Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl isonipecotate (27.6 g, 175 mmol) in dichloromethane (50 ml) was added dropwise over 10 minutes to a solution of 3-chlorobenzoyl chloride (20 ml, 160 mmol) and triethylamine (28 ml, 200 mmol) in dichloromethane (500 ml) cooled to between 10 and 15° C. The reaction was then stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was diluted with ether, the solution washed with 1N hydrochloric acid, sodium carbonate solution (×3) and brine. It was then dried over MgSO4 and evaporated under reduced pressure, to give the title compound as a solid, 44.4 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][O:14][CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1[CH:20]=O>>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][O:14][CH3:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CONS(=O)(=O)c1ccc(C(C)=O)cc1
Product: CONS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4n3C)c(OC)cc2OC)cc1
Yield: 94 %

Procedure:
The title compound was prepared in an analogous way as Ex-1 using 4-acetyl-N-methoxy-benzenesulfonamide (Ex-30A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 94% yield, yellow solid, mp 214–216° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.11 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.25–7.26 (m, 1H), 7.11–7.16 (m, 2H), 6.59 (s, 1H), 6.50 (s, 1H), 4.03 (s, 3H) 3.90 (s, 3H), 3.84 (s, 3H), 3.58 (s, 3H). MS m/z: 506 ([M]+, 30%), 476 (100%).
Reaction SMILES: C(O[C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[CH2:8][CH2:7]1)=[NH:5])C.[NH3:17]>>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:6]1([C:4]([NH2:5])=[NH:17])[CH2:8][CH2:7]1
Reactant: N
Reactant: CCOC(=N)C1(c2ccc(Cl)cc2Cl)CC1
Product: N=C(N)C1(c2ccc(Cl)cc2Cl)CC1
Reaction time: 96 h

Procedure:
The crude 1-(2,4-Dichloro-phenyl)cyclopropanecarboximidic acid ethyl ester was dissolved in a solution NH3 (2.0 M in EtOH; 40 mL). Anhydrous NH3 (g) was bubbled into the solution until it was apparently saturated (60 min). The reaction mixture was stirred for 4 days. The solvent was evaporated and the desired product recrystallized from Ethyl acetate. (350 mg, 31%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:19][O:20][C:21]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[CH:18][C:17]=1[CH:15]([OH:16])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: C1CCOC1
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Product: COc1ccc(OC)c(C(O)c2cnccc2C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (110 mg, 0.52 mmol) in THF (3 mL) at −78° C. was added 1.0 M 2,5-dimethoxymagnesium bromide in THF (1.04 mL) and the reaction mixture was stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by chromatography of silica gel with 5% methanol in dichloromethane to yield {3-[(2,5-dimethoxy-phenyl)-hydroxy-methyl]-pyridin-4-yl}-phenyl-methanone as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].S(=O)(=O)(O)O.[CH3:30]O>>[CH3:30][O:6][CH2:5][C:4]1[C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:2]([F:1])[C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2COC)CC1
Temperature: 25 °C

Procedure:
3,6-Difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (7.14 g) is dissolved in methanol (770 ml), and thereto is added dropwise conc. sulfuric acid (145 ml) while cooling on an ice bath. The mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and is poured into ice water (1.5 liter), and then extracted with dichloromethane. The extract is dried over magnesium sulfate and sodium sulfate, and then the solvent is distilled off under reduced pressure to give 3-methoxymethyl-2,5-difluoro-4-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene (7.39 g) as yellow powder, m.p. 85°-86° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:7][C:8]([O:10][CH3:11])=[O:9].C(C1(C)[O:19][C:18](=O)[CH:17]=[C:16]([CH3:21])O1)C>C1(C)C(C)=CC=CC=1>[CH3:21][C:16]1[N:1]2[C:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:18](=[O:19])[CH:17]=1
Reactant: CCC1(C)OC(=O)C=C(C)O1
Reactant: COC(=O)C=C1CCCCN1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2n(c(C)cc1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A mixture of 3.10 g of methyl α-(hexahydro-2-pyridinylidene)acetate and 10 ml of xylene was gently refluxed, to which a solution of 7.81 g of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in 10 ml of xylene was dropwise added, taking 20 minutes. The mixture was further refluxed for 2 hours, removing the by-product a methyl ethyl ketone through Dean-Stark apparatus. The reaction mixture was cooled to room temperature. The resultant crystals were filtered, washed and dried under reduced pressure to obtain 4.11 g (Yield 93%) of methyl 6,7,8,9-tetrahydro-4-methyl-2-oxo-2H-quinolizine-1-carboxylate.
Reaction SMILES: C(OCC)C.[F:6][C:7]([F:31])([F:30])[C:8]1[CH:9]=[C:10]([C:14]2[CH2:15][CH2:16][N:17]([C:20](=O)[CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1.[ClH:32]>O>[ClH:32].[F:31][C:7]([F:6])([F:30])[C:8]1[CH:9]=[C:10]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCC1CCCCC1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1cccc(C2=CCN(CCCC3CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.152 mole of LiAlH(OCH3)3 and 60 ml of anhydrous diethyl ether at room temperature 0.038 mole of 4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropionyl)-1,2,3,6-tetrahydropyridine and 50 ml of anhydrous diethyl ether are added in 30 minutes. The product is left for 2 hours with stirring at room temperature, then water is added, the ethereal phase is decanted, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The oily residue, constituted by 4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridine base, is dissolved in isopropanol and the solution thus obtained is acidified with hydrogen chloride. In this way is obtained the 4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridine hydrochloride which, after crystallization from acetone, melts at 219°-222° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 1.0 mmol) was dissolved in CH2Cl2 (25 mL) and BBr3 (1 M solution in DCM, 4.91 mL, 4.91 mmol) was added and stirred at room temperature over night. The reaction was quenched using water, extracted with CH2Cl2, and dried using a phase separator. Concentration gave 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (232.1 mg, 100%) which was used as such in the next step.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)=[O:35])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1ccc(SCCNS(=O)(=O)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(S(=O)CCNS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-[2-(phenylsulfonylamino)ethylthio]phenoxyacetate (2 g) obtained in Example 3 in methylene chloride (30 ml) was added dropwise under ice cooling a solution of m-chloroperbenzoic acid (0.87 g) in methylene chloride (20 ml). The reaction mixture was stirred at room temperature for an hour, washed with an aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue, which was then chromatographed on silica gel column (eluent; ethyl acetate) and recrystallized from ethyl acetate to give ethyl 4-[2-(phenylsulfonylamino)ethylsulfinyl]phenoxyacetate (Compound No. 38) (1.76 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][CH2:13][C:12](=O)[CH2:11]2)=[CH:2]1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][CH:12]1[CH2:13][CH2:14][CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)C1
Product: c1ccc(CNC2CCC(c3c[nH]c4ccccc34)C2)cc1
Yield: 107.9 %

Procedure:
This compound was prepared in similar manner as for Intermediate 17, using 3-(1H-indol-3-yl)-cyclopentanone (3.0 g, 15 mmol) and benzylamine (1.95 g, 18 mmol) to give 4.7 g of the desired product as a mixture of cis and trans isomers, which were separated by flash chromatography to afford 0.6 g of the cis isomer (first eluting) and 1.0 g of the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[I:11].C([N:15]([CH:18]([CH3:20])[CH3:19])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:18]2[CH2:20][CH2:19]2)=[O:8])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(NC1CC1)c1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodobenzoic acid (9.00 g, 31.9 mmol) was heated to 75° C. in thionyl chloride (15 mL) for 4 h. The reaction mixture became homogeneous and was concentrated and dried azeotropically with toluene. The mixture was dissolved in 1,4-dioxane (10 mL), and diisopropylethylamine (11 mL mL, 64 mmol), and cyclopropylamine (2.45 mL, 35 mmol) and stirred at ambient temperature for about 2 h. The reaction was diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with 3 N HCl (aqueous). The organic layers were combined, washed 2 times with 50 mL of 3 N HCl (aqueous), and 2 times with 50 mL of sodium bicarbonate, dried over sodium sulfate, and concentrated via rotovap to give the title compound. Found MS (ES+): 322(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:42])[CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g, 1.6 mmol) in pyridine (11 mL) at 0° C. was treated with hydrocinnamoyl chloride (0.324 g, 1.92 mmol). The reaction mixture was stirred at 0° C. for 20 min and the ice bath was removed to stir at room temperature. The reaction was complete after 5.5 hours. Sodium hydroxide solution (1 N, 20 mL) was added and stirred for 30 minutes. The organic layer was removed under reduced pressure. Dichloromethane (20 mL) was added, and the layers were partitioned. The aqueous layer was extracted with dichloromethane (80 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of 5% methanol in dichloromethane to 50% methanol in dichloromethane on a 35 g ISCO silica gel column to give 0.569 g (63%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.569 g, 1 mmol) in warmed ethyl acetate was treated with a warmed solution of maleic acid (0.384 g, 3 mmol) in ethyl acetate. The formed precipitate was filtered under a nitrogen atmosphere and dried under high vacuum to give the tri maleate salt. 1H NMR (d6-DMSO) δ 9.238 (s, 1H), 8.2216 (s, 1H), 8.1991-8.1786 (d, 1H, J=8.2 Hz), 7.3147-7.2664 (m, 4H), 7.2366-7.2330 (m, 1H), 7.2026-7.1732 (dd, 2H), 6.171 (s, 6H), 4.6649-4.6083 (m, 1H), 4.0948-4.0697 (m, 1H), 3.8916 (s, 3H), 3.1750-3.1632 (d, 2H, J=4.72 Hz), 2.9364-2.8984 (m, 2H), 2.7885-2.7506 (m, 2H), 2.5290 (s, 2H), 2.3905-2.3231 (m, 4H), 2.1489 (s, 3H), 2.0549-1.9243 (m, 6H), 1.4821-1.4457 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 1.75 min (100%), M+569.4.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[O:15]>O>[CH3:11][S:12][C:13](=[O:22])[C:14]([C:16]1[N:17]=[C:18]([NH:21][CH:1]=[O:3])[S:19][CH:20]=1)=[O:15]
Reactant: CSC(=O)C(=O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: CSC(=O)C(=O)c1csc(NC=O)n1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 40.8 g of acetic anhydride and 18.4 g of formic acid was stirred at 40° to 45° C. for 1 hour. To the resulting mixture was added 20.2 g of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid metyl ester, with water-cooling, after which the resulting mixture was stirred at 25° C. for 1 hour. Subsequently, 160 ml of water was added dropwise to the thus obtained reaction mixture with ice-cooling, after which the resulting mixture was stirred with water-cooling for 30 minutes, and the deposited crystals were collected by filtration. The crystals were washed successively with water and acetone and then dried to obtain 21.9 g (94.4% yield) of 2-(2-formylaminothiazol-4-yl)thioglyoxylic S-acid methyl ester having a melting point of above 230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCCC1.[F:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)(=[O:38])=[O:37])=[CH:10][CH:9]=2)[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Yield: 74.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole, 15 ml of tetrahydrofuran, 0.36 ml of triethylamine and 0.27 g of 3-fluorobenzenesulfonyl chloride. 0.45 g of N-(N-tert-butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of an ochre solid melting at 100° C.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Br-].[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:19][CH2:20]2)=[CH:16][CH:15]=1.[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O>CCCCCC>[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:18]1[C:17]2[C:21](=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH2:20][CH:19]=1
Reactant: COC(=O)CCCCCC=O
Reactant: COc1ccc2c(c1)CCC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COC(=O)CCCCCCC1=CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 9.625 g. of potassium t-butoxide in 60 ml. of dimethylsulfoxide is added dropwise a solution of 40 g. of the phosphonium salt of Example 1 in 300 ml. of dimethylsulfoxide. After six minutes an equimolar amount (12.93 g.) of methyl-6-formylhexanoate is added dropwise just discharging the red color of the reaction mixture. The mixture is stirred for 1 hour at room temperature, and then poured into 1 liter of ice-water and 350 ml. of hexane. It is shaken, the white triphenylphosphine oxide is filtered off and the aqueous layer is extracted with ten 75 ml. portions of hexane. The combined hexane extracts are successively washed with four 250 ml. portions of (1:1) dimethylsulfoxide-water, four portions of water and one 300 ml. portion of saturated salt solution. After drying over magnesium sulfate the hexane mixture is concentrated to a yellow oil containing 6-methoxy-Δ3,ω -indanheptanoic acid methyl ester (Compound 3). The yellow oil is dissolved in chloroform (200 ml.) and to this is added 5 drops of trifluoroacetic acid. The mixture is allowed to stand at room temperature for 4.5 hours and then concentrated to dryness in vacuo. Upon trituration with hexane (15 ml.) 6-methoxy-3-indeneheptanoic acid methyl ester (Compound 4) separates in crystalline form, m.p. 30°-31.5°C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)C.N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1S.CC(OC(C)=O)=O>C1C=CC=CC=1>[NH:2]1[C:1]2[C:12](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]=[CH:4]1
Reactant: CN(C)C=O
Reactant: Nc1ccccc1S
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: c1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A dry DMF solution of the compound (A-2) (0.01 mole) was added o-aminothiophenol (0.013 mole) and Ac2O (0.5ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred benzene and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford target compound (A) (32% yield). 1H-NMR spectrum is shown in FIG. 3. Photoluminescence spectrum is shown in FIG. 4.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.C([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=O)C>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[OH:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (180 mg, 0.74 mmol) and triethylamine (150 μL, 1.1 mmol) in methylene chloride (20 mL) was added dropwise acetylsalicyloyl chloride (160 mg, 0.78 mmol) in methylene chloride (10 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in 99.5% ethanol (25 mL) and concentrated hydrochloric acid (3 mL) was added. After 17 h, the pH was adjusted to 8 and the solvent was evaporated in vacuo. The residue was partitioned between water and methylene chloride. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 170 mg (63%) of the title compound as white crystals: mp 87° C. decomp; [α]21D −18° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 365 (33, M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3cccnc3)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 207 from methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206) and pyridine-3-boronic acid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7].CN(C)C=O.[CH2:19]([SH:22])[CH2:20][CH3:21].[OH-].[K+]>O>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([S:22][CH2:19][CH2:20][CH3:21])[C:5]=1[C:6]#[N:7]
Reactant: CCCS
Reactant: N#Cc1c(F)cccc1OC(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1cccc(OC(F)F)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
180 g (0.96 mol) 2-difluoromethoxy-6-fluorobenzonitrile were introduced into 1.5 l of dimethylformamide at room temperature. 73.2 g (0.96 mol) of propanethiol were added dropwise and, after cooling to 0° C., 70 g (1.25 mol) of potassium hydroxide pellets, dissolved in 600 ml of water, were added dropwise at 0° C. The mixture was stirred for one hour and then warmed to room temperature. The reaction mixture was stirred into 3.5 l of ice-water and extracted three times with 500 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of 1N hydrochloric acid and dried over sodium sulfate. Then, the solvent was distilled off in vacuo. The oil obtained was distilled in vacuo (b.p.: 180-185° C./0.5 mbar). Yield: 76% of theory.