Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][OH:3].C[O-].[Mg+2].C[O-].[CH2:9]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:9]([C:18]1[CH:19]=[C:20]([CH:2]=[O:3])[C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CO
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium (24 g, 0.98 mol), methanol (570 ml), toluene (240 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (224 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off to an internal temperature of 70° C. at a pressure of 350 mm Hg. The mixture was cooled to 25° C. and toluene (300 ml) was added. Anhydrous hydrochloric acid (38 g) was added to the reaction mixture over a period of 1.5 hours. Methanol (200 ml) was then added to the mixture and the pot was rigged for an atmospheric pressure fractional distillation. An azeotrope of methanol/toluene was distilled off to a pot temperature of 100° C. The pot was then cooled to 90° C. and paraformaldehyde (94.8 g, a commercial sample containing 5-7% by weight water) slurried in toluene (200 ml) was added over a 1 hour period. During the addition of paraformaldehyde, volatile reaction by-products were continually removed. The reaction mixture was maintained at a temperature of 90° C. for an additional hour after the paraformaldehyde addition was complete. The reaction temperature was then cooled to 70° C. and sulfuric acid (300 ml, 10% w/w) was added to the reaction mixture, which was then stirred for 30 minutes. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-nonyl salicylaldehyde. A 62% yield was obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8](Cl)[N:7]=[CH:6][N:5]=2.C(N(C(C)C)CC)(C)C.Cl.[C:23]([C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)#[N:24]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8]([N:28]1[CH2:27][CH2:26][C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:23]#[N:24])[CH2:30][CH2:29]1)[N:7]=[CH:6][N:5]=2
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Cn1c(Br)nc2c(Cl)ncnc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Br)nc2c(N3CCC(C#N)(c4ccccc4)CC3)ncnc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
8-bromo-6-chloro-9-methyl-9H-purine (200 mg, 0.80 mmol) was dissolved in DMF (4 mL). To this solution was added diisopropylethylamine (0.21 mL, 1.21 mmol). To this stirred mixture was added 4-cyano-4-phenylpiperidine hydrochloride (165 mg, 0.88 mmol) dissolved in a small amount of DMF. The resulting mixture was heated to 70° C. and stirred for 30 minutes. The solvent was removed in vacuo and the crude material was used without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[S:23]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:22])(=[O:25])=[O:24]
Reactant: Nc1ccc([N+](=O)[O-])cc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1cc([N+](=O)[O-])ccc1N
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred suspension of 2 (42 g) and triethylamine (30.4 g) in dichloromethan (400 ml) in an ice bath was added dropwise a solution of methanesulfonyl chloride (25.2 g) in dichloromethane (100 ml). The mixture was stirred for 30 min. and the precipitate was collected by filtration and recrystallized from ethyl acetate to give 33.77 g (58%) of 3: mp 132°-135° C.; MS m/e 276 (M+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[F:27][C:26]1[C:25]([F:28])=[CH:24][CH:23]=[C:22]([N+:29]([O-:31])=[O:30])[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol) in 100 ml anhydrous THF at 0° C., 47 ml of a 1M solution of LHMDS in THF (47 mmol) was added dropwise. The color of the solution turned dark purple. The solution was transferred via cannula to a dropping funnel, and the solution (containing the amine free base) was added in small portions to a solution of 2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF (50 ml) at 0° C. After completion of addition the mixture was stirred under argon at room temperature for 15 hours. The volume of the solvent was reduced, followed by extraction using ethyl acetate and brine. The organic layer was dried over sodium sulfate, the solvent was removed, and the obtained dark oil was purified by flash chromatography (EtOAc/hexane 1:5, Rf=0.58) yielding the crude product, which became a brown solid upon drying in vacuo (yield: 6.23 g, 33.6%); m/z=393 [M−1]−.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:25]=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C)C=O>O>[CH:26]([C:27]1[CH:35]=[CH:34][C:32]([O:33][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=2[CH3:8])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:25]
Reactant: COC(=O)c1cccc(-c2nc(CCl)c(C)o2)c1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of methyl 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (3.0 g), potassium carbonate (1.42 g), vanillin (1.57 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (3.76 g, 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCCCO)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCCCOS(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
9.25 g (0.056 mole) 4-aminobenzenebutanol is dissolved in 100 ml pyridine and the solution is cooled to ca. -10° C. 17.33 ml (25.65 g) (0.244 mole) methanesulfonyl chloride is added dropwise with vigorous stirring at a rate such that the methanesulfonyl chloride is added, the reaction mixture is left in the freezer for two days. The reaction mixture is poured onto 300 ml ice water and extracted with 3×200 ml methylene chloride. The combined organic layers are washed with 1 liter cold 5% HCl in 3 portions. The organic layer is dried over sodium sulfate, filtered, and stripped. The residue is crystallized from ethyl acetate/ether to obtain the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[O:19][CH:20]=1.[I-].[Na+]>CN(C)C=O.O>[F:27][C:25]1[CH:24]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=[C:21]([C:18]2[O:19][CH:20]=[C:16]([CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[N:17]=2)[CH:26]=1
Reactant: Fc1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1coc(-c2cc(F)cc(C(F)(F)F)c2)n1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottomed flask was placed diethyl malonate (3.72 g, 23.25 mmol, 5 equiv.) and N,N-dimethylformamide (10 mL). To the solution was added sodium hydride (60% suspension in mineral oil, 744.0 mg, 18.6 mmol, 4.0 equiv.) at room temperature portionwise over 10 minutes. After stirring for 30 minutes a solution of 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole (1.30 g, 4.65 mmol) in N,N-dimethylformamide (10 mL) was added at 0° C. over 15 minutes, and the reaction mixture allowed to warm up to ambient temperature. To the mixture was added sodium iodide (697.0 mg, 4.65 mmol, 1 equiv) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water was then added to the reaction mixture (30 mL) and the whole was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine (30 mL) and dried with sodium sulfate. After removal of the solvent under reduced pressure the crude mixture was purified by a silica-gel column chromatography (SiO2=80 g, hexane:EtOAc=7:1) repeatedly. The desired product, diethyl 2-({2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl)propane-1,3-dioate, was obtained as colorless powder (1.75 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13].[CH3:18][O:19][C:20]1[C:21]([N+:32]([O-:34])=[O:33])=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=[O:24]>O1CCCC1>[OH:24][CH:23]([C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[C:21]=1[N+:32]([O-:34])=[O:33])[C:13]#[C:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1OC
Reactant: C#CC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Temperature: -58 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A 1.0 M solution (1.9 ml) of lithium bistrimethylsilylamide in tetrahydrofuran was added to tetrahydrofuran (4.0 ml) at -78° C. under an argon atmosphere, and the mixture was stirred for 30 min. A solution of ethyl propiolate (176 μl, 1.74 mmol) in tetrahydrofuran (1.0 ml) was added thereto, and the mixture was stirred for 30 min. A solution of 3,4,5-trimethoxy-2-nitrobenzaldehyde (280 mg, 1.16 mmol), prepared in the step (b), in tetrahydrofuran (2.5 ml) was added thereto, and the temperature was raised to -58° C., followed by stirring for 30 min. The reaction mixture was poured into an ice-cold 10% aqueous ammonium chloride solution, and the mixture was vigorously stirred for 5 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(3,4,5-trimethoxy-2-nitrophenyl)-2-butynoate as an oil (268 mg, 68%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Product: O=C(C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 7d and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. ESI m/z: 492 (M−H−, 100%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:46][CH2:47]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-[3-(methylsulfonyl)propyl]-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3'25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H47Cl2N6O4S [(M+H)+] 729.2751, observed 729.2749.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][CH3:30])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH2:29]([C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:13][CH:12]=3)=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=1)[CH3:30]
Reactant: O=C1CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3)CC2)c(C)c1
Yield: 55.9 %

Procedure:
Using pyrrolidin-2-one (49 mg) and (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 145 and by the reaction and treatment in the same manner as in Example 1, the title compound (113 mg) was obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=O>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][C:20]3[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cn1ccnc1C=O
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(Cc3nccn3C)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 1 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 1-methyl-1H-imidazole-2-carbaldehyde (commercially available).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][NH:19][C:20]([NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1)=[O:21].O([CH2:48][C:49]([F:52])([F:51])[F:50])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[CH2:48][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][NH:19][C:20]([NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1)=[O:21]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCCN3)cnc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCCN3CC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
DIPEA (0.13 mL, 0.732 mmol) was added at 0° C. to a suspension of 1-piperidin-2-ylmethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.080 g, 0.198 mmol) in 10 mL of DCM. The resulting mixture was stirred at RT for 15 minutes before adding 2,2,2-trifluoroethyl triflate (0.056 mL, 0.396 mmol) was added. The reaction mixture was stirred at RT overnight before being evaporated. The residue was purified by SiO2 flash chromatography to give 0.053 mg of racemic 1-[1-(2,2,2-trifluoro-ethyl)-piperidin-2-ylmethyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (55% yield).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[CH:11]=[C:10](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)[N:9]=[N:8]1)=[O:4].[C:39]([OH:42])(=[S:41])[CH3:40].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl-].[Na+]>C1(C)C=CC=CC=1>[C:39]([S:41][CH:18]1[CH2:17][CH2:16][N:15]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14]/[C:13]/1=[CH:12]\[C:10]1[N:9]=[N:8][N:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:11]=1)(=[O:42])[CH3:40]
Reactant: COC(=O)CCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)nn1
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-4-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (13.15 g) in toluene (200 ml) were added thioacetic acid (3.7 ml) and N,N-dimethylformamide dineopentyl acetal (14.5 ml) at room temperature and the resulting mixture was stirred at the same temperature for 30 minutes. After aqueous sodium chloride solution was added, products were extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate and hexane (1:1) as the eluent to afford a mixture (12.92 g) of (E)-4-(acetylsulfanyl)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-4-yl}methylidene)-1-(triphenylmethyl)piperidine and 5-((acetylsulfanyl){1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-4-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(O)CC(C)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Agent: Cl
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(c3nc4c(c(=O)[nH]3)CCCC4)CC2)c1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 1-(3-methoxyphenyl)piperazine hydrochloride (116.5 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 79 mg (45%), crystals;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:62][C:63]1[C:64]([C:68]2[C:77]3[N:76]=[CH:75][CH:74]=[N:73][C:72]=3[C:71]([C:78]([OH:80])=O)=[CH:70][CH:69]=2)=[CH:65][S:66][CH:67]=1.CC1C(B(O)O)=CSC=1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:78]([C:71]3[C:72]4[N:73]=[CH:74][CH:75]=[N:76][C:77]=4[C:68]([C:64]4[C:63]([CH3:62])=[CH:67][S:66][CH:65]=4)=[CH:69][CH:70]=3)=[O:80])=[N:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cscc1B(O)O
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cscc1-c1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cn2)c2nccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture at rt overnight, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 4-methyl-3-thiopheneboronic acid in Step 1.4. Title compound: ESI-MS: 459.1 [M+H]+; tR=3.41 min (System 1); TLC: Rf=0.25 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].NC1C=CC([S-])=CC=1.[K+].Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=2)[N:22]=1>CS(C)=O.O>[Cl:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH:30]=[N:29]2
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: Nc1ccc([S-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Sc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
5.7 g (0.045 mol) of p-aminothiophenol together with 3 g (0.045 mol) of 86% potassium hydroxide and 2 ml of water in 80 ml of dimethylsulfoxide was heated under stirring at 80°-90° C. for 5 hours to make the potassium p-aminothiophenolate. The water generated was removed off by azeotropic distillation under reduced pressure. To this solution which was allowed to be cooled to room temperature was added a solution of 9 g (0.045 mol) of 2,6-dichloroquinoxaline dissolved in 100 ml of dimethylsulfoxide. The mixture was subjected to the reaction, while stirring, at 80°-90° C. for 8 hours. After the reaction mixture was cooled to the room temperature, it was poured into a great deal of water and stirred. The precipitating solid was filtered off, washed with 5% aqueous solution of sodium hydroxide and then washed with water, followed by drying. The crude crystals thus obtained were recrystallized from a mixed solution of ethanol-benzene to produce 6.7 g (yield 52%) of the intended compound (Compound No. 10) as light-yellow crystals, m.p. 144°-147° C.