Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+].C(O)C>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(CC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-c2c(C(CC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoate (0.039 g; 0.089 mmol) in methanol (2.7 mL) was added a 5% sodium hydroxide solution (2.68 mmol; 2.15 mL) and the reaction mixture was heated at 60° C. 18 h. An extra volume of 5% sodium hydroxide solution (1 mL) and ethanol (1 mL) were added and the reaction mixture was heated at 60° C. for 12 additional hours. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in water. The mixture was acidified with HCl (1N) until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. The white solid was crystallized in a mixture ethyl acetate-heptane to furnish 0.025 g (67%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]3[O:17][C:16]([CH3:19])(O)[CH2:15][CH2:14][C:13]=3[C:20]=2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24]>CCOCC>[Cl:24][C:16]1([CH3:19])[CH2:15][CH2:14][C:13]2[C:20]([CH3:21])=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]=2[O:17]1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(O)O2
Reactant: Cl
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of 5 g (16 mmol) of rac-3,4-dihydro-6-(phenylmethoxy)-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol in 50 mL of anhydrous ether was added 5 g of 4A molecular sieves. The mixture was stirred mechanically with ice-bath cooling while HCl gas was bubbled in for 30 min. Stirring was continued at 0° C. for 30 min and then the solvent was removed in vacuo. The residue was treated with 500 mL of hexane and the solution was decanted. The hexane solution was then treated with 10 g of anhydrous CaCl2 and the mixture stirred for 2 hr. The solids were filtered and the filtrate was concentrated in vacuo to a volume of ca. 20 mL. Crystallization was induced by cooling to -10° C. and stirring, then the remaining solvent was removed in vacuo giving 4.9 g (92.8% yield) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran as a colorless solid. The chlorochroman decomposed upon attempted column or thin layer chromatography. It was stored at 0° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O.B.C1COCC1.C1COCC1>CO>[CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][CH2:5][C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: CC(C)CNC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CNC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 54.9 %

Procedure:
A 500-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-((2-methylpropyl)carbamoyl)-1,4-piperazinedicarboxylate (1.77 g, 4.60 mmol), BH3.THF (1.0 M in THF, 13.8 mL, 13.8 mmol, Sigma-Aldrich, St. Louis, Mo.) and THF (60 mL). The reaction mixture was heated at 50° C. for 12 h. The mixture was allowed to cool to room temperature and then MeOH was added until the bubbling ceased. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (100 g of silica gel, 0 to 10% iPrOH (with 10% NH4OH) in CHCl3) to obtain di-tert-butyl (2S)-2-(((2-methylpropyl)amino)methyl)-1,4-piperazinedicarboxylate (0.939 g) as a clear oil which solidified upon standing.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8](=[O:12])[C:9](Cl)=[O:10])[CH3:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:12])[C:9]([C:18]1[CH:17]=[CH:16][C:15]([S:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([Cl:13])[CH:19]=1)=[O:10])[CH3:6]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Clc1ccccc1SC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC2CCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask is placed methylene chloride (100 mL) and aluminum trichloride (1.39 equiv) and it is cooled to 0° C. in an ice bath. To this solution is then added dropwise chloro-oxo-acetic acid ethyl ester (1.09 equiv.) keeping the temperature of the solution below 5° C. and it is then stirred for 30 min at 0° C. After this time a solution of 1-chloro-2-cyclopentylsulfanyl-benzene (50.0 mmol) in methylene chloride (5 mL) is added dropwise while keeping the temperature of the solution below 5° C. The ice bath is then removed and the reaction is allowed to warm up to 25° C. and is stirred for 3 h. The reaction is then cooled back down to 0° C. in an ice bath and ice water (20 mL) is then added dropwise keeping the temperature of the solution below 20° C. It is then stirred for 15 min and then transferred to a separatory funnel and separated. The organic phase is then washed with water (2×25 mL), saturated aqueous sodium bicarbonate solution (2×25 mL) and water (25 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford (3-chloro-4-cyclopentylsulfanyl-phenyl)-oxo-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[O:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1ncoc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ncoc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 84.7 %

Procedure:
In the same manner as in Example 259 and using 4-methyl-1,3-oxazole-5-carboxylic acid (76 mg, 0.59 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.71 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting material, the title compound (170 mg, 84%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:22]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([O:9][CH3:22])=[O:8])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (20 g, 85 mmol) in MeOH (200 mL) was added H2SO4 (12 mL, 225 mmol) at 0° C. dropwise, then the mixture was stirred for 16 h at 25° C. Then the solvent was concentrated and was adjusted pH=9 with NaHCO3 solution. The solvent was concentrated to give the residue which was extracted with DCM (200 mL×2), dried over Na2SO4, filtered, and concentrated to yield an oil of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 76 mmol, 90% yield): 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 4.01 (s, 3H); ES-LCMS m/z 250 (M+1).
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[N:13][CH:14]=2)[S:3]1.Cl.C([OH:33])C>>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:33])[NH:6][C:5]2=[O:7])=[CH:14][N:13]=1
Reactant: CCO
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=N)NC2=O)cn1
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cn1
Yield: 59 %

Procedure:
A mixture of 2-imino-5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methyl]-4-thiazolidinone (0.76 g), 1N HCl (10 ml) and ethanol (10 ml) was heated for 20 hours while refluxing, followed by concentration under reduced pressure. The residual crystal was collected by filtration, washed with water and then recrystallized from ethanol-chloroform to yield 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methyl]-2,4-thiazolidinedione (0.45 g, 59%) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18](O)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][CH2:25][N:26](CC)CC.ClC(OCC)=O.C(N)C>C(Cl)(Cl)Cl>[CH2:25]([NH:26][C:18]([C:15]1[C:14](=[O:21])[N:13]2[CH:22]=[CH:23][C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:11][C:12]2=[N:17][CH:16]=1)=[O:19])[CH3:24]
Reactant: O=C(O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCNC(=O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reaction time: 0.17 h

Procedure:
To a solution of 8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (50 mg, 0.62 mmol, 1 equiv) and Et3N (0.5 mL) in CHCl3 (20 mL) at 0° C. was added ethyl chloroformate (0.4 mL) dropwise. After the reaction mixture was stirred for 10 min, aq. ethanamine (3 mL) was added. Then the mixture was stirred for 10 min and extracted with CHCl3 (3×30 mL), dried over Na2SO4 and concentrated to give the desired product (30 mg). MS (ESI): 336 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.37 (s, 1H), 9.17-9.14 (d, J=7.32 Hz, 1H), 8.96-8.95 (m, 1H), 7.91 (s, 1H), 7.44-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.23-7.18 (m, 1H), 3.60-3.50 (m, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H). mGluR5 PAM EC50: ++++.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:19]([NH:27][C:28]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=S)NC(=O)c3ccccc3)nc12
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To a suspension of 2-amino-4-methoxy-7-phenyl-benzothiazole (1.52 g, 6 mmol) in dioxane (60 ml) was added benzoylisothiocyanate (1.45 g, 8.9 mmol) and the mixture heated to 100° C. for 2 h, during which time the suspension dissolved. After cooling the solvent was removed and the solids suspended in hot acetonitrile (100 ml) and filtered while warm (50° C.). The solid collected was washed with acetonitrile (20 ml) then dried under vacuum (0.05 mmHg), at 60° C. to afford the title compound as a pale yellow amorphous solid (1.38 g, 55% yield), MS: m/e=419.0 (M+).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+]>O>[CH2:18]([O:24][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To dimethylformamide solution (91 ml) containing 2-chloro-5-nitrobenzonitrile (18.2 g) and n-hexanol (11.2 g) was added sodium hydride (60% content, 4.8 g) under ice-cooling and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give 2-n-hexyloxy-5-nitrobenzonitrile (16.2 g). Then, ammonium chloride (0.2 g) and iron powder (1.6 g) were added to a mixed solvent of water (6.3 ml) and ethanol (17 ml), and the mixture was heated to 65° C. Then, the obtained ethanol solution (4 ml) containing 5-nitro-2-n-hexyloxybenzonitrile (16.2 g) was added dropwise thereto, and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated and the solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (6.0 g).
Reaction SMILES: [CH2:1]([N:8]([CH:28]1[CH2:31][N:30]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:29]1)[CH2:9][CH:10]([OH:27])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)N(C)CCC1.O>[CH3:51][O:50][C:48](=[O:49])[CH2:47][N:41]([C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:30]2[CH2:29][CH:28]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH:10]([OH:27])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[CH2:31]2)(=[O:34])=[O:33])=[CH:40][CH:39]=1)[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COC(=O)CBr
Reactant: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCCCN(CC(=O)OC)c1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
To a solution of 1-{benzyl-[1-(4-butylamino-benzenesulfonyl)-azetidin-3-yl]amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol (0.10 g, 0.15 mmol) in N,N′-dimethylpropyleneurea (1 ml) was added methyl bromoacetate (46 mg, 0.3 mmol) and potassium carbonate (28 mg, 0.2 mmol), and the mixture was stirred at 50° C. for 2 days. It was then cooled to room temperature and diluted with water (20 ml). The aqueous phase was removed, and the residue dissolved in ethyl acetate (20 ml). The organic solution was washed with brine, and dried over anhydrous sodium sulfate. It was then filtered and evaporated, and the residue was chromatographed on silica gel (ethyl acetate-hexanes/1:1) to give 50 mg of a colorless gum; MS (ES) m/z 702.2 (MH+); HRMS (FAB) Calcd. for C39H48N3O7S (MH+): 702.3213, Found: 702.3231.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][CH2:31][CH2:32]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCCCBr
Reactant: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCN1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
5.00 g (12.44 mmol) of the compound from Example 20A are dissolved in 57 ml of acetonitrile, and 4.51 g (24.89 mmol) of 3-bromopropyl acetate and 3.44 g (24.89 mmol) of potassium carbonate are added. The reaction mixture is stirred at +80° C. for 8 h. After filtration, the solvent is removed on a rotary evaporator. The residue is taken up in 50 ml of ethyl acetate and washed in each case once with 10 ml of water and 10 ml of saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The crude product is used in the next reaction without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1>>[Cl:27][C:28]1[CH:33]=[C:32]([CH2:34][O:35][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH:31]=[CH:30][N:29]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1ccnc(Cl)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccnc(Cl)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and (2-chloro-pyridin-4-yl)-methanol (111 mg; 0.736 mmol), example 88 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:30])([CH3:29])[CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[C:6]=2[N:7]=1.[CH:31]1([C:34]2[N:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=2)[CH2:33][CH2:32]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:18]=[C:17]([NH:19][C:40](=[O:41])[CH2:39][N:37]4[CH:38]=[C:34]([CH:31]5[CH2:32][CH2:33]5)[N:35]=[N:36]4)[CH:16]=[N:15][CH:14]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:30])([CH3:29])[CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[C:6]=2[N:7]=1
Reactant: O=C(O)Cn1cc(C2CC2)nn1
Reactant: CC(C)(COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Product: CC(C)(COC1CCCCO1)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)nn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 using {2-amino-7-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}(5-aminopyridin-3-yl)methanone (see Preparation 49) and (4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetic acid (see Preparation 83) to afford the title compound as a yellow solid in 86% yield, 70 mg.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]([Cl:16])([Cl:15])[Cl:14].S(=O)(=O)(O)O>>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[C:13]([Cl:16])([Cl:14])[Cl:15]
Reactant: Clc1cccc(C(Cl)(Cl)Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)c(C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
62 g of fuming nitric acid were added dropwise to 100 g of 2,3-dichlorobenzotrichloride at −10 to +10° C. in the course of 10 minutes, followed by 62 g of 96% by weight sulphuric acid. The reaction mixture was initially stirred at 20 to 30° C. for 2 hours, then cooled down, discharged onto ice and extracted 3× with 100 ml of dichloromethane each time. The combined organic phases were washed with 100 ml of water, 3×100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product (99 g, purity 100%, 84.4% of theory) was recrystallized from ethanol to obtain 68 g (=58.2% of theory) of 2,3-dichloro-5-nitro-benzotrichloride (mp. 97 to 99° C.), while the other isomers ended up in the residue.
Reaction SMILES: O.NN.[OH-].[K+].C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[OH:33])=[CH:20][C:19]=2[F:35])[CH2:13][CH2:12]1)=O)C.[Cl-].[NH4+]>C(O)CO.O>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([OH:33])=[C:26]([CH:31]=1)[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[C:19]([F:35])[CH:20]=1)=[O:34]
Reactant: CCOC(=O)N1CCC(Nc2ccc(NC(=O)c3cc(Cl)ccc3O)cc2F)CC1
Agent: NN
Agent: [Cl-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O=C(Nc1ccc(NC2CCNCC2)c(F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 64.4 %

Procedure:
Hydrazine monohydrate (0.227 ml, 5.70 mmol) and potassium hydroxide (0.641 g, 11.4 mmol) were added to a solution of 4-{[4-(5-chloro-2-hydroxybenzoylamino)-2-fluorophenyl]amino}piperidine-1-carboxylic acid ethyl ester (compound of Reference Example 189; 0.500 g, 1.14 mmol) in ethyleneglycol (10 ml), and the mixture was refluxed for 1 hour. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride and water were added. The precipitated solid was collected by filtration and washed with water to give the title compound (0.267 g, 64%) as an ivory solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1[CH:28]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1/[CH:28]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.8 %

Procedure:
A solution 4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide (Ex-55A, 830 mg, 2.44 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 575 mg, 2.44 mmol) in DMF (10.8 mL) and MeOH (4.4 mL) was treated with lithium methoxide (278 mg, 7.32 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Column chromatography (5% MeOH in dichloromethane) gave 772 mg (57%) of the title compound as a brown solid, mp 64–68° C. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.76 (t, 1H, J=4.8 Hz), 7.63 (d, 1H, J=15.3 Hz), 7.16 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.16 (br s, 4H), 2.76 (quartet, 2H, J=6.9 Hz), 2.15 (m, 10H), 2.06 (s, 3H), 1.80 (br s, 4H), 1.45 (quintet, 2H, J=6.9 Hz). HRMS (ESI) Calcd. for C29H40N4O5S: 557.2798 [(M+H)+]; Found: 557.2798.