Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:28]3[CH2:29][CH2:30][N:25]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:26][CH2:27]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1ccccc1O2
Temperature: 25 °C
Yield: 95.6 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.3 g; 1.22 mmol) in dry toluene (10 mL) at room temperature was added 1-benzyl piperazine (1.0 mL; 5.61 mmol; Aldrich) followed by the dropwise addition of TiCl4 (1M in toluene, 1.47 mL; 1.47 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×50 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give 0.471 g (95%) of the title compound as a yellow solid; m.p. 50°-52° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH2:17]([O:19][C:20](=[O:35])[CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]1[CH:33]=O)[CH3:18]>COCCOC>[CH2:17]([O:19][C:20](=[O:35])[CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:27]1[C@@H:28](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:29][CH2:30][C:31]1=[O:32])[CH3:18]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CC[C@@H]1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1C/C=C\COCC(=O)OCC
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (95%, 0.02 g, 0.78 mmol) in 10 mL of anhydrous 1,2-dimethoxyethane at 0° C. under a nitrogen atmosphere was added dimethyl 2-oxoheptylphosphonate (0.17 mL, 0.78 mmol), and the reaction was stirred for 1 hour. A solution of [(Z)-4-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester (0.21 g, 0.78 mmol) in 2 mL anhydrous 1,2-dimethoxyethane was added. The reaction was allowed to come to room temperature, stirred for 3 hours and then quenched with an aqueous solution of saturated ammonium chloride. After extraction with ethyl acetate, the organic solution was dried (brine, Na2SO4), evaporated and purified by chromatography to yield {(Z)-4-[(R)-2-oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester as an oil. This material was taken directly on to the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Br:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[O:25][CH:26]1[CH2:27][CH2:28][CH2:29]1)([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Br)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(Br)cc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
The mixture 5-bromo-2-(2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (100) (442 mg, 0.94 mmol) and KOH (700 mg, 12 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (101) as white solid (390 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol) and 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.6 mg, 0.30 mmol) and piperidine (3 drops) in ethanol was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 124 mg (100%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (s, 1H, NH), 11.77 (br s, 1H, NH), 9.22 (br s, 1H), 8.32 (s, 1H), 7.72 (dd, J=2.7 & 6.6 Hz, 1H), 7.42 (m, 1H), 7.32-7.37 (m, 2H), 6.58 (d, J=1.8 Hz, 1H), 3.68 (m, 4H, 2×CH2), 2.36 (m, 4H, 2×CH2), 2.22 (s, 3H, CH3), 2.20 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15](C)=[CH:14][C:13]=1[Cl:20].[H-].[CH2:24]([Al+]CC(C)C)C(C)C.CO>C1COCC1>[Cl:18][C:17]1[C:16]([CH3:24])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:21]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CON(C)C(=O)c1ccccc1Nc1c(Cl)cc(C)cc1Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a magnetically stirred 0° C. solution in dry THF (25 mL) of N-methoxy-N-methyl-2-[(2,6-dichloro-4-methylphenyl)amino]benzamide (3.8 g, 11.2 mmol), prepared as in step 1, was added dropwise diisobutylaluminum hydride (1.0M in THF, 24.6 mL) and the reaction mixture was stirred at ambient temperature for 16 hours. Methanol (5 mL) was added dropwise and the mixture was stirred for 15 minutes until a white precipitate had formed. The reaction mixture was concentrated, the residue was taken up in methanol (10 mL), the insoluble white solid was filtered, and the filtrate was evaporated in vacuo and then purified by chromatography on silica gel (5:1 hexane/CH2Cl2) to provide 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (1.98 g; 63%) and over reduced alcohol side product (0.70 g; 22%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[C:15]=1[OH:16])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(Cl)c(O)c(S(=O)(=O)Cl)c1
Temperature: 65 °C
Yield: 74.2 %

Procedure:
To a flask charged with chlorosulfonic acid (13.9 mL, 209.0 mmol) was added 3-chloro-4-hydroxybenzoic acid (6.0 g, 34.8 mmol) portionwise over ten minutes. The mixture was then heated for 2 h at 65° C. under a nitrogen atmosphere. After cooling the mixture to room temperature, the reaction mixture was carefully poured over crushed ice with vigorous stirring, and extracted with Et2O until no further product remained in the aqueous layer. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-chloro-5-(chlorosulfonyl)-4-hydroxy-benzoic acid as a white solid (7.0 g, 74%) which was used without further purification.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].S(OCC)(O[CH2:14][CH3:15])(=O)=O.[OH-].[K+].C([Li])CCC.CCCCCC>>[C:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)CNC(C)(C)C
Agent: [K+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: CCCCCC
Product: CCN(CC(C)C)C(C)(C)C
Temperature: 70 °C
Yield: 72 %

Procedure:
A mixture of tert-butylisobutylamine (25.84 g, 0.2 mol) and diethyl sulfate (46.26 g, 0.3 mol) was warmed to 70° C. with stirring. An exothermic reaction started and in a few minutes the temperature rose to 150° C. with vigorous boiling of the mixture. After cooling to ˜50° C., 5 M aqueous potassium hydroxide (100 ml, 0.5 mol) was added. The organic layer was separated and dried over anhydrous magnesium sulfate. Diethyl sulfate (10 ml) was added and the mixture was stirred at 100° C. for 1 h. Aqueous 5 M potassium hydroxide (100 ml) was added and the mixture was stirred at 80° C. for 1 h. The organic layer was separated and the aqueous layer was extracted with diethyl ether (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate and the product was isolated by distillation. A small amount (1-2%) of tert-butylisobutylamine which was removed by the addition of 2.5 M n-butyllithium in hexane (5.0 ml, 10 mmol) and the product distilled to yield 22.56 g, (72%) of product, bp 68-70° C./40 mm Hg; 1H NMR (CDCl3) δ0.85 (d, J=6.5 Hz, 6H, CH3), 0.98 (t, J=6.5 Hz, 3H, CH3), 1.01 (s, 9H, CH3), 1.66 (n, J=6.5 Hz, 1H, CH), 2.04 (d, J=6.57 Hz, 2H, CH2), 2.51 (q, J=6.5 Hz, 2H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:35])[CH2:33][CH3:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Product: CCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and propanoyl chloride (14 mg, 150 μmol). Yield 17 mg (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-chloro-2-fluoronitrobenzene (250 mg), aniline (0.40 mL) and potassium carbonate (500 mg) were dissolved in dimethyl sulfoxide (1.5 mL) and stirred at 50° C. overnight. The mixture was added with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, and the water was removed with sodium sulfate. The reaction solution was removed of the solvent by distillation under reduced pressure, and the subsequent reaction was proceeded without further purification of the thus obtained compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:2]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccnc2)cs1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3cccnc3)cs2)cc1

Procedure:
The title compound was prepared from 4-(3-pyridyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (2.3 mg) with purity >90%. MS (pos) m/z 360.2.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]([CH3:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:23][CH:24]=1
Reactant: CC(C(=O)c1ccc(O)cc1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C(=O)c1ccc(OC2CCCCO2)cc1)c1ccccc1
Yield: 38.3 %

Procedure:
2,3-Dihydropyran (4.6 g.) and a few crystals of toluene-p-sulphonic acid were added to a solution of 4-hydroxy-α-methyldesoxybenzoin (11.3 g.) in chloroform (100 ml.). The resulting solution was heated under reflux for 5 mins., cooled and washed with 5% w/v aqueous sodium bicarbonate solution. The chloroform solution was then dried and evaporated, and the residue crystallised from acetone to give 4-(2-tetrahydropyranyloxy)-α-methyldesoxybenzoin (5.93 g.), m.p. 94°-96° C.
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC=C(Cl)C=2)C(NO)=O)=CC=1)C#CC.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28]>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])(=[O:5])=[O:37])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2cccc(Cl)c2)cc1
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2cccc(Cl)c2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2cccc(Cl)c2)cc1
Yield: 27 %

Procedure:
Starting from a mixture of 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(3-chlorophenyl)-N-hydroxyacetamide and 2{[4-(2-butynyloxy)phenyl]sulfinyl}-2-(3-chlorophenyl) N-hydroxyacetamide (210 mg, 0.56 mmol), and following the procedure as outlined in Example 75, 60 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl)-2-(3-chlorophenyl)-N-hydroxyacetamide was isolated as a white powder. mp: 50° C.; Yield: 27%; MS: 394.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ1.84 (t, J=2.22 Hz, 3H), 4.86 (d, J=2.31 Hz, 2H), 5.06 (s, 1H), 7.12 (d, J=8.97 Hz, 2H), 7.19-7.39 (band, 2H), 7.48 (m, 4H), 9.33 (d, J=1.2 Hz, 1H), 10.9 (s, 1H).
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5](O)[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.[N+:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18].C(OCC)C.C>CO>[N+:17]([CH:20]([CH:5]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: OC1c2ccccc2C=Cc2ccccc21
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 41.3 %

Procedure:
Dibenzosuberenol (42 g, 0.2 mol) is combined with ethyl nitroacetate (25 mL, 0.23 mol) and the mixture is heated at 120° C. (oil bath) until melted and then kept at 110° C. for 2.5 hours. The oil bath is removed and the cooled reaction mixture is dissolved in 50 mL of methanol and taken up into 350 mL of boiling diethyl ether. The dark solution is treated with charcoal, filtered, and cooled overnight. A precipitate is collected by filtration, washed with hexane, diethyl ether, dried under vacuum at room temperature to give 26.7 g of the title compound; mp 101°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([OH:29])=O)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH3:36][NH2:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](=[O:29])[NH:37][CH3:36])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CN
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 33.8 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (2 g, 3.6 mmol) was reacted with methanamine hydrochloride (0.49 g, 7.2 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (0.69 g, 34%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]4[CH:30]=[N:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:31]N1C(=O)CCC1=O>CN(C)C=O>[Br:31][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:30]=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[CH:1]2
Reactant: c1ccc2c(-c3ccc(-c4cnc5ccccc5n4)cc3)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccc(-c3cnc4ccccc4n3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 520.9 %

Procedure:
Dissolving 2.2 g (6.2 mmol) of 2-(4-anthracen-9-yl-phenyl) quinoxaline obtained in the foregoing step (2) into 20 milliliter of N,N-dimethylformamide, and adding 1.2 g (6.7 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 14.9 g of 2-[4-(10-bromo-anthracen-9-yl)-phenyl]-quinoxaline (yield: 78%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)CC)(C)C.[NH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:30][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiimidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.FC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:15]=[CH:16][N:17]=[CH:5]2)=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc2cnccc2c1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: Fc1cc2ccncc2cc1Br

Procedure:
Starting from 3-bromo-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt=0.91 min (Method B). Detected mass: 226.0/228.0 (M+H+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[N:25][CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:44][S:45][CH2:46][CH2:47][CH2:48]O>C1COCC1>[Br:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([O:27][CH2:48][CH2:47][CH2:46][S:45][CH3:44])[CH:22]=1
Reactant: Oc1cncc(Br)c1
Reactant: CSCCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCCOc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of PPh3 (20 g, 76 mmol) in THF (20 mL) is added a solution of 5-bromo-pyridin-3-ol (5.0 g, 29 mmol) in THF (10 mL). Then a solution of di-tert-butyl azodicarboxylate (16 g, 69 mmol) in THF (10 ml) is added. The mixture is stirred at room temperature for 30 min and 3-methylsulfanyl-propan-1-ol (3.3 g, 31 mmol) is added. The mixture is stirred at room temperature for 16 hrs. Then the solid is filtered and the filterate is concentrated. The residue is purified by flash column chromatography to give 4.5 g of 3-bromo-5-(3-methylsulfanyl-propoxy)-pyridine.
Reaction SMILES: N[C:2]1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[S:30]([NH:33][C:34]1[CH:35]=[C:36](C)[CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:31]>>[NH2:27][C:25]1[CH:24]=[CH:23][C:22]([S:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH3:2])=[CH:36][CH:35]=2)(=[O:31])=[O:32])=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cccc(C)c1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: COc1cc(N)ccc1S(=O)(=O)Nc1ccc(C)cc1
Yield: 93 %

Procedure:
(RK1-1-42) I This compound was prepared according to the procedure described for compound 12a except using 11i to obtain the required product as a light yellow solid (130 mg, 93%). Mp=158-160° C.; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.2 Hz, 2H), 6.93 (d, J=8.2 Hz, 2H) 6.70 (br s, 1H), 6.16 (s, 1H), 6.14 (app d, J=2.0 Hz, 1H), 4.05 (br s, 2H), 3.95 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:15]#[CH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.7 %

Procedure:
To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargyl bromide, 1.5 mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4×40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:16]=[O:17]>CO.C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2cnc(C)[nH]2)c1
Reactant: C=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Yield: 21 %

Procedure:
Heated was a solution of 7.0 g (3.2 mmol) of 5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazole (5b) in 37% aqueous formaline (20 ml) at 120° C. for 15 hours in a sealed tube. The reaction mixture was dissolved in methanol/methylene chloride, and the aqueous layer was separated off. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methanol:ethyl acetate=2:98), and the crude product was washed with isopropyl ether to obtain 1.7 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d) (yield 21%). mp 199-201° C.