Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30](/[C:34](/[CH3:39])=[CH:35]/[C:36](O)=[O:37])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][CH:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30](/[C:34](/[CH3:39])=[CH:35]/[C:36]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:37])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(C)c2ccccc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(C)c2ccccc2)c1

Procedure:
111 mg of compound 38 was obtained in a similar manner to those described in the Examples 1 and 2 using 393 mg of ethyl 4-(2-aminophenoxy)butyrate and 268 mg of 3-[1-(α-methylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:19][CH2:20][OH:21])[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[CH2:19][CH:20]=[O:21])[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: CN(CC(CCO)c1ccc(C#N)cc1)C(=O)c1cc(C#N)cc2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CN(CC(CC=O)c1ccc(C#N)cc1)C(=O)c1cc(C#N)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
3-Cyano-N-[2-(4-cyanophenyl)-4-hydroxybutyl]-N-methyl-1-naphthamide (0.70 g, 1.8 mmol) was dissolved in CH2Cl2 (15 mL) and to the resultant solution was added Dess Martin Periodinane (0.85 g, 2.0 mmol) in portions. The mixture was stirred at room temperature overnight and then sodium thiosulfate (1.9 g, 12 mmol), dissolved in saturated NaHCO3 solution (30 mL), was added. The mixture was stirred vigorously for 2 h and then the organic solution was washed with brine and dried over Na2SO4. The solvent was removed by evaporation and the residue purified by flash chromatography (ethyl acetate-heptane, 4:1). There was obtained 0.50 g, (43%) of 3-cyano-N-[2-(4-cyanophenyl)-4-oxobutyl]-N-methyl-1-naphthamide as a white solid. 1H NMR (400 MHz, CDCl3): 2.7 (s, 3H), 2.9-4.4 (cm, 5H), 6.4-7.8 (cm, 8H), 7.9 (d, 1H), 8.2 (s, 1H), 9.8 (s, 1H); LCMS: m/z 382 (M+1)+.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[N:17][C:26](=[O:27])[O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: C1CCOC1
Product: CSC(=NC(=O)OCc1ccccc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 66 °C

Procedure:
To a stirred solution of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea hydroiodide (Intermediate I) (50 g, 0.129 mol) in dry THF (1 L) is added TEA (18 mL, 0.129 mol), followed by N-(benzyloxycarbonyloxy)-succinimide (32.1 g, 0.129 mol). The reaction mixture is then heated to reflux (66° C.) for 6 hours. The reaction is allowed to cool to room temperature, then concentrated in vacuo to a yellow solid. The crude is suspended in EtOAc (500 mL) and water (500 mL) and is triturated vigorously for a period of 30 minutes. The resulting suspension is filtered and dried in a vacuum oven (40° C.) over P2O5 to give the product as a pale yellow solid. [M+H]+ 395
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](O)=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH2:7]([C:8]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1
Reactant: O=C(O)CCCCCCC(=O)O
Reactant: NNC(N)=S
Product: Nc1nnc(CCCCCCc2nnc(N)s2)s1

Procedure:
The title compound was synthesized from octanedioic acid I-59 and thiosemicarbazide by following the general procedure as described for compound I-2.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=O)[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:10]1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C)S(C(F)(F)F)(=O)=O.[CH2:38]([NH2:41])[CH2:39][CH3:40]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[N:15]=[C:16]([NH:41][CH2:38][CH2:39][CH3:40])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:10]1[OH:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](O)[C@@H](COCc3ccccc3)C[C@@H]2O1
Reactant: CCCN
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](O)[C@@H](COCc3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4-(benzyloxy)-6-((benzyloxy)methyl)-5-hydroxyhexahydrobenzo[d]oxazol-2(3H)-one (60 mg, 0.16 mmol) in dry DCM (2 mL) under N2 at 0° C. was added methyl triflate (0.035 mL, 0.32 mmol) dropwise. The mixture was stirred at room temperature for 18 h, cooled to 0° C. and n-propylamine (0.131 mL, 1.6 mmol) was added. The mixture was further stirred at 0° C. for 5 h. The mixture was diluted with aqueous satd. NaHCO3 (15 mL) and extracted with DCM (2×15 mL). The extracts were dried (Na2SO4) and concentrated to give the crude product (75 mg). This was purified by silica gel chromatography, eluted with 92:6:2 DCM-MeOH—NH4OH to give the product (3aS,4R,5R,6R,7aS)-4-(benzyloxy)-6-((benzyloxy)methyl)-2-(propylamino)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (21 mg, 30.6%). 1H NMR (600 MHz, CDCl3) δ 7.35-7.27 (m, 10H), 4.94 (d, J=11.6, 1H), 4.85 (m, 1H), 4.71 (d, J=8.2, 1H), 4.53 (s, 2H), 4.02 (t, J=6.8, 1H), 3.68 (m, 3H), 3.50 (t, J=6.4, 1H), 3.75 (m, 2H), 2.18-2.15 (dt, J=14.8, 3.0, 1H), 1.98-1.94 (m, 1H), 1.80-1.78 (m, 1H), 1.62-1.58 (m, 2H), 0.98 (t, J=7.2, 3H).
Reaction SMILES: C1(C#C[N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:18](=[O:22])[NH:19][CH2:20][CH2:21][C:11]([C:12]=34)=[CH:10]2)C=CC=CC=1>CO.[Pt]=O>[CH2:10]([C:10]1[NH:9][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:22])[NH:19][CH2:20][CH2:21][C:11]=1[C:12]=23)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NCCc2cn(C#Cc3ccccc3)c3cccc1c23
Agent: O=[Pt]
Solvent: CO
Product: O=C1NCCc2c(CCc3ccccc3)[nH]c3cccc1c23
Temperature: 24 °C
Reaction time: 20 h

Procedure:
2-Phenylethynyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (Compound 17) (37 mg, 0.13 mmol) and platinum oxide (1.5 mg, 0.05 mmol) were suspended in 2 mL MeOH under an argon atmosphere. The flask was flushed with hydrogen gas and the resulting mixture stirred at 24° C. under 1 atmosphere of hydrogen for 20 h. The catalyst was filtered off and the resulting solution concentrated, leaving a pale-yellow crystalline solid. Purification by radial chromatography (5% MeOH in CHCl3) followed by recrystallization (MeOH/CHCl3/hexanes) yielded 2-phenethyl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 14 mg (37%), as a pale-yellow solid. mp 207-208° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.60 (m, 2H), 2.95 (m, 4H), 3.26 (m, 2H), 7.17 (m, 6H), 7.46 (dd, 1H, J=7.8, 0.6 Hz), 7.61 (dd, 1H, J=7.5, 0.6 Hz), 7.90 (br t, 1H), 11.16 (br s, 1H); MS (FAB, MH+) 291; Anal. (C19H18N2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3([CH2:25][OH:26])[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.OI1(=O)C2C=CC=CC=2C(=O)O1>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([C:22]3([CH:25]=[O:26])[CH2:23][CH2:24]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(-c2noc(C3(CO)CC3)c2-c2ccccc2)cc1
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: ClCCl
Product: COCOc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a mixture consisting of the substrate {1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropyl}-methanol (Examples 4-13 General Procedures, Coupling Method C, Step iii, 0.500 g) in dichloromethane (8 mL) is added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (1.19 g.) The stirring mixture is brought to reflux till the substrate is not detected by methods such as thin layer chromatography or mass spectrometry. The mixture is then cooled to room temperature and filtered. The filtrate is concentrated under reduced pressure to afford the solid 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarbaldehyde.
Reaction SMILES: O.[CH3:2]/[C:3](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:4]\[CH2:5][N:6]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:2]/[C:3](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:4]\[CH2:5][NH2:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (46 μL) was added to a stirred mixture of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylazide (0.8 g, 3.2 mmol) and triphenylphosphine (0.94 g, 3.62 mmol) in THF (3 mL) and stirred at room temperature overnight. An additional amount of water (46 ML) was added and stirred for another two hours. The reaction mixture was evaporated to dryness and the residue was redissolved in methylene chloride, then MgSO4 was added and filtered. The filtrate was concentrated in vacuo to give the crude title compound as an oily solid which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.C1O[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19]C1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.C(O)C>[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCC(=O)CC3)c2cc1OC
Yield: 98 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (30 g), 4-piperidone ethylene ketal hydrochloride (25 g), triethylamine (35 g) and ethanol (250 ml.) were refluxed together for 3 hours. Aqueous sodium carbonate was added followed by extraction with chloroform after which the chloroform extract was dried and evaporated in vacuo to give an oil. The oil was redissolved in aqueous hydrochloric acid (1.5N, 200 ml.) and refluxed for 2 hours followed by cooling, basification (Na2CO3 10% soln) and extraction into chlororform. Evaporation of the dried chloroform extract gave 4-(4-oxo-piperidino)-6,7-dimethoxyquinazoline (37.6 g) m.p. 176°-8° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F)([O-:13])=[O:12].O>CC(C)=O>[CH2:7]([NH:10][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a suspension of potassium carbonate (1.0 g) in acetone (10 ml) was added 2-propyn-1-amine (0.26 g, 473×10-3 mole). 2,4-Dinitrofluorobenzene (1.32 g, 7.10×10-3 mole) was gradually added with stirring and the reaction mixture was refluxed two hours. After cooling it was poured into excess water and filtered. Recrystallization of the crude solid from ethanol afforded yellow needles; m.p. 151°-152° C. Yield: 0.99 g (95%). IR (KBr): 3367 (NH), 3268 (=CH), 1618, 1590, 1333 and 1311 cm-1 (Ar--NO2).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: NCCCN
Reactant: Brc1nsc2ncccc12
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCCNc1nsc2ncccc12
Temperature: 64 °C

Procedure:
A mixture of 3-bromoisothiazolo[5,4-b]pyridine (1.9 g, 8.8 mmol), and 1, 3-diaminopropane (6.7 g, 90 mmol) in methanol (10 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water mixture yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.53 (d, 1H), 7.73 (br s, 1H), 7.40 (dd, 1H), 3.46 (dd, 2H), 2.85 (t, 2H), 1.75 (t, 2H), 1.45 ppm (t, 2H). MW=208 confirmed by LC-MS, tr=5.55 min (Method Y) MH+=209.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:12]>O1CCOCC1>[Cl:1][C:2]1[C:3](=[S:12])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Cl
Solvent: C1COCCO1
Product: Cc1[nH]c(=O)[nH]c(=S)c1Cl
Yield: 75 %

Procedure:
5-Chloro-6-methyluracil (prepared as described in Johnson, B. T. J. Amer. Chem. Soc. 65 (1943) (1220) (0.018 mol) and phosphorus pentasulphide (0.019 mol) were heated together in refluxing dioxan (200 ml) for 45 min. The hot reaction mixture was then filtered and the cold filtrate concentrated and diluted with ether. The participate collected after a few hours in the cold, was recrystallised from water; yield 75% m.p. 297°-300° C. (decomp.); (Found: C, 32.69; H, 3.96. Calc. for C5H5ClN2OS.1/2H2O: C, 32.35; H, 3.25).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:64])[CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59](Br)[CH:58]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:45][C:46]([N:48]1[CH2:49][CH2:50][N:51]([C:54](=[O:64])[CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:58]=2)[CH2:52][CH2:53]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2cccc(Br)c2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 4-[3-(3-bromo-phenyl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (220 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-{3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-189) as a pale yellow powder (50 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl.CO.O.C(OCC)C>[CH2:24]([C:25]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH2:9][OH:10])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Cl)ccc1CO
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(Cc1ccccc1)Nc1cc(Cl)ccc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-chloro-2-hydroxymethyl aniline (8.00 g) in dichloromethane (400 ml) under nitrogen at room temperature, was added triethylamine (15.6 ml). The reaction mixture was cooled to 0° C. then phenyl acetyl chloride (14.80 ml) was added dropwise over 10 mins, and the reaction mixture was allowed to warm to room temperature and stir for 2 h. The mixture was washed with 1N HCl (2×250 ml) and brine (1×250 ml). The aqueous layers were re-extracted using CH2Cl2 (1×250 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent was removed under vacuum to leave an orange solid. The solid was suspended in MeOH (400 ml), sodium hydroxide (2.20 g) was added in water (100 ml) and the reaction mixture was allowed to stir under gentle heating (50° C.) for 45 mins. The methanol was removed in vacuo, then the aqueous residue was extracted with dichloromethane (1×200 ml) and the organic layer was washed with brine (1×150 ml) and saturated sodium hydrogen carbonate solution (1×150 ml). The organic layer was dried (MgSO4), filtered and the solvent was removed under vacuum to leave a solid. Trituration with diethyl ether gave the required compound (10.00 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[S:5])[CH3:2].[C:15]1(C)C=CC(S(OC)(=O)=O)=CC=1>CO>[CH3:15][S:5][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CCNC(=S)N1CC2(C=N1)CCCC2
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: CCN=C(SC)N1CC2(C=N1)CCCC2
Yield: 31.9 %

Procedure:
To a solution of 1.0 g (4.7 mmol) 2,3-diazaspiro[4.4]non-3-ene-2-carbothioic acid ethylamide in 10 mL methanol was added 1.1 g (5.7 mmol) methyl p-toluenesulfonate. The mixture was refluxed for 48 hrs and concentrated under reduced pressure. The residue was triturated with 30 mL diethyl ether and all volatiles were removed from the isolated oily product under reduced pressure. The residual oil was taken up in 40 mL dichloromethane and extracted 3 times with a saturated aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and evaporated to dryness under reduced pressure to afford 0.33 g (1.5 mmol, 31%) of N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester as a light-brown oil. 1H NMR identical to spectrum obtained from material prepared by using iodomethane as methylating agent (vide supra).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][Br:21])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a solution of tert-butyl-4-(4-tolyl)benzoate (32 g, 0.12 mol) in carbontetrachloride (500 mL) was added N-bromosuccinimide (23.3 g, 0.13 mol) and benzoyl peroxide (4.0 g). The reaction mixture was refluxed for 10 h. After cooling to RT, the reaction mixture was filtered. The filtrate was concentrated and the crude was recrystallised from petEther to give 4-(4-tert-butoxycarbonylphenyl)benzylbromide (26 g, 69%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[CH:17][C:18]([C:19]([O:21]CC)=[O:20])=[C:12]3[N:11]=2)[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[F:24][C:2]([F:1])([F:25])[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]3[N:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[C:12]3[N:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnn2ccc(Nc3cccc(C(F)(F)F)n3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2ccc(Nc3cccc(C(F)(F)F)n3)nc12
Yield: 112.1 %

Procedure:
A mixture of ethyl 5-(6-(trifluoromethyl)pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (344 mg, 0.98 mmol, 1.0 equiv), 2M aqueous sodium hydroxide solution (1.50 mL, 3.0 equiv) and ethanol (15 mL) was heated to reflux for 5 hours. After cooling, the precipitate was collected by filtration, washed with ethanol, and air dried. The resultant solid was suspended in 1.25 M HCl in methanol (16 mL) and then concentrated under vacuum. The residue was triturated (diethyl ether) to afford 355 mg (quant. yield) of 5-(6-trifluoromethyl-pyridin-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid which was used without further purification. LCMS (ESI) m+H=324.2; 1H NMR (300 MHz, DMSO-d6) δ: 11.03 (s, 1H), 9.01 (d, 1H), 8.95 (d, 1H), 8.35 (s, 1H), 8.10-8.02 (m, 1H), 7.54 (d, 1H), 7.16 (d, 1H).
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:51])[CH:37](Br)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:36]([O:35][CH2:33][CH3:34])=[O:51])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(CCCCCCCCCCCC)C(=O)OCC)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromomyristate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained. 1H NMR (CDCl3): δ5.47-5.41 (m, 1H); 4.25-4.17 (q, 2H); 2.94-2.88 (t, 2H); 2.45-2.26 (m, 2H); 1.82-1.65 (m, 2H); 1.33-1.20 (m, 41H); and 0.90-0.85 (t, 6H) ppm.
Reaction SMILES: CC(OC([NH:8][NH:9][CH2:10][CH2:11][C@H:12]([N:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]=[CH:15]1)[CH3:13])=O)(C)C.Cl>CO>[NH:9]([CH2:10][CH2:11][C@H:12]([N:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]=[CH:15]1)[CH3:13])[NH2:8]
Reactant: C[C@H](CCNNC(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Agent: Cl
Solvent: CO
Product: C[C@H](CCNN)n1cnc(-c2cccnc2)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of (1,1-dimethylethyl)1-[(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]-2-hydrazinecarboxylate (32) in methanol is added 6N hydrochloric acid. The reaction is heated to 50° C. and stirred 18 h.