Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: Clc1cnccn1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(-c2cnccn2)c1
Temperature: 80 °C

Procedure:
To a solution of commercial 3-isopropyl-benzene boronic acid (1.0 g) in a 2:2:1 mixture of toluene/1M Na2CO3/EtOH (122 mL), at r.t.,2-chloropyrazine (599 μL) and the bis[1.2-bis(diphenylphosphino)ethane]-palladium(0) catalyst (110 mg) were added. The reaction mixture was heated at 80° C. for 3 hr. It was then cooled down and partitioned between AcOEt/sat.aq. NaCl. The phases were separated and the organic layer was dried. The solids were filtered and the solvent evaporated. The crude oil was purified by flash chromatography (CH/AcOEt 7:3) obtaining the title compound as a clear oil (468 mg).
Reaction SMILES: [CH:1]1([N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:7][CH2:6][CH2:5][N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NCCN(Cc1ccccc1)C1CC1
Product: CC(=O)NCCN(Cc1ccccc1)C1CC1
Reaction time: 0.5 h

Procedure:
19 g (0.1 mole) of N-cyclopropyl-N-benzylethylenediamine are added at 50° C. to 15.3 g (0.15 mole) of acetic anhydride. When the exothermic phase is over, the mixture is kept for further 30 minutes at 70° C., then cooled down and poured into ice. The organic phase is extracted with toluene and, after drying and evaporation, it gives a residue of gas-chromatographically pure N-acetyl-N'-cyclopropyl-N'-benzylethylenediamine with an almost quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42].O>CN(C=O)C>[CH3:42][O:41][CH2:40][CH2:39][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:6]
Reactant: COCCBr
Reactant: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cccc(O)c4)c3)ncnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
41 mg (0.1 mmol) 4-[3-(3-Hydroxy-benzoylamino)-benzylamino]-quinazoline-8-carboxylic acid amide were dissolved in 1 ml DMF. 97 mg (0.3 mmol) Cs2CO3 and 15 mg (0.11 mmol) 1-Bromo-2-methoxy-ethane were added. The mixture was stirred for 5 days at 50° C. Water was added to the reaction mixture, the percipitate was filtered and dried. 15.9 mg, off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](O)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CC1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:23])[NH:41][CH:40]3[CH2:38][CH2:39]3)[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC3CC3)c1)N2
Yield: 100.4 %

Procedure:
The mixture solution of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.52 g, 4.0 mmol), triethylamine (2.0 mL), cyclopropylamine (330.6 mg, 5.8 mmol) in dry dichloromethane (20.0 mL) was stirred at room temperature for 1 hour, LC/MS showed that reaction finished completely. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-cyclopropylcarbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.3 g, quant.) as a light yellow solid which was used for next step without further purification: MS (ESI) M+1=393.1.
Reaction SMILES: O[C:2]1[C:7]([C:8](=[O:18])[CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=[CH:4][C:3]=1[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CCOCC>ClCCl>[N:12]1([C:10]2[O:11][C:2]3[C:7]([C:8](=[O:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C(CC(=O)N1CCOCC1)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Temperature: 25 °C

Procedure:
Trifluoro-methanesulfonic acid 2-hydroxy-3-(3-morpholin-4-yl-3-oxo-propionyl)-phenyl ester [D] (1.06 g, 2.7 mmol) in dichloromethane (30 ml) was treated with trifluoromethanesulphonic anhydride and stirred over night at room temperature. The reaction mixture was then concentrated, re-dissolved in methanol and stirred for a further 2 hours. The solution was diluted with water and basified to pH8. It was then extracted three times with dichloromethane. The extracts were combined, washed with brine, dried with magnesium sulphate and evaporated to give the crude product as a brown oil. Trituration with ether gave trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl ester [E] as a brown solid. Yield 210 mg, 20%.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23](SC)=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6].CC(C)([O-])C.[K+].P(=O)(O)(O)O>C(O)C.O>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23]([NH:3][C:2]#[N:1])=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]
Reactant: N#CN
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Agent: CC(C)(C)[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN1C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N=C1NC#N
Reaction time: 2.5 h
Yield: 50.6 %

Procedure:
Cyanamide (0.2 g, 4.8 mmols) is added to a solution of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one (1.5 g, 3.9 mmols) and potassium tert-butoxide (0.5 g, 4.3 mmols) in ethanol (25 mL) and the mixture is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is allowed to cool, and is then poured into water (200 mL), acidified with phosphoric acid, and stirred. After half an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-cyanamide (0.7 g), mp 257°-259° C. (dec).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24](O)=[O:25])[CH:18]=1>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:24]([C:19]1[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[N:20]=1)=[O:25]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(Cl)cc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-dichloro-pyridine-2-carboxylic acid (CAS RN 88912-25-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (7%). MS (ESI): m/z=372.07 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH:27]1[CH2:28][CH2:29][N:30]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:31][CH2:32]1
Reactant: Clc1cccc(OC2CCNCC2)c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2cccc(Cl)c2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(3-chlorophenoxy)-piperidine (Table No.1, SM 7) in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=497.
Reaction SMILES: [ClH:1].Cl.CN1C2CCCC1CC([NH:13][C:14]([C:16]1[CH:17]=[C:18]([NH2:31])[CH:19]=[C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][C:21]=13)=[O:15])C2.Cl>CO.C(OCC)C>[ClH:1].[ClH:1].[NH2:31][C:18]1[CH:19]=[C:20]2[O:24][C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:22][C:21]2=[C:16]([C:14]([NH2:13])=[O:15])[CH:17]=1
Reactant: CN1C2CCCC1CC(NC(=O)c1cc(N)cc3oc(-c4ccccc4)nc13)C2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC(=O)c1cc(N)cc2oc(-c3ccccc3)nc12
Yield: 106.8 %

Procedure:
To a solution of the amide from Step B (120 mg, 0.31 mmol) in methanol (1.0 mL) was added a solution of HCl in diethyl ether (1 N, 0.93 mL, 0.93 mmol) at room temperature slowly. The reaction mixture was diluted with diethyl ether. The resulting solid was filtered and washed with diethyl ether to afford N-(9-methyl-9-azabicyclo[3.3.1]non-6-amino-2-phenylbenzoxazole-4-carboxamide dihydrochloride (54 mg, 38%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.48 (br s, 0.4H), 9.69 (br s, 0.6H), 9.16 (d, J=5.8 Hz, 0.6H), 8.88 (d, J=6.9 Hz, 0.4H), 8.23-8.15 (m, 2H), 7.70-7.60 (m, 3H), 7.55-7.50 (m, 1H), 7.36 (s, 1H), 4.90-4.35 (m, 4H), 3.70-3.65 (m, 1.4H), 3.60-3.55 (m, 0.6H), 2.90-2.80 (m, 4H), 2.75-2.60 (m, 2H), 2.40-2.10 (m, 3H), 1.95-1.82 (m, 2H), 1.60-1.50 (m, 2H); MS (ESI+) m/z 391 (M+H); HPLC>99% (AUC), tR=11.49 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]1>CO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:14][CH:15]([OH:13])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CCCCC1CO1
Solvent: CO
Product: CCCCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Yield: 37.6 %

Procedure:
A solution (50 ml) of 4-methanesulfonylbenzylamine (5.0 g) and 1,2-epoxyhexane (3.25 g) in methanol was stirred at room temperature for 96 hrs. The reaction-mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (2.9 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>N1C=CC=CC=1>[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH:22]([NH:25][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=2)[CH2:21][CH2:20]1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: CC1(C)CCC(N)CC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)NC2CCC(C)(C)CC2)ccc1OC(C)=O
Yield: 86.9 %

Procedure:
Using 8.9 g of 4-acetoxy-3-methoxycinnamoyl chloride, 3.81 g of 4,4-dimethyl-1-cyclohexylamine, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 8.99 g of N-(4,4-dimethylcyclohexyl)-4-acetoxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:16][NH:15][CH2:14]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:14][N:15]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:16]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: CC(C)(C)N=C=O
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4) (3 mmol) in dichloromethane (10 mL) was added tert-butyl isocyanate (3 mmol) and triethylamine (catalytic amount) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was eluted through a pre-wetted (CH2Cl2) SCX-2 (2 g) cartridge with dichloromethane to yield the desired product as a white foam (424 mg, 33%).
Reaction SMILES: [ClH:1].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)=O.[C:29]([C:31]1[CH:56]=[CH:55][C:34]([CH2:35][N:36]2[CH2:43][CH:42]3[O:44][CH:38]([CH2:39][N:40]([CH2:45][CH2:46][NH:47]C(=O)OC(C)(C)C)[CH2:41]3)[CH2:37]2)=[CH:33][CH:32]=1)#[N:30]>C(OCC)(=O)C>[ClH:1].[NH2:47][CH2:46][CH2:45][N:40]1[CH2:41][CH:42]2[O:44][CH:38]([CH2:37][N:36]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:56][CH:55]=3)[CH2:43]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: N#Cc1ccc(CN2CC3CN(CCN)CC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A saturated solution of HCl in ethyl acetate (200 mL) was added to an ice-cooled slurry of the acetic and formic acid salt of tert-butyl {2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}carbamate (7.00 g, 14.2 mmol). The reaction mixture was stirred at room temperature for 3 hours after which it was filtered and the resultant solid was washed with ethyl acetate. Drying in vacuo gave 6.12 g (96%) of the title compound with one equivalent of residual ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2.0 g 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester in 5 ml DMF, 360 mg NaH (60% in mineral oil) and subsequently 2.8 g 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] were added and the mixture was stirred at 80° C. for 1 h. After the addition of 5 ml water the mixture was filtered through a Chem Elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 4 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:41][O:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([C:47]3[CH:46]=[N:45][CH:44]=[C:43]([O:42][CH3:41])[CH:48]=3)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cncc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)c(F)c2)c1
Temperature: 150 °C
Yield: 38.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (130 mg, 0.2 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (70 mg, 0.3 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine) palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified with Prep HPLC to give 51 mg of (S)-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[2-fluoro-4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[N:13]([CH2:14][C:5]=2[C:4]([Cl:15])=[C:3]([Cl:16])[CH:2]=1)[CH2:12][C:10](=[O:11])[NH:9]3.NC1C(CN[CH2:26][C:27](OCC)=[O:28])=C(Cl)C(Cl)=CC=1.N#CBr>C1(C)C=CC=CC=1>[Cl:15][C:4]1[C:3]([Cl:16])=[CH:2][CH:1]=[C:6]2[C:5]=1[CH2:14][N:13]([CH2:12][C:10]([O:28][CH2:27][CH3:26])=[O:11])[C:8](=[NH:9])[NH:7]2
Reactant: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
Reactant: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Agent: N#CBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1Cc2c(ccc(Cl)c2Cl)NC1=N

Procedure:
Anagrelide is an imidazoquinazoline that is sparingly soluble in dimethylsulfoxide and N,N-dimethylformamide and very slightly soluble in water. Anagrelide is insoluble in diethyl ether or n-heptane. Anagrelide can be made using any of the processes known in the art (e.g., see U.S. Pat. Nos. 3,932,407; 4,146,718; 4,208,521; 4,357,330; Re 31,617; 5,801,245, and 6,388,073 and WO/2002/008228). Commercially, as discussed in U.S. Pat. No. 5,801,245, anagrelide has been prepared as the hydrochloride monohydrate from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide (CNBr) in an aprotic solvent to give the iminoquinazoline intermediate, which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base. For example, anagrelide can be prepared as shown in Scheme I below, by treating ethyl 2-(6-amino-2,3-dichlorobenzyl-amino)acetate with CNBr in toluene under reflux to produce ethyl 2-(5,6-dichloro-2-imino-1,2-dihydroquinazolin-3(4H)-yl)acetate, which, when treated with triethylamine in ethanol under reflux, yields anagrelide free base. The free base can be converted to anagrelide hydrochloride monohydrate by appropriate treatment with HCl. The CAS® Registry Number for anagrelide monohydrochloride is 58579-51-4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)C(C)(C)C)cn2)cc1

Procedure:
N-{6-{2-(5-Aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and pivaloyl chloride are treated in the same manner as in Example 135 to give N-[6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl]pivalamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[F:12]C(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([F:12])=[C:4]2[N:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C)n2nccc2n1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C)n2ncc(F)c2n1
Temperature: 0 °C

Procedure:
A mixture of 5,7-dimethyl pyrazolo[1,5-a]pyrimidine [1.47g (10 mmoles)], trifluoroacetic anhydride (2.0 ml), and boron trifluoride etherate (2.0 ml) in CH2Cl2 (30 ml) was heated at reflux for 24 hours. At the end of this time the red solution was cooled and added to an ice cold solution of NaOH (30 ml, 2N). The organic layer was separated and the alkaline layer extracted with CH2Cl2 3(20 ml). The combined CH2Cl2 extracts were washed with water 2(20 ml) and dried over Na2SO4. The CH2Cl2 extract was evaporated and the residue covered with n-petane qnd chilled. The yellow white crystalline plates were separated by filtration, and recrystallized from n-heptane to yield an analytically pure product; mp 129°-30°.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[OH:12][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: Nc1cccc2c1CCC2
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc2c1CCC2
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
4-Aminoindan (3.0 g) was added to a solution of concentrated sulphuric acid (2.4 mL) in water (15 mL). More water (15 mL) was added and the mixture cooled to 5° C. A solution of sodium nitrite (1.71 g) in water (4.5 mL) was added portionwise to the mixture while maintaining the temperature below 5° C. After addition was complete the mixture was allowed to warm to room temperature and urea (0.29 g) was added. The mixture was stirred for a further 5 minutes before being heated at 45° C. for 30 minutes. The mixture was then cooled to room temperature and extracted with ethyl acetate. The combined organic extracts were washed with 2M aqueous sodium hydroxide (2×100 mL) and these aqueous extracts were then acidified with hydrochloric acid and extracted with ethyl acetate (3×100 mL). The combined organic extracts were then washed with brine and dried (Na2SO4) before being concentrated in vacuo. The resulting crude product was chromatographed over silica gel. Elution with ethyl acetate/hexanes (1:7) gave 4-hydroxyindan as an orange oil (1.0 g).