Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[C:11]1=[O:36])[CH3:9])(C)(C)C.N1C=CC=CC=1.F>N1C=CC=CC=1>[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([N:12]2[CH2:13][C:14]3[C:15](=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:18][CH:19]=3)[N:10]([C@H:8]([CH3:9])[CH2:7][OH:6])[C:11]2=[O:36])=[CH:29][CH:30]=1)[CH3:35]
Reactant: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Agent: F
Solvent: c1ccncc1
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H](C)CO)C2=O)cc1

Procedure:
(R)-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (100 mg, 0.18 mmol) (from Example 38f supra) in pyridine (1.5 mL) (Fisher) was treated at room temperature with hydrogen fluoride-pyridine (0.6 mL) (Aldrich) for 15 minutes. The reaction mixture was quenched with 1 N aqueous hydrochloric acid at 0° C., then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to give (R)-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-1-(2-hydroxy-1-methyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a colorless viscous oil. (Yield 45 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(Cl)Cl.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>C(N(CC)CC)C>[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH:23][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:13])[C:10]([NH2:12])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:19]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Reaction time: 18 h
Yield: 60.5 %

Procedure:
2-Methoxy-4-amino-5-chlorobenzoic acid (1.0 g) and 1-methanesulfoyloxy-1,2,3-benzotriazole (1.07 g) are suspended into chloroform (15 ml) and therto is added dropwise triethylamine (0.7 ml) with stirring under ice-cooling to give a clear solution. To the solution is added 2-(diethylamino)ethylamine (0.6 g) at room temperature and the mixture is allowed to stand for 18 hours. The solvent is then distilled off and thereto are added water and 1 N aqueous sodium hydroxide. The resulting crystals are separated by filtration, washed with water and then dried to give N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide (0.9 g), melting point: 145°-146° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)C.[ClH:23]>O>[ClH:23].[ClH:23].[NH2:1][CH:2]1[CH:6]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(OCC(F)(F)F)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1CNCC1OCC(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of 1.61 g (0.006 mole) of 3-amino-1-t-butoxycarbonyl-4-(2,2,2-trifluoroethoxy)pyrrolidine [prepared as described in step (b) above], 30 ml of ethanol, 2 ml of concentrated aqueous hydrochloric acid and 4 ml of water was allowed to stand overnight at room temperature after which it was evaporated to dryness under reduced pressure, to afford 1.60 g of 3-amino-4-(2,2,2-trifluoroethoxy)pyrrolidine dihydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Temperature: 23 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate (278 mg, 0.640 mmol) in CH2Cl2 (5 mL) and AcOH (500 uL) was added acetaldehyde (359 mg, 6.40 mmol) and sodium triacetoxyborohydride (428 mg, 1.92 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 7 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (236 mg, 80% yield.). 1H-NMR (400 MHz, CDCl3) δppm; 7.79 (s, 1H), 7.43 (s, 1H), 7.21-7.36 (m, 5H), 3.92 (s, 3H), 3.87 (d, J=14.0 Hz, 1H), 3.38 (d, J=14.0 Hz, 1H), 3.04-3.15 (m, 4H), 2.73-2.80 (m, 1H), 2.53 (s, 3H), 1.76-1.82 (m, 1H), 1.51-1.63 (m, 2H), 1.34-1.42 (m, 1H), 1.06 (d, J=6.0 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 0.86 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[H-].[Na+].[CH3:25][O:26][C:27]([C:29]1[O:30][C:31]([N+]([O-])=O)=[CH:32][CH:33]=1)=[O:28]>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:31]4[O:30][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:33][CH:32]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(-c3nn(C4CCCC4)c4ncnc(N)c34)cc2)o1
Temperature: 90 °C
Yield: 47.2 %

Procedure:
A mixture of 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (0.107 g, 0.362 mmol, 1.0 equiv), DMSO (0.5 mL), sodium hydride (60%, 0.030 g, 0.72 mmol, 2.0 equiv), and methyl-5-nitro-2-furoate (0.062 g, 0.36 mmol, 1.0 equiv) was heated at 90° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water (10 mL), and extracted with three portions of CH2Cl2 (50 mL each). The combined organic extracts were washed with 5% aqueous KOH (50 mL) and the organic layer was dried over MgSO4, filtered, and concentrated to afford a red oil which was purified by column chromatography on silica gel (elution with 300 mL of 5% MeOH/CH2Cl2) to afford methyl 5-[4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenoxy]-2-furoate as a red solid (0.070 g, 0.17 mmol):
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:44][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: OCCCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 3-(4-fluorophenyl)propan-1-ol (0.066 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, cold bath was removed and stirred overnight (13 h) at rt. LCMS at this point showed presence of about 50% unreacted phenol. So, added additional 3-(4-fluorophenyl)propan-1-ol (0.066 g, 0.427 mmol), Ph3P (0.067 g, 0.256 mmol) and DEAD (0.041 ml, 0.256 mmol) at r. After stirring for 5 h, reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0351 g, 0.058 mmol, 68.0% yield) as glassy solid. 1H NMR (500 MHz, CDCl3) δ 7.14-7.23 (m, 3H), 7.06-7.09 (m, 1H), 6.95-7.03 (m, 4H), 6.09 (s, 1H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.18 (qd, J=7.1, 10.7 Hz, 1H), 3.99-4.07 (m, 2H), 3.19 (d, J=12.0 Hz, 1H), 2.88 (t, J=12.3 Hz, 1H), 2.82-2.91 (t, J=7.6 Hz, 2H), 2.61 (s, 3H), 2.28 (d, J=12.0 Hz, 1H), 2.21 (s, 3H), 2.11-2.18 (m, 2H), 2.06 (t, J=11.5 Hz, 1H), 1.56 (dt, J=3.9, 12.6 Hz, 1H), 1.38 (dt, J=3.6, 12.7 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.18-1.21 (m, 1H), 1.08 (d, J=12.1 Hz, 1H), 0.91 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=605.3.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]1[S:17]([N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)(=[O:18])=[O:19]
Reactant: CN(C)CCCl
Reactant: O=S(=O)(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCCCC1
Agent: Cl
Product: CN(C)CCn1c(S(=O)(=O)N2CCCCC2)c(C(c2ccccc2)c2ccccc2)c2ccccc21
Yield: 75.3 %

Procedure:
Substantially the same procedure as in Example 243 was repeated using Compound 263 (1.0 g, 2.25 mmol) obtained in Example 264 and 2-dimethylaminoethylchloride hydrochloride (360 mg, 2.47 mmol) to give 0.85 g (yield: 75%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])#[N:21]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cccc(C#N)c2)c(=O)[nH]c1=O
Yield: 57.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (216 mg, yield: 57.5%).
Reaction SMILES: [CH2:1]([C:5]1([CH3:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].Cl.O1CCOCC1>>[CH2:1]([C:5]1([CH3:18])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCCC1(C)CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-(but-3-en-1-yl)-4-methylpiperidine-1-carboxylate (3.5 g, 13.81 mmol) and 4M HCl/dioxane (17.27 ml, 69.1 mmol) was stirred at room temp for 3 h. Mixture was then concentrated and dried under high vac to afford 4-(but-3-en-1-yl)-4-methylpiperidine.HCl (2.6 g, 13.70 mmol, 99% yield) as off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 5.83 (ddt, J=17.0, 10.3, 6.6 Hz, 1H), 5.05 (dq, J=17.1, 1.7 Hz, 1H), 5.00-4.80 (m, 1H), 3.11-2.90 (m, 5H), 2.05-1.90 (m, 2H), 1.56-1.42 (m, 5H), 1.38-1.26 (m, 2H), 0.95 (s, 3H). LCMS (M+H)=154.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[C:13]([C:16]#[N:17])[C:14]#[N:15])SC.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:15][C:14]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[C:13]=1[C:16]#[N:17]
Reactant: NNc1ccccc1
Reactant: CSC(=C(C#N)C#N)c1cc2ccccc2s1
Product: N#Cc1c(-c2cc3ccccc3s2)nn(-c2ccccc2)c1N

Procedure:
Using 2.56 g (10 mmol) of (benzothiophen-2-yl) (methylthio)methylenepropanedinitrile and 1.1 g (10 mmol) of phenylhydrazine, the entitled product having a melting point of 260° to 262° C. was obtained in the same manner as in Example 1-(1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.C(Cl)(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=1
Reactant: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC1(c2cccnc2)CCNCC1
Temperature: 68 °C

Procedure:
(Apparatus: 1 I three-necked flask with condenser) Palladium on charcoal (10%, catalytic amount) was added to a solution of 1-benzyl-4-(pyridin-3-yl)piperidin-4-ol (32 g) in methanol (220 ml), followed by ammonium formate solution (22.7 g in 50 ml of water). The reaction mixture was refluxed at 68° C. overnight. Thin layer chromatography control: 20% methanol in chloroform. The mixture was filtered over Celite and the filtrate was concentrated in vacuo. The residue was washed with acetone (100 ml) in order to obtain the desired compound in a pure form. Yield: 17.3 g (81%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)[CH:14]([CH3:16])[CH3:15])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:38]([O:34][CH2:12][C@@H:13]([CH2:17][CH:10]([OH:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)[CH:14]([CH3:16])[CH3:15])[CH:14]([CH3:16])[CH3:15])[C:37]1[CH:3]=[CH:1][CH:2]=[CH:35][CH:36]=1
Reactant: C1CCOC1
Reactant: COCCCOc1cc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: [Cl-]
Agent: [NH4+]
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(O)C[C@H](COCc2ccccc2)C(C)C)C(C)C)ccc1OC
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
The reaction mixture is stirred for a further 20 minutes at 55° C. and then cooled to 5° C. A solution of 2(S)-(tert-butoxycarbonyl)amino-4(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-5-methyl-hexanal (190 g) in tetrahydrofuran (700 ml) is then added dropwise. The reaction mixture is stirred for a further 3 hours at room temperature, then at 5° C. saturated ammonium chloride solution is added and the mixture is extracted with diethyl ether. The organic phases are concentrated and purified by FC (4 kg of silica gel, ethyl acetate/hexane 1:3). The title compound is obtained in the form of a colourless oil (139 g): Rf (ethyl acetate/hexane 1:2)=0.26; HPLC Rt =22.7 and 22.8 min ((4:6)-diastereoisomeric mixture).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)NCCSCc1ccccn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=S)NCCSCc1ccccn1

Procedure:
The benzoyl thiourea is added to a solution of potassium carbonate (1.4 g.) in water (80 ml.) at 60°. The solution is maintained at this temperature for one hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid is removed by filtration and the filtrate is basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohol and concentration, the product is N-[2-(2-pyridylmethylthio)ethyl]thiourea.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10](COCC[Si](C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.N>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[NH:10][CH:9]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccccc3F)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(-c5ccccc5F)c34)n(-c3ccccc3)c(=O)c12
Yield: 52.1 %

Procedure:
(S)-2-(1-((5-(2-Fluorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (35 mg, 0.06 mmol) was treated with trifluoroacetic acid (600 μl, 7.79 mmol) and a solution of ammonia (7N in methanol, 600 μl, 4.2 mmol) according to the method described in Example 27 to give 15 mg (54% yield) of the title compound as a white solid. Purity 89%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH3:36])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH3:36])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(Nc3cc(N)ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Yield: 42.5 %

Procedure:
A solution of the product from Example 63C (0.150 g, 0.303 mmole), iron powder (0.10 g, 1.86 mmol) and ammonium chloride (0.10 g, 1.98 mmol) in a methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.06 g, 42%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: Cc1ncc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cnc(CBr)nc2)cc1
Temperature: 75 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
0.31 g (1.3 mmol) of 2-methyl-5-(4-trifluoromethyl-phenyl)-pyrimidine, 0.255 g (1.43 mmol) of N-bromosuccinimide and 0.15 g (0.91 mmol) of 2,2′-azobis-(2-methyl-propionitril) were dissolved in 5 ml of carbon tetrachloride and the mixture was stirred at 75° C. Two portions of 0.13 g (0.73 mmol) of N-bromosuccinimide and 0.075 g (0.046 mmol) of 2,2′-azobis-(2-methyl-propionitril) were added to the reaction mixture, after 4 and 8 hours, respectively, and the heating was continued for additional 16 hours. After cooling to ambient temperature, the mixture was chromatographed on silicagel with dichloromethane as eluent. 0.145 g of the title compound were obtained as pale yellow solid. MS: 316.0 (M, 1Br)+.
Reaction SMILES: C([Li])CCC.C(S)CC.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C@@H:24]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([O:63][CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])([C:59]([F:62])([F:61])[F:60])[C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)[CH:25]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)C(N3[C@H]4CC5C(C)(C)[C@@]4(CC5)CS3(=O)=O)=O)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1.O.[OH-].[Li+].CC(O)=O>C1COCC1.O>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C@@H:24]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([O:63][CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])([C:55]([F:56])([F:57])[F:58])[C:59]([F:62])([F:61])[F:60])=[CH:50][CH:49]=3)[CH2:25][C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc([C@@H](c2ccc(C(OCOCC[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)cc2)C(C(=O)N2[C@H]3CC4CC[C@@]3(CS2(=O)=O)C4(C)C)c2ccncc2)cc1OC1CCCC1
Agent: CCCS
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C(OCOCC[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
n-Butyllithium (2.4M solution in hexane; 7.76 mL, 18.6 mmol) was added dropwise to a solution of 1-propanethiol (2.06 mL, 22.8 mmol) in THF (100 mL) at 0° C. After 1.5 h, a solution of (1R, 5S)-N-{(3R)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[4-(2-(2-(trimethylsilyl)ethoxymethoxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-(4-pyridyl)propanoyl}-10,10-dimethyl-3-thia-4-azatricyclo[5.2.1.01,5 ]decane-3,3-dioxide from Step 3 (9.43 g, 10.4 mmol) in THF (25 mL) was added dropwise, at 0° C., and the reaction mixture was stirred at room temperature for 3 h. The reaction was then quenched by the addition of 25% aqueous NH4OAc buffer. The aqueous layer was extracted with EtOAc (2×), and the combined organics were washed successively with 25% aqueous NH4OAc buffer and brine, dried (MgSO4) and concentrated. The residue was dissolved in EtOH (170 mL) and water (57 mL), lithium hydroxide monohydrate (2.20 g, 52.0 mmol) was added and the mixture heated to reflux for 2.5 h. The reaction mixture was cooled to room temperature before the addition of AcOH (3.56 mL, 62.1 mmol). After 30 min., 25% aqueous NH4OAc buffer was added and the aqueous layer extracted with EtOAc (2×). The combined organics were washed successively with 25% aqueous NH4OAc buffer and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc/hexane 1:1) to afford the title compound as a colorless gum (4.08 g, 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH3:17][NH:18][CH3:19]>C(N(CC)CC)C>[CH3:17][N:18]([CH3:19])[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1
Reactant: CNC
Reactant: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(N(C)C)nc(C)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 98.4 %

Procedure:
10 ml of triethylamine are added to a solution of 15.9 g of 2-chloro-4-sec. butylamino-5-nitro-6-methylpyrimidine (0.065 mole) in 250 ml of alcohol. Then 4.5 g (0.1 mole) of dimethylamine are passed in and the mixture is boiled for 4 hours at 100° C. After it has cooled, the mixture is evaporated and the residue is suspended in water. The resultant precipitate is filtered off with suction and washed with water until no more chlorine ions are dissolved out. The product is dried in a water jet vacuum at 50° C to yield 16.2 g of 2-dimethylamino-4-sec. butylamino-5-nitro-6-methylpyrimidine (=98.5% yield) of m.p. 98°-100° C. On recrystallisation from petroleum ether, the melting point of the product rises to 109°-110° C.