Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[Na+].[I-:17].CNCCNC>O1CCOCC1.[Cu]I>[I:17][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cc1sc(Br)cc1Cc1ccc(O)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1sc(I)cc1Cc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of bromide 12 (960 mg, 3.39 mmol) in 1.4-dioxane (10 mL) were added NaI (1.1 g, 6.78 mmol), CuI (100 mg, 0.34 mmol) and N1,N2-dimethylethane-1,2-diamine (0.1 mL, 0.68 mmol) at room temperature. The reaction mixture was evacuated and backfilled with nitrogen. The mixture was stirred 120° C. for 18 hours. The mixture was cooled to room temperature and filtered off through celite. The filtrate was extracted with EtOAc/H2O (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 23 was dried under high vacuum and used without further purification (540 mg, 48%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][C:38]=1[CH3:39])[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[N:26]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(OCC)(=O)C.O1CCCC1>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:36]=[CH:37][C:38]([CH3:39])=[C:17]([NH:16][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:18]=4)=[N:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ccnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (106 mg, 0.84 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (1 drop), oxalyl chloride (91 μL, 1.0 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the obtained 1-methyl-1H-pyrazole-5-carbonylchloride was dissolved in N,N-dimethylacetamide (2 mL). This was added to a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol) in N,N-dimethylacetamide (5 mL), and the mixture was stirred at room temperature for 30 min. To the mixture were added ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→90/10) to give the title compound (230 mg, 83%) as a white solid.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[C:34]2[CH2:43][CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:46]=2[F:53])=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[C:34]2[CH2:43][CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:46]=2[F:53])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-fluorophenyl)-2-(2,3,6-trifluorophenethyl)-1H-imidazole-5-carboxylic acid (19) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenethyl)-1H-imidazole-5-carboxylate (18) (50 mg, 0.13 mmol), lithium hydroxide (12 mg, 0.51 mmol), THF (0.2 mL), methanol (0.4 mL), and water (0.8 mL).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:29][CH:27]([CH3:28])[CH2:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[N:7]=1
Reactant: CC(N)CCc1ccc(F)cc1
Reactant: CC(C)c1nc(N)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(CCc1ccc(F)cc1)Nc1nc(N)nc(C(C)C)n1

Procedure:
2.6 g (0.015 mol) of 2-amino-4-chloro-6-isopropyl-1,3,5-triazine and 2.1 g (0.015 mol) of K2CO3 are initially introduced in 50 ml of acetonitrile. 2.5 g (0.015 mol) of 1-(4-fluorophenyl)-3-butylamine, dissolved in 20 ml of acetonitrile, are added dropwise to this solution. It is then heated to reflux for 3 hours. The solid constituents are then filtered off with suction and the filtrate is concentrated in a rotary evaporator. The residue is purified by means of column chromatography (eluent: ethyl acetate). Yield: 4.1 g (90% of theory).
Reaction SMILES: I[C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]([CH3:7])[N:6]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:7][N:5]1[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=2[C:2]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[N:6]1
Reactant: Cn1nc(I)c2c1CCC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC2
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-Iodo-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (177 mg, 714 μmol) was dissolved in THF (3 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath). isopropylmagnesium chloride 2 M in THF (400 μL, 799 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (267 mg, 223 μL, 821 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution and then extracted with EtOAc (3×30 mL), the combined organics were washed with water (20 mL), brine (2×20 mL), dried over MgSO4 and concentrated. The residue was dried under high vacuum yielding 1-methyl-3-(tributylstannyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole which was taken into the next step without further treatment.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:15]=[C:16]([CH2:21][C:22]([NH:24][C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][N:29]4C(OC(C)(C)C)=O)=[O:23])[NH:17][C:18](=[O:20])[CH:19]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>ClCCl>[NH:29]1[C:30]2[C:26](=[C:25]([NH:24][C:22](=[O:23])[CH2:21][C:16]3[NH:17][C:18](=[O:20])[CH:19]=[C:14]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:15]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(NC(=O)Cc3nc(N4CCOCC4)cc(=O)[nH]3)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
0.940 ml of trifluoroacetic acid is added dropwise to a solution of 200 mg of 2-methylpropan-2-yl 4-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)-1H-indole-1-carboxylate in 8 ml of dichloromethane. After stirring at ambient temperature for 3 hours, the reaction medium is concentrated under reduced pressure, taken up with toluene and concentrated under reduced pressure. After purification by silica column chromatography, eluent: 90/10 CH2Cl2/MeOH, 48 mg of N-(1H-indol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained, the characteristics of which are the following:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: c1ccc(CNCc2ccccn2)nc1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)N(Cc2ccccn2)Cc2ccccn2)cc1

Procedure:
To a suspension of 4-isothiocyanatobenzenesulfonamide (401 mg, 1.87 mmol) in dry acetonitrile (10 mL) was added bis(pyridin-2-ylmethyl)amine (373 mg, 1.87 mmol). The reaction mixture went clear and a white precipitate formed. The solid was filtered, washed with acetonitrile and dried to afford MIP-1138 as a white sold (710 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.61 (br, 2H), 7.79-7.64 (m, 6H), 7.34-7.25 (m, 6H), 5.14 (br, 4H); (M+H)+ (414).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:7](/[CH:19]=[C:20](\[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[C:21]([O:23]CC)=[O:22])=[C:8]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:7](/[CH:19]=[C:20](\[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[C:21]([OH:23])=[O:22])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(/C=C(\Cc2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(CO)c(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A solution of ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-t-butyldimethylsilyloxymethyl-1H-imidazol-5-yl]-2-benzyl-2-propenoate (167 mg, 0.287 mmol) in absolute ethanol (3 mL) was treated portionwise at 6 hour intervals with 10% sodium hydroxide solution (3×1 mL). After being stirred overnight at 25° C., the reaction was heated to 50° C. for 4 hours, then concentrated in vacuo. The residual product was take0 up in water, acidified to pH 5-6 and extracted with methylene chloride. The isolated, dried, concentrated product was triturated with methanol/ether to provide 78 mg (62%) of the title compound; mp 176°-179° C. (d).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])([CH3:9])([CH3:8])[CH3:7].O>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(CNc1c(F)cccc1F)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(CN(C(=O)CBr)c1c(F)cccc1F)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1.17 ml of bromoacetyl bromide (13.4 mmol) was added to a solution of 3.66 g of [2-(2,6-difluorophenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (60a) (12.2 mmol) in N,N-dimethylacetamide (61 ml) under ice-cooling, and the mixture was stirred at the same temperature for five minutes. Water was added to the reaction mixture, followed by extraction with diethyl ether. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1) to obtain 5.14 g of the title compound (yield: quant.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([NH:17][CH3:18])=[O:16])[C:4]=2[N:5]=[C:6](Cl)[N:7]=1.[OH-].[Na+].[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)[CH3:25].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([NH:17][CH3:18])=[O:16])[C:4]=2[N:5]=[C:6]([NH:38][C:35]2[CH:36]=[N:37][C:32]([N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)=[CH:33][CH:34]=2)[N:7]=1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: CNC(=O)c1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3nc(N)c4scc(-c5cccc(C(=O)NC)c5)c4n3)cn2)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
3-(4-Amino-2-chlorothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzamide (20 mg, 0.063 mmol) was dissolved in dioxane (1 mL) and then sodium hydroxide (13 mg, 0.31 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (19 mg, 0.094 mmol) were added. After flowing nitrogen gas to the reaction mixture for 10 minutes, Pd2(dba)3 (4 mg, 0.004 mmol) and X-phos (1 mg, 0.12 mmol) were added. The reaction mixture was stirred at 120° C. for 2 hours and filtered with celite. The filtrate was diluted with ethyl acetate and then washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (5% methanol/dichloromethane) yielded the target compound (17 mg, 55% yield) of Example 1.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2([CH2:14][CH2:13]2)[O:11][CH:10]1[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:49]=[CH:48][C:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][CH:9]1[CH:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2([CH2:14][CH2:13]2)[O:11][CH:10]1[O:33][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][C:39]1[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:49][CH:48]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2ccccc2O)cc1
Reactant: OC1OC2(CC2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccccc2OC2OC3(CC3)C(OCc3ccccc3)C(OCc3ccccc3)C2OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
(6R,7S,8S)-6,7,8-Tris-benzyloxy-4-oxaspiro[2.5]octan-5-ol (prepared according to an analogous procedure as described in J. Org. Chem. 2002, 67, 3733; Helv. Chim, Acta 1990, 73, 1329; Tetrahedron Lett. 1998, 39, 2021) (220 mg, 0.49 mmol) 2-(4-methoxybenzyl)-phenol (105 mg, 0.49 mmol) and triphenyl phosphine (155 mg, 0.59 mmol) were mixed under argon atmosphere followed by the addition of dry THF. The contents were cooled to 0° C. and DIAD (0.12 ml, 0.59 mmol) was added drop wise. The reaction mixture was refluxed for 12 hours and quenched with 1N dil. HCl (2 mL) and extracted with ethyl acetate (10×3 mL). Organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to give the crude product which was purified by flash column chromatography using 1:4 (Ethyl acetate:Hexane) as eluent to yield 200 mg of 5R,6R,7S,8S)-6,7,8-tris-benzyloxy-5-[2-(4-methoxy-benzyl)-phenoxy]-4-oxa-spiro[2.5]octane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH2:28](O)[CH:29]([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: CC(C)CO
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)OCC(C)C)CC3)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (250 mg, 685 μmol), isobutanol (100 μL, 1.37 mmol), DMAP (250 mg, 2.05 mmol) and EDCI.HCl (262 mg, 1.37 mmol) in DCM (14 mL) was stirred at 50° C. for 2 hours in a sealed vial, before it was diluted with DCM (80 mL), washed with an aqueous 1 M solution of HCl (40 mL) and evaporated to dryness. The crude mixture was redissolved in MeCN (˜2 mL) and the crude product was crystallized upon addition of water (˜2 mL). Column chromatography (gradient EtOAc 20 to 100% in pet. ether) and subsequent recrystallization in MeCN and water afforded the title compound as colorless crystals (178 mg, 62%). HPLC-Retention time (XE Metode 7 CM): 2.34 minutes. Detected “M+1”-mass: 422.16. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 600 MHz): δ=8.22 (br s, 1H), 8.13 (dd, 1H, J=8.1 Hz, 1.5 Hz), 8.00 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.04 (s, 3H), 3.84 (d, 2H, J=6.5 Hz), 1.79 (m, 1H), 1.61-1.54 (m, 2H), 1.54-1.46 (m, 2H), 0.78 (d, 6H, J=6.7 Hz) ppm.
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[N:13]([CH2:14][C:5]=2[C:4](Cl)=[C:3](Cl)[CH:2]=1)CC(=O)[NH:9]3.O.Cl.C(N(CC1C(N)=CC=C(Cl)C=1Cl)CC(O)=O)C.N#CBr>C1(C)C=CC=CC=1>[NH:9]=[C:8]1[N:13]=[CH:14][C:5]2[C:6](=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:7]1
Reactant: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Agent: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl
Agent: Cl
Agent: N#CBr
Solvent: Cc1ccccc1
Solvent: O
Product: N=c1ncc2ccccc2[nH]1

Procedure:
Commercially, as discussed in U.S. Pat. No. 5,801,245, and as shown in Scheme 1 below, anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I), either by reaction with cyanogen bromide in hot alcoholic solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent such as toluene to give the iminoquinazoline intermediate (compound II), which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base (compound III).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: Brc1cncc(N2CCOCC2)c1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(N4CCOCC4)c3)cnc21
Temperature: 90 °C

Procedure:
In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-(5-bromo-pyridin-3-yl)-morpholine (228 mg, 0.94 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Argon for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Argon for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h. The reaction mixture is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is purified by flash silica gel column (MeOH/DCM 0 to 4% gradient, then 4%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and are extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 60 mg of the title compound.
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][C:5](=[O:16])[NH:4]1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:22]([N:4]2[C@@H:3]([CH2:1][CH3:2])[C@H:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[O:6][C:5]2=[O:16])[CH:23]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CC[C@H]1NC(=O)O[C@@H]1c1ccc(OC)cc1
Solvent: CN(C)C=O
Product: CC[C@H]1[C@H](c2ccc(OC)cc2)OC(=O)N1c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a solution of (4R*,5R*)-4-ethyl-5-(4-methoxyphenyl)oxazolidin-2-one (217 mg, 0.98 mmol) in DMF (2 mL) was added at room temperature under argon NaH (51.4 mg, 1.18 mmol). After 20 minutes, a suspension of 4-(4,6-dichloropyrimidin-2-yl)morpholine (230 mg, 0.98 mmol in DMF (1 mL) was added, and the reaction mixture was stirred at 85° C. for 20 minutes. The solution was quenched at 0° C. with aqueous NH4Cl, extracted with ethyl acetate, and the organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using EtOAc in hexane from 0% to 20% in order to give the title compound as a white solid (375 mg, 91%). LC-MS: [M+H] 419.1; Rt 1.26 min; (LCMS method 1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].F[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH3:17])=[O:10])=[CH:7][CH:6]=1>C(O)C>[CH3:1][N:2]([CH3:3])[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH3:17])=[O:10])=[CH:7][CH:6]=1
Reactant: Cc1[nH]c(=O)sc1C(=O)c1ccc(F)cc1
Reactant: CNC
Solvent: CCO
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(N(C)C)cc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Dimethylamine (100 ml of 40% solution) was added to a solution of 5-(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone. (4.7 g) in ethanol (200 ml). The mixture as stirred in a sealed stainless steel vessel at 120° C. for 16 hours. After cooling to ambient temperature the solvent and excess dimethylamine was evaporated. The residue was recrystallized twice from ethanol to give the title compound mp. 224°-226° C.