Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2S[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[CH3:2].C(=O)([O-])O.[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:47]([O-:50])(O)=[O:48].[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[S:47](=[O:50])(=[O:48])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:4]=1[CH3:30])[CH3:2]
Reactant: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Reactant: O=S([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a mixture of N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogen carbonate (250 mg, 0.590 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (283 mg, 1.65 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous sodium hydrogensulfite solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 74 mg (yield: 28%) of the title compound. Amorphous powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[C:14]([CH:21]4[O:25][CH2:24][CH2:23][O:22]4)[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH2:12][CH2:11][C:10]2=[O:26])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[C:18]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:26])[N:9]2[CH2:8][C:5]1[CH:6]=[N:7][C:2]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(Cl)nc1)C(=O)CC2
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(-c3ccsc3)nc1)C(=O)CC2
Yield: 99.8 %

Procedure:
1-(6-Chloropyridin-3-ylmethyl)-5-(1,3-dioxolan-2-yl)-8-methoxy-3,4-dihydro-1H-quinolin-2-one (0.4 g), tetrakis(triphenylphosphine)palladium (0.12 g) and a 2N aqueous solution of sodium carbonate (2.5 ml) were suspended in 8 ml of 1,2-dimethoxyethane, and 0.20 g of 3-thiopheneboronic acid was added, followed by heating under reflux in an argon atmosphere for 4 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1). The purified product was concentrated under reduced pressure to thereby obtain 0.45 g (yield: 95%) of 5-(1,3-dioxolan-2-yl)-8-methoxy-1-(6-thiophen-3-ylpyridin-3-ylmethyl)-3,4-dihydro-1H-quinolin-2-one as a light brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1ccc(F)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 4-fluorophenethylamine (68 mg, 0.49 mmol). The title compound was obtained as a solid (50 mg, 26% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, s), 8.93 (1H, m), 8.39 (1H, s), 37.23 (2H, dd), 7.10 (2H, dd), 3.41 (2H, m), 2.77 (2H, m). MS m/z: 470.04, 472.03 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[S:9]1[C:13]([Sn](C)(C)C)=[CH:12][N:11]=[CH:10]1>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:4]1[CH:3]=[C:2]([C:13]2[S:9][CH:10]=[N:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(Br)ccn1
Reactant: C[Sn](C)(C)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1cc(-c2cncs2)ccn1
Temperature: 25 °C

Procedure:
At room temperature, tetrakis(triphenylphosphine)palladium (470 mg) was added to a solution of 4-bromo-2-methylpyridine (1.65 g) and (5-thiazolyl)trimethyltin (1.56 g) in benzene (80 ml), followed by heating under reflux for 14 hours. After allowed to cool down to room temperature, the reaction mixture was washed with a saturated aqueous solution (100 ml) of sodium bicarbonate. The water layer was extracted with ethyl acetate (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=4:1→1:1), whereby 2-methyl-4-(5-thiazolyl)pyridine was obtained as a colorless solid. The resulting solid was dissolved in diethyl ether (30 ml) and tetrahydrofuran (30 ml), followed by the dropwise addition of n-butyl lithium (a 1.52N hexane solution, 4.35 ml) at −78° C. After stirring for 30 minutes, a carbon dioxide gas was blown into the reaction mixture. Thirty minutes later, the reaction mixture was heated gradually to room temperature. The reaction mixture was concentrated, whereby the residue of lithium 5-(2-methylpyridin-4-yl)thiazole-2-carboxylate was obtained as a colorless solid. To a solution of the resulting residue in N,N-dimethylformamide (40 ml) were added 1-(tert-butoxycarbonyl)piperazine (1.30 g), 1-hydroxybenzotriazole monohydrate (945 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g) at room temperature. After stirring for 3 days, ethyl acetate (200 ml) and water (800 ml) were added to the reaction mixture to separate it into layers. The water layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with water (800 ml) and a saturated aqueous solution (200 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=6:1), whereby the title compound (810 mg) was obtained as a colorless transparent viscous substance.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[NH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][NH:16][C:4](=[O:6])[C:3]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[N:12][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Reactant: NCCO
Solvent: CCO
Product: Cc1ncc([N+](=O)[O-])cc1C(=O)NCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-methyl-5-nitronicotinate (1 g.) and 2-aminoethanol (4 ml.) in ethanol (5ml.) was stirred at room temperature for 16 hours. The solvent was distilled off, the residue was purified by silica gel chromatography and recrystallized from ethyl acetate n-hexane to give the desired yellow crystals. mp 144° - 145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]=[O:11].[BH4-].[Na+].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][CH2:25]Cl>CO.O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:23][O:24][CH3:25]
Reactant: COCCl
Reactant: O=CCc1cc(F)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COCOCCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of 21a (3.60 g, 16.6 mmol) in methanol (40 mL) was added sodium borohydride (640 mg, 16.6 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue were added dichloromethane (50 mL), diisopropylethylamine (3.5 mL, 20 mmol) and chloromethyl methyl ether (1.5 mL, 20 mmol) at 0° C., and the reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (15:1 hexane/ethyl acetate) to give 22a (2.99 g, 2 steps 68%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.04 (t, J=6.7 Hz, 2H), 3.31 (s, 3H), 3.77 (t, J=6.7 Hz, 2H), 4.62 (s, 2H), 6.82 (td, J=8.2, 3.2 Hz, 1H), 7.04 (dd, J=9.4, 2.9 Hz, 1H), 7.48 (dd, J=8.8, 5.3 Hz, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[N:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1.N1C=CC=CC=1>C1COCC1.C(Cl)Cl>[N:5]([C:6]1[N:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1)=[C:1]=[S:2]
Reactant: N#Cc1cnc(N)cn1
Reactant: S=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cnc(N=C=S)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of thiophosgene (1.86 g, 15 mmol) in THF (4 mL) is added dropwise to a solution of 5-aminopyrazine-2-carbonitrile (1.20 g, 10 mmol) and pyridine (2 mL) in CH2Cl2 (200 mL) and THF (25 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 h. The mixture is concentrated and the crude product is diluted with ethyl acetate, filtered and concentrated to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.O[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C1(C)C=CC=CC=1.N1CCCCC1>O.C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:10][CH:11]=1
Reactant: OCn1cncn1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)C(Cn1cncn1)n1cncn1
Yield: 78.5 %

Procedure:
A mixture of 44.3 g of 4-chlorophenyl 1,2,4-triazol-1-yl-methyl ketone, 19.6 g of 1-hydroxymethyl-1,2,4-triazole, 300 ml of toluene, 6 g of acetic acid and 2 ml of piperidine is heated under a water separator until separation of water is complete. The mixture is allowed to cool, and the crystalline precipitate formed is filtered off under suction and washed with diisopropyl ether. 47 g (76% of theory) of 1-(4-chlorophenyl)-2,3-di-(1,2,4-triazol-1-yl)-propan-1-one of melting point 240° C. are obtained.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[OH:8][NH:9][CH:10]([CH2:35][CH2:36][CH2:37][C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]>O1CCCC1.C(O)=O>[OH:8][N:9]([CH:10]([CH2:11][S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][N:26]=2)[CH2:19][CH2:20]1)(=[O:14])=[O:13])[CH2:35][CH2:36][CH2:37][C:38]1[N:39]=[CH:40][CH:41]=[CH:42][N:43]=1)[CH:5]=[O:7]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(C#Cc3ccccn3)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(C#Cc3ccccn3)cn2)CC1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
Formic acid (1.8 mL, 50 mmol) and acetic anhydride (0.5 mL, 5 mmol) were mixed together at 0° C. for 30 minutes, before being added to a solution 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(pyridin-2-ylethynyl)pyrimidine (190 mg, 0.37 mmol) in tetrahydrofuran (5 mL) and formic acid (1.8 mL) at 0° C. The reaction was allowed to reach room temperature and was stirred for 45 minutes. The reaction was then evaporated in vacuo, and azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH and heated to 45° C. for one hour. The solution was evaporated in vacuo, and the residue triturated with Et2O to give a white solid which was collected by filtration, washed with Et2O and dried in vacuo to give hydroxy {1-[({4-[5-(pyridin-2-ylethynyl)pyrimidin-2-yl]piperazin 1-yl}sulfonyl)methyl]-4-pyrimidin-2-ylbutyl}formamide as a white solid. (64 mg, 32%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(/C=C/C2C=CC=CC=2)C=CC=CC=1.C1(CCC2C=CC=CC=2)C=CC=CC=1>[Pd].C(O)C>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C\c1ccccc1)\c1ccccc1
Agent: [Pd]
Agent: C(=C/c1ccccc1)\c1ccccc1
Solvent: c1ccc(CCc2ccccc2)cc1
Solvent: CCO
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The relevant reactions are shown in equations below. the first step, hydrogenation of the triple bond to form an olefin, can give two isomeric products, designated cis or trans depending on the orientation of the substituents about the double bond. These molecules can be further hydrogenated to the saturated product as also shown in such equations ##STR5## The palladium-loaded pyridyl catalyst of Example 6 hydrogenated diphenylacetylene under only 50 psig pressure of H2 : an ethanol solution of the substrate was 100% converted to a product mixture consisting of 80.7% cis-stilbene, 16.1% trans-stilbene, and 3.2% 1,2-diphenylethane. The low pressure used in this experiment made it difficult to monitor the course of the reaction, for the pressure gauge on the Parr bomb is not very sensitive or accurate in this regime. No pressure decrease was observed when the reaction mixture was stirred at room temperature for 3 hrs. and upon warming to 80° C. the pressure increased to 60 psig (the ideal gas law predicts 59 psig if no reaction occurred). No pressure increase was observed when the temperature was next raised to 100° C., and it remained steady on holding the reactor at this temperature for 1 hr. Upon cooling to room temperature the pressure was found to be 35 psig; it thus appears that the reaction occurred during the warming from 80° C.
Reaction SMILES: Cl[Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([CH:16]([N:18]2[C:22](=[O:23])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]5[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=5)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH:20]=[N:19]2)[CH3:17])=[O:15])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[Br:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([CH:16]([N:18]2[C:22](=[O:23])[N:21]([C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][N:33]([C:36]5[CH:41]=[CH:40][C:39]([O:42][Si:2]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:8])[CH3:7])=[CH:38][CH:37]=5)[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[CH:20]=[N:19]2)[CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O[Si](C)(C)C(C)(C)C)cc4)CC3)cc2)c1=O
Yield: 45.3 %

Procedure:
A solution of 2-(chlorodimethylsilyl)-2-methylpropane (0.011 mol) in dichloromethane (20 ml) was added to a stirred solution of 2-[1-(4-bromobenzoyl)ethyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.009 mol) in pyridine (20 ml) under a nitrogen atmosphere. Stirring was continued for 1 week at room temperature. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. This solution was purified over silica gel on a glass filter (eluent: dichloromethane). The pure fractions were collected and the solvent was evaporated. The residue (3.5 g) was recrystallized from ethyl acetate. The product was filtered off and dried, yielding 2.7 g (45 %) of 2-[1-(4-bromobenzoyl)ethyl]-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 177.8° C. (comp. 47).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6](S)[CH:5]=[C:4]([CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([OH:1])[N:7]=1)[NH2:12]
Reactant: NN
Reactant: Cc1cc(S)nc(O)n1
Solvent: CCO
Solvent: O
Product: Cc1cc(NN)nc(O)n1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
The product obtained in Step 1 (3.0 g) was suspended in 30 ml of ethanol at room temperature. Hydrazine monohydrate (3.17 g) was added dropwise to this suspension and the mixture was refluxed for two hours. After cooling to room temperature, the formed crystals were collected by filtration and washed with 20 ml of ethanol, giving 2.6 g of the objective compound as red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH:13]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:12]3[CH2:16][CH2:15][CH2:14][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=CC1=CCCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1=CCCC1
Yield: 30.7 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2.51 g, 15 mmol) (Alfa) was reacted with cyclopent-1-enecarbaldehyde (1.45 g, 15 mmol) (Aldrich) and piperidine (1.49 mL, 15 mmol) in methanol to give E/Z-6-chloro-3-cyclopent-1-enylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.13 g, 30%)
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[C:8]1([O:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[O:14]([C:15]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)Oc1ccccc1

Procedure:
From 10.0 ml (85 mmole) of trimethylphosphite and 10.0 g (64 mmole) of phenylchloroformate (100°, 2 hours). Yield 11.0 g (75%). B.p.0.5 125°-7°, nD25 1.4907. NMR (CDCl3)δ: 3.90 and 4.09 (CH3), 7.10-7.60 (C6H5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]([O:19]CC)=O)[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[NH3:22]>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]([NH2:22])=[O:19])[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)c1nc(-c2cc(Cl)c(OC)c(OC)c2)cs1
Reactant: N
Solvent: OCCO
Product: COc1cc(-c2csc(C(N)=O)n2)cc(Cl)c1OC

Procedure:
A solution of ethyl 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxylate (21.8 g) in 1,2-ethanediol (150 ml) at 120° C. was treated with ammonia gas for 25 min. The mixture was cooled in an ice-bath and the resultant suspension was filtered, washed with methanol, and dried at 60° C. under vacuum to give 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxamide (18.7 g), m.p. 178°-180° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH2:13][CH3:14])[CH2:11][OH:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([S:21]([NH2:24])(=[O:23])=[O:22])[S:19][CH:20]=1.NC1SC(S(N)(=O)=O)=CC=1>C(O)C.Cl>[Br:1][C:2]1[C:3]([NH:9][CH:10]([CH2:11][OH:12])[CH2:13][CH3:14])=[N:4][C:5]([NH:15][C:16]2[CH:17]=[C:18]([S:21]([NH2:24])(=[O:23])=[O:22])[S:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: Nc1csc(S(N)(=O)=O)c1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: Nc1ccc(S(N)(=O)=O)s1
Solvent: CCO
Product: CCC(CO)Nc1nc(Nc2csc(S(N)(=O)=O)c2)ncc1Br
Reaction time: 21 h

Procedure:
530 mg (1.9 mmol) of (R)-2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butan-1-ol is added to a suspension of 303 mg of a mixture that consists of 4-amino-thiophene-2-sulfonic acid amide and 5-amino-thiophene-2-sulfonic acid amide (ratio: 2:1) in 7 ml of ethanol and 170 μl of concentrated HCl. The reaction mixture is stirred for 21 hours under reflux. After cooling, the batch is purified by chromatography (Flashmaster II, hexane/EE 2:8). The crude product that is obtained is then recrystallized (ethyl acetate/diisopropyl ether). 47 mg (0.11 mmol, 7% of theory) of the product 4-[5-bromo-4-(1-hydroxymethyl-propylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonic acid amide is obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:5]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]([C:1](=[O:3])[CH3:2])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)c1ccc(CCN(C(C)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.57 g. (45.5 mmole) acetyl chloride in 50 ml. methylene chloride is slowly added dropwise to an ice-cold mixture of 16.0 g. (45.5 mmole) 4-chlorobenzenesulphonic acid-(4-propionylphenethylamide), 5.1 ml. (50 mmole) triethylamine and 200 ml. methylene chloride. The reaction mixture is then stirred for 3 hours at ambient temperature, extracted with 2N hydrochloric acid and several times with water, dried with anhydrous sodium sulphate and evaporated. After chromatography with silica gel/toluene +ethyl acetate (12:1 v/v), there are obtained 10.2 g. (57% of theory) of the desired product; m.p. 91°-92° C. (after recrystallisation from heptane +toluene).
Reaction SMILES: [CH3:1][C@H:2]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]#[CH:16])[CH:11]=2)[CH:6]=[N:5]1>C1(C)C=C(C)C=C(C)C=1>[CH3:1][C@H:2]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:13][CH2:14][CH:15]=[CH:16][C:11]3=2)[CH:6]=[N:5]1
Reactant: C#CCOc1ccc2cnn(C[C@H](C)NC(=O)OCc3ccccc3)c2c1
Solvent: Cc1cc(C)cc(C)c1
Product: C[C@@H](Cn1ncc2ccc3c(c21)C=CCO3)NC(=O)OCc1ccccc1

Procedure:
The product from Step B (2.37 g, 6.53 mmol) was heated in mesitylene (40 mL) in a manner similar to that described in Example 4, Step B to give, following purification (silica, 20% to 50% ethyl acetate in hexane), an oil (1.01 g, 43%): LC/MS (+APCI) m/z 364(M+H).
Reaction SMILES: [OH-].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH:21]2[CH2:26][CH2:25][CH:24]([O:27][N:28]3[C:33]([CH3:35])([CH3:34])[CH2:32][CH:31]([O:36]C(=O)C4C=CC=CC=4)[CH2:30][C:29]3([CH3:46])[CH3:45])[CH2:23][CH2:22]2)[C:14]([CH3:48])([CH3:47])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:36][CH:31]1[CH2:32][C:33]([CH3:35])([CH3:34])[N:28]([O:27][CH:24]2[CH2:25][CH2:26][CH:21]([O:20][N:15]3[C:14]([CH3:48])([CH3:47])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]3([CH3:19])[CH3:18])[CH2:22][CH2:23]2)[C:29]([CH3:46])([CH3:45])[CH2:30]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCC(ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCC(ON2C(C)(C)CC(O)CC2(C)C)CC1

Procedure:
The title compound is prepared by the basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 21C.