Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:14]([NH:17][NH2:18])([NH2:16])=[NH:15].Cl>CO>[NH2:16][C:14]1[N:15]=[C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:18][N:17]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1n[nH]c(C#Cc2ccccc2)n1
Yield: 75 %

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (5.63 g) obtained in (1) above, methanol (85 ml), metallic sodium (3.29 g) and aminoguanidine hydrochloride (15.8 g) were used as reagents to give 4.87 g of a pale-brown solid (yield 75%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:7][CH2:8][CH2:9][CH:10]([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[O:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1C#N.[Cl:26]C1C=CC(Cl)=CC=1F>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:26][C:13]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:12]=1[O:11][CH:10]([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH2:9][CH2:8][NH2:7]
Reactant: N#Cc1ccc(Cl)cc1OC(CCN)c1ncco1
Reactant: Fc1cc(Cl)ccc1Cl
Agent: O=C(O)C(=O)O
Product: NCCC(Oc1cc(Cl)ccc1Cl)c1ncco1

Procedure:
The title compound was prepared from the product from Example 56 (b) and 1,4-dichloro-2-fluoro-benzene using similar procedures to Example 56 (c). Final purification was by recrystallisation (2-propanol/methanol/diethyl ether) to afford a beige solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>O.CS(C)=O>[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([N:1]=[N+:2]=[N-:3])[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1nc(N)nc2nc[nH]c12
Yield: 89.3 %

Procedure:
A solution of sodium azide (14.08 g, 0.216 mol) in water (35 mL) was added to a solution of 2-amino-6-chloropurine (28.27 g, 0.166 mol) in dimethyl sulfoxide (DMSO, 280 mL). The mixture was heated at 100°-110° C. for 24 h, then the resulting suspension was cooled and poured into 1.3 L of water. The precipitate was collected by filtration, washed with water and dried to afford 26.11 g of 2-amino-6-azidopurine, mp>260° C.; IR (KBr) 3313, 3146, 1678, 1641, 1551 cm-1 ; 1H NMR (DMSO-d6, 360 MHz) δ8.18 (s, 1H), 8.25 (bs, 2H), 13 (vbs, 1H); 13C NMR (DMSO-d6, 90 MHz), 110.8, 138.7, 143.4, 145.7 , 146.1 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][NH2:42]>C(O)C>[CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11](=[N:41][NH2:42])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=S)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NN
Solvent: CCO
Product: CC(C)c1cc(C(=NN)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-[4-(morpholin-4-yl)-phenyl]thiobenzamide (F370-IM3; crude product, 4.2 g) was suspended in ethanol (30 mL), mixed with 80% aqueous hydrazine solution (15 mL) and heated under reflux for 4 hours. At this time, it was observed that the suspension was decolored and became a homogeneous solution. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue thus obtained (crude F370-IM4) was used for the next reaction without purification.
Reaction SMILES: C([N:8]1[CH2:31][CH:30]([C:32]([OH:35])([CH3:34])[CH3:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:35][C:32]([CH:30]1[CH2:31][NH:8][CH2:9][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[O:29]1)([CH3:34])[CH3:33]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(C)(C)O)O3)ccc1OC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CNCC(C(C)(C)O)O3)ccc1OC(C)C
Temperature: 75 °C
Yield: 96 %

Procedure:
[8-Benzyl-10-(1-hydroxy-1-methyl-ethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (75 mg, 0.16 mmol) was dissolved in ethanol (3 mL) and Pd (8 mg, 0.008 mmol) and ammonium formate (50 mg, 0.80 mmol) were added and the reaction mixture was heated at 75° C. for 30 minutes. The reaction mixture was filtered, concentrated in vacuo, diluted with ethyl acetate, washed with 3M NaOH, dried over MgSO4, filtered and concentrated in vacuo to give (2-(2-hydroxypropan-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (60 mg, 94%). ESI-MS m/z calc. 390.3. found 391.5 (M+1)+; Retention time: 1.27 minutes (3 min run).
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([S:18][CH2:20][C:21]#[N:22])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.49 g, 1.981 mmol) in DMF (5 mL), were added 2-bromoacetonitrile (0.253 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring for 2 h, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.52 g). LCMS m/z=292.1
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]([O:21]CC)=O)=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[C:8]1[C:16]([CH:17]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1.[NH2:24][NH2:25]>>[CH3:1][C:2]1[C:3]([C:19]([NH:24][NH2:25])=[O:21])=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[CH:8][C:16]1[C:17]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CCOC(=O)C1=Nc2cc3c(c(C)c2=C1C)N=c1ccccc1=3
Reactant: NN
Product: CC1=c2c(C)cc3c(c2N=C1C(=O)NN)N=c1ccccc1=3
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethyl 3,4-dimethylpyrrolo[3,2-b]carbazole-2-carboxylate (500 mg) and 95% hydrazine (5 cm3) were stirred and heated at 120° C. for 6 h in a Readi-Vial. The mixture was allowed to stand overnight, cooled in ice and filtered. The resulting yellow solid was washed carefully with water and dried. Yield of title compound 350 mg (73%), no sharp m.p. but decomposes at 285° C. (Found: C, 69;19; H, 5.57; N, 19.38. Calc. for C17H16N4O. 0.1H2O requires C, 69.42; H, 5.55; N, 19.05%); δH [2H6 ]-DMSO) 10.80 (1H, s, exchangeable, NH), 10.55 (1H, s, exchangeable, NH), 9.20 (1H, s, exchangeable, NH), 8.06 (1H, d, J7.5 9-H), 7.81 (1H, s, 10-H), 7.42-7.28 (2H, m, 6-H and 7-H) 7.12-7.01 (1H, m, 8-H, 4.5 (2H, br, s, exchangeable, NH2), and 2.4 and 2.3 (2×s, 4-CH3 and 3-CH3), m/z 293 (M+1)+, FAB)].
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[C:15]1([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:21])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc(Nc2ccccc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Nc2ccccc2)c1C(=O)O
Yield: 96.3 %

Procedure:
A mixture of 3-phenylaminophthalic acid dimethyl ester (0.60 g, 2.1 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 2.5 hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.52 g of the product in 97% yield: 1H NMR (DMSO-d6) δ 6.92 (t, J=7.3 Hz, 1H), 7.06-7.09 (m, 2H), 7.18-7.29 (m, 3H), 7.33-7.42 (m, 2H), 7.98 (s, 1H).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:31][S:28]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:30])=[O:29])=[O:21])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)C1CCCC1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1CCCC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclopentanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 1.66 (m, 2), 1.83 (m, 2), 2.08 (overlapping m, 4), 3.69 (s, 3), 4.10 (p, 1, J=8), 4.79 (s, 2), 6.53 (s, 1), 7.01 (m, 2), 7.29 (m, 2), 8.84 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 20.55, 22.24, 42.90, 57.27, 57.80, 87.06, 110.29, 110.46, 124.85, 124.91, 125.66, 153.94, 154.50, 156.29, 158.25, 165.53.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([C:12]#[C:13][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1cc2c(cc1C)SCCC2(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)SCCC3(C)C)nc1
Temperature: 55 °C

Procedure:
A mixture of 86 mg (0.4 mmol) of 4,4,7-trimethyl-6-ethynylthiochroman, 85 mg (0.46 mmol) of ethyl 6-chloronicotinate and 0.8 ml of triethylamine was degassed under nitrogen and then treated with a mixture of 10 mg (0.05 mmol) of cuprous iodide and 20 mg (0.03 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was heated at 55° C. under a nitrogen atmosphere for 18 hours. The mixture was then extracted with 1.5 ml of 40% ethyl acetate in hexanes and purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25](OC)=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]3)=[CH:29][CH:30]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1-{3-[4-(3-chloro-indazol-2-yl)-phenoxy]-propyl}-piperidine-4-carboxylate (0.1 g, 0.21 mmol) in THF (10 mL) was added NaBH4 (23 mg, 0.63 mmol) at 0° C. in portions. The reaction mixture was stirred at room temperature for 4 h. After it was quenched with water, the mixture was extracted with ethyl acetate, washed with brine and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a column chromatography on silica gel eluting with 20% ethyl acetate in hexane to the title compound (0.43 g 50%). 1H NMR (400 MHz, CDCl3) δ 7.71(d, J=8.8 Hz, 1H), 7.59-7.56 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.14 (m, 2H), 7.04 (d, J=8.8 Hz, 2H), 4.10 (t, J=6 Hz, 2H), 3.22 (m, 2H), 3.01 (br d, J=12 Hz, 1H), 2.54 (t, J=6 Hz, 2H), 2.10-1.73 (m, 9H).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][C:11]([CH3:10])([OH:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(O)CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC1(O)CCN(Cc2ccc(I)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-methylpiperidin-4-ol. Yield: 0.22 g (30% of theory); C13H18INO (M=331.19); calc.: molecular ion peak (M+H)+: 332; found: molecular ion peak (M+H)+: 332; Rf value: 0.45 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(NS(C)(=O)=O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(NS(C)(=O)=O)cc5)c34)n(-c3ccccc3)c(=O)c12
Yield: 69.9 %

Procedure:
(S)—N-(4-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (65 mg, 0.08 mmol, 82% purity) was treated with trifluoroacetic acid (1.30 ml, 16.87 mmol) and a solution of ammonia (7N in methanol, 1.30 ml, 8.10 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 31 mg (70% yield) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:60])([CH3:59])[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([C:53](OC)=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:30][CH2:29][CH2:28][O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].Cl.N[C@@H](CC1C=CC(OCC#CC)=CC=1)CO.C(OC1C=CC(C[C@H](NC([C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(OC(C)(C)C)=O)=O)C(OC)=O)=CC=1)C#CC>>[C:1]([Si:5]([CH3:60])([CH3:59])[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([CH2:53][OH:54])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:46][CH:47]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:30][CH2:29][CH2:28][O:27]1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: CC#CCOc1ccc(C[C@H](N)CO)cc1
Agent: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl
Product: CC#CCOc1ccc(C[C@@H](CO)NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1

Procedure:
An intermediate, tert-butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-hydroxymethyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (ESI (LC/MS positive mode) m/z 831 (M+H); Rt 3.98 min.) was synthesized by the synthetic method similar to that of No. 5327507, tert-butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate, except that (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propan-1-ol hydrochloride was used instead of methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate hydrochloride. From the obtained intermediate, No. 6801976 (ESI (LC/MS positive mode) m/z 672 (M+H); Rt 2.70 min.) was synthesized by a synthetic method similar to that of No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1ccc2c(c1)C(C(F)(F)F)NCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccc(F)cc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
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: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Reactant: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
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: [C:1]1([CH:7]=[CH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(C(OO)=[O:23])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]1([CH:7]=[CH:8][CH2:9][C:10]23[O:23][CH:15]2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=Cc1ccccc1)Cc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=Cc2ccccc2)C=C1
Reaction time: 96 h
Yield: 71 %

Procedure:
7.8 g of o-phenylallylbenzene was added to 120 ml of chloroform solution containing perbenzoic acid prepared from 25 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 4 days. The resulting mixture was washed with sodium hydroxide solution, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to obtain a fraction having a boiling point of 145° to 155° C/3 mmHg, which was chromatographed on a silica gel, eluted with chloroform, and there was obtained 6.0 g (yield 71%) of o-penylallylbenzene oxide as an oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](COCC[Si](C)(C)C)[N:11]=[C:10]2[C:24]1[N:28](COCC[Si](C)(C)C)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH:28]1[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=[C:24]1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:41])[CH:8]=2)[NH:12][N:11]=1
Reactant: CN(C)CCCNc1ccc2c(c1)c(-c1nc3ccccc3n1COCC[Si](C)(C)C)nn2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: CN(C)CCCNc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 70 °C

Procedure:
A solution of N,N-dimethyl-N′-{1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-propane-1,3-diamine in THF was treated with ethylene diamine (20 equivalents) and tetrabutylammonium fluoride (20 equivalents) and heated at 70° C. overnight. The resulting crude residue was purified by reverse phase HPLC to N′-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-N,N-dimethyl-propane-1,3-diamine. LC/MS (m/z) 335.1 (MH+), Rt 1.30 minutes.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]#[N:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26]>CN(C)C(=O)C>[CH3:26][O:25][CH:24]([O:27][CH3:28])[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]#[N:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(CBr)OC
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)OC
Temperature: 80 °C
Yield: 57.7 %

Procedure:
2-(1H-Indazol-5-yloxy)-5-fluorobenzonitrile (5.000 g, 19.7 mmol) was suspended in N,N-dimethylacetamide (50 mL) and sodium hydride (0.684 g, 25.7 mmol) was added portionwise at room temperature. 2-Bromo-1,1-dimethoxyethane (3.49 mL, 29.6 mmol) was added dropwise in one portion and the reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material, which was partitioned between EtOAc and saturated aqueous NH4Cl. The combined organic layers were washed with water (3×), brine and dried (MgSO4) and then concentrated under reduced pressure to afford the crude material. The crude product was purified by flash column chromatography (eluant 25% EtOAc/Hexanes) to furnish 3.88 g (57.6%) of the desired compound. The N-2 isomer was not isolated. MS (APCI+) m/z 342 (M+1) was detected. 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.54 (d, 1H, J=9 Hz), 7.36 (m, 2H), 7.16 (m, 2H), 6.82 (dd, 1H, J=4.3 Hz, J=9.3 Hz), 4.76 (t, 1H, J=5.3 Hz), 4.49 (d, 2H, J=5.3 Hz), 3.41 (s, 6H).