Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[C:3]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:2]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:6]2[CH2:7][CH2:8][C:9]3[O:1][N:2]=[C:3]([C:10]([N:12]4[CH2:17][CH2:16][N:15]([C:18]5[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=5)[CH2:14][CH2:13]4)=[O:11])[C:4]=3[CH2:5]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3noc4c3CNCC4)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3noc4c3CN(S(=O)(=O)c3ccc(C)cc3)CC4)CC2)cc1
Yield: 28.1 %

Procedure:
In a manner similar to the general method, 170 mg (0.42 mmol) of 1-[4-[4-(4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carbonyl)-piperazin-1-yl]-phenyl]-ethanone were reacted with 120 mg (0.63 mmol) of p-toluenesulfonic acid chloride to yield 60 mg (28% of theoretical) of 1-(4-{4-[5-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carbonyl]-piperazin-1-yl}-phenyl)-ethanone (86), which were obtained in the form of a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:15][C:16](=[O:19])[CH2:17]Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:15][C:16](=[O:19])[CH2:17][NH:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CNCc1ccccc1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester (1.85 g) in N,N-dimethylformamide (15 ml) were added successively benzylamine (1.65 g) and potassium carbonate (1.28 g) at 20° C. After stirring at 35° C. for 1.5 hour, the mixture was poured into a mixture of ice-water (20 ml) and dichloromethane (20 ml). After adjusting the mixture to pH 9 with a diluted aqueous hydrochloric acid solution with stirring, the organic layer was separated, washed with an aqueous sodium chloride solution (20 ml), dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give (2R)-2-[N-(benzylaminoacetyl)amino]-3-(3-methoxy-4-methylphenyl)-propionic acid methyl ester in the form of an oily substance. A solution of (2R)-2-[N-(benzylaminoacetyl)-amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester obtained by the above process and acetic acid (0.18 ml) in isopropyl alcohol (10 ml) was stirred under reflux for 12 hours. After cooling the mixture to room temperature, isopropyl ether was added to the mixture. The produced precipitates were collected by filtration and washed with isopropyl ether to give (3R)-1-benzyl-3-(3-methoxy-4-methylbenzyl)piperazine-2,5-dione (1.45 g) in the form of colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1.I[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][P:42]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:49])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CCOP(=O)(CCOCCOCCI)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCOCCP(=O)(OCC)OCC)cc3C)cc12
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (13) (1.0 equiv.) dissolved in DMF (0.14M) was added a solution of diethyl 2-(2-(2-iodoethoxyl)ethoxy)ethylphosphonate (14): from step 11 above (1.3 equiv.) in DMF (0.7M) and cesium carbonate (4 equiv.). The reaction was stirred at 60° C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5% MeOH in DCM to give ethyl 3-(5-amino-2-{2-[4-(2-{2-[2-(diethoxyphosphoryl)ethoxy]ethoxy}ethoxy)-2-methylphenyl]ethyl}benzo[f]1,7-naphthyridin-8-yl)propanoate (15).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([F:16])[CH:5]=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([F:16])[CH:5]=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccccc1-c1cc(N)cc(F)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cc(F)cc(Br)c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A warm solution of 5′-amino-3′-fluorobiphenyl-2-carbonitrile (4.5 g, 21 mmol) in 1,4-dioxane (20 ml) was treated with 48% hydrobromic acid (100 ml) and the resulting suspension stirred and cooled to 3° C. (internal temperature). A solution of sodium nitrite (1.7 g, 24 mmol) in water (4 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before adding a cooled (5° C.) solution of copper(I) bromide (9.1 g, 3 mmol) in 48% hydrobromic acid (30 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (2×200 ml). The organics were combined, washed with 5% aqueous sodium sulphite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification on silica, eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (5-15%) afforded 5′-bromo-3′-fluorobiphenyl-2-carbonitrile as a white solid (5.52 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]#[N:11].[CH:12]1([C:15](=[O:21])[CH:16]=[C:17](OC)[CH3:18])[CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Sn](Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:11][C:10]1[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:17]([CH3:18])[C:16]=1[C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:21]
Reactant: COC(C)=CC(=O)C1CC1
Reactant: N#Cc1c(N)sc2c1CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2sc3c(c2c(N)c1C(=O)C1CC1)CCC3
Yield: 5 %

Procedure:
To a stirred solution of 0.30 g (1.83 mmol) of 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile in 6 ml toluene was added 0.30 g (2.14 mmol) 1-cyclopropyl-3-methoxy-but-2-en-1-one and 3 mg of p-toluenesulfonic acid. The mixture was heated at reflux for 2 hours, concentrated in vacuo, partitioned between ethyl acetate and water. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was taken up in n-butyl acetate 6 ml and 1.018 g (3.91 mmol) tin (IV) chloride was heated under reflux for 30 minute and allowed to cool. The mixture was partitioned between aqueous sodium hydroxide and ethyl acetate. Flash chromatography (heptane/ethyl acetate 3:1) afforded 25 mg (5%) (4-amino-6-methyl-2,3-dihydro-1H-8-thia-7-aza-cyclopenta[a]inden-5-yl)-cyclopropyl-methanone as a white solid. ES-MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1I.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].Cl>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1[C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)Nc1cc(F)c(Cl)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(F)c(Cl)cc1C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Pd(PPh3)2Cl2 (153 mg, 0.22 mmol) and copper(I)iodide (42 mg, 0.22 mmol) were dissolved in triethylamine (40 ml) and refluxed under argon for 20 min. The reaction mixture was then cooled down to 0° C. and (4-chloro-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester (7.2 g, 21 mmol) was added. After 10 min stirring at rt, ethinyltrimethylsilane (3.45 ml, 24.9 mmol) was added dropwise (exothermic, temperature raises from 18 to 33° C.) and the reaction mixture was stirred for one hour at rt. The reaction mixture was then poured on 1N aq. HCl solution (180 ml) and ice and extracted twice with ethyl acetate (180 ml). The combined organic phases were washed with water and sat. aq. NaCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo to yield crude (4-chloro-5-fluoro-2-trimethylsilanylethynyl-phenyl)-carbamic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:4]2[N:3]=1.[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[CH:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]([C:11]2[CH:10]=[N:9][N:5]3[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=23)=[O:14])=[CH:19][CH:18]=1)#[CH:16]
Reactant: Cc1cc(C)n2ncc(C(=O)O)c2n1
Reactant: C#Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc(NC(=O)c2cnn3c(C)cc(C)nc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
5,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (722 mg, 3.78 mmol), 4-ethynylaniline (442 mg, 3.78 mmol), and HATU (1436 mg, 3.78 mmol) were taken up in DMF (10 ml) and then treated with diisopropylethylamine (1.979 ml, 11.33 mmol). The contents stirred at room temperature overnight. The product had precipitated from reaction mixture. The reaction was diluted with water, filtered through a Büchner funnel under house vacuum. The residue was washed with water (×2), then CH2Cl2, diethyl ether, and air dried to obtain N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (500 mg, 1.72 mmol, 46% yield). LC-MS: rt (min)=3.65. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H), 2.77 (s, 3H), 4.11 (s, 1H), 7.21 (s, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 8.65 (s, 1H), 10.31 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH2:43][S:44][CH3:45])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21]([NH:41][C@@H:40]([CH2:42][CH2:43][S:44][CH3:45])[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:46])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Product: CSCC[C@H](NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
The title compound was prepared in 80% yield from 5-(1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy)-2-(4-fluorophenethyl)benzoic acid and L-methionine tert-butyl ester by a similar method to that used for Example 34. 1H NMR (DMSO-d6, 300 MHz) δ: 1.38 (9H,s); 1.88-2.0 (2H,m); 2.02 (3H,d); 2.62-2.75 (2H,m); 2.75-2.9 (2H,m); 4.32-4.42 (1H, m); 4.68 (2H,d); 5.83 (1H,m); 6.79-6.83 (2H,md); 6.95-7.1 (3H,m); 7.1-7.28 (4H,m); 7.45-7.52 (2H,dd); 7.61 (1H,s); 7.68 (1H,s); 8.62 (1H,t); 9.08 (1H,s). MS (ES+) m/z 636.4 (MH+); Anal.calculated for C35H39F2N3O4S.2.7H2O C, 61.4; H, 6.5; N, 6.1%; Found: C, 61.1; H, 6.2; N, 5.7%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:29])[CH:3]=1.[CH3:30][C@@H:31]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[NH:32]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:32]5[C@H:31]([CH3:30])[CH2:35][CH2:34][S:33]5(=[O:37])=[O:36])=[CH:3][C:4]=4[F:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3C3CC3)CC2)c(F)c1
Yield: 29.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 123 and (R)-3-methylisothiazolidine 1,1-dioxide (107 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 4, the title compound (122 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]>CN(C=O)C.CCOCC>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(COc2cccc(CO)c2)c1OCC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-hydroxybenzyl alcohol (202 mg, 1.63 mmol) in DMF (5.4 mL) is added K2CO3 (247 mg, 1.79 mmol) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile (430 mg, 1.79 mmol, example 24). Heated resulting mixture to 60° C. and stirred for 3 hrs then cooled to room temp and diluted with ether. Washed organic layer with water, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound. MS (EI) 283 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13]([CH3:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13]([CH3:19])=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)[nH]cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: [K+]
Solvent: CI
Product: Cc1cc(=O)n(C)cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-4-methyl-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=424.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH2:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19](=[O:21])[CH3:20]
Reactant: Nc1nc(-c2cccnc2)nc2ccc(Br)cc12
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(-c2cccnc2)nc2ccc(Br)cc12
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
A 100 mL round bottom flask was fitted with a reflux condenser and charged with 6-bromo-2-(pyridin-3-yl)quinazolin-4-amine (2.45 g, 8.14 mmol), acetic anhydride (5.81 g, 57.0 mmol) and acetic acid (30 mL). The reaction mixture was stirred at 90° C. for 20 min and then cooled to room temperature. A precipitate formed during the reaction and was collected by filtration and washed with water (100 mL). The solid was dried at 60° C. to give N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)acetamide as a white powder (1.83 g, 66%). 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 8.84-8.69 (m, 3H), 8.22 (s, 1H), 8.02-7.90 (m, 2H), 7.53-7.41 (m, 1H), 2.83 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Yield: 103 %

Procedure:
Dissolve 5-bromo-2-fluoronitrobenzene (28.8 mmol, 3.55 mL), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (28.8 mmol, 4.96 g), and triethylamine (35.9 mmol, 5.00 mL) in ethyl acetate (100 mL) and reflux under nitrogen for 48 h. Cool to room temperature. Wash with 0.5 M hydrochloric acid twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain a bright orange solid (11.04 g, >100%). LC-MS m/z (79Br/81Br) 394.0/396.0 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:29][CH:28]=1
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 85 %

Procedure:
First, 3 g of 16-bromo-1-hexadecanol, 1.9 g of 2,3-difluoro-4'-hydroxybiphenyl, 2.6 g of potassium carbonate, and 50 ml of methyl ethyl ketone were placed in a 100 ml flask. The reaction mixture was stirred under reflux for 32 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 3.5 g of 2,3-difluoro-4'-(16-hydroxyhexadecyl)oxybiphenyl (Y: 84%). The compound thus obtained had a purity of 97.4% by GC.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:3][CH2:2]1.CN.[C:39](P(=O)(OCC)OCC)#[N:40]>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:40][CH3:39])=[O:22])[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:2][CH2:3]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1
Agent: CN
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-(cyclopropylmethyl)-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methylamine using diethyl cyanophosphonate as a coupling reagent Mass: 500.25 (M+H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18](=[O:20])[CH3:19])=O)C1C=CC=CC=1.[N:21]1[C:30]2[C:25](=[N:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.N1CCCCC1>CC(O)C>[N:26]1[C:25]2[C:30](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:28][C:27]=1[CH:31]=[C:15]1[NH:11][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[N:13][C:14]1=[O:16]
Reactant: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C

Procedure:
To a mixture of 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (47.1 mg, 0.17 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration to give N-(5-[1, 5]-naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-acetamide as a yellow solid, 15.3 mg (31.8%). HR-ES (+) m/e calcd. for C14H11N5O2: (M+H)+ 282.0986. Found: 282.0985.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C#N)cs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1csc(CBr)n1
Temperature: 95 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a mixture of 2-methyl-thiazole-4-carbonitrile (3.0 g, 24.1 mmol), N-bromosuccinimide (4.3 g, 24.1 mmol) in CCl4 (50 mL) was added benzoyl peroxide (0.583 g, 0.10 mmol). The resulting mixture was stirred at 95° C. for 15 h, concentrated under reduced pressure, diluted with EtOAc (100 mL) and washed with saturated Na2S2O3 (50 mL), NaHCO3 (50 mL) and brine (20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel column chromatography using EtOAc/n-hexane as eluent to afford the title compound (4.6 g, 83%) as yellow oil. Rf0.39 (silica gel,EtOAc/hexane,3/7).
Reaction SMILES: [CH3:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([Cl:16])[CH:8]=1)=[O:5].S(Cl)([Cl:24])=O>>[CH3:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[C:9]([Cl:16])[CH:8]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1

Procedure:
A mixture of 1.85 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-2-chlorobenzoic acid in 30 ml of thionyl chloride under argon is heated at reflux for 1 hour. The thionyl chloride is evaporated in vauco to a residue which is stirred with hexane and collected to give 1.94 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-2-chlorobenzoyl chloride which is dissolved in 25 ml of methylene chloride and 0.49 g of N,N-diisopropylethylamine added, followed by 0.65 g of 6,11-dihydro-5H-dibenz[b,e]azepine. The reactants are stirred at room temperature for 18 hours and washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate to give 1.19 g of the desired product as a glass.