Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1([CH3:17])[CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C.[Cu]I.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>[CH3:17][C:14]1([C:12]#[C:13][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:16][CH2:15]1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC1(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 mL) was added CuI (76 mg, 0.40 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.20 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). 1H NMR (300 MHz, CDCl3) 8.15-8.14 (m, 1H), 7.98-7.95 (m, 1H), 6.63 (d, J=6.9 Hz, 1H), 4.80 (brs, 2H), 1.38 (s, 3H), 1.04-1.01 (m, 2H), 0.76-0.73 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[C:13]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)[CH:12]=2)=[C:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:6]=1)#[N:2].[CH2:40]([C:44]1[CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH:41]([CH3:43])[CH3:42].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.CCO.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>[CH2:40]([C:44]1[CH:45]=[C:46]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][C:1]#[N:2])=[CH:6][C:7]=3[CH2:36][CH:37]([CH3:38])[CH3:39])=[CH:12][C:13]=2[CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH:41]([CH3:42])[CH3:43]
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2cccc3ccccc23)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CC(C)C
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: COCCOC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2cccc3ccccc23)cc1CC(C)C
Temperature: 80 °C
Yield: 93.8 %

Procedure:
439.6 mg (0.80 mmol) Trifluoro-methanesulfonic acid 4′-(2-cyano-ethyl)-2′-isobutyl-3-naphthalen-1-ylmethyl-biphenyl-4-yl-ester (67), 266.2 mg (0.92 mmol, 1.15 eq.) 2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11, FIG. 6) and 140.4 mg (121.4 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 15 ml DME/EtOH (9+1). To this yellow solution 0.80 ml (1.60 mmol, 2.00 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 9 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (CH2Cl2) yielded 426.5 mg (0.75 mmol, 94.23%) 3-(3,2″-Diisobutyl-4-methoxy-2′-naphthalen-1-ylmethyl-[1,1′:4′, 1″]-terphenyl-4″-yl)propionitrile (68) as a clear oil. Rf (hexanes/EtOAc (6+1))=0.12. 1H-NMR (500 MHz, CDCl3): δ=0.52 (d, 6H, J=6.62 Hz, 2*CH3), 0.77 (d, 6H, J=6.62 Hz, 2*CH3), 1.47 (m, 1H, CH), 1.74 (m, 1H, CH), 2.24 (d, 2H, J=7.41 Hz, CH2), 2.41 (d, 2H, J=7.25 Hz, CH2), 2.58 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.90 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.79 (s, 3H, OCH3), 4.39 (s, 2H, CH2Naphthyl), 6.83 (d, 1H, J=8.36 Hz), 6.96 (m, 2H), 6.99 (dd, 1H, J1=7.88 Hz, J2=1.89 Hz), 7.08 (d, 1H, J=7.57 Hz), 7.11-7.17 (m, 3H), 7.22 (m, 1H), 7.30-7.35 (m, 3H), 7.38 (m, 1H), 7.67 (dm, 1H, J=7.88 Hz), 7.72 (dm, 1H, J=8.20 Hz), 7.78 (dm, 1H, J=8.20 Hz). MS (EI): m/z=565 (14), 452 (11), 410 (10), 404 (19), 403 (59), 349 (24), 306 (10), 290 (13), 247 (35), 191 (13), 142 (14), 141 (100). HR-MS (EI): Calcd. for C41H43NO: 565.334464. Found: 565.334575.
Reaction SMILES: O1CCOCC1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:10][CH:9]=1.[Br:18]Br.[CH2:20]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH3:16][CH:15]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29]1)[CH:14]([OH:17])[C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1.[BrH:18]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Br
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
To a mixture of 3 ml of dioxane and 1 ml of methanol were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then nitrogen was introduced thereinto at a flow rate of 400 ml/minute for 15 minutes at 60° C. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 5 hours. The reaction mixture was then treated in the same manner as described in Example 5, whereby 11.4 g (70.4%) of ifenprodil hydrobromide were obtained as white crystals.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl.O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a mixture of 2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (preparation 4; 0.2 g, 0.58 mmol), 2-aminothiazole (0.070 g, 0.70 mmol), HOBt (0.095 g), and EDCl (0.134 g, 0.70 mmol) in methylene chloride (6 mL), was added N-methyl morpholine (0.08 mL, 0.70 mmol). The resulting mixture was stirred at room temperature overnight followed by dilution with methylene chloride. The reaction mixture was poured into water; organic layer was washed with water, brine, dried over sodium sulfate, and the organic solvent evaporated to get a residue which was purified by preparative TLC to obtain a title compound (0.118 g)
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.CC(C)=O.OC[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: OCCN1CCCC1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCCN4CCCC4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 32 %

Procedure:
A solution of mitomycin A (100 mg) in 4 ml of 1-(2-hydroxyethyl)pyrrolidine was stirred at room temperature and under nitrogen for 45 minutes with 240 mg of a 1.6% solution of potassium hydroxide in 1-(2-hydroxyethyl)pyrrolidine. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The reaction product was isolated twice on silica gel plate using triethylamine as a solvent in the first isolation and acetone in the second isolation. The pink band was cut and extracted with a mixture of acetone-triethylamine (4:1). The extract was concentrated under reduced pressure to give 40 mg (32%) of the title compound, having no definite melting point and providing the following analysis:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]#[CH:20])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7].[N+:21](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-:22].C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC=CC=1.O1CCCC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([N:5]1[CH2:4][CH2:3][CH2:2][N:22]2[N:21]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[C:19]2[CH2:18]1)(=[O:8])=[O:7])([O-:17])=[O:16]
Reactant: C#CCN(CCCCl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 140 °C
Yield: 50.1 %

Procedure:
To a solution of N-(3-chloropropyl)-2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.5 g, 1.59 mmol) and ethyl diazoacetate (0.251 mL, 2.384 mmol) in benzene (1.5 mL) was added N,N-diisopropylethylamine (0.27 mL, 1.6 mmol). The resulting solution was heated in a microwave reactor at 140° C. for 1 hour. Upon cooling to room temperature, cesium carbonate (0.621 g, 1.91 mmol) and tetrahydrofuran (1 mL) was added and the reaction mixture again heated at 140° C. for 30 minutes. Upon cooling to room temperature, the solvents were evaporated and the residue obtained was partitioned between water (10 mL) and EtOAc (15 mL). The aqueous layer was washed with additional EtOAc (15 mL), the combined organic layers were dried over anhydrous MgSO4, concentrated and purified via silica chromatography (20-90% EtOAc/hexane) to afford Intermediate 19 as a yellow oil (0.314 g, 50%). LC-MS: (FA) ES+395; 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=7.8, 1.5 Hz, 1H), 7.73-7.60 (m, 3H), 6.77 (s, 1H), 4.58 (s, 2H), 4.52-4.47 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72-3.65 (m, 2H), 2.10-2.04 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@H:6]([NH:17][C:18]([C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:22]=2[CH:23]=[N:24][CH:25]=1)=[O:19])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(#N)C>C1COCC1>[NH2:1][CH2:4][CH2:5][C@H:6]([NH:17][C:18]([C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:22]=2[CH:23]=[N:24][CH:25]=1)=[O:19])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:8]=1
Reactant: CS(=O)(=O)c1cc([C@H](CCN=[N+]=[N-])NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc([C@H](CCN)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 75 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3-azido-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (86 mg, 0.17 mmol) in THF (7 mL) was added triphenylphosphine (57 mg, 0.22 mmol) (gas evolved) followed by water (700 μL). After 75 hours, the mixture was concentrated acetonitrile was added and the solution was filtered through a 0.45 um nylon Acrodisc and purified by reversed-phase HPLC using a 20 minute gradient of 5-95% MeCN (0.1% TFA) in H2O (0.1% TFA) (flow rate=25 mL/minute). The desired fractions were lyophilized to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([CH2:18][S:19][CH3:20])[CH:9]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:13])[CH2:1][C:2]([CH:4]2[CH2:6][CH2:5]2)=[O:3])=[C:10]([CH2:18][S:19][CH3:20])[CH:9]=1
Reactant: COC(=O)c1ccc(Br)cc1CSC
Reactant: CC(=O)C1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1cc(Br)ccc1C(=O)CC(=O)C1CC1
Temperature: 0 °C
Yield: 52.1 %

Procedure:
A solution of cyclopropyl methyl ketone (1.1 g) and methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (3.6 g) in tetrahydrofuran was added to a refluxing suspension of sodium hydride (80%, 0.9 g) in tetrahydrofuran. After the addition was complete, the mixture was maintained at reflux temperature for 30 minutes. It was then cooled and poured onto 100 g of ice and 50 ml of saturated aqueous sodium bicarbonate. The mixture was extracted with hexane, the organic solution dried (anhydrous sodium sulphate) and the solvent evaporated to give 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropylpropan-1,3-dione as an orange oil (2.23 g), NMR (CDCl3): 1.00 (2H,m), 1.20 (2H,m), 1.75 (1H,m), 2.03 (3H,s), 3.92 (2H,s), 6.00 (1H,s), 7.35 (1H,m), 7.45 (1H,m), 7.58 (1H,m) 14.74 (1H,s).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[C:23]([O:29][CH2:30]I)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O:14][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccccc3O)C[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccccc3O)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (106 mg) in dry dimethylformamide (4.5 ml) was cooled with ice, and thereto pivaloyloxymethyl iodide (123 mg) was added. The mixture was stirred for 1 hour at the same temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was separated with a separating funnel. After the organic layer was washed with a cold saturated aqueous sodium chloride solution (4 times), it was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to give [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (36 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH3:12])[CH:6]=[CH:7][CH:8]=1.ClC(C)[CH2:26][NH:27]C1C=CC=C(C(F)(F)F)C=1.CC1C=CC=C(C)C=1N.Cl.CC1C=CC=C(C)C=1N>>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH:11]([CH3:12])[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:21])[C:26]2=[NH:27])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(C)c1NC(C)CNc1cccc(C(F)(F)F)c1
Reactant: CC(Cl)CNc1cccc(C(F)(F)F)c1
Agent: Cc1cccc(C)c1N
Agent: Cl
Product: Cc1cccc(C)c1N1C(=N)N(c2cccc(C(F)(F)F)c2)CC1C
Yield: 55.6 %

Procedure:
1-(3'-Trifluoromethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-3-trifluoromethylaniline, a compound obtained as described in Example 23, point (b), with 2,6-dimethylaniline. The reaction is performed as described in Example 16, point (c) with the difference that crystalline 2,6-dimethylaniline hydrochloride is separated from the reaction mixture by trituration with ethyl acetate. The aimed product is obtained with a yield of 55.6%; m.p.: 95°-98° C. (dhydrochloride).
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH:10]([O:12]C(C)(C)C)[CH2:9][NH:8]1)(C)(C)C.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.[C:30]([S:33][CH2:34][CH2:35][C:36](Cl)=[O:37])(=[O:32])[CH3:31].C(SCC(C)C(Cl)=O)(=O)C>>[C:30]([S:33][CH2:34][CH2:35][C:36]([N:8]1[CH2:9][CH:10]([OH:12])[CH:11]=[C:7]1[C:6]([OH:5])=[O:17])=[O:37])(=[O:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(OC(C)(C)C)CN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: CC(=O)SCCC(=O)N1CC(O)C=C1C(=O)O

Procedure:
By substituting 4-tert-butoxy-L-proline tert-butyl ester for the L-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1, 1-(3-acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]([CH3:17])=[N:10]1.[H-].[Na+].I[CH3:21].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:21])[C:12](=[O:16])[C:11]([CH3:17])=[N:10]1
Reactant: CI
Reactant: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)n(C)c1=O
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of 1.1 g (0.0040 mole) of 2-(2,4-dichlorophenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione in 5 mL of N,N-dimethylformamide was added to a stirred mixture of 0.11 g (0.0045 mole) of sodium hydride in 10 mL of N,N-dimethylformamide. After 0.5 hour, 0.63 g (0.0045 mole) of iodomethane in 5 mL of N,N-dimethylformamide was added, and the resultant mixture was stirred for approximately 18 hours. The mixture was poured into water and the resulting precipitate was collected and dissolved in ethyl acetate. The organic solution was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to leave a solid. The solid was purified by recrystallization from heptane to yield 0.52 g of 2-(2,4-dichlorophenyl)-4,6-dimethyl-1,2,4-triazine-3,5(2H,4H)-dione (mp 109°-110° C.), Compound 5 in the tables.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH:21]=[CH:20]2)[C:13](=[O:28])[CH2:12]1)=O)C1C=CC=CC=1.C(O)=O.CO.[Cl:34][C:35]1[S:39][C:38]([CH:40]=[CH:41][S:42](Cl)(=[O:44])=[O:43])=[CH:37][CH:36]=1>[Pd].C(#N)C>[Cl:34][C:35]1[S:39][C:38]([CH:40]=[CH:41][S:42]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH:21]=[CH:20]3)[C:13](=[O:28])[CH2:12]2)(=[O:44])=[O:43])=[CH:37][CH:36]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CCn1ccc2cnccc21
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Agent: [Pd]
Solvent: CO
Solvent: CC#N
Solvent: O=CO
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1CCn1ccc2cnccc21

Procedure:
4-(Benzyloxycarbonyl)-1-(2-pyrrolo[3,2-c]pyridin-1-ylethyl)-piperazin-2-one (0.028 g, 0.074 mmol), EXAMPLE 98, is treated with 4% HCO2H/MeOH (5 mL) and a catalytic amount of Pd black for 5 minutes. The reaction mixture is filtered washed with methanol and the filtrate is concentrated to a residue. The residue is treated with acetonitrile (3 mL) excess N-methylmorpholine (0.04 mL) and 2-(5-chlorothiophen-2-yl)ethene-sulfonyl chloride (0.018 g, 0.074 mmol), EXAMPLE 3, and processed as usual (EXAMPLE 719). Further chromatographic purification (NH4OH/MeOH/CH2Cl2: 1/4/95) yields the title compound: MS m/z 451, 453 (M+H); 1H NMR (CDCl3, 300 MHz) δ8.93 (bs, 1H), 8.24 (bs, 1H), 7.41 (d, 1H), 7.23 (d, 1H), 7.14 (m, 2H), 6.94 (d, 1H), 6.68 (d. 1H), 6.18 (d, 1H), 4.43 (t, 2H), 3.67 (t, 2H), 2.88 (t, 2H), 2.66 (t, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O.O1CCCC1.C(O)C>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1CN[C@@H](C)CN1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1C[C@@H](C)NC[C@@H]1C
Temperature: 20 °C
Yield: 74.2 %

Procedure:
A 12 L, 3-necked round bottom flask was charged with trans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had been recrystallized from toluene to mp=115-119° C., and 600 mL of water. The flask was cooled in an ice bath and a solution of methanesulfonic acid (1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring and cooling to maintain the temperature below 40° C. The solution was cooled to 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel was filled with 60% aqueous potassium acetate from a 2 L reservoir of the solution, and potassium acetate was added to the reaction flask to adjust the pH to 4.0. A second addition funnel was charged with a solution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL of tetrahydrofuran. The ethyl chloroformate and potassium acetate solutions were simultaneously added dropwise at a rate to maintain the reaction solution at pH 4.0±0.1, with cooling as necessary to maintain temperature at 25° C. After addition of the ethyl chloroformate was complete, the reaction was stirred for 1 hour with continued addition of potassium acetate solution to maintain a pH of 4.0. The organic solvents were removed by distillation under vacuum. The remaining aqueous solution was washed with 1500 mL of ethyl acetate to remove any bis-carbamate impurity. The ethyl acetate wash was extracted with two 500 mL portions of 1 M hydrochloric acid to recover desired product. The acid extracts were combined with the original aqueous solution and the pH was adjusted to 11 by addition of 10 M sodium hydroxide, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with two 1500 mL portions of ethyl acetate, the combined extracts were dried over magnesium sulfate, and the solvent was removed to give 927 g (74%) ethyl trans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)c1
Solvent: CC#N
Product: COc1cccc(Nc2nccc(-c3sc(NC(=O)CCN4CCOCC4)nc3C)n2)c1

Procedure:
By treatment of 3-bromo-N-{5-[2-(3-methoxyphenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity >94%). 1H-NMR (DMSO-D6) δ: 1.20 (m, 2H, CH2), 2.48 (m, 4H, CH2), 2.58 (s, 3H, CH3), 3.41-3.57 (m, 6H, CH2), 3.79 (s, 3H, CH3), 6.52 (d, 1H, J=7.0 Hz, Ph-H), 7.07 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.15 (t, 1H, J=7.3 Hz, Ph-H), 7.22 (m, 1H, Ph-H), 7.62 (brs, 1H, Ph-H), 8.46 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.58 (brs, 1H, NH). MS (ESI+) m/z 456.01 [M+H]+ (C22H26N6SO3 requires 454.55).