in the presence of 1.00 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 3.87 g of the title compound, melting at 90-92° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1cccc(Cl)c1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of 3-chlorophenol and 20 ml of dry dimethylformamide is stirred at room temperature for 5 days, then poured into 60 ml of water and extracted four times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel while eluting with ethyl acetate and then crystallized from ethanol. There is obtained m-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 194°-195°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:32])[CH2:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:19]([O:23][C:24](=[O:32])[CH2:25][N:26]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valine (50.0 g) and N-cyclopentylglycine t-butyl ester (39.8 g) in dichloromethane (1.3 liter), stirred under nitrogen and cooled in an ice bath to 0°-5° C., was added triethylamine (44.5 g) then bis(2-oxo-3-oxazolidinyl)phosphinic chloride (56.0 g) at 0° C. The stirred mixture was allowed to warm to room temperature overnight before it was evaporated. After the residue was partitioned between water (1 liter) and ethyl acetate (1 liter), the ethyl acetate solution was washed (1N hydrochloric acid (twice), water, saturated sodium bicarbonate, brine), dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with ethyl acetate:dichloromethane (0:100, 5:95, 10:90 and 25:75, successively). A first, mixed fraction was rechromatographed and the product obtained combined with the product obtained from the first chromatography to afford the ester (73.4 g, 85%); TLC, Rf =0.30, ethyl acetate:dichloromethane (5:95); MS, m/e=433 (M+1), 377, 325, 269, 234, 286, 162, 144 91(base).
Reaction SMILES: [S:1]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:3])=[O:2].[F:14][C:15]([F:22])([F:21])[S:16]([O:19]C)(=[O:18])=[O:17]>C(Cl)Cl>[F:14][C:15]([F:22])([F:21])[S:16]([O-:19])(=[O:18])=[O:17].[N:4]1([S:1]([N:9]2[CH:13]=[CH:12][N+:11]([CH3:15])=[CH:10]2)(=[O:2])=[O:3])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 198 %

Procedure:
To a solution of 1,1′-sulfonyldiimidazole (3.50 g, 17.7 mmol) in DCM (75 mL) at about 0° C. was added methyl trifluoromethanesulfonate (1.94 mL, 17.7 mmol). The reaction mixture was stirred at about 0° C. for about 1 h, then warmed to ambient temperature and stirred for about 5 h. The solid was collected by vacuum filtration and washed with DCM (10 mL) to give 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (6.35 g, 98%) as a white solid: LC/MS (Table 1, Method a) Rt=0.082 min; MS m/z 213 (M+H)+.
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[S:16])[S-:15].C([NH+](CC)CC)C>C(#N)C>[CH3:5][C:2]1([CH3:6])[S:16][C:14](=[S:15])[N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH:3]1[OH:4]
Reactant: S=C([S-])Nc1ccccn1
Reactant: CC(C)(Br)CO
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: CC1(C)SC(=S)N(c2ccccn2)C1O
Temperature: 2 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
2-Bromo-2-methylpropanol (39.7 g) is added, at about 5° C., to a suspension of triethylammonium pyrid-2-yl-dithiocarbamate (71.2 g) in anhydrous acetonitrile (330 cc). The reaction is allowed to proceed for 1 hour at 20° C. The insoluble triethylamine hydrobromide is removed by filtration. The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 40° C. The residual oil is treated with methylene chloride (300 cc). The organic solution is washed twice with distilled water (100 cc in total), dried over sodium sulphate and evaporated. The resulting product (60 g) is dissolved in methylene chloride (300 cc), and the solution is filtered through silica (0.2-0.5 mm., 850 g) contained in a column of diameter 5 cm. Elution is carried out with methylene chloride (9 liters). After evaporating off the solvent under reduced pressure (20 mm Hg) at 40° C., the resulting product (50 g) is dissolved in boiling methylcyclohexane (150 cc). After cooling for 16 hours at 2° C., the crystals which have appeared are filtered off, washed with methylcyclohexane (50 cc) and dried under reduced pressure (0.1 mm Hg) at 40° C. 5,5-Dimethyl-4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione (44.1 g), which melts at 80° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[O:4][CH:5]([C:10](OC)=[O:11])[C:6](OC)=[O:7].[NH2:20][C:21]([NH2:23])=[S:22].[CH3:24]O>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([OH:11])=[N:20][C:21]([S:22][CH3:24])=[N:23][C:6]=1[OH:7]
Reactant: NC(N)=S
Reactant: CO
Reactant: COC(=O)C(Oc1cc(OC)ccc1Cl)C(=O)OC
Product: COc1ccc(Cl)c(Oc2c(O)nc(SC)nc2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 230 mg of Na methylate in 15 ml of methanol, 1.45 g of dimethyl (2-chloro-5-methoxy-phenoxy)-malonate and 381 mg of thiourea was held at reflux for 5 hours. Then, the solvent was distilled off and the residue was dissolved in 10 ml of H2O. 630 mg of dimethyl sulfate were added to this solution and it was stirred at room temperature for 2 hours. 300 mg of acetic acid were then added, whereby the 5-(2-chloro-5-methoxy-phenoxy)-4,6-dihydroxy-2-methylsulfanyl-pyrimidine which formed separated. MS: 314 (M).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[N:5]=[C:4](F)[N:3]=1.[CH3:14][NH2:15]>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[N:5]=[C:4]([NH:15][CH3:14])[N:3]=1
Reactant: CN
Reactant: Fc1nc(F)c(OC(F)F)c(Cl)n1
Solvent: C1CCOC1
Product: CNc1nc(F)c(OC(F)F)c(Cl)n1
Temperature: -65 °C

Procedure:
20.3 g (0.0938 mol) of 4-chlorodifluoromethoxy-2,6-difluoropyrimidine were introduced into 150 ml of tetrahydrofuran and, while stirring at −70 to −60° C., 5.8 g (0.188 mol) of gaseous methylamine were added over the course of 30 minutes. The mixture was stirred for 1 hour each at −70° C., 0° C. and 25° C. and concentrated under reduced pressure. The residue was stirred with water, the mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate. The residue from concentration under reduced pressure was chromatographed on silica gel with 5:1 petroleum ether/ether. The first fractions contained the title compound of melting point 57-61° C. in a yield of 12.5 g (58.5%).
Reaction SMILES: ClCC1C=C2C(C(Cl)=CN=C2Cl)=CC=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26](OCC)=[O:27])=[CH:23][CH:24]=2)[C:19](=[O:31])[NH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][OH:27])=[CH:23][CH:24]=2)[C:19](=[O:31])[NH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(Cl)c[nH]c(=O)c2c1
Agent: ClCc1ccc2c(Cl)cnc(Cl)c2c1
Solvent: C1CCOC1
Product: O=c1[nH]cc(Cl)c2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
7-(Chloromethyl)-1,4-dichloro-isoquinoline ##STR186## LiBH4 (530 mg, 24.3 mmol) was added portionwise to a stirred solution of ethyl 4-chloro-1-oxo-1,2-dihydro-7-isoquinolinecarboxylate (3.06 g, 12.2 mmol) in THF (100 mL) and the mixture was stirred at room temperature for 1 h. The heterogeneous mixture was quenched with dilute HCl (2 M), and extracted with CH2Cl7 (2×100 mL) and EtOAc (5×100 mL). The remaining solid was taken up in hot EtOH, and allowed to cool to yield a white fluffy solid. This solid was combined with the combined organic extracts, evaporated in vacuo and crystallised with EtOH to give 4-chloro-7-(hydroxymethyl)-1(2H)-isoquinolone (2.19 g, 10.49 mmol) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH3:10])=[O:18])[CH2:3]2
Reactant: COc1ccccc1C(=O)N=C=O
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1ccccc1C(=O)NC(=O)N[C@H]1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from (R)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.33 g, 7.5 mmol). The product (1.49 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[C:8]([CH3:10])[CH:7]=1)#[N:6]
Reactant: Cc1cc(N)cc(C#N)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: Cc1cc(C#N)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 48.9 %

Procedure:
3-amino-5-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure similar to the one described in Example 3.03 to give 8-(1-(3-cyano-5-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 48%) as a white solid. Mass Spectrum: M+H+ 461. NMR Spectrum (DMSOd6): 1.53 (d, 3H), 2.16 (s, 3H), 2.71 (bs, 3H), 2.94 (bs, 3H), 3.51-3.64 (m, 4H), 3.69-3.80 (m, 4H), 5.00-5.10 (m, 1H), 5.61 (s, 1H), 6.60 (s, 1H), 6.67 (s, 1H), 6.73 (d, 1H), 6.74 (s, 1H), 7.54 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]1[N:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:24])[C:20]([OH:34])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)(C)(C)C.C(NCC)(C)C.[Cl:42][CH2:43][C:44](Cl)=[O:45]>O1CCOCC1>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23]([C:21]2[C:20]([OH:34])=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([CH2:12][CH2:11][N:10]([CH2:9][CH2:8][NH2:7])[C:44](=[O:45])[CH2:43][Cl:42])[N:22]=2)=[O:24])=[CH:32][CH:31]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Agent: CCNC(C)C
Solvent: C1COCCO1
Product: NCCN(CCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)C(=O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-Butyl-2-{[2-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)ethyl]amino}ethylcarbamate (Example 150, Step 1) (0.10 g, 0.21 mmol), isopropylethylamine (0.11 mL, 0.62 mmol), and chloroacetyl chloride (18 μL, 0.23 mmol) in dioxane (10 mL) was stirred at room temperature for 1 hour. The resultant mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.5 mL) and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum and used in the following step without further purification. ES MS M+1=406
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)c(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2NC(=O)c2[nH]c(C)c(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 71; 1.46 g) was dissolved in dry pyridine (20 ml) and cooled to 0° C. Tosylchloride (822 mg) was added in a single portion. The reaction was allowed to slowly warm to room temperature and stirred overnight. The mixture was diluted with EtOAc and washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The foam was purified by flash column chromatography eluting with (40% EtOAc/60% hexanes) to give title compound (1.58 g). MS (ES)(MH+): 560 for C24H31Cl2N3O6S; NMR (CDCl3): 1.46 (brs, 11H), 1.89 (m, 1H), 1.98 (m, 1H), 2.31 (s, 3H), 2.35 (s, 3H), 2.8 (m, 2H), 3.96-4.23 (m, 4H), 6.4 (d, 1H), 7.19 (d, 2H), 7.68 (d, 2H), 10.3 (brs, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:15]2[C:18]3[C:8]=1[CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][C:14]=2[C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl)=[O:6].[I-].[K+].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[ClH:1].[ClH:1].[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:15]2[C:18]3[C:8]=1[CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][C:14]=2[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[O:6])[CH3:28]
Reactant: CCNCC
Reactant: O=C(CCCCl)c1ccc2c(C(=O)CCCCl)ccc3c2c1CC3
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCC(=O)c1ccc2c(C(=O)CCCN(CC)CC)ccc3c2c1CC3
Product: Cl
Temperature: 120 °C

Procedure:
A mixture of 36.1 g (0.10 mole) of 3,6-bis(4-chlorobutyryl)acenaphthene, 2 g of potassium iodide, 100 ml of diethylamine and 100 ml of tetrahydrofuran is placed in a bomb and heated for 24 hours at 120° C. Upon cooling, the mixture is filtered and the filtrate evaporated to dryness. The cooled residue is dissolved in 300 ml of 10% hydrochloric acid, filtered and the acid filtrate made alkaline with a 20% sodium hydroxide solution. The resulting 3,6-bis[4-(diethylamino)butyryl]acenaphthene so obtained is filtered and subsequently recrystallized from a methanol-ethyl acetate solution.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][CH:16]=[C:15]2[C:23]1[N:31]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[C:15]2[C:23]1[N:31]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CC(=O)OC(C)(C)C)c2cc1OC
Yield: 89.6 %

Procedure:
tert-Butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}-acetate is prepared by following the procedure described in example 89c, but using 1.91 g of tert-butyl bromoacetate and 4 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. 4.5 g of tert-butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}acetate are obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>C(Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:16](=[O:17])[NH:1][CH:2]2[CH3:15])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc(C(O)C(C)N)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2OC(=O)NC2C)cc1OC
Reaction time: 8 h
Yield: 24 %

Procedure:
5.5 mmol of 2-amino-(3,4-dimethoxyphenyl)-propanol is dissolved in 50 ml. of chloroform and stirred with 1.05 g. (6.5 mmol) of carbonyl diimidazole for 2 hours under the exclusion of moisture. After allowing the reaction mixture to stand overnight, the mixture is extracted with the use of 50 ml. of distilled water, dried, filtered, and concentrated. After chromatography of the residue over 50 g. of silica gel with chloroform/methanol (95:5) as the eluent and recrystallization from ethyl acetate/petroleum ether, a 24% yield is obtained of 5-(3,4-dimethoxyphenyl)-4-methyl-2-oxazolidinone, m.p. 98°-99°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][CH2:10][CH:11]1[O:16]CCCO1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1.C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:17]([CH:11]([OH:16])[CH2:10][CH2:9][O:8]2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cccc(OCCC2OCCCO2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)OCCC2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The intermediate from step A was dissolved in 20 ml tetrahydrofuran. Concentrated hydrochloric acid (20 mL) was added, and the reaction mixture was stirred at ambient temperature for 4 hours, diluted with diethyl ether and washed with water. The isolated organic layer was dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 2.87 g of crude 7-tert-butyl-chroman-4-ol which was used without further purification.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH:16][C:25]([NH:24][C:22](=[O:23])[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[Cl:19])=[O:26])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2cccc3ccccc23)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4.7 g (0.020 mol) of 4-(α-naphthoxy)-aniline in 100 ml of absolute toluene were added 3.65 g (0.020 mol) of o-chlorobenzoyl isocyanate. The reaction solution thus obtained was stirred at room temperature for 15 hours. During this time the product crystallized out. It was removed by suction filtration, washed with toluene, and dried.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2.CS(O[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[N:12]=[CH:11]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium tert-butoxide (37.25 g) in tetrahydrofuran (1000 mL) was added 5-bromoindazole (54.52 g), and the mixture was stirred at room temperature for 15 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (98.74 g), and the reaction solution was heated at reflux for 1 day. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 as the eluting solvent) to give Compound Q17 (45.68 g).
Reaction SMILES: C(P(C1C=C[C:10]([NH2:11])=C(OC)C=1)(CC)=O)C.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([P:39]([CH2:43][CH3:44])([CH2:41][CH3:42])=[O:40])=[CH:35][C:34]=2[O:45][CH3:46])[C:29]([Cl:47])=[CH:28][N:27]=1.[CH:48]1([C:51]2[O:55][C:54]([NH2:56])=NC=2)[CH2:50][CH2:49]1>>[Cl:47][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([P:39]([CH2:43][CH3:44])([CH2:41][CH3:42])=[O:40])=[CH:35][C:34]=2[O:45][CH3:46])=[N:31][C:26]([NH:56][C:54]2[O:55][C:51]([CH:48]3[CH2:49][CH2:50]3)=[N:11][CH:10]=2)=[N:27][CH:28]=1
Reactant: CCP(=O)(CC)c1ccc(N)c(OC)c1
Reactant: CCP(=O)(CC)c1ccc(Nc2nc(Cl)ncc2Cl)c(OC)c1
Reactant: Nc1ncc(C2CC2)o1
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CCP(=O)(CC)c1ccc(Nc2nc(Nc3cnc(C4CC4)o3)ncc2Cl)c(OC)c1

Procedure:
This compound can be prepared as in Example 32 by reacting 4-(diethylphosphoryl)-2-methoxyaniline with 2,4,5-trichloropyrimidine to 2,5-dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amine. 2,5-dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amine is then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to the procedure described in Example 32.