Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=O)C.[OH-].[NH4+]>Cl>[NH2:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(c1[N+](=O)[O-])CCCC2=O

Procedure:
The product from Example 81 (1 g) was treated with 6N hydrochloric acid (30 ml) at reflux for 2 hours and the reaction cooled then basified with ammonium hydroxide. The desired product was filtered, washed and dried.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1ccc(CC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-1,4-dibenzyl-2-(2-(4-fluoro-phenyl)-ethyl)-piperazine (1.94 g, 4.99 mmol), ammonium formate (1.57 g, 24.95 mmol), 5% Pd/C (241.1 mg), and ethanol (50 mL) and stir and heat the mixture at reflux. After 4 hours 30 minutes, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and dissolve it in 1N NaOH. Extract with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give the title compound as a white solid: mp 112–114° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis for C12H17FN2: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 68.97; H, 8.14; N, 13.21.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].C1(=[O:20])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:20])=[O:9])=[C:6]([CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[CH3:13]
Reactant: O=C1CCCCC1
Reactant: Cc1c(C)c(C)c(C=O)c(C)c1C
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1c(C)c(C)c(C(=O)O)c(C)c1C
Yield: 78.8 %

Procedure:
To a flask equipped with a stirrer, oxygen inlet and condenser were added pentamethylbenzaldehyde (12.0 g, 68 mmol), 40 mL (0.387 mol) of cyclohexanone and 6 mg of cobalt (II) acetate dissolved in several drops of acetic acid. Oxygen was bubbled in while the solution was stirred rapidly and heated at 50° for 4 hours. The solution was mixed with 100 mL of cyclohexane and the mixture was extracted with 100 mL of 6% aqueous sodium bicarbonate solution. The aqueous layer was separated and the organic layer was washed with 50 mL of water. The combined aqueous layers were acidified with concentrated hydrochloric acid. The white crystalline solid product was collected by filtration, washed with water and air dried. A total of 10.3 g (78% yield) of pentamethylbenzoic acid was obtained: mp 202°-206°.
Reaction SMILES: BrC1C=C(F)C=CC=1O[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1.[NH3:37]>>[NH2:37][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: N
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1cc2c(N)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an analogous procedure to that described in the second last paragraph of the portion of Example 1 that is concerned with the preparation of starting materials, 4-(2-bromo-4-fluorophenoxy)-7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxyquinazoline was reacted with ammonia to give 4-amino-7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxyquinazoline; NMR Spectrum: (DMSOd6) 1.21 (m, 2H), 1.4 (s, 9H), 1.76 (d, 2H), 2.0 (br s, 1H), 2.77 (t, 2H), 3.88 (s, 3H), 3.97 (d, 2H), 3.99 (br s, 2H), 7.05 (s, 1H), 7.36 (br s, 2H), 7.55 (s, 1H), 8.24 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: Br[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: CC1(C)CC(=O)C=C(Br)C1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Product: CC1(C)CC(=O)C=C(c2ccc3[nH]ccc3c2)C1
Yield: 95 %

Procedure:
Synthesized from 3-Bromo-5,5-dimethyl-cyclohex-2-enone and indole-5-boronic acid pinacol ester according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (177 mg, 95%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 8.97 (bs, 1H), 7.84 (s, 1H), 7.39 (d, J=1.2 Hz, 2H), 7.22 (dd, J=3.0, 2.1 Hz, 1H), 6.56 (dd, J=3.0, 2.1 Hz, 1H), 6.49 (t, J=1.5 Hz, 1H), 2.74 (d, J=1.2 Hz, 2H), 2.35 (s, 2H), 1.25 (s, 3H), 1.14 (s, 3H). 13C (75 MHz, CDCl3): 200.4, 159.5, 136.8, 130.2, 127.9, 125.5, 122.4, 120.1, 119.1, 111.3, 103.1, 50.9, 42.6, 33.8, 28.4, 24.9. HRMS (LCT Electrospray): mass calcd for (C16H17NO+Na) m/z 262.1208; measured [M+Na]+: m/z 262.1204.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9].ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1)=[O:33]>CN(C)C=O.O.C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:10][CH2:11][C:12]([NH:30][CH2:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1)=[O:33])=[O:14])=[O:9]
Reactant: O=C(O)CNC(=O)CN1CCCC1=O
Reactant: NCC(=O)N1CCC(C(N)=O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(C(=O)CNC(=O)CNC(=O)CN2CCCC2=O)CC1
Reaction time: 0.25 h

Procedure:
8.01 g of N- [(2-oxo-1-pyrrolidinyl)acetyl] glycine was dissolved in 200 ml of dimethylformamide and the solution was cooled to -15° C., to which 5.57 g of isobutyl chloroformate was added and then 4.09 g of triethylamine was added dropwise at -15° to -5° C. This was stirred at -10° to -5° C. for 15 minutes and 7.41 g of 1 glycyl-4-piperidinecarboxamide was added while maintaining the temperature at -10° to -5° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The solid filtered off was suspended in 300 ml of ethanol and the suspension was stirred for 30 minutes and filtered to obtain the solid. This solid was dissolved in the mixture of 20 ml of water and 100 ml of ethanol with heating. The resultant solution was concentrated to 30 ml under atmospheric pressure and 180 ml of ethanol was added followed by allowing to stand to form the precipitate, which was filtered to obtain the titled compound.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[I:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH2:11][CH2:12][C:13](=[O:15])[CH3:14]
Reactant: II
Reactant: COc1cccc(CCC(C)=O)c1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(I)c(CCC(C)=O)c1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Samples of iodine (42.4 g, 0.167 mole) and silver acetate (27.87 g, 0.167 mole) were added in portions to a solution of 29.8 g (0.167 mole) of 1-(3-methoxyphenyl)-butane-3-one in 167 ml of glacial acetic acid. The mixture was stirred one hour. The silver iodide was removed by filtration and washed with acetic acid. The filtrate was partitioned between ether and water. The ether layer was washed with water, sodium bicarbonate solution and sodium thiosulfate solution. The ether solution was dried with MgSO4 and evaporated to dryness in vacuo. There was obtained 41.8 g (82% yield) of oily 1-(2-iodo-5-methoxyphenyl)butane-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[O:8]CC1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
To 1.01 g of ([3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene, were added 3 ml of ethyl acetate, 1 ml of ethanol and 50 mg of 10% palladium/carbon, and the mixture was stirred for 5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, the filtrate was concentrated to obtain 0.68 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(I)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(I)cc1
Yield: 48 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-iodophenyl)-5-methylpyrazole-4-carboxylic acid (1.2 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1 g), the title compound (1.0 g) was obtained, melting point: 280° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.[F:21][C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>C1COCC1>[F:21][C:22]1[C:23]([CH:24]([OH:25])[CH2:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:26][CH:27]=[CH:28][N:29]=1
Reactant: O=Cc1cccnc1F
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1CC(O)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
A solution of tert-butyl (3-methylpyridin-4-yl)carbamate (1.00 g, 4.80 mmol, Intermediate D-2) in THF (50 mL) was cooled to −78° C. under an atmosphere of nitrogen. A solution of n-butyllithium (4.80 mL, 2.5 M in hexane, 12.0 mmol) was added slowly maintaining the internal temperature below −65° C. After the addition, the mixture was warmed to 0° C. for 20 minutes (orange suspension turned homogeneous). The solution was then cooled to −78° C. and 2-fluoronicotinaldehyde (0.901 g, 7.20 mol, Intermediate D-1) in THF (5 mL) was added dropwise. After 10 minutes, the dark red/brown mixture was allowed to slowly warm to 0° C. After 30 minutes, the reaction was quenched with NH4Cl/water. The mixture was further diluted with NaHCO3/water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with 75% ethyl acetate/hexane. Pure fractions were combined, concentrated and then triturated with ethyl acetate to provide the desired product as a white solid (0.55 g, 34%). 1H NMR (DMSO-d6) δ 9.09 (s, 1H), 8.23 (d, 1H), 8.09 (d, 1H), 8.02 (s, 1H), 7.85 (m, 1H), 7.67 (d, 1H), 7.29 (m, 1H), 6.32 (d, 1H), 5.03 (m, 1H), 3.00 (m, 2H), 1.47 (s, 9H). LC/MS: 334 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:6]1.[Cl:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]3[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=3)=[N:6]2)[CH:22]=[CH:21][N:20]=1
Reactant: CNCCn1nc(-c2cc(C)cs2)ccc1=O
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc(=O)n(CCN(C)c3ccnc(Cl)c3)n2)c1
Temperature: 75 °C

Procedure:
A suspension of 2-(2-(methylamino)ethyl)-6-(4-methylthiophen-2-yl)pyridazin-3(2H)-one (200 mg, 802 μmol), 2-chloro-4-fluoropyridine (116 mg, 882 μmol), and potassium carbonate (222 mg, 1604 μmol) in DMF (1 mL) was heated to 75° C. for 90 min. The reaction mixture was partitioned between CH2Cl2 (50 mL) and 5% NaHCO3 (20 mL). The organic layer was dried over MgSO4 and concentrated to a solid from toluene under reduced pressure. The solid was triturated with toluene and dried under reduced pressure to give a white solid. MS (ESI pos. ion) m/z (MH+): 361. Calc'd exact mass for C17H17ClN4OS: 360. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.28 (s, 3 H) 3.02 (s, 3 H) 3.83 (t, J=6.27 Hz, 2 H) 4.40 (t, J=6.27 Hz, 2 H) 6.40-6.52 (m, 2 H) 6.85 (d, J=9.54 Hz, 1 H) 6.96 (s, 1 H) 7.13 (s, 1 H) 7.46 (d, J=9.54 Hz, 1 H) 7.86 (d, J=6.02 Hz, 1 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 15.74, 37.62, 48.39, 49.09, 105.64, 105.90, 123.48, 128.03, 129.65, 129.74, 138.18, 138.63, 141.27, 149.19, 152.43, 155.53, 159.78.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18]CC)=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([OH:18])=[O:17])[CH:8]([C:12]([F:14])([F:13])[F:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1=Cc2ccc(I)cc2OC1C(F)(F)F

Procedure:
To a suspension of ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.50 g, 3.9 mmol) in 5 mL EtOH was added NaOH (0.46 g, 11.6 mmol) in 2.5 mL of H2O. After heating for 1.5 h, reaction solvent was removed under vacuum. The resulting sodium salt was used immediately.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]Br.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].CO>O>[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][NH:26][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: Br
Solvent: CO
Solvent: O
Product: CCCCNCc1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Reaction time: 24 h

Procedure:
A mixture of 3-amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide (1.1 g; prepared as described in Example 61), n-butylamine (5.0 ml) and methanol (10 ml) is stirred at 22°-25° C. for 24 hours. The resulting solution is then diluted with water (20 ml) to precipitate crude (3-amino-4-benzyl-5-sulfamylbenzyl)-n-butylamine. After filtration and recrystallization from aqueous ethanol it is obtained with a melting point of 141°-143° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[C:5](Br)=[C:4]([CH3:20])[N:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[C:5](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([CH3:20])[N:3]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1nc(N)nc(N[C@H]2CC[C@@H](OCCO)CC2)c1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@@H](OCCO)CC1
Temperature: 130 °C
Yield: 41.9 %

Procedure:
In a sealed tube a solution of 2-(cis-4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexyloxy)ethanol (695 mg, 4.03 mmol) and ethyl acrylate (438 uL, 4.03 mmol) in triethylamine (10 mL) was bubbled with argon for ˜5 minutes. Tetrakis(triphenylphosphin)-palladium (0) (232 mg, 0.201 mmol) was added, the vial was sealed and the mixture was bubbled again with argon (5 minutes). The reaction was heated to 130° C. overnight, cooled to room temperature and concentrated. The residue was dissolved in chloroform (500 mL) and washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-4%) to afford the title compound (615 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O.[F:18][C:19]([F:27])([F:26])[C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23]>C(O)(=O)C.S(=O)(=O)(O)O>[F:18][C:19]([F:27])([F:26])[C:20]([C:21]1[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:22]=1[CH3:23])=[O:25]
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCCC2
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2cccs2)c1C(=O)C(F)(F)F)CCCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-thiophen-2-yl-methanone in 1.5 ml acetic acid was added 0.024 ml (0.20 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 17 mg (23%) 2,2,2-trifluoro-1-(2-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as an orange oil. ES-MS m/e (%): 382 (M+H+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][C:9](=[O:22])[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:36][CH:35]=[CH:34][CH2:33]4)=[O:31])=[CH:26][CH:25]=3)[C:7]=2[CH:37]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13](=[O:21])[C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[CH2:10][C:9](=[O:22])[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:36][CH:35]=[CH:34][CH2:33]4)=[O:31])=[CH:26][CH:25]=3)[C:7]=2[CH:37]=1)(=[O:48])=[O:47]
Reactant: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(CO)cc32)cc1)N1CC=CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 2 h

Procedure:
450 mg (0.87 mmol) of 8-hydroxymethyl-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 0.18 ml (1.31 mmol) of triethylamine and 0.08 1 ml (1.05 mmol) of methanesulfonyl chloride were added to the obtained solution under cooling with ice, and the obtained mixture was stirred for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:11][CH2:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]2=[CH:6][N:7]=1)(=[O:14])[CH3:13]
Reactant: OCc1cc2ccoc2cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2ccoc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethanol (7.70 g, 51.63 mmol) is dissolved in pyridine (45 mL), treated with acetic anhydride (14.36 mL, 154.9 mmol) and stirred for 18 h at rt. The pyridine is removed in vaeuo and the resulting residue dissolved in EtOAc (200 mL), washed with 50% saturated sodium bicarbonate (4×90 mL), dried over MgSO4 and concentrated in vacuo to afford 9.32 g (94%) of furo[2,3-c]pyridin-5-ylmethyl acetate as a yellow oil. MS (EI) m/z: 191 (M+), 277, 148, 119, 118, 86, 84, 77, 63, 51, 50.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][F:22])=[C:7]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:16])[CH3:15])=O)[CH:8]=1)#[N:2]>CC(O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][F:22])[C:10]([CH2:12][O:13][C:14](=[O:16])[CH3:15])=[N:9][C:7]=2[CH:8]=1)#[N:2]
Reactant: CC(=O)OCC(=O)Nc1cc(C#N)ccc1NCCCCF
Solvent: CC(=O)O
Product: CC(=O)OCc1nc2cc(C#N)ccc2n1CCCCF
Yield: 55.2 %

Procedure:
Acetic acid [5-cyano-2-(4-fluoro-butylamino)-phenylcarbamoyl]-methyl ester (2.5 g, 8.14 mmol)was dissolved in AcOH (20 mL) and heated to reflux for 2 h. The reaction mixture was concentrated and the residue dissolved in EtOAc and washed with saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated to give 1.3 g (55%) of acetic acid 5-cyano-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl ester as a dark solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.Cl.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 16.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (253 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (74 mg) was obtained.