Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](O)=[O:19])([CH3:14])([CH3:13])[CH3:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>>[C:25]([C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]=1[OH:24])[C:18]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)c1cc(C(=O)Oc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of o-nitrophenol (1.39 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (2.50 g) and trifluoroacetic anhydride (8.5 ml) was stirred at room temperature overnight. The mixture was poured into ice water, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, saturated saline, and dried over anhydrous MgSO4. The solvent was distilled off and crystallization of the residue from diisopropyl ether afforded 2-nitrophenyl 3,5-di-t-butyl-4-hydroxybenzoate (2.60 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:9][C:10]1[C:11]([S:16](Cl)(=[O:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:16]([C:11]2[C:10]([CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ncccc2C)cc1

Procedure:
prepared by reaction of p-tolylamine with 3-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br>ClCCl.Cl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4cscn4)ccc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(OCc4cscn4)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-[4-amino-2-ethoxymethyl-7-(thiazol-4-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (400 mg, 0.94 mmol, which can be prepared as described in International Application No. PCT/US04/28021 Example 137) in dichloromethane (50 mL) was cooled to 0° C. in an ice bath. A solution to of boron tribromide in dichloromethane (3.76 mL of 1.0 M) was added slowly. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was diluted with hydrochloric acid (20 mL of 6 N) and stirred for 30 minutes. The layers were separated. The organic layer was washed with 6 N hydrochloric acid (3×20 mL) and then discarded. The aqueous layer was made basic by the addition of solid potassium carbonate. A precipitate was isolated by filtration, dissolved in hot chloroform, and then purified by prep HPLC (HORIZON HPFC system eluting with 0-10% CMA in chloroform over 192 mL and then with 10-40% CMA in chloroform over 1400 mL) to provide a solid. This material was crystallized from acetonitrile to provide 181 mg of 1-[4-amino-2-hydroxymethyl-7-(thiazol-4-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 260-262° C. Anal. calcd for C19H21N5O3S: % C, 56.81; % H, 5.41; % N, 17.26. Found: % C, 56.82; % H, 5.54; % N, 17.23.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]1.O>CS(C)=O>[O:9]1[C:10]2([CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2
Yield: 240.8 %

Procedure:
to a stirred solution of trimethylsulfoxonium iodide (56.1 g, 255 mmol) in anhydrous DMSO (150 ml) was added a mixture of NaH (18.5 gram 1.5 equiv., 60% in mineral oil) under a nitrogen atmosphere. The mixture was stirred at 65° C. for 1 hour, whereafter compound 2 (32 g, 150 mmol) was added as a solution in DMSO (10 ml). The mixture was refluxed overnight under a nitrogen atmosphere. The solution was allowed to reach room temperature, water was added and the mixture was extracted with diethyl ether (3×200 ml). The combined organic layer was washed with H2O, with brine and dried over Na2SO4. The Et2O was evaporated to yield 82.1 gram (32 g, 95%) compound 3. 1H-NMR (300 MHz, CDCl3): δ (ppm)=1.45 (s, 9H, BOC); 1.50-2.10 (m, 6H), 2.60-2.70 (m, 2H), 3.5-3.60 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14](Cl)([F:16])[F:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH:14]([F:15])[F:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)Cl)nc1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
The compound obtained in Step B (5.57 g) was dissolved in ethanol (110 ml) and after degassing, palladium on charcoal (10% by weight) (1 g) was added. Under a hydrogen atmosphere, the reaction mixture was stirred at ambient temperature for 5 hours. Filtration on Celite® furnished (6-difluoromethyl-pyridin-3-yl)-carbamic acid tert-butyl ester (4.8 g) as a foam. MS (ES+) 245/246 (MH+); 1H NMR (400 MHz, CDCl3) 1.54 (s, 9H), 7.15 (t, 1H), 7.91 (m, 1H), 9.03 (m, 1H), 9.33 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([NH:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17].[H-].[Na+].[CH3:42]I>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17]
Reactant: CI
Reactant: COCCCCn1c(C(=O)N[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-({[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}amino)-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (290 mg) was dissolved in DMF (5 ml), sodium hydride (60% in oil) (880 mg) was added, and the mixture was stirred at room temperature for 1 hr. Methyl iodide (98 μl) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-7:3) was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: [K].Cl[CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[N:13]=1.C(O)(=O)C>C(O)C>[NH2:18][C:14]1[N:13]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(N)n1
Reactant: CCOC(=O)C(Cl)C=O
Agent: [K]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc2cccc(N)n12
Yield: 40.2 %

Procedure:
In 1250 ml of ether was suspended 56.0 g (500 mM) of potassium tert-butoxide and while the suspension was stirred vigorously, a solution of 37.0 g (500 mM) of ethyl formate and 61.3 g (500 mM) of ethyl chloroacetate in 100 ml of ether was added dropwise at room temperature over 15 minutes. The reaction mixture was stirred at room temperature for 30 minutes and the precipitate that formed was recovered by filtration. The precipitate was rinsed with 50 ml of ether and dried in vacuo to give 93.13 g of ethyl 2-chloro-2-formylacetate potassium salt as light-yellow solid. In 40 ml of ethanol was suspended 7.59 g (40.0 mM) of this ethyl 2-chloro-2-formylacetate potassium salt as well as 2.18 g (20.0 mM) of 2,6-diaminopyridine and following addition of 2.3 ml (40 mM) of acetic acid, the mixture was refluxed for 3 hours. After completion of the reaction, the precipitate that formed was recovered by filtration and rinsed with 10 ml of ethanol. The filtrate and the washes were pooled and neutralized with aqueous NaCO3 solution, and the solvent was distilled off under reduced pressure. The residue was extracted with 100 ml of ethyl acetate and the organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was distilled off under reduced pressure and the residue was washed with ether to provide 1.65 g of the title compound as light-yellow solid. The washes were concentrated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 0.61 g of the title compound (total yield 2.26 g, percent yield 55.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:8]=2)=[O:46])[CH:43]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 2.5 °C
Yield: 14.9 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (150 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL), and pyridine (83 mg, 1.05 mmol, 3.01 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (130 mg, 0.42 mmol, 1.20 equiv) in dichloromethane (10 mL) with stirring at 0-5° C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 30 mL of dichloromethane. The resulting mixture was washed with 1×20 mL of NH4Cl and 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.7 mg (15%) of a yellow solid. 1H-NMR (400 MHz, DMSO, ppm): δ 11.43-11.33(m, 2H), 9.70(s, 1H), 9.43(s, 1H), 8.77(s, 1H), 8.26-8.18 (m, 3H), 8.06-7.93 (m, 2H), 7.86-7.79(m, 2H), 7.68-7.62(m, 2H), 7.52(s, 1H), 7.30-7.28(d, J=6.9 Hz, 1H), 4.59-4.57(m, 1H), 4.18-3.83(m, 27H), 3.44(s, 3H), 3.27-3.26 (m, 5H), 3.18 (s, 3H), 2.96(s, 4H), 1.69(s, 4H), 1.59-1.52(m, 3H). MS (ES, m/z): 705 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[O:5][CH2:16][CH3:17]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccccc1I
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1ccccc1I

Procedure:
starting from o-iodobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl o-iodobenzimidate as an oil; 1H-NMR(CDCl3): 1.42 (t, CH3), 4.38 (q, CH2), 6.8-7.6 (3 aromatic H+NH), 7.8-8.05 (1 aromatic H);
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:17]N>CCO>[CH2:12]([C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][NH:2][N:17]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)CC(C)C
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1CC(C)C
Yield: 74.7 %

Procedure:
According to Scheme 1 Step 2: A solution of ethyl 2-((dimethylamino)methylene)-5-methyl-3-oxohexanoate (11.6 mmol, 2.64 g) and hydrazine (11.6 mmol, 1.47 mL) in EtOH (10 mL) was stirred for 1 hour at room temperature. After evaporation of the solvent, the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (80:20) as eluent to yield ethyl 3-isobutyl-1H-pyrazole-4-carboxylate (8.66 mmol, 1.70 g, 75%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([O:11][C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C=CCc1c(O)ccc([N+](=O)[O-])c1C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1c(OC(C)=O)ccc([N+](=O)[O-])c1C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 3-methyl-4-nitro-2-(2-propenyl)-phenol (5.19 g, 26.9 mmol) in dichloromethane (200 ml) at 0° was added triethylamine (5.43 g, 53.8 mmol) and acetic anhydride (3.29 g, 32.3 mmol). After 30 min, the reaction mixture was evaporated to a residue which was purified by chromatography (silica, 2% to 10% ethyl acetate in hexane) to give an orange oil (4.80 g, 76%).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:17]([C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCCC(=O)C(=O)OCC
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccccc2c1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A solution of phenylhydrazine (1.0 g, 6.92 mmol) in absolute ethanol (50 mL) was placed in an oil bath at 60° C. and a reflux condenser attached. Ethyl 2-oxopentanoate (1.0 g, 6.94 mmol) (prepared according to Singh, J; Kissick, T. P.; Mueller, R. H. Organic Preparations and Procedures International (1989), 21(4), 501-4.) was added dropwise. The reaction mixture was heated to reflux and stirred overnight. The solution was cooled to RT and the solvent concentrated. Purification was accomplished by column chromatography (hexanes:EtOAc) to afford ethyl 3-ethyl-1H-indole-2-carboxylate (0.625 g, 41%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.45 (s, 1H) 7.66 (d, 1H) 7.41 (d, 1H) 7.25 (t, 1H) 7.05 (t, 1H) 4.34 (q, 2H) 3.05 (q, 2H) 1.35 (t, 3H) 1.19 (t, 3H). MS: m/z 218.0 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:24]=2[O:23][CH3:22])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)cc3OC)sc2Cc2ccccc2)cc1
Yield: 71 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 2,4-dimethoxy-benzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 71.0%, mp: 196-197 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.85 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.08 (3H, s, OCH3), 4.20 (2H, s, CH2), 6.54 (1H, d, J=2.24 Hz, ArH), 6.65 (1H, dd, J=8.96 Hz, 2.24 Hz, ArH), 6.97 (2H, d, J=8.96 Hz, ArH), 7.22˜7.34 (5H, m, ArH), 7.56 (2H, d, J=8.96 Hz, ArH), 8.22 (1H, d, J=8.68 Hz, ArH), 11.01 (1H, br, CONH); EI-MS m/e (%): 460.1 (M+, 58), 165.0 (100); HREI-MS Calcd. for C26H24N2O4S: 460.1457. found: 460.1454. Anal. Calcd. for C26H24N2O4S: C, 67.81; H, 5.25; N, 6.08. found: C, 68.04; H, 5.16; N, 6.19.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(O[C:13](=O)[N:14](C)[CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[CH:32]2)[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(C)(C)C>C(OCC)(=O)C>[ClH:7].[ClH:7].[ClH:7].[CH3:39][N:35]1[C:36]2[C:31](=[CH:30][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:17]([CH2:16][CH2:15][NH:14][CH3:13])[CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]1=[O:40]
Reactant: CN(CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (4.2 ml) was added to an ethyl acetate solution (30 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (1.0 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was condensed under reduced pressure to give the title compound (1.0 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:13]([CH3:14])=[CH:12][NH:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1.[H-].[Na+].[F:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>COCCOC>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][N:11]3[C:5]4[N:6]=[C:7]([S:9][CH3:10])[N:8]=[C:3]([O:2][CH3:1])[C:4]=4[C:13]([CH3:14])=[CH:12]3)=[CH:26][CH:25]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: COc1nc(SC)nc2[nH]cc(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Yield: 84 %

Procedure:
Under argon gas, 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (4.18 g) was dissolved in anhydrous DME (120 ml). Then, with ice-cooling and stirring, 60% sodium hydride-oil (0.88 g) was added in 3 installments. After completion of addition, the mixture was stirred for 30 minutes, at the end of which time a solution of 4-(4-fluorobenzoyl)benzyl bromide (6.74 g) in anhydrous DME (20 ml) was added. Then, at room temperature, the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, whereupon colorless needles separated out. These crystals were collected by filtration, rinsed with ethyl acetate, and dried to provide the title compound (7.07 g). 1H-NMR (CDCl3) 5: 2.33(3H,d,J=1.2Hz), 2.61(3H,s), 4.09(3H,s), 5.37(2H,s), 6.58(1H,d,J=1.2Hz), 7.15(2H,t,J=8.6Hz), 7.29(2H,d,J=8.4Hz), 7.71(2H,d,J=8.4Hz), 7.82(2H,dd,J=5.4&8.8Hz).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[CH:18][CH:19]=1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.67 g (4 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 2.76 g (18 mmol) of 3,6-dichloropyridazine and 1.76 ml (13.6 mmol) N-ethyldiisopropylamine was heated for 3.5 h at 80° C., diluted with 1 ml DMF and heated for 4 days at 80° C. and one day at 120° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (MeCl2/Et2O 95:5 to 9:1) gave 0.61 g (54%) of trans-3-{4-[(6-Chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 280 (MH+, 1Cl).
Reaction SMILES: [N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[CH:3]=[C:4]4[O:5][CH2:6][CH2:7][CH2:8][N:9]4[N:1]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cc2n(n1)CCCO2
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCCO2
Yield: 53.3 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid (0.078 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by recrystallization from acetonitrile and by flash-chromatography, respectively. Yield 53.3%. 1H-NMR (400 MHz; CDCl3): δ 1.19 (d, 3H), 2.26-2.34 (m, 2H), 4.18-4.34 (m, 5H), 4.41 (dd, 1H), 4.52-4.62 (m, 1H), 6.01 (s, 1H), 6.62 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.70-7.75 (m, 21-1).