Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([O:25][CH3:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:27])[C:3]=1[OH:28].O[C@@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].BrBr>>[Br:27][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([O:25][CH3:26])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:28][C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COc1c2ccccc2c(-c2cc(Br)c(O)c(Br)c2)c2c1sc1ccccc12
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(OC)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from 2,6-dibromo-4-(6-methoxy-benzo[b]naphtho[2,3-d]thiophen-11-yl )-phenol (Example 63) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96) according to the procedure of Example 107. White solid (0.608 g, 96%): NMR (THF-d8); δ8.29-8.26 (m, 1 H), 7.87 (d., J=8 Hz, 1 H), 7.72 - 7.68 (dd, 2 H, J=4, 2 Hz), 7.60 - 7.56 (m, 2 H), 7.48-7.37 (m, 4 H), 7.32 - 7.28 (m, 2 H), 7.25-7.23 (m, 2 H), 7.20 - 7.15 (m, 2 H), 6.85 - 6.82 (m, 1 H), 5.22(dd, 1 H, J=14, 2, Hz), 4.17 (s, 1 H), 3.71 (s, 1 H), 3.58(s, 6 H), ; MS (FAB+): [M+], 2 bromine isotope pattern, 674 (40%), 676 (66%), 678 (45%); Anal. Calc. for C33H24Br2O4S: C, 58.60, H, 3.58, N, 0.00. Found: C, 58.11, H, 3.53, N, 0.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C([Li])CCC.[Br:18]CCBr.[OH-].[Na+]>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].C1COCC1>[Br:18][C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=1
Reactant: COc1ccc2ccccc2c1
Reactant: BrCCBr
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
A RBF was charged 2-methoxynaphthalene (2.00 g, 12.64 mmol) and THF (30 mL) to give a clear solution. n-butyllithium (2.5M in hexanes) (5.66 mL, 14.16 mmol) was added dropwise. The flask was cooled in a dry ice-acetone bath for 10 min and 1,2-dibromoethane (1.634 mL, 18.96 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 16 hours. NaOH (1 M, 10 mL, 10 mmol 0 was added and the reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature and extracted with DCM (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude solid was recrystallized from heptane to give 2-bromo-3-methoxynaphthalene (1.75 g, 7.38 mmol, 58.4% yield) as an off-white solid. m/z (ESI) 237.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[C:28]([CH3:31])[CH:27]=3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:18]3[N:17]=[C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[O:30][N:29]=[C:28]([CH3:31])[CH:27]=5)=[C:22]([O:32][CH3:33])[CH:21]=4)[N:15]=[C:14]23)=[CH:8][CH:9]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)ccc1-c1cc(C)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(F)cc2)ccc1-c1cc(C)no1
Temperature: 55 °C
Yield: 24.4 %

Procedure:
A mixture of 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(3-methoxy-4-(3-methylisoxazol-5-yl)phenyl)-1H-1,2,4-triazol-3-amine (580 mg, 1.234 mmol), potassium carbonate (682 mg, 4.94 mmol), and potassium iodide (410 mg, 2.468 mmol) in DMF (8 mL) was heated at 55° C. for 16 hrs. The solvent was removed in vacuo. The crude product was purified using reverse phase preparatory-HPLC (Column: Phenomenex Luna C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 water/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 water/ACN. Flow rate: 40 ml/mM, 30-85% B, 25 min) to afford 9-(4-fluorophenyl)-N-(3-methoxy-4-(3-methylisoxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (145 mg, 0.301 mmol, 24% yield). LC-MS (M+H)+ 434.3. 1H NMR (400 MHz, methanol-d4) δ ppm 7.67 (d, J=8.56 Hz, 1 H) 7.49 (d, J=2.01 Hz, 1 H) 7.23 (dd, J=8.56, 5.29 Hz, 2H) 7.09 (t, J=8.69 Hz, 2 H) 6.99 (dd, J=8.56, 2.01 Hz, 1 H) 4.35-4.44 (m, 1H) 4.15-4.35 (m, 2 H) 3.87 (s, 3 H) 2.30 (s, 3 H) 2.19-2.28 (m, 1 H) 2.00-2.10 (m, 1 H) 1.72-1.94 (m, 4 H).
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:21][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:16][CH:17]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1
Reactant: CCCN
Product: CCCNC(=O)c1ccc(CCc2ccccc2)cc1

Procedure:
Using preparation method 1, 76C (226 mg, 1 mmol) was reacted with n-propylamine (90 μL, 65 mg, 1.1 mmol). No purification was necessary. White crystals were obtained (103 mg, 39%). NMR 1H (ppm, CDCl3): 7.65 (d, J3=8.1 Hz, 2H), 7.28-7.12 (m, 7H), 6.05 (br. s, 1H), 3.44-3.38 (m, 2H), 3.01-2.92 (m, 4H), 1.63 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [C-:1]#[N:2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[Co:13].[Co].[Cl-].[Zn+2:16].[Cl-]>O.C(O)(C)(C)C>[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[Co+3:13].[Co+3:13].[Zn+2:16].[Zn+2:16].[Zn+2:16]
Reactant: [Co]
Agent: [C-]#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: O
Product: [Co+3]
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A one-liter round-bottom flask equipped with mechanical stirrer, addition funnel, and thermometer is charged with distilled water (604 g), potassium hexacyanocobaltate (14.8 g), and tert-butyl alcohol (78 g). The mixture is stirred until all of the cobalt salt dissolves. The resulting solution is heated to 30° C. A solution of zinc chloride in water (50 wt. % zinc chloride, 304 g of solution) is added over 50 min. with stirring. Stirring continues for another 30 min. at 30° C. The resulting white suspension is centrifuged. A wet cake of solids is isolated, and is resuspended with vigorous stirring in a solution of tert-butyl alcohol (204 g) and water (112 g). After all of the solids are completely suspended in the wash solution, the mixture is stirred for 30 min. The suspension is again centrifuged, and the wet solids are isolated. The solids are resuspended in 99.5% tert-butyl alcohol (288 g), centrifuged, and isolated as described above. The resulting paste contains about 24 wt. % zinc hexacyanocobaltate complex, the remainder being tert-butyl alcohol (about 64 wt. %), and water (about 12 wt. %). A sample of this paste catalyst is used "as is" as a catalyst for polyol synthesis. See Tables 1-5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH2:37][CH2:38][CH2:39][Cl:40].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:4]([C:5]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=3)=[O:6])=[CH:3][C:2]=2[O:1][CH2:37][CH2:38][CH2:39][Cl:40])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(O)c2)c2ccccc21
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(OCCCCl)c2)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 82.9 %

Procedure:
Ethyl 4-{3-[3-hydroxy-4-(4-methylphenylmethoxy) benzoyl]indol-1-yl}butanoate (2.77 g) obtained in Step 1 was dissolved in N,N-dimethylformamide (30 ml). 1-Bromo-3-chloropropane (1.39 g) and potassium carbonate (0.97 g) were added to the resultant solution and stirred for 6 hours at 60° C. The reaction mixture was poured into 2N HCl and extracted with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 2.67 g of ethyl 4-{3-[4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate as a light yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nc(-n2c(C)ccc2C)nc(N[C@H]2CC[C@@H](O)CC2)c1Br
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (5.00 g, 17.0 mmol), cis-4-aminocyclohexanol hydrochloride (2.77 g, 18.3 mmol), and diisopropylethyl amine (8.69 mL, 49.9 mmol) in dimethylacetamide (60.0 mL) was heated at 160° C. in a sealed tube overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography eluting with chloroform/methanol (0-3%). Combined fractions containing the desired product were concentrated. The resulting gum was dissolved in methyl tert-butyl ether (450 mL) and the solution was washed with 50% brine, dried (MgSO4), filtered and concentrated to afford the title compound as a orange foamy solid (5.53 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:9][OH:10])=[N:6][CH:7]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH:12]([CH2:11][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C=CCO
Reactant: ON=Cc1ccc(Br)cn1
Solvent: C1CCOC1
Product: OCC1CC(c2ccc(Br)cn2)=NO1
Reaction time: 4 h

Procedure:
5-Bromo-pyridine-2-carbaldehyde oxime (60 g, 298.5 mmol) and allyl alcohol (49.7 ml) were added to tetrahydrofuran (200 ml) and then bleach (2016 ml) was added. The reaction was stirred for four hours followed by extraction with tetrahydrofuran (2×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (38.8 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH:17]2[CH2:18][CH2:19][CH:13]1[CH2:14][CH:15]([NH:20]C(=O)C)[CH2:16]2.Cl.[OH-].[Na+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH:13]2[CH2:19][CH2:18][CH:17]1[CH2:16][CH:15]([NH2:20])[CH2:14]2
Reactant: CC(=O)NC1CC2CCC(C1)N2Cc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC1CC2CCC(C1)N2Cc1ccc2ccccc2c1
Yield: 93.1 %

Procedure:
4 g (12.9 mmol) of N-[8-(naphthalen-2-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide are poured into 13 mL of 5N hydrochloric acid. The mixture is refluxed for 4 hours and then cooled in an ice bath, basified with 35% sodium hydroxide and extracted three times with ethyl acetate. The combined extracts are washed with water and with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. 3.2 g of oily product are obtained (94% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:22]=[C:23]=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([NH:22][C:23]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCc2ccccc2)cn1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (287 mg, 1.49 mmol) and benzyl isocyanate (199 mg, 1.49 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled down to room temperature and concentrated. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) and triturated with ethyl acetate/hexanes (1/9) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (246 mg, 51%) as a white solid. LC/MS; [M+H] calculated for C17H19N5O2; expected 326.15; found 326.10.
Reaction SMILES: CON(C)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][CH2:16][CH2:17][CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:16]([NH:15][C:6]1[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:19])[CH2:17][CH3:18]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNc1cc(C(F)(F)F)ccc1C=O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
N-Methoxy-N-methyl-2-propylamino-4-trifluoromethyl-benzamide (98.3 mg, 0.339 mmol) was reacted with 1M lithium aluminum hydride (0.6 ml) in THF (20 ml) at −40° C. for 1 hr. The reaction mixture was quenched by adding saturated potassium hydrogen sulfate solution. The mixture was stirred for 30 min. The reactions solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with CH2Cl2 (30 ml×3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield 2-propylamino-4-trifluoromethyl-benzaldehyde (78 mg). 2-Propylamino-4-trifluoromethyl-benzaldehyde in toluene was reacted with methyl (triphenylphosphoranylidene) acetate (137 mg) at 100° C. overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4 and filtered. The filterate was concentrated in vacuo and purified with column chromatography to yield title compound (67 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:28]CC[CH2:25]4)=[CH:17][CH:16]=3)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CN(C)CCOC1C=CC(NC(N)=S)=CC=1>C(Cl)Cl.CO>[CH3:25][N:24]([CH3:28])[CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[S:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Agent: CN(C)CCOc1ccc(NC(N)=S)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2cnc(Nc3ccc(OCCN(C)C)cc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 3 for [5-(4-methoxy-phenyl)-thiazol-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using [4-(2-dimethylamino-ethoxy)-phenyl]-thiourea. Title compound: ES-MS: 370.0 [M+H]+; single peak at tR=6.13 min (System 1); Rf=0.13 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)#[N:6]>C(O)(=O)C>[CH2:1]([O:3][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[NH:6])[CH3:2]
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Reactant: CCO
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=N)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C

Procedure:
To a dry flask equipped with stirrer, thermometer and reflux condenser is placed 25 ml. of ethanol and sodium metal, 0.253 g. (0.011 g. atom) is added in portions. When the sodium is completely reacted, 3.14 g. (0.01 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline is added and the resulting mixture is refluxed for 5 hours. After cooling to room temperature, glacial acetic acid is added to neutralize the mixture. After evaporation to dryness, 25 ml. of water and 50 ml. of chloroform are added to the residue. The mixture is transferred to a separatory funnel and the chloroform layer washed again with water, dried over anhydrous sodium sulfate then concentrated to dryness to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[S-:10][C:11]#[N:12].[NH4+].OOS([O-])=O.[K+]>CO>[N:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[C:11]=[S:10]
Reactant: N#C[S-]
Reactant: c1ccc2[nH]ccc2c1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: S=C=Nc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A solution of indole (2.0 g, 17.1 mmol) and ammonium thiocyanate (1.95 g, 25.6 mmol) in methanol (150 mL) was treated with oxone (15.7 g, 25.6 mmol) and allowed to stir at RT for overnight till TLC showed all starting material consumed. The reaction solution was evaporated in vacuum. The residue was purified by chromatography on silica gel (EtOAc:PE=5/95) to afford 2.2 g of 3-isothiocyanato-1H-indole as yellow solid (yield: 73%). MS obsd. (ESI+) [(M+H)+] 175.1, 1H NMR: (400 MHz, CDCl3) δ ppm: 8.67 (brs, 1H), 7.82-7.80 (m, 1H), 7.52 (d, J=3.0 Hz, 1H), 7.44-7.43 (m, 1H), 7.34-7.30 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([OH:16])=O)=[C:7]2[N:6]=[N:5]1.CN(C(O[N:25]1N=[N:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:14]([C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:3][O:2][CH3:1])[N:5]=[N:6][C:7]=12)=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COCn1nnc2c(C(=O)O)ncn2c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: COCn1nnc2c(C(=O)Nc3ccccc3N)ncn2c1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (512 mg; 2.28 mmol) in DMF (50 mL) was added HBTU (908 mg; 2.40 mmol). The solution was stirred for 20 minutes, then added dropwise over 20 minutes to a solution of phenylenediamine (370 mg; 6.84 mmol) in DMF (50 mL). The reaction mixture was stirred for 24 hours, then poured onto ice (1 kg), and allowed to stand until the ice had melted. The resulting orange solid was filtered, and purified by column chromatography (DCM:MeOH 98:2) to give N-(2-aminophenyl)-3-(methoxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide as an orange solid. (474 mg; 70%). δH (DMSO d6): 9.76 (1H, s), 8.99 (1H, s), 7.43 (1H, dd, J=7.9, 1.0), 6.99 (1H, td, J=7.6, 1.5), 6.84 (1H, dd, J=8.0, 1.3), 6.67 (1H, dd, J=7.6, 1.3), 5.64 (2H, s), 4.91 (2H, s), 3.44 (3H, s).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[C:39]1([Si:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:52]1([Si:45]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-Triphenylsilyl-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared as a colourless foam from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using triphenylsilylchloride instead of benzophenone).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:29])[C:25]=1[C:26](O)=[O:27])=[O:20].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:29][N:24]1[C:25]([C:26](=[O:27])[NH:15][C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:16]=[C:10]3[CH:11]=2)=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=[N:23]1
Reactant: COC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (1.534 g, 7.3 mmol), 4-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1.61 g, 8.76 mmol), propylphosphonic anhydride (50% in ethyl acetate, 10.7 ml, 18.2 mmol) and diisopropylethylamine (5.1 ml, 29.2 mmol) in tetrahydrofurane (54 ml) is stirred at 70° C. for 1.25 hr giving a white suspension. The cooled suspension is poured in sat. aqueous sodium bicarbonate solution (200 ml), stirred at room temperature for 15 min and the solid is collected by filtration, washed with water and dried affording methyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (2.596 g, 94.5%) as a white solid. mp.: 243-7° C. MS: m/z=377.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1>CO.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 24 h

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a, 8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (50 mg, 0.092 mmol) and a catalytic amount of Pd/C (9.77 mg, 0.092 mmol) was dissolved in a mixture of methanol (1 mL) and ethyl acetate (1 mL) and stirred under 1 ATM of H2 for 24 hours. LCMS indicated the completion of the reaction. The reaction mixture was filtered to remove the catalyst. The solution was concentrated in vacuo and the residue was purified using reverse phase prep HPLC to afford the title compound as a white solid. LCMS: m/e 529.29 (M+H−H2O)+, 0.15 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.80 (d, 3H), 0.88 (d, J=6.71 Hz, 3H), 0.97 (s, 6H), 1.02 (s, 6H), 1.12 (s, 3H), 1.18-2.23 (m, 24H), 3.36 (d, J=10.99 Hz, 1H), 3.84 (d, J=10.68 Hz, 1H), 5.27-5.42 (m, 1H), 7.26 (d, J=7.93 Hz, 2H), 8.01 (d, J=8.24 Hz, 2H).