Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](S)[CH3:2].[H-].[Na+].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]C)[C:18]([C:23]([CH3:25])=[CH2:24])=[C:17]([O:26][CH3:27])[CH:16]=2)=[CH:9][N:8]=1>CN(C)C=O>[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:16]=[C:17]([O:26][CH3:27])[C:18]([C:23]([CH3:25])=[CH2:24])=[C:19]([O:21][CH2:1][CH3:2])[CH:20]=2)=[CH:9][N:8]=1
Reactant: CCS
Reactant: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OCC

Procedure:
A solution of 16.1 ml. of ethylmercaptan in 130 ml. of dimethylformamide was added dropwise while stirring and gassing with nitrogen to a suspension of 10.4 g. of sodium hydride (50%) in 130 ml. of dimethylformamide. After the evolution of gas had ceased, the mixture was stirred at room temperature for an additional 15 minutes and treated with a solution 13 g. of 2,4-diamino-5-(4-isopropenyl-3,5-dimethoxybenzyl)-pyrimidine in 260 ml. of dimethylformamide. The mixture was stirred at 120° C. for 6 hours. The solvent was removed under a high vacuum. The solid residue was dissolved in water, filtered and the filtrate was adjusted to pH 4 with 1-N hydrochloric acid. The acid solution was then adjusted to pH 8 with ammonia and the solid crude product was isolated in a yield of 98%. Recrystallization from methanol yielded pure 2,4-diamino-5-(3-hydroxy-4-isopropenyl-5-methoxybenzyl)-pyrimidine, having a melting point of 218°-219° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.ClC1C2[C:29](=[O:31])C3C(=CC=CC=3)C(=O)C=2C=CC=1>>[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:29]=[O:31])[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: Clc1cccc2cc3ccccc3cc12
Product: O=Cc1c2ccccc2cc2c(Cl)cccc12

Procedure:
1-Chloroanthracene prepared from 1-chloroanthraquinone (Aldrich) by the method of H. O. House et. al. (J. Org. Chem. 38 1167 (1973)) was formylated by the procedure outlined in 14A to give 4-chloro-9-anthracenecarbaldehyde mp 129°-131°, (PhCH3 /CH3OH), (C, H, Cl).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Clc1cccc(I)c1
Product: C[Si](C)(C)c1cccc(Cl)c1

Procedure:
1-Chloro-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and la utilizing chlorotrimethylsilane and 1-chloro-3-iodobenzene as the dihalo compound of formula (III).
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:36][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
The compound (348 mg, 0.67 mmol) obtained in Example 52-3) was dissolved in methanol (3 mL). A 4 N solution (1.67 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (50 mL) and methanol (2 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=10% to 60%) to obtain the title compound (216 mg, 79%) in a white solid form.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:32][N:33](C)C=O>O>[C:32]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1)#[N:33]
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(-c2cc(-c3ccc([N+](=O)[O-])cc3)cc(-c3ccccn3)n2)n1
Temperature: 160 °C
Reaction time: 4.5 h

Procedure:
A mixture of 6-bromo-4'-(4-nitrophenyl)-2,2':6',2"-terpyridine (5.63 g), cuprous cyanide (4.66 g), sodium cyanide (2.55 g), and dimethylformamide (35 ml) was heated under argon with stirring to 160° C. for 4.5 hours, cooled to room temperature, and treated with 175 of water. After 15 min, the resulting slurry was filtered, the dark brown paste so obtained was placed in water (85 ml) containing sodium cyanide (3.2 g), and the reaction mixture was stirred for 15 minutes. The solid product was isolated by filtration, washed with water and dried under vacuum. Yield: 4.38 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:22])[O:8][CH:7]([CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:6][O:5]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1>CO>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])/[CH:31]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([S:11]([NH:10][CH2:9][CH:7]3[CH2:6][O:5][C:4]([CH3:22])([CH3:3])[O:8]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[C:26]([NH:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:25]=1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC1(C)OCC(CNS(=O)(=O)c2ccc(C=O)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OCC(CNS(=O)(=O)c2ccc(/C=C/C(=O)c3ccc(Cl)cc3Nc3ccccc3)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
NaOH (2 M aq, 0.91 mL, 1.8 mmol) was added to a solution of N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-4-formyl-benzenesulfonamide (305 mg, 1 mmol) and 1-(4-chloro-2-phenylamino-phenyl)-ethanone (250 mg, 1 mmol) in MeOH (10 mL), and the resulting mixture stirred at RT overnight. A second aliquot of NaOH (2 M aq, 0.1 mL) was added, and the reaction mixture was again stirred at RT overnight. The resulting mixture was evaporated under reduced pressure, and the crude residue partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give an oil. The crude residue was purified twice by flash chromatography (EtOAc/hexane) to give 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-N-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)-benzenesulfonamide (70 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH3:13])=[CH:7][CH:6]=1.N1C=CC=CC=1>C(OCC)C>[Br:2][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)[CH2:12][CH3:13]
Reactant: CCC(O)c1ccc(C)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(Br)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
4.5 g (1.6 ml, 16.7 mmol) Phosphorus tribromide were added portion-wise, with stirring to a solution of 4.98 g (33.0 mmol) rac-1-p-tolyl-propan-1-ol and 0.37 ml pyridine in 17 ml anhydrous diethyl ether at 0° C. The reaction mixture was warmed to ambient temperature and the reaction monitored by HPLC to completion. The reaction mixture was poured onto ice-water and the whole was extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4 and evaporated to give rac-1-(1-bromo-propyl)-4-methyl-benzene as a colourless oil that did not require further purification: NMR (CDCl3, ppm): 1.01 (3H, t), 2.28 (2H, m), 2.40 (3H, s), 4.92 (1H, t), 7.20 (4H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.CN(C)CCN(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([CH2:33]Br)[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][CH:30]=1)[CH2:31][C:3]1([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[CH2:33]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12Cc1ccc(Br)cc1C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) drop wise, followed by the drop wise addition of tetramethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) was added drop wise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH4Cl (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:28](=[O:29])[C:27]([OH:26])([CH3:32])[CH3:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (12.3 mg, 42.2%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 2-hydroxy-2-methylpropanoic acid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15]([NH:19][C:20](=[O:24])[C:21](O)=[O:22])([CH3:18])([CH3:17])[CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[C:15]([NH:19][C:20](=[O:24])[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NC(=O)C(=O)O
Reactant: COc1cc(N)ccc1-c1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)C)ccc1-c1cnco1
Yield: 80.7 %

Procedure:
A solution of 95 mg (0.5 mmol) of 3-methoxy-4-(5-oxazolyl)aniline, 73 mg (0.5 mmol) of N-tert-butyloxalamic acid, 134 mg (0.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 75 mg (0.55 mmol) of 1-hydroxy-7-azabenzotriazole in 4 ml of dichloromethane was stirred a room temperature for 18 hours. The resulting mixture was washed with 2M hydrochloric acid and saturated sodium bicarbonate, dried over magnesium sulphate and evaporated to dryness. The residue was triturated with petrol and collected by filtration to give 128 mg of N-tert-butyl-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a pale yellow solid. MS: 318 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3](=[O:10])[NH:2]1.C(N(CC)C(C)C)(C)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([N:2]1[C:1](=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]1=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)c2cnccc21
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccncc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (5.00 g) and N,N-diisopropylethylamine (20.00 mL) in acetone was added benzyl bromide (5.0 mL). The reaction mixture was heated to reflux for 5 h, then cooled to rt and filtered. The filtrate was poured into water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as a brown solid (4.00 g, 50.00%), HPLC: 92.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 239.2 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 4.92 (s, 2H), 7.26-7.34 (m, 3H), 7.45 (m, 2H), 7.60 (m, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.96 (d, J=10.4 Hz, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.S(Cl)([Cl:21])(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([Cl:21])[CH:10]=[N:9]1
Reactant: CC(C(=O)O)c1ccc(-n2cccn2)c(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 91.2 %

Procedure:
2.5 g (10 mmoles) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid are dissolved in 30 ml of methylene chloride. A solution of 2.01 g (15 mmoles) of sulfuryl chloride in 10 ml of chloroform is added dropwise, with cooling to the resulting solution; heating is effected gradually to room temperature; and this is followed by boiling under reflux for 2 hours. The reaction solution is allowed to cool; the solvent is distilled off; 50 ml of 2 N solution of sodium hydroxide are added to the thus-obtained residue, and boiling up is effected for a few minutes. The reaction solution is extracted with diethyl ether and then acidified with hydrochloric acid. After renewed extraction with diethyl ether, the combined ether phases are dried and evaporated to produce 2.6 g (90% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid, m.p. 102° to 103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=[O:28])[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>O1CCCC1.C(Cl)Cl>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2Cl)C1=O
Yield: 10.3 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 3.0 grams (0.012 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.8 grams (0.012 mole) of phthalic anhydride in 125 mL of tetrahydrofuran. The reaction mixture was dissolved in 200 mL of methylene chloride and washed with four 50 mL portions of an aqueous 10% hydrochloric acid solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was stirred and heated in ethyl acetate-heptane. The resultant solid was collected by filtration and was recrystallized from acetate/hexane to yield 0.5 gram of 2-[[2-chloro-4-[(2-carboxyphenyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 172° C., dec.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCOCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1N1CCOCC1
Temperature: 50 °C
Yield: 9.6 %

Procedure:
To a stirred solution of methyl 3-methyl-4-morpholin-4-ylbenzoate obtained in step 1 (4 g, 169.3 mmol) in THF (100 mL) and water (5 mL) was added lithium hydroxide (2 g, 84.6 mol). The resulting mixture was heated at 50° C. for 12 h. Solvents were removed under vacuum and the resulting mass was diluted with water. The aqueous layer was washed with DCM (2×50 mL) and was acidified with conc HCl (pH=4). It was extracted with EtOAc (2×100 mL). The EtOAc layer was washed with brine and dried over sodium sulfate, affording the title compound as a yellow solid (3.6 g, 97%). 1H NMR (DMSO-d6, 400 MHz) δ 12.5 (bs, 1H), 7.72-7.74 (m, 2H), 7.04-7.06 (m, 1H), 3.72-3.75 (m, 4H), 2.88-2.90 (m, 4H), 2.33 (s, 3H). LC/MS (Method A): 222.1 (M+H)+. HPLC (Method B) Rt 1.42 min (Purity: 98.3%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1.Br[C:45]1[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][N:46]=1>>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[C:28]([CH2:27][O:26][CH:14]3[CH:13]([C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:45]5[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][N:46]=5)=[CH:8][CH:9]=4)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15]3)[CH:37]=2)[CH2:32][CH2:33][C:34]1=[O:43]
Reactant: COc1cccnc1Br
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCN)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCNc4ncccc4OC)cc3)cc21

Procedure:
Analogously to Example 125a, 0.200 g of tert-butyl 4-[4-(4-aminobutoxy)phenyl]-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 125b) and 0.076 g of 2-bromo-3-methoxypyridine are reacted. The title compound is obtained as a colourless oil. Rf=0.34 (3:1:0.04 EtOAc-heptane-triethylamine); Rt=4.65.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[CH:6]=1)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([C:16]([F:19])([F:18])[F:17])[CH:8]=[C:9]([S:11][C:12]2[C:26]3[C:25](=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[NH:29][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(SCC(C)=O)cc(C(F)(F)F)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-trifluoromethyl-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4].[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 93.1 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(toluene-4-sulfonyloxy)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (0.9 g, 1.55 mmol), 4-(methanesulfonyl)phenylboronic acid (930 mg, 4.6 mmol) and dichlorobis(triphenylphosphine)palladium (II) (110 mg, 0.15 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.3 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (815 mg, 73%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.1.
Reaction SMILES: [CH3:1][C:2](CC)=O.C(=O)([O-])[O-].[K+].[K+].C(I)C.[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[OH:26])[O:22][C:21]([CH3:28])([CH3:27])[CH2:20][C:19]2=[O:29]>>[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:1][CH3:2])[O:22][C:21]([CH3:27])([CH3:28])[CH2:20][C:19]2=[O:29]
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reaction time: 3 h
Yield: 85 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved. To the solution 4.1 g (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is heated to boiling for 3 hours. The reaction mixture is worked up according to Example 17. Thus 4.0 g of the title compound are obtained, yield 85%. Mp.: 129°-130° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:14])[CH:11](Br)[CH3:12])[CH3:8].[C:15]1([C:25]2[N:30]=[N:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=3[OH:38])[C:26]=2[C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:15]1([C:25]2[N:30]=[N:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH:11]([C:10]([O:9][CH2:7][CH3:8])=[O:14])[CH3:12])=[CH:33][C:32]=3[OH:38])[C:26]=2[C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Temperature: 125 °C

Procedure:
9.39 g of potassium carbonate and 9.02 g of 2-bromopropionic acid ethyl ester are added to a solution of 20.0 g of the product from Example A6 in 200 ml of DMF. The reaction mixture is heated at 125° C. for 3.5 h. The solid which precipitates is filtered off and washed with toluene. The combined organic phase is freed of solvent in vac. Chromatography of the residue on silica gel yields the product of melting point: 124–125° C.