Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=[P:6](Cl)([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[P:4](Cl)([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[N+:31]([C:34]1[CH:40]=[CH:39][C:37]([O-:38])=[CH:36][CH:35]=1)([O-:33])=[O:32].[Na+]>O1CCCC1>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][P:2]2([O:38][C:37]3[CH:39]=[CH:40][CH:34]=[CH:35][CH:36]=3)[N:7]=[P:6]([O:38][C:37]3[CH:39]=[CH:40][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=3)([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[P:4]([O:38][C:37]3[CH:39]=[CH:40][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=3)([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: ClP1(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=N1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1

Procedure:
This material is obtained as a white solid by the treatment of sodium and phenol with hexachlorocyclotriphosphazene at -78° C. to produce the trichlorotriphenoxycyclotriphosphazene, according to D. Dell et al., J. Chem. Soc., 4072 (1965), which is incorporated herein by reference. This material is further reacted with sodium 4-nitrophenoxide in refluxing tetrahydrofuran to give the title compound in good yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:44]1([O:49][C:50](=[O:60])[C@H:51]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH2:52])[CH2:48][CH2:47][CH2:46][CH2:45]1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:52][C@@H:51]([CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:50]([O:49][CH:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:60])=[CH:21][CH:22]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Reactant: CS(=O)(=O)OCCCOc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1ccc(OCCCN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1

Procedure:
From Intermediate 4B and L-phenylalanine cyclopentyl ester (Intermediate 16), LCMS purity 93%, m/z 598 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.50-2.10 (8H, m), 2.50 (2H, m), 3.35-3.40 (1H, m), 3.55-3.70 (2H, m), 4.40-4.50 (2H, m), 4.60 (1H, m), 5.40-5.45 (1H, m), 6.05-6.10 (1H, d), 7.40-7.65 (11H, m), 7.85 (2H, m). 7.90 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[BH4-].[Na+]>C(O)C>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
In 800 ml of ethanol was dissolved 122 g of 3-hydroxybenzaldehyde and thereto was gradually added 210 g of piperidine. To the mixture was added 38 g of sodium borohydride under cooling with ice and the mixture was stirred for 8 hours at room temperature. The resulting mixture was concentrated at a reduced pressure. To a residue were added ice-cold water and hydrochloric acid to render a solution acidic. The solution was washed with diethyl ether. An aqueous layer was made alkaline with addition of sodium carbonate and then extracted with ethyl acetate. After removing the solvent, 106 g (yield 55%) of 3-(1-piperidinomethyl)phenol was obtained in the form of white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Cl:16][C:17](Cl)([Cl:21])[CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:17]([Cl:21])=[CH:18][CH2:19][O:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[C:6]([Cl:14])[CH:5]=1
Reactant: OCCCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 61.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 9.3 grams (0.036 mole) of 3,5-dichloro-4-(4-hydroxybutoxy)phenol, 7.7 grams (0.042 mole) of 1,1,1,3-tetrachloropropane and 11.7 grams (0.080 mole) of potassium carbonate in 300 mL of DMF. The crude product was purified with column chromatography on silica gel using mixtures of 1:4 and 1:1 ethyl acetate and hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 8.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([S:13][CH3:14])[CH:5]=1)[CH3:2].O.NN>CCO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([S:13][CH3:14])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(SC)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)c(SC)c1
Temperature: 90 °C

Procedure:
To a solution of 4-ethoxy-2-methylsulfanyl-1-nitro-benzene (1.0 g, 5.4 mmol) in absolute EtOH (25 mL) at rt was added 40 mg of Pd/C (Aldrich, 10 wt. % on active carbon), followed by slow addition of hydrazine hydrate (0.5 mL). The resulting reaction mixture was refluxed at 90° C. for 3 h. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford 4-ethoxy-2-methylsulfanyl-phenyl amine as a pale yellow oil: MS (ESI) 184 (M+H)+.
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][OH:15])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)C1CCN(CCO)CC1
Temperature: 60 °C
Yield: 66.3 %

Procedure:
A mixture of 4-(methylsulfonyl)piperidine hydrochloride (900 mg, 4.51 mmol), 2-bromoethanol (1126 mg, 9.01 mmol) and potassium carbonate (1869 mg, 13.52 mmol) in acetonitrile (4 mL) was heated up at 60° C. for 13 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the crude, the crude was purified by 0-35% ethyl acetate/methanol to provide the desired product as colorless oil (620 mg, 66%). LCMS: m/e 208.1 (M+H)+, 0.27 min (method 6).
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([N:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:20]([C:22]1[N:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)N.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:20]2[C:4](=[O:19])[C:5]([N:10]3[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]=[CH:11]3)=[CH:6][NH:7]2)=[N:27][CH:26]=1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C(F)(F)F)c1
Reactant: NNc1ccc(CO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=c1c(-n2cnc(C(F)(F)F)c2)c[nH]n1-c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (3.6 mmol) of the compound from Example 44A and 502 mg (3.6 mmol) of the compound from Example 4A are dissolved in 1 ml glacial acetic acid and the mixture is stirred at RT for 16 h. Thereafter, 200 mg (1.4 mmol) of the compound from Example 4A are again added and the mixture is stirred at RT for a further 20 h. The reaction mixture is taken up in 5 ml ethyl acetate and the mixture is adjusted to pH 7 with dilute aqueous sodium bicarbonate solution. The aqueous phase is concentrated in vacuo, 1.5 ml (4.0 mmol) 21% strength ethanolic sodium ethylate solution are added to the residue and the mixture is stirred at RT for 4 h. The precipitate is filtered off and washed with ethanol.
Reaction SMILES: [OH:1][CH:2]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:15][Si:16]([CH:19]=[N+]=[N-])([CH3:18])[CH3:17]>ClCCl>[OH:1][CH:2]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(O)c1occc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Product: CC(C)CC(O)c1occc1C(=O)OC[Si](C)(C)C
Reaction time: 20 h

Procedure:
2-(1-Hydroxy-3-methylbutyl)furan-3carboxylic acid (800 mg) was dissolved in dichloromethane (30 ml) an d a solution of trimethysilyldiazomethane (2M in hexane, 2.1 ml) was added. The mixture was stirred for 20 h, then diluted with dichloromethane and washed twice with hydrochloric acid. The organic phase was washed with brine, then dried, filtered and evaporated. Chromatography, eluting with diethylether:isohexane (1:1), gave the sub-title compound (435 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH:14][CH3:15])=[O:13].C(OC(=O)C)(=O)C>>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[N:14]([CH3:15])[C:12]1=[O:13]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: CNC(=O)NC
Solvent: CC(=O)OC(C)=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (4.31 g; 30.8 mmoles), 1,3-dimethylurea (2.75 g; 31.2 mmoles) and acetic anhydride (17 ml) was heated at 100° C. with stirring for one hour. The solvent was evaporated under reduced pressure, and the residue was purified by a column chromatography on silica gel (CHCl3) to give 5.50 g (yield: 84%) of 1,3-dimethyl-5-trifluoromethyldihydrouracil.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.NC(N)=S>CCOCC>[C:1]12([NH:11][C:12]([NH:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NC1CCCCC1
Agent: NC(N)=S
Solvent: CCOCC
Product: S=C(NC1CCCCC1)NC12CC3CC(CC(C3)C1)C2

Procedure:
The thiourea is prepared by reacting 19.3 g. (0.1 mole) of 1-adamantyl isothiocyanate with 10 g. (0.1 mole) of cyclohexylamine in 250 ml. of ether at room temperature for 3 hrs. The thiourea which separates from solution is collected: 23.5 g., mp. 175-175.5. Evaporation of the ether filtrate to a small volume gives a second crop, 5.2 g., mp. 176-178. The combined yield is 28.7 g. (98.5 percent). A sample is recrystallized from alcohol and melts at 176°-177°.
Reaction SMILES: [ClH:1].CCOC(C)=O.[N:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[H][H]>[Pt]=O.C(O)C>[ClH:1].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/c2ccncc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCNCC2)CC1

Procedure:
A 4 M hydrogen chloride/EtOAc solution (0.88 ml) and platinum oxide (100 mg) were added to an ethanol (25 ml) solution of tert-butyl 4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.02 g), followed by stirring in the presence of hydrogen (3.5 atm) for 24 hours. This was purged with argon, diluted with methanol, filtered through Celite, and concentrated under reduced pressure. The solid precipitated was washed with EtOAc/hexane, and dried under reduced pressure to obtain tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (850 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(O)(C(F)(F)F)=O>>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNS(C)(=O)=O)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with methane sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 445.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.62 (s, 1H), 8.50 (d, 1H, J=5.0 Hz), 8.05 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 4.54 (s, 2H), 4.36 (m, 1H), 4.28 (m, 1H), 3.31 (s, 3H), 2.77 (s, 3H), 2.01˜1.58 (m, 10H), 0.78 (t, 3H, J=7.5 Hz).
Reaction SMILES: Br[CH:2]([CH:13]([CH3:15])[CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:13]([CH:2]1[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12]1)([CH3:15])[CH3:14]
Reactant: CC(C)C(Br)C(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C1Oc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-bromo-3-methylbutyryl)aminophenol (58.0 g), powdered potassium carbonate (38.3 g) and N,N-dimethylformamide (200 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water and the precipitate was collected to yield 2-isopropyl-2H-1,4-benzoxazin-3(4H)-one as crystals. Yield was 38.1 g (93.4%). Recrystallization from ethanol gave colorless plates, mp 118°-119° C. In the same manner as in Reference Example 1, the following compounds were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])=[CH:17][CH:16]=1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1ccc(Br)cc1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc(Br)cc1

Procedure:
4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one was condensed with 4-bromobenzaldehyde using method B to give 3-(4-bromobenzylidene)-4-(2-hydroxy-ethyl)-1,3-dihydroindol-2-one as a yellow solid which was reduced using method E to give 0.2 g (91%) of 3-benzyl-4-(2-hydroxyethyl)-1,3-dihydroindol-2-one as a yellow/orange foam.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>O>[CH2:5]([N:8]([CH2:3][CH2:2][C:1]#[N:4])[CH2:3][CH2:2][C:1]#[N:4])[CH2:6][N:7]([CH2:3][CH2:2][C:1]#[N:4])[CH2:3][CH2:2][C:1]#[N:4]
Reactant: C=CC#N
Reactant: NCCN
Solvent: O
Product: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Acrylonitrile (110 g, 137 cm3, 2.08 mol) was added to a vigorously stirred mixture of ethylenediamine (25 g, 27.8 cm3, 0.416 mol) and water (294 cm3) at 40° C. over 30 min. During the addition, it was necessary to cool the mixture with a 25° C. water bath to maintain temperature at 40° C. The mixture was then stirred for additional 2 hours at 40° C. and 2 hours at 80° C. Excess acrylonitrile and half of the water were evaporated off and the residue, on cooling to room temperature, gave a white solid which was recrystallised from MeOH-water (9:1) to give pure product 3,3′,3″,3′″-(ethane-1,2-diylbis(azanetriyl))tetrapropanenitrile (86.6 g, 76.4%) as white crystals, mp 63-65° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:24][CH2:25]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([N:24]=[N+:25]=[N-:26])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a suspension of nicotinic acid (1.23 g, 10.0 mmol) in DMF (15 mL) was added diphenylphosphoryl azide (2.60 mL, 12.0 mmol) followed by triethylamine (1.67 mL, 12.0 mmol). The mixture was stirred at room temperature for 2.5 h and diluted with water (50 mL). The mixture was extracted three times with EtOAc and the combined organic extracts were washed three times with water, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc 7:3) provided I-3a as a white solid (1.13 g).
Reaction SMILES: C([O:3][CH:4]1C[CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]4[S:26][CH:27]=[C:28]([CH:30]5[CH2:33][CH2:32][CH2:31]5)[N:29]=4)[CH:20]=[CH:19][N:13]3[C:14](=[O:18])[C:15]=2[CH:16]=[O:17])[CH2:5]1)=O.C1(C2N=C(CCC3C=CN4C(=O)C=C(N5CCOCC5)N=C4C=3)SC=2)CCC1>>[CH:30]1([C:28]2[N:29]=[C:25]([CH2:24][CH2:23][C:21]3[CH:20]=[CH:19][N:13]4[C:14](=[O:18])[C:15]([CH:16]=[O:17])=[C:10]([N:6]5[CH2:5][CH2:4][O:3][CH2:8][CH2:7]5)[N:11]=[C:12]4[CH:22]=3)[S:26][CH:27]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: O=COC1CCCN(c2nc3cc(CCc4nc(C5CCC5)cs4)ccn3c(=O)c2C=O)C1
Agent: O=c1cc(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn12
Product: O=Cc1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Yield: 82 %

Procedure:
Reactions were performed in the same manner as in Example 1, (I) by using 8-[2-(4-cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (346 mg, 0.8726 mmol) to obtain 305 mg (82%) of the title compound as ocher solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:36]=[CH:37][C:38](/[CH:41]=[CH:42]/[CH2:43][CH2:44][O:45][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:39][CH:40]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCO)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCOS(C)(=O)=O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-hydroxybut-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.2 mmol) in dichloromethane (50 mL) and triethylamine (3.6 mmol) at room temperature, add methanesulfonyl chloride (1.56 mmol) dropwise over 5 minutes. Stir at room temperature for 1 hour, then dilute the reaction with dichloromethane (100 mL). Wash the organics with water (2×100 mL) followed by brine (100 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield the title compound as a light yellow foam (0.84g, 1.2 mmol). Use this material in the next step (Scheme II, step B) without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].I[CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:52][CH2:53][CH3:54])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1c(CC)nc(CCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
1.32 g of 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, 0.39 mL of iodopropane and 0.55 g potassium carbonate were added to 6 mL DMF. The reaction was allowed to stir for 24 hours then diluted with 12 mL water and 90 mL ethyl acetate. The organic layer was separated and washed five times with water, once with brine and dried with MgSO4. Chromatography with a gradient from 5 to 50% ethyl acetate in hexane gave 0.96 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:15])([F:14])[F:13])[CH:9]=O)=[CH:4][CH:3]=1.[C:33]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:13])([F:14])[F:15])[C:9]#[CH:33])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(C=O)(CC(F)(F)F)c1ccc(Cl)cc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Step C (120 mg, 0.25 mmol) in methanol (5 mL) was added K2CO3 (69 mg, 0.5 mmol), dimethyl 1-diazo-2-oxopropylphosphonate (96 mg, 0.5 mmol). The mixture was stirred at room temperature for 2 h. After removing the organic solvent, the residue was added H2O (10 mL), extracted with ethyl acetate, and washed with brine (10 mL), dried over sodium sulfate, then filtered. The organic solvent was evaporated, and the residue was purified by silica gel chromatography (EA/PE=1:8) to obtain the title compound as colorless oil. LC/MS m/z=464.1[M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:4]1)[CH3:2].[CH3:29][C@H](OC1N=C2C(N=C(OC)N2CCC2CCCNC2)=C(N)N=1)CCC.IC(C)C>>[CH3:28][C@H:24]([O:23][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[C:19]([O:20][CH3:21])[N:11]2[CH2:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH:1]([CH3:29])[CH3:2])[CH2:4]2)=[C:16]([NH2:22])[N:15]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodopropane.